Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16][CH2:15]1.O(CC)CC.[ClH:29]>C(#N)C.CCOCC>[ClH:29].[CH:17]1([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:15][NH:16]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)CC1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 77 %

Procedure:
A solution of ethyl bromoacetate (20.9 g) in acetonitrile (30 mL) was added to a mixture of K2CO3 (27.6 g, 0.2 mol) and 1,2,3,4-tetrahydro-2-isoquinoline (13.3 g, 0.1 mol) in acetonitrile (220 mL). The reaction mixture was stirred at room temperature for about 2 days, and then was refluxed for 4 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue was partitoned between ether and water. The ether layer was separated, dried over MgSO4 and concentrated in vacuo to afford a liquid which was dissolved in ether (200 mL), cooled and treated with Et2O·HCl to afford 12,5 g (77%) of ethyl 1,2,3,4-tetrahydro-2-isoquinolinylacetate hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:6]=2[CH:34]=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=4)[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:6]=2[CH:34]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2F)=NC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2F)=NC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.3 %

Procedure:
A mixture of [9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-nitro-phenyl)-amine (I-212, 500 mg, 1.05 mmol), stannous chloride dihydrate (1.42 g, 6.3 mmol) and ethyl acetate (15 mL) was refluxed for 28 hours, then cooled to room temperature and allowed to sit overnight. The mustard-yellow reaction mixture was poured onto ˜50 g cracked ice with stirring, and sat. NaHCO3 solution was added to adjust the pH to 8. The mixture was extracted with ethyl acetate (3×100 mL). The extracts were combined, dried (Na2SO4), filtered and evaporated in vacuo to provide N-[9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-benzene-1,4-diamine as an orange/yellow solid (500 mg, 100%) MS m/z=448 (M+H). A solution of this product (50 mg, 0.1 mmol), 4-methylpiperazine-1-carbonylchloride (89 mg, 0.6 mmol), diisopropylethylamine (142 mg, 1.1 mmol), in dioxane (0.5 mL) was submitted to microwave irradiation (300 W) for 60 minutes at 160° C. The reaction solution was cooled to room temperature and slowly poured into a stirring saline solution (10 mL). The resulting precipitate was collected by filtration, washed with water and purified by RP-HPLC (C18, 0 to 100% CH3CN in 0.1% aqueous HCO2H) to yield 1-280 as a pale yellow solid (6 mg, 10%) MS m/z=574 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=4)[C:33]([NH:35][C:36]([CH3:41])([CH3:40])[C:37]([OH:39])=O)=[O:34])=[CH:26][C:20]=3[C:21]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:13][CH:12]=1.[CH3:45][C:46]1[O:50][N:49]=[C:48]([NH2:51])[CH:47]=1.[H-].[Na+]>CN(C=O)C.CO>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:44]=[CH:43][CH:42]=[C:32]([C:33](=[O:34])[NH:35][C:36]([CH3:40])([CH3:41])[C:37]([NH:51][C:48]5[CH:47]=[C:46]([CH3:45])[O:50][N:49]=5)=[O:39])[CH:31]=4)=[CH:26][C:20]=3[C:21]=2[C:22]([NH:23][CH3:24])=[O:25])=[CH:15][CH:16]=1
Reactant: Cc1cc(N)no1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)O)c3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)Nc4cc(C)on4)c3)cc12
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
DIEA (28 μL, 0.158 mmol) was added to a stirring solution of 2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid (25 mg, 0.053 mmol), 5-methylisoxazol-3-amine (11 mg, 0.105 mmol) in DMF (527 μL) at rt. It was allowed to stir for 30 min. NaH (11 mg, 0.263 mmol) was added and the reaction was allowed to stir overnight. The mixture was treated with a drop of MeOH and was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (2.8 mg, 9%). 1H NMR (500 MHz, CD3OD) δ ppm 8.17-8.25 (1H, m), 7.92-8.00 (3H, m), 7.83-7.91 (2H, m), 7.66-7.76 (2H, m), 7.58 (1H, t, J=7.78 Hz), 7.27 (2H, t, J=8.85 Hz), 6.63 (1H, s), 2.98 (3H, s), 2.39 (3H, s), 1.65 (6H, s), LC-MS retention time: 1.69 min; m/z (MH+): 555. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=12.20 min, purity=95%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=11.30 min, purity=90%.
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].C([O-])([O-])=[O:19].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[C:3]([C:14]([F:15])([F:16])[F:17])=[CH:4][C:5]([C:6]([NH2:7])=[O:19])=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13]
Reactant: N#Cc1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.8 %

