Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH2:23]Br)=[CH:21][C:20]3[C:19]([CH3:26])([CH3:25])[C:18](=[O:27])[CH2:17][C:16]([CH3:29])([CH3:28])[C:15]=3[CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:30]1[CH:34]=[CH:33][CH:32]=[N:31]1>CN1CCCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH2:23][N:30]3[CH:34]=[CH:33][CH:32]=[N:31]3)=[CH:21][C:20]3[C:19]([CH3:26])([CH3:25])[C:18](=[O:27])[CH2:17][C:16]([CH3:29])([CH3:28])[C:15]=3[CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(/C=C/c2cc3c(cc2CBr)C(C)(C)C(=O)CC3(C)C)ccc1C(=O)O
Reactant: c1cn[nH]c1
Agent: CN1CCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(/C=C/c2cc3c(cc2Cn2cccn2)C(C)(C)C(=O)CC3(C)C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
A solution of 1.0 g (2.2 mmol) of methyl-4-[(E)-2-(5,5,8,8-tetramethyl-3-bromomethyl-6-oxo -5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]-benzoic acid and 0.6 g (8.8 mmol) of pyrazole in 15 ml of N-methylpyrrolidine was heated at 100°. After 2 h, the reaction mixture was cooled to room temperature, poured into brine, extracted with ethyl acetate, washed with brine and dried over sodium sulfate. The organic solution was adsorbed onto silica gel and purified by flash chromatography (gradient elution: hexane-18% ethyl acetate/hexane) to afford 0.71 g (73%) of Methyl-4-[(E)-2-(5,5,8,8-tetramethyl-3-pyrazol-1-ylmethyl-6-oxo -5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]-benzoic acid (MH+=443).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:24]([F:35])([F:34])[F:23])[CH:30]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1cccc(C(F)(F)F)c1
Yield: 60.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 3-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.047 g (60%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C1COCC1>[C:21]([O:24][CH2:25][C:26](=[O:27])[NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11])(=[O:23])[CH3:22]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 75 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added (chlorocarbonyl)methyl acetate (0.55 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.56 g (75%) of product as an off-white solid: mp 234-236° C.; 1H NMR (DMSO-d6) , 11.15 (s, 1H), 10.06 (s, 1H), 8.55 (d, J=8.3 Hz, 1H), 7.87 (t, J=8.0 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 5.17 (dd, J=5.0 and 12.4 Hz, 1H), 4.78 (s, 2H), 2.99-2.85 (m, 1H), 2.65-2.52 (m, 2H), 2.22 (s, 2H), 2.11-2.07 (m, 1H); 13C NMR (DMSO-d6) δ 172.70, 169.69, 169.50, 167.99, 166.57, 136.40, 135.59, 131.35, 125.34, 118.72, 116.96, 62.60, 48.98, 30.90, 21.91, 20.41; Anal. Calcd. For C17H15N3O7: C, 54.69; H, 4.05; N, 11.26. Found: C, 54.43; H, 4.05; N, 10.97.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][CH2:10][CH2:11][S:12][CH2:13][CH2:14]C1OCCO1.[CH:20](O)=[O:21]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][CH2:10][CH2:11][S:12][CH:13]([CH3:14])[CH:20]=[O:21]
Reactant: O=CO
Reactant: c1ccc(CCOCCSCCC2OCCO2)nc1
Product: CC(C=O)SCCOCCc1ccccn1
Reaction time: 22 h

Procedure:
The material from step b) (0.850 g) was dissolved in 80% formic acid (10 ml) and left to stand at room temperature for 22 hours. The mixture was partitioned between ether and water. The layers were separated and the aqueous layer extracted with ether. The ethereal extracts were combined, washed with brine, dried (MgSO4) and evaporated is under reduced pressure to yield the subtitled compound as an oil (0.70 g).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:15])[CH:9]2[O:14][CH:10]2[C:11]([O-:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].C(O)=O>O>[C:1]1([NH:7][C:8](=[O:15])[CH:9]2[O:14][CH:10]2[C:11]([OH:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])C1OC1C(=O)Nc1ccccc1
Agent: [K+]
Solvent: O
Solvent: O=CO
Product: O=C(O)C1OC1C(=O)Nc1ccccc1
Yield: 77.9 %

