Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:19]1([C:25]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[PH2:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[C:28]1([C:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([PH2:26]=[O:27])[N:34]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:4](=[O:5])[C:3]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:2]=2[F:1])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(F)c(C(=O)Cl)c1
Reactant: COc1ccc(CNC([PH2]=O)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)c2cc(OC)ccc2F)C([PH2]=O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a mixture of 2-fluoro-5-methoxy-benzoyl chloride (4.77 g, 25.0 mmol) and sodium carbonate (13.4 g, 126.7 mmol) in dichloromethane (100 mL) cooled to 0° C. a solution of (diphenyl-phosphinoylmethyl)-(4-methoxy-benzyl)-amine (8.9 g, 25.3 mmol) in dichloromethane (50 mL) was added and the resulting mixture allowed to warm up to RT overnight. Then the mixture was filtered and evaporated and the residue was purified by chromatography (SiO2, Hexane:Acetone 1:1) to afford the title product (7.3 g, 57%) as a light yellow solid. MS m/e=504.3 (M+H+).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[S:12][C:11]([CH2:13][O:14][CH3:15])=[N:10][C:9]=1[CH3:16])=[O:7])C>C(O)C>[CH3:15][O:14][CH2:13][C:11]1[S:12][C:8]([C:6]([OH:7])=[O:5])=[C:9]([CH3:16])[N:10]=1
Reactant: CCOC(=O)c1sc(COC)nc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COCc1nc(C)c(C(=O)O)s1

Procedure:
6.7 g of 85% potassium hydroxide in 100 ml of ethanol are added at room temperature to 22.1 g of 2-methoxymethyl-4-methylthiazole-5-carboxylic acid ethyl ester and the reaction mixture is then heated under reflux for 18 hours. After cooling, the ethanol is evaporated off and the residue is dissolved in 200 ml of water. After stirring with active carbon, the mixture is filtered over Hyflo and the filtrate is acidified with concentrated hydrochloric acid with vigorous stirring. The resulting yellowish crystals are filtered off, washed with water and dried. After recrystallisation from tetrahydrofuran/petroleum ether (30°-45° C.) (=10:1) the yellowish crystals melt at 168°-169.5° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1B(O)O.[I:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1>CO>[I:13][C:14]1[N:15]=[CH:16][N:17]([C:3]2[CH:4]=[C:5]([F:9])[CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH:18]=1
Reactant: OB(O)c1cc(F)cc(F)c1F
Reactant: Ic1c[nH]cn1
Solvent: CO
Product: Fc1cc(F)c(F)c(-n2cnc(I)c2)c1
Reaction time: 21 h
Yield: 26.9 %

Procedure:
Following a procedure similar to that outlined in Synthesis 2008, 795-799: A mixture of 2,3,5-trifluorophenylboronic acid (0.302 g, 1.72 mmol), 4-iodo-1H-imidazole (0.498 g, 2.57 mmol), 2 mL of methanol, and Cu2O (0.049 g, 0.34 mmol) was stirred under air for 21 h, then filtered through Celite and concentrated to an oily white solid. Column chromatography (0->33% EtOAc/hexanes) afforded 0.150 g (27%) of 4-iodo-1-(2,3,5-trifluorophenyl)-1H-imidazole as a white solid. MS: (M+H)+=325.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].CN1C=CN=C1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].C(N(CCCC)CCCC)CCC>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([NH:4][C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[CH3:17])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CNC(C)=O
Reactant: Cc1ccccc1C(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: CCOC(=O)[C@@H](NC(C)=O)C(=O)c1ccccc1C
Temperature: -45 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl N-acetylglycinate (98%, 7.41 g, 50.0 mmol) and 1-methyl-1H-imidazole (99%, 4.81 mL, 60.0 mmol) in dichloromethane (100 mL) was cooled to −45° C. and treated with 2-methylbenzoyl chloride (99%, 6.59 mL, 50.0 mmol). The reaction was stirred at −45° C. for 10 minutes. Titanium(IV) chloride (19.2 mL, 175 mmol) was added, followed by tri-n-butylamine (98%, 48.6 mL, 200 mmol), and stirring was continued at the same temperature for 30 minutes. The reaction was quenched with water and extracted with diethyl ether; the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (Eluents: 1:5 ethyl acetate/heptane followed by 1:2 ethyl acetate/heptane) afforded the product. Yield: 6.00 g, 22.8 mmol, 46%. APCI m/z 264.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.93 (dd, J=7.8, 1.2 Hz, 1H), 7.44 (ddd, J=7.6, 7.5, 1.4 Hz, 1H), 7.26-7.34 (m, 2H), 6.89 (br d, J=7 Hz, 1H), 6.05 (d, J=7.2 Hz, 1H), 4.04-4.19 (m, 2H), 2.45 (br s, 3H), 2.11 (s, 3H), 1.06 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]([C@H:4]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31]>>[NH2:1][C:2]([C@H:4]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3]
Reactant: Fc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(N)=O)CC[C@H]1c1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1[C@@H](C(N)=O)CC[C@H]1c1ccc(OCc2ccccc2F)cc1