Procedure:
4-Chloro-3,5-bis(trifluoromethyl)benzonitrile (1 g, 1.0 eq.) was dissolved in DMSO (10 mL). K2CO3 (0.55 g, 1.1 eq.) and H2O2 (1 mL) were added to the reaction mixture and stirred at room temperature for 2-3 h, then poured into ice water (20 mL). The precipitate formed was collected by filtration and washed with petroleum ether to afford 1.0 g of crude product (90% yield), which was used without further purification in the next step.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CO>[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:10][C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:4]=2)=[CH:13][CH:12]=1
Reactant: NC(=O)c1ccccc1N
Reactant: O=Cc1ccncc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Product: O=c1[nH]c(-c2ccncc2)nc2ccccc12
Yield: 85 %

Procedure:
To a flask of anthranilamide (1 mmol) was added 4-pyridine carboxaldehyde (1 mmol) to form a paste. Followed by the careful addition of 2,3 dichloro-5,6-dicyano-1,4-benzoquinone, (0.5 mmol), the well blended mixture was microwaved in a beaker with silica for 9 min. To the resultant solid was added methanol with subsequent sonication. The collected filtrate was concentrated and dried in vacuo to afford the desired product as a brown solid (85% yield). 1H NMR (400 MHz, d6-DMSO): δ 12.80 (br s, 1H), 8.80 (d, 2H), 8.20 (d, 1H), 8.12 (d, 2H), 7.88 (t, 1H), 7.80 (d, 1H), 7.60 (t, 1H). MS (EI) for C13H9N3O: 224 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].C(N(CC)CC)C.O1CCCC1.[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[C:28](Cl)=[O:29]>O>[Br:7][C:5]1[S:4][C:3]([C:8](=[O:9])[NH2:10])=[C:2]([NH:1][C:28]([C:24]2[S:23][CH:27]=[CH:26][N:25]=2)=[O:29])[CH:6]=1
Reactant: O=C(Cl)c1nccs1
Reactant: NC(=O)c1sc(Br)cc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1sc(Br)cc1NC(=O)c1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a mixture of 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D, triethylamine (0.19 mL) and tetrahydrofuran (4.0 μL) was added 1,3-thiazole-2-carbonyl chloride (0.22 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. Water was poured into the reaction system, and the precipitate was collected by filtration to give N-(5-bromo-2-carbamoylthiophen-3-yl)-1,3-thiazole-2-carboxamide (290 mg) as a pale-yellow solid. To N-(5-bromo-2-carbamoylthiophen-3-yl)-1,3-thiazole-2-carboxamide produced above were added 2M aqueous sodium hydroxide solution (1.75 mL) and 1,2-dimethoxyethane (4.0 mL), and the mixture was stirred at 100° C. for 18 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. The precipitate was collected by filtration to give the title compound (236 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1>CN1C(=O)CCC1.ClCCl.[Cu]>[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:14]2[C:15]3[C:11](=[CH:10][CH:9]=[C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[CH:16]=3)[CH:12]=[CH:13]2)=[CH:26][CH:25]=1
Reactant: CN1CCN(c2ccc3cc[nH]c3c2)CC1
Reactant: Fc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CN1CCN(c2ccc3ccn(-c4ccc(F)cc4)c3c2)CC1
Yield: 36.7 %

Procedure:
A mixture of 6-(4-Methylpiperazinyl)-indole (14.8 mg, 0.0687 mmol), K2CO3 (37.9 mg, 0.275 mmol), CuBr (4.9 mg, 0.0353 mmol), a little copper powder and 1-Fluoro-4-iodobenzene (30.5 mg, 0.37 mmol) in 1 ml of NMP was heated at 170° C., under argon, overnight. After cooling, the mixture was diluted with dichloromethane and the organic layer washed with water 10 times before being passed through a silica gel column (eluting with 1% 2M ammonia/methanol in dichloromethane) to give the title product (7.8 mg, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][NH2:10])=[C:4]([F:11])[CH:3]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:10][CH2:9][C:5]3[C:4]([F:11])=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=3[F:8])=[O:23])[N:21]=2)[CH:18]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: NCc1c(F)cc(Cl)cc1F
Product: O=C(NCc1c(F)cc(Cl)cc1F)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using (4-chloro-2,6-difluorophenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][N:19]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16])=O)[CH3:2].O(Cl)Cl.[P+5]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:17]=[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]2[C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16])=[O:24])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccncn1)C(=O)Nc1ccc(I)cc1F
Agent: ClOCl
Agent: [P+5]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2ccncn2c1Nc1ccc(I)cc1F
Yield: 16.4 %