Procedure:
Potassium N-phenyl-2,3-epoxysuccinamate (Compound No. 95) (2.31 g) was dissolved in water (10 ml) and the solution was made acidic by addition of 25% HCOOH under ice-cooling with stirring. The reaction mixture was extracted with chloroform, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness. The residue was recrystallized from a mixture of n-hexane-acetone to give 1.52 g of N-phenyl-2,3-epoxysuccinamic acid (Compound No. 105) as colorless needles melting at 124°-128° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH:18]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:19][C:20]([O-:22])=O)=[N:6][O:7][C:8]=2[CH:9]2[CH2:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10]2)[CH2:3][CH2:2]1.[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[NH2:37].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)(O)[O-].[Na+]>O.C(N(CC)CC)C.CN(C=O)C>[CH:1]1([C:4]2[C:5]([CH:18]([CH2:19][C:20](=[O:22])[NH:37][C:31]3[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:30]=3[CH3:29])[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[N:6][O:7][C:8]=2[CH:9]2[CH2:10][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:12]2)[CH2:3][CH2:2]1
Reactant: COC(=O)CCC(CC(=O)[O-])c1noc(C2CC(CC(C)(C)C)C2)c1C1CC1
Reactant: Cc1ccc(N)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCC(CC(=O)Nc1ccc(C)cc1C)c1noc(C2CC(CC(C)(C)C)C2)c1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Methyl 3-{4-cyclopropyl-5-[3-(2,2-dimethylpropyl)cyclobutyl]isoxazol-3-yl}adipate (100 mg), 2,4-dimethylphenylamine (0.0379 mL) and DMF (1 mL) were mixed. To the mixture were added triethylamine (0.0354 mL), HOBt.H2O (47 mg) and WSC.HCl (58.8 mg) at ice temperature. The mixture was stirred at RT overnight. To the reaction mixture was added saturated aqueous sodium bicarbonate at ice temperature. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by preparative chromatography (Eluent: ethyl acetate/hexane=1/4) to give the title compound (115 mg).
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1(/[CH:29]=[N:1]/[N:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[N:13][N:14]([CH:16]5[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]5)[CH:15]=4)[CH:9]=3)[CH:4]=[CH:3]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(N)c4c3)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(/N=C/c5ccccc5)c4c3)cn2)CC1
Temperature: 60 °C
Yield: 81 %

Procedure:
A mixture of tert-butyl 4-[4-(1-amino-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (30 mg, 0.078 mmol) and benzaldehyde (2.0 mL, excess) was heated to 60° C. for 10 min. Heptanes (4.0 ml) was added and the mixture was heated to reflux for 10 min. The product was purified by column chromatography (EtOAc:MeOH=100:5) and the entitled intermediate was isolated as a white solid (30 mg, 81% yield).
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)=[O:5])C.C1(C)C=CC=CC=1.CCOCC.[CH2:30]([NH:32][CH2:33][CH2:34][NH2:35])[CH3:31]>C(OCC)(=O)C>[CH2:30]([NH:32][CH2:33][CH2:34][NH:35][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)=[O:5])[CH3:31]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CCNCCN
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCNCCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reaction time: 8 h
Yield: 82 %

Procedure:
A fine powder of 5-nitro-2-indolecarboxylic acid ethyl ester (0.8 g, 3.41 mmol) was suspended in 2 ml of N-ethylethylenediamine under argon and the reaction mixture was stood at 55° C. overnight. The mixture was co-evaporated with toluene to dryness. The brown solid obtained was dissolved in 6 ml of ethyl acetate and 40 ml of ether was added to precipitate the product. After centrifugation, the liquid was poured out and the solid was washed with 30 ml of ether and dried to give small brown crystals (0.77 g, 82%). ESI MS: 277.11 (M+H+), 299.09 (M+Na+). 1H NMR (DMSO-d6) δ8.67 (d, 1H), 8.04 (dd, 1H), 7.55 (d, 1H), 7.37 (s), 3.36 (m, 3H), 2.69 (q, 2H), 2.55 (q, 2H), 0.99 (t, 3H).
Reaction SMILES: [CH3:1][N:2]([CH:23]([CH3:25])[CH3:24])[C:3]1[C:4]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+].O>CO.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH:23]([CH3:25])[CH3:24])[C:3]1[C:4]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3cnn(C)c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-carboxylate (80 mg, 0.24 mmol) in methanol (20 mL) and CHCl3 (5 mL) was added sodium hydroxide (75 mg, 0.72 mmol) and water (1 mL). The resulting solution was stirred for overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (15 mL) and adjusted to pH 5 with hydrochloric acid (3N). The solids were collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-carboxylic acid as a yellow solid (70 mg, 91%).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:12]=[C:11]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[CH:10]=[CH:9][C:7]=1[NH2:8])([O-])=O.NN>CO>[NH2:8][C:7]1[CH:9]=[CH:10][C:11]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[CH:12][C:6]=1[NH2:3]
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1[N+](=O)[O-]
Agent: NN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(C(=O)N2CCOCC2)cc1N
Reaction time: 0.08 h