Procedure:
The title compound was synthesized (145 mg, 79%) following a similar procedure as set out earlier in Description 14 starting from 1,1-dimethylethyl (2R,5S)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1-pyrrolidine carboxylate (D39, 130 mg, 0.44 mmol) and 1-(bromomethyl)-2-fluorobenzene (166 mg, 0.88 mmol); Rt (HPLC) 5.55; MS: (ES/+) 437 m/z: [M+Na+], C23H27FN2O4 requires 414; 1H NMR (300 MHz, DMSO-d6) δ (ppm): 7.48-7.63 (m, 3H); 4.30-4.45 (m, 2H); 4.18-4.29 (m, 2H); 6.90-7.06 (m, 3H); 5.10 (s, 2H); 4.56-4.82 (m, 1H); 4.10-4.18 (m, 1H); 2.12-2.26 (m, 1H); 1.98-2.12 (m, 1H); 1.60-1.95 (m, 2H); 0.98-1.42 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7]([C:13](OC)=[O:14])=[C:6]2[C:17]([O:19]C)=O.O.[NH2:22][NH2:23]>C(O)C>[Cl:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C:6]3[C:17](=[O:19])[N:23]=[N:22][C:13](=[O:14])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: NN
Reactant: COC(=O)c1[nH]c2cc(Cl)c(OC)cc2c1C(=O)OC
Solvent: O
Solvent: CCO
Product: COc1cc2c3c([nH]c2cc1Cl)C(=O)N=NC3=O
Temperature: 25 °C
Yield: 30.3 %

Procedure:
To a solution of ethanol (15 ml) and dimethyl 5-methoxy-6-chloroindole-2,3-dicarboxylate (0.67 g, 2.30 mM), was added hydrazine hydrate (3.45 g, 0.69 mM). The resulting heterogeneous mixture was refluxed for 5 hr and then cooled to room temperature. The ethanol was removed under reduced pressure, acetic acid (15 ml) was added, and the resulting mixture refluxed for 2 hr. The reaction was cooled to room temperature, filtered, and dried. This afforded the titled compound as a white solid (0.18 g, 30%).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:4]=1.BrCC1CCCCO1.[F:20][C:21]([F:44])([F:43])[C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[NH:29][C:28](=[O:31])[C:27]12[C:35]2=[CH:36][C:37]3[O:41][CH2:40][O:39][C:38]=3[CH:42]=[C:34]2[O:33][CH2:32]1>>[F:44][C:21]([F:20])([F:43])[C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[N:29]([CH2:2][C:3]1[O:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:4]=1)[C:28](=[O:31])[C:27]12[C:35]2=[CH:36][C:37]3[O:41][CH2:40][O:39][C:38]=3[CH:42]=[C:34]2[O:33][CH2:32]1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: O=C1Nc2c(C(F)(F)F)cccc2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2c(C(F)(F)F)cccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-bromomethyl-2-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 7′-(trifluoromethyl)-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (43%) as a colorless solid: mp 95-98° C.; 1H NMR (300 MHz, CDCl3) δ7.59 (d, J=8.1 Hz, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.15 (dd, J=7.8, 7.8 Hz, 1H), 6.69 (d, J=3.2 Hz, 1H), 6.50 (s, 1H), 6.23 (d, J=3.0 Hz, 1H), 6.10 (s, 1H), 5.86 (d, J=3.0 Hz, 2H), 5.23 (ABq, 2H), 4.78 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ178.6, 156.0, 152.2, 149.3, 142.7, 141.4 (q), 139.1, 135.1, 127.9, 127.0 (m), 122.9 (d), 121.1 (d), 119.3 (d), 118.7, 113.4 (q), 112.5, 108.2, 102.8, 101.7, 93.7, 80.8, 56.9, 39.4; MS (ES+) m/z 498.4 (M+1).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])=O)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>C(Cl)Cl>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]
Reactant: CC(C)(C)OC(=O)NCCCCN1C(=O)c2ccccc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
5.13 g (16.11 mmol) of N-[4-(tert-butoxycarbonylamino)butyl]phthalimide was dissolved in 100 ml of methylene chloride and 6.21 ml (80.56 mmol) of trifluoroacetic acid was added thereto. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness, then dried by heating in vacuum at 50° C. to obtain 5.35 g (16.10 mmol) of N-(4-aminobutyl)phthalimide trifluoroacetate as a pale brown solid.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[C:18]([OH:23])(=[O:22])[C:19]([CH3:21])=[O:20].[OH-].[Na+].Cl>C(O)C.O>[C:18]([C:19](=[O:20])[CH:21]=[CH:1][C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)([OH:23])=[O:22]
Reactant: CC(=O)C(=O)O
Reactant: O=Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=O)C=Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Reaction time: 0.17 h