Procedure:
To a solution of N-(2-fluoro-4-iodo-phenyl)-2-pyrimidin-4-ylmethyl-malonamic acid ethyl ester (4 g, 9.02 mmol) in toluene (120 mL) was added phosphorous (V) oxychloride (4.2 mL, 45.1 mmol). The reaction was heated at reflux for 16 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (30 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-40% ethyl acetate in cyclohexane) to yield a dark brown solid. The solid was triturated with ether (10 mL) to yield the title compound as a light brown solid (0.63 g, 16%). LCMS (Method B): RT=3.95 min, M+H+=426.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:18])[CH3:17]>>[Br:15][C:12]1[CH:13]=[N:14][C:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:16](=[O:18])[CH3:17])=[N:10][CH:11]=1
Reactant: Brc1cnc(NCc2ccccc2)nc1
Reactant: CC(=O)Cl
Product: CC(=O)N(Cc1ccccc1)c1ncc(Br)cn1

Procedure:
The subtitle compound was prepared by the method of example 38 step (i) using benzyl-(5-bromo-pyrimidin-2-yl)-amine and acetylchloride, yield 0.21 g.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].O.[CH2:14](Cl)/[CH:15]=[C:16](\[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])/[CH3:17]>CO>[CH3:17]/[C:16](/[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[CH:15]/[CH2:14][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CC(C)=CCC/C(C)=C\CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)=CCC/C(C)=C\CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-mercaptobenzimidazole (5.1 g, 34 mmol) and 2N NaOH/H2O (pH 11) in methanol (100 mL) was added neryl chloride (5.85 g, 34 mmol). The reaction mixture was stirred at ambient temperature for 16 hours, evaporated in vacuo, dissolved in CH2Cl2, washed with saturated NaHCO3 and brine, and dried over Na2SO4. Evaporation of the solvent gave an oil which was flash chromatographed (Merck Kieselgel, 5% MeOH/CH2Cl2) to give the title compound which was crystallized from Et2O/pentane to give a white solid (3.4 g, 35%). m.p. 98°-101° C. NMR (CDCl3)δ7.35(m 4H) 5.25(m 2H) 4.0(d,J=6 Hz,2H), 2.05(m,4H), 1.68(s,3H), 1.62(s,3H), 1.60(s,3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][Br:7].Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10].[OH-].[Na+].Cl>O>[CH2:12]([O:11][C:9](=[O:10])[N:4]([CH2:5][CH2:6][Br:7])[CH2:3][CH2:2][Br:1])[CH3:13]
Reactant: CCOC(=O)Cl
Reactant: BrCCNCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)N(CCBr)CCBr
Yield: 30.7 %

Procedure:
To a stirred solution of bis-(2-bromo-ethyl)-amine (1 g, 3.21 mmol) in water (10 mL) at 0° C. was added ethyl chloroformate (0.293 mL, 3.08 mmol) and then NaOH (4.01 mL, 8.02 mmol), and stirred for 10 min at 0° C. The reaction mixture was acidified by 2 N HCl to pH 5, and extracted three times with 20 mL of ethyl acetate, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (gradient of 85:15 to 70:30 heptane/ethyl acetate in 30 min) to give the title compound (287 mg, 0.947 mmol, 29.5% yield). MS calculated for C7H14Br2NO2 304.0. found (ESI) m/z 304.2 (M+H)+, retention time 0.56 min.
Reaction SMILES: [H-].[Na+].F[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:11]([C:13]1[C:18]([OH:19])=[CH:17][C:16]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:15][C:14]=1[OH:26])=[O:12].CCOC(C)=O>CN(C=O)C>[F:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[O:26][C:14]1[CH:15]=[C:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:17]=[C:18]([OH:19])[C:13]=1[C:11]2=[O:12]
Reactant: O=C(c1cccc(F)c1F)c1c(O)cc(N2CCOCC2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1c2cccc(F)c2oc2cc(N3CCOCC3)cc(O)c12
Temperature: 75 °C
Yield: 6.3 %