Procedure:
A solution of 0.14 g of ferrous sulfate heptahydrate in 15 ml of methanol is treated under nitrogen with 0.02 g of sodium borohydride. After 5 minutes, 2.5 g of 2-nitro-4-morpholinocarbonylaniline (as prepared in Example XXXIX) and 1 ml 64% hydrazine are added. The mixture is refluxed until reduction is complete (~4-6 hours) to afford 1,2-diamino-4-morpholinocarbonylbenzene.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][S:7]1(=[O:12])=[O:11])([C:4]#[CH:5])[CH3:3].C[OH:14]>S(=O)(=O)(O)O.[Hg]=O>[O:11]=[S:7]1(=[O:12])[CH2:8][CH2:9][CH2:10][N:6]1[C:2]([CH3:1])([CH3:3])[C:4](=[O:14])[CH3:5]
Reactant: C#CC(C)(C)N1CCCS1(=O)=O
Reactant: CO
Agent: O=S(=O)(O)O
Agent: O=[Hg]
Product: CC(=O)C(C)(C)N1CCCS1(=O)=O
Temperature: 90 °C
Yield: 43 %

Procedure:
A mixture of 2-(2-methylbut-3-yn-2-yl)isothiazolidine-1,1-dioxide (3.500 g, 18.7 mmol) and mercury(II) oxide (0.810 g, 3.7 mmol) in methanol (100 mL) and 2 N aqueous sulfuric acid (50 mL) was heated at 90° C. for 3 hrs. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo. The residue was treated with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to afford the desired product as a yellow oil (1.65 g, 43%). 1H NMR (300 MHz, CDCl3) δ 3.38 (t, 2H, J=6.6 Hz), 3.21 (t, 2H, J=7.5 Hz), 2.42-2.30 (m, 2H), 2.28 (s, 3H), 1.60 (s, 6H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][C:35]=2[C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:38][CH:37]=2)[N:32](COCC[Si](C)(C)C)[N:31]=[C:30]3[NH:58][C:59](=[O:63])[CH2:60][CH2:61][CH3:62])=[CH:23][CH:22]=1)[CH3:20].C(OCC)(=O)C>O1CCCC1>[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][C:35]=2[C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:38][CH:37]=2)[NH:32][N:31]=[C:30]3[NH:58][C:59](=[O:63])[CH2:60][CH2:61][CH3:62])=[CH:23][CH:22]=1)[CH3:20]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccc(CC)cc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccc(CC)cc3)cc12
Yield: 98.3 %

Procedure:
8.3 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 850 mg of N-[5-(4-ethylphenyl)-6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 50 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours; after cooling, 75 cm3 of ethyl acetate are added and the organic phase is washed successively with 2×100 cm3 of saturated sodium hydrogen carbonate solution and with 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 1.5 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is dried (90 Pa; 45° C.) to give 660 mg of N-[5-(4-ethylphenyl)-6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide in the form of grey crystals.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[O:22]([C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(Oc2ccccc2)nc1C(F)(F)F
Yield: 75.6 %