Procedure:
0.5 g of 5-formyl-2,2':5',2"-terthiophene was dissolved in 40 ml of ethanol, followed by dropping in 3 ml of water containing 0.3 g of pyruvic acid salt and stirring for 10 minutes. 1 ml of 50% NaOH solution was dropped into the solution and stirred overnight. The reaction solution was acidified by diluted HCl and extracted with 100 ml of ethyl acetate. The extract was treated in situ and separated by column chromatography. Unreactive materials were eluted by ethyl acetate/n-hexane (1/9). The black solid product was eluted by ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]1[OH:56]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]1[OH:56])=[O:9]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: NC1CCCCC1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCCC1O)c1cnc(OCC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
5-Bromo-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (75.0 g, 0.25 mol) was dissolved in DMF (850 mL). To the solution was added TBTU (91.0 g, 0.275 mol), N,N-diisopropylethyl amine (214 mL, 1.25 mol) and (1SR,2RS)-2-amino-cyclohexanol hydrochloride (41.7 g, 0.275 mol). The reaction mixture was stirred for 1.5 h at room temperature. The solvent was evaporated in vacuo, the residue was partitioned between ethyl acetate (2500 mL) and 1 N sodium hydroxide solution (2000 mL), the water phase was separated, extracted once more with ethyl acetate (1000 mL) and the organic phases were washed 2 times with water (2×1500 mL). Organic phases were pooled, dried with MgSO4 and concentrated to about 900 mL. The product precipitated upon stirring and cooling to 0° C. Filtration, washing with ethyl acetate/n-heptane (1:1) and drying in vacuo gave the title compound (81.1 g) as a white solid; MS (ISP) 397, 399 (M)+.
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)[C:9](=[O:28])[CH:8]=1.[H-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38]OS(C)(=O)=O)=[CH:34][N:33]=1>C(OCC)(=O)C>[F:31][C:32]1[N:33]=[CH:34][C:35]([CH2:38][O:6][C:7]2[CH:12]=[CH:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:17][CH:18]=3)[C:9](=[O:28])[CH:8]=2)=[CH:36][CH:37]=1
Reactant: O=c1cc(O)ccn1-c1ccc(OCCN2CCCCC2)cc1
Reactant: CS(=O)(=O)OCc1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1cc(OCc2ccc(F)nc2)ccn1-c1ccc(OCCN2CCCCC2)cc1
Reaction time: 0.33 h
Yield: 45.4 %

Procedure:
Into a DMF solution (0.8 mL) of 4-hydroxy-1-{4-[2-(1-piperidinyl)ethoxy]phenyl}-1H-pyridin-2-one (20 mg, 0.065 mmol), NaH (60% oiliness, 3 mg, 0.078 mmol) was added and stinred at room temeture for 20 minutes, followed by addition of DMF solution (0.2 mL) of 2-fluoro-5-methanesulfonyloxymethylpyridine (20 mg, 0.097 mmol), stirring at the same temperature for 2.5 hours and further an overnight stirring at 80° C. Ethyl acetate was added to the reaction liquid, which was then washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine and dried over anhydrous sodium sulfate. Concentrating the solvent under reduced pressure, the resulting residue was purified on silica gel column chromatography (C-300; methanol:chloroform=1:10) to provide the title compound (12.5 mg, 45%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:30][C@@H:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:32][OH:33])=[N:4][C:5]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([F:19])[CH:17]=3)[N:12]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:11]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[CH3:45][S:46]([O:33][CH2:32][C@@H:31]([NH:30][C:3]1[C:2]([F:1])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([F:19])[CH:17]=3)[N:12]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[CH:11]=2)[N:4]=1)[C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:48])=[O:47]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](CO)C(C)(C)C)c(F)cc3C#N)c3cc(F)cnc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](COS(C)(=O)=O)C(C)(C)C)c(F)cc3C#N)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of (S)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-((1-hydroxy-3,3-dimethylbutan-2-yl)amino)nicotinonitrile, 98a, (3.77 g, 7.17 mmol) and triethylamine (1.25 mL, 8.96 mmol) in dichloromethane (75 mL) was added methanesulfonyl chloride (0.69 mL, 8.96 mmol). The solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and water (100 mL) and EtOAc (200 mL) were added. The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to afford 4.22 g of the desired product as a yellow foamy solid that was used without further purification: LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 604.45 (M+H) retention time=2.03 minutes.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[S:10]([NH2:13])(=[O:12])=[O:11])[CH:3]=[CH:2]1.C[O:15][C:16](=O)[NH:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([CH3:26])[N:19]=1.C[Al](C)C.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:25][O:24][C:22]1[CH:21]=[C:20]([CH3:26])[N:19]=[C:18]([NH:17][C:16]([NH:13][S:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)(=[O:11])=[O:12])=[O:15])[N:23]=1
Reactant: NS(=O)(=O)c1cccc2cc[nH]c12
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3cc[nH]c23)n1