Procedure:
Sodium hydride (24 mg, 1.0 mmol, 60%) was added to a solution of a compound of Example 24 (168 Mg, 0.50 mmol) in DMF (2 mL), then the mixture was heated at 75° C. for 4 h. The reaction was cooled to 22° C., and EtOAc (70 mL) was added to produce a yellow precipitate. The precipitate was filtered and dried to yield 10 mg (7%) of 5-fluoro-1-hydroxy-3-morpholin-4-yl-xanthen-9-one. 1H NMR (CDCl3, 400 MHz) δ: 12.59 (s, 1H), 7.95 (d, 1H), 7.75 (m, 1H), 7.40 (m, 1H), 6.60 (s, 1H), 6.38 (s, 1H), 3.65-3.63 (m, 4H), 3.40-3.38 (m, 4H). LRMS (APCI, positive): 316.3 (m+1).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH3:5].[NH2:7][C:8]1[N:13]=[CH:12][C:11]([I:14])=[CH:10][N:9]=1>C(O)C>[CH2:4]([C:3]1[N:7]=[C:8]2[N:13]=[CH:12][C:11]([I:14])=[CH:10][N:9]2[CH:2]=1)[CH3:5]
Reactant: CCC(=O)CBr
Reactant: Nc1ncc(I)cn1
Solvent: CCO
Product: CCc1cn2cc(I)cnc2n1
Temperature: 25 °C
Yield: 8.9 %

Procedure:
755 mg of 1-bromo-2-butanone was dissolved in 15 ml of ethanol, 1.0 g of 2-amino-5-iodopyrimidine was added and the mixture was stirred all night by heating under reflux. After cooling down to room temperature, the solvents were distilled outunder reflux, ethyl acetate followed by saturated sodium bicarbonate aqueous solution were added. Organic layer was dried with anhydrous sodium sulfate, and the solvents were distilled outunder reduced pressure. The obtained residues were purified by silicagel column chromatography (ethyl acetate) to obtain 110 mg of the above compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:11][OH:12])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1>C1COCC1.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[N:6][C:5]2[NH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[CH:11]=[O:12]
Reactant: OCc1c(F)cnc2[nH]ccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1c(F)cnc2[nH]ccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a 250 mL round bottom flask equipped with a stirring bar was added (5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (2.01 g, 12.10 mmol) in THF (100 mL) under nitrogen. Manganese dioxide (10.52 g, 121 mmol) was added and the reaction mixture was stirred at 60° C. for 2 h. The organics were filtered through a pad of Celite, rinsed with EtOAc (100 mL) and concentrated. The resulting solid was triturated with EtOAc (50 mL) and filtered to give the title compound as a light yellow solid (1.3 g, 65.5%). 1H NMR (400 MHz, CD3OD) δ 4.59 (s, 1 H) 5.34 (d, J=3.54 Hz, 1 H) 5.86-6.08 (m, 1 H) 6.58 (d, J=3.28 Hz, 1 H). [M+H] calc'd for C8H5FN2O, 165; found, 165.5.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[N:17][CH:18]=1.B(OC)(OC)[O:25]C>C1COCC1.[OH-].[Na+].OO>[CH2:20]([O:19][C:16]1[N:17]=[CH:18][C:13]([OH:25])=[CH:14][CH:15]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: COB(OC)OC
Reactant: CC(C)COc1ccc(Br)cn1
Agent: OO
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)COc1ccc(O)cn1
Reaction time: 1 h
Yield: 30.7 %