Procedure:
A mixture of 5.2 g (0.02 mole) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate, 1.88 g (0.02 mole) of phenol, 2.76 g (0.02 mole) of K2CO3 and 50 ml. of acetone was held at reflux for 3 days. Acetone was removed under reduced pressure. The residue was treated with water, extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residual solid was heated with hexane, cooled and filtered to give 4.8 g (76%) of the desired product, m.p. 52°-54° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O1CCOCC1>[CH2:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCC1CCCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCCCC1CCO
Temperature: 0 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
2-Piperidine ethanol (39.6 ml, 0.31 mol) was dissolved in 5M aq NaOH (62 ml, 0.31 mol) and dioxan (100 ml). The mixture was cooled to 0° C. and treated with benzyl chloroformate (45.3 ml, 0.32 mol) and 5M NaOH (62 ml, 0.31 mol). Stirring was continued at room temp. for 18 hours. Dioxan was removed in vacuo and the aqueous phase extracted with ether before acidifying with 5N HCl and extracting again with ether. The organic phase was dried and evaporated in vacuo and the residue purified by chromatography on silica gel to give the title compound (77.2 g. 95%). MH+ 264.
Reaction SMILES: C[Si]([O:5][PH:6][O:7][Si](C)(C)C)(C)C.[PH2]([O-])=O.[NH4+].[C:16]([O:20][C:21]([NH:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][C:31](=[CH2:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CO>C(Cl)Cl.O>[C:16]([O:20][C:21]([NH:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:37][PH:6](=[O:7])[OH:5])=[CH:26][CH:25]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: C=C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Reactant: C[Si](C)(C)OPO[Si](C)(C)C
Agent: O=[PH2][O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C[PH](=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Bis(trimethylsilyl)phosphonite was generated as described in WO 01/042252 using N,O-bis-(trimethylsilyl)acetamide (3.0 mL; 12.1 mmol) and ammonium hypophosphite (1.0 g; 12.0 mmol). The resulting reaction mixture was cooled to 0° C. and a solution of ethyl 2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)acrylate (0.72 g; 2.35 mmol), in methylene chloride (4 mL) was added dropwise. The reaction was stirred overnight at room temperature. Methanol was added at 0° C. followed by water. The reaction mixture was concentrated. The remaining residue was dissolved in water and purified by preparative HPLC (0.1 M NH4Ac (aq)/CH3CN, 1/0→0/1), concentrated and lyophilized to afford 0.56 g (64%) of 2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-3-ethoxy-3-oxopropylphosphinic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[NH:4][C:5]1[C:6]([CH2:10][C:11](O)=[O:12])=[CH:7][S:8][CH:9]=1.P(Cl)(Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[N:4]1[C:11](=[O:12])[CH2:10][C:6]2=[CH:7][S:8][CH:9]=[C:5]12
Reactant: O=C(O)Cc1cscc1Nc1c(Cl)cccc1Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1Cc2cscc2N1c1c(Cl)cccc1Cl

Procedure:
1 g (0.33 mmole) of 4-(2,6-dichloroanilino)-3-thiophenacetic acid and 0.7 g (0.33 mmole) of phosphorus pentachloride are stirred in 10 ml of toluene at room temperature for half an hour. The mixture is extracted with water and sodium bicarbonate solution, clarified with bleaching earth (for example Tonsil®) and concentrated. Recrystallization of the residue from isopropanol yields N-(2,6-dichlorophenyl)-2,3-dihydro-2-oxothieno[3,4-b]pyrrole (m. 187° to 188°).
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:32])[CH3:31])[CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[C:33]1([Mg]Br)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)([OH:32])[CH3:31])[CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3]
Reactant: CC(=O)c1cccc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c1
Reactant: Br[Mg]c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1cccc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)quinolin-8-yl]-biphenyl-3-yl}-ethanone from Step 1 (1.0 eq.) in THF (0.1M) was added CeCl3 (1.1 eq.). The mixture was put in an ultrasonic bath for 15 min, cooled to −78° C. then phenyl magnesium bromide was added (5.0 eq.). The final mixture was stirred for 12 h at −20° C., poured in NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1 to 1:9 over 20 min) afforded the title compound as a white solid. 1H NMR (400 MHz, acetone-d6): δ 8.91 (dd, 1H), 8.46 (dd, 1H), 8.29 (d, 1H), 8.18 (d, 1H), 7.97 (d, 1H), 7.86 (d, 1H), 7.68 (dd, 1H), 7.64 (dd, 1H), 7.59–7.50 (m, 5H), 7.48 (d, 1H), 7.39 (t, 1H), 7.27 (t, 2H), 7.16 (t, 1H), 4.73 (s, 1H), 2.72 (s, 3H), 1.99 (s, 6H), 1.98 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=[CH:5]1)[CH:2]=[CH2:3].[Br:14]N1C(=O)CCC1=O>C1COCC1>[CH2:1]([N:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[C:6]([Br:14])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCn1ccc2ncnc(Cl)c21
Solvent: C1CCOC1
Product: C=CCn1cc(Br)c2ncnc(Cl)c21
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a room temperature solution of 5-allyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (960 mg, 5 mmol, 1 equiv.) in 100 mL of THF was added N-bromosuccinimide (1.1 g, 6 mmol, 1.1 equiv.). After 1 hour, the THF was concentrated and the residue diluted with water and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The solids were sonicated in water/saturated aqueous NaHCO3/MeOH and filtered to provide 1.26 g (93%) of 5-allyl-7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine as an off-white solid which was used without further purification.