Procedure:
A solution of nBuLi in hexane (2.5 M, 70 mL, 0.176 mol) was added to a solution of 5-bromo-2-isobutoxy-pyridine (Preparation 8, 27 g, 0.117 mol) in THF (300 mL) under a nitrogen atmosphere at −78° C. After stirring for 1 hour, trimethyl borate (18.3 g, 0.176 mol) was added. The mixture was stirred at 0° C. for 1 hour then diluted with 3N NaOH (15 mL) and hydrogen peroxide (30%, 175 mL). The resulting mixture was stirred at room temperature for 1 hour and extracted with EtOAc (3×500 mL). The combined organics were washed with saturated aqueous sodium sufite (3×500 mL), brine (300 mL) then dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield the crude product that was purified by silica gel chromatography (petroleum ether/EtOAc 100:1 to 10:1) to give the title compound as an off-white solid (6.0 g).
Reaction SMILES: C1(C2C=CC(CNCCC3C=CC(F)=C(C(F)(F)F)C=3)=CC=2)CC1.[C:25]([C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][C:30]=1[Cl:37])([CH3:28])([CH3:27])[CH3:26].[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH2:48])[CH:42]=[CH:43][C:44]=1[Cl:45].[BH4-].[Na+]>>[C:25]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:48][CH2:47][CH2:46][C:41]2[CH:42]=[CH:43][C:44]([Cl:45])=[C:39]([Cl:38])[CH:40]=2)=[CH:31][C:30]=1[Cl:37])([CH3:28])([CH3:27])[CH3:26]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1Cl
Agent: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1Cl
Yield: 85.3 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 4-tert-butyl-3-chloro-benzaldehyde (prepared as described in example S110) (72 mg, 0.37 mmol), 2-(3,4-dichlorophenyl)-ethylamine (70 mg, 0.37 mmol) and sodium borohydride (21 mg, 0.55 mmol). The desired product (117 mg, 86%) was isolated without further purification as a colorless oil. MS (ISP) 370.1 (M+H)+.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(C(C)C)C(C)C)C.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([O:43][CH3:44])=[C:38]([CH:42]=1)[C:39](Cl)=[O:40]>C1C=CC=CC=1>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([O:43][CH3:44])=[C:38]([CH:42]=1)[C:39]([N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:40]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)CCCCCNc1ccccc1-c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCN(C(=O)c1cc(Cl)ccc1OC)c1ccccc1-c1ccccc1
Yield: 90 %

Procedure:
8.0 g of ethyl 6-(biphenyl-2-yl)aminocaproate and 3.3 g of ethyldiisopropylamine in 50 ml of benzene are reacted with a solution of 5.3 g of 5-chloro-2-methoxybenzoyl chloride in 20 ml of benzene, analogously to Example 47a), to obtain, as reaction product, 11.1 g (90% of theory) of ethyl 6-[5-chloro-2-methoxy-N-(biphenyl-2-yl)benzamido]caproate as a viscous non-distillable oil. The saponification of this ester yields 7.0 g (67% of theory) of 6-[5-chloro-2-methoxy-N-(biphenyl-2-yl)benzamido]-caproic acid, MP 164° to 165°.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][NH2:1])=[C:8]([C:14]([F:15])([F:16])[F:17])[CH:9]=1
Reactant: [N-]=[N+]=NCCOc1ccc(Br)cc1C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NCCOc1ccc(Br)cc1C(F)(F)F

Procedure:
1-(2-Azidoethoxy)-4-bromo-2-(trifluoromethyl)benzene (7.32 mmol, 2.271 g) and triphenylphosphine (10.99 mmol, 2.88 g) were combined and stirred for 1 hour in THF (5 ml). The reaction mixture was concentrated in vacuo. The residue was taken up in EtOAc/water, the layers separated and the organic dried over sodium sulfate and concentrated in vacuo. The resulting residue was passed down an SCX column to afford 2-(4-bromo-2-(trifluoromethyl)phenoxy)ethanamine. (1.30 g)
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>C(OCC)(=O)C.O.O1CCOCC1>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Brc1cnccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccccc1-c1cnccn1
Temperature: 25 °C

Procedure:
2-Bromopyrazine (100 mg, 0.630 mmol) and ((2-chlorophenyl)boronic acid (103 mg, 0.660 mmol) were added to a 5 mL sealable vial equipped with a stir-bar. A solution consisting of 1,4-dioxane (3 mL) and Na2CO3 (1.6 mL, 2 M) was added and the mixture sparged with argon for 10 minutes before adding Pd(ddp)Cl2.CH2Cl2 (23 mg, 0.031 mmol) and heating at 80° Celsius for 15 hours. The reaction was then cooled to rt, diluted with 5 mL of ethyl acetate and 5 mL of water, and the mixture extracted with ethyl acetate (3×20 mL). The combined organic extracts were then dried with sodium sulfate and concentrated to dryness. The resultant residue was subjected to FCC to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.98-8.96 (d, J=1.6, 1H), 8.70-8.68 (dd, J=2.5, 1.6, 1H), 8.58-8.56 (d, J=2.6, 1H), 7.66-7.58 (m, 1H), 7.54-7.50 (m, 1H), 7.43-7.39 (m, 2H).