Procedure:
To a solution of 1H-indole-7-sulfonamide (1.0 g) and (4-methoxy-6-methylpyrimidin-2-yl)carbamic acid methyl ester (1.0 g) in methylene chloride (100 ml) was added trimethylaluminum (3.2 ml of a 2.0M solution in toluene). The mixture was heated at reflux for 18 hours under a nitrogen atmosphere. Work-up was achieved by careful addition of 100 ml of 1N HCl followed by separation of the organic layer. The methylene chloride was dried over MgSO4 and evaporated to an oil. The oil was dissolved in ether from which it quickly crystallized to give pure product (TLC) (0.56 g, m.p. 207°-209° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[CH:13]=[C:12]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=3[O:20][CH3:21])[CH:13]=[C:12]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(OC)c2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Oc1ccc(F)cc1
Product: COc1cc(OC)c2c(Oc3ccc(F)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 400 was used, starting from 4-Fluorophenol and (1-Chloro-6,8-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-Fluoro-phenoxy)-6,8-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 395(MH+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([CH:22]([CH2:27][CH2:28][CH3:29])[CH2:23][C:24]([OH:26])=[O:25])[C:14]2=[O:30])[CH:3]=1.C([O-])=[O:32].[NH4+]>CO>[CH3:11][N:8]1[C:9]2[C:5](=[C:4]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]([CH:22]([CH2:27][CH2:28][CH3:29])[CH2:23][C:24]([OH:26])=[O:25])[C:14]3=[O:30])[CH:3]=[CH:2][CH:10]=2)[CH2:6][C:7]1=[O:32]
Reactant: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Br)cc3c2ccn3C)c2ccccc21
Reactant: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cccc3c2CC(=O)N3C)c2ccccc21
Reaction time: 60 h
Yield: 34.4 %

Procedure:
To a solution of 3-[3-(6-bromo-1-methyl-1H-indol-4-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid (25 mg, 0.05 mmol) in methanol (2 mL) was added ammonium formate (150 mg, 2.4 mmol) and PdC 10% (5 mg). The resulting mixture was agitated for 60 h, filtered and concentrated. The resulting residue was dispersed in DCM (2 mL), filtered, and the filtrate was washed with DCM (1×2 mL). The mother liquors were concentrated and the residue was purified by preparative HPLC using an acetonitrile/water/formic acid gradient to provide 7 mg (35%) of the title compound. LCMS (ESMS): m/z 408 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[N:48]1[N:49]=[CH:50][N:51]2[CH2:56][CH2:55][NH:54][CH2:53][C:52]=12.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:48]1[N:49]=[CH:50][N:51]2[CH2:56][CH2:55][N:54]([C:4]([C:3]3[CH:7]=[C:8]([CH2:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[O:22])[NH:14][N:13]=4)[CH:9]=[CH:10][C:2]=3[F:1])=[O:5])[CH2:53][C:52]=12
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: c1nnc2n1CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2cnnc2C1
Reaction time: 12 h
Yield: 21.7 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (170 mg, 0.57 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (323 mg, 0.85 mmol), 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 17a (100 mg, 0.63 mmol, prepared according to a known method “Journal of Medicinal Chemistry, 2005, 48(1), 141-151”) and N,N-diisopropylethylamine (302 mg, 1.70 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-(6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 17 (50 mg, yield 21.7%) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=O.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[N:25][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Temperature: 70 °C
Yield: 57 %

Procedure:
A suspension of 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one (20 g, 60.9 mmol), (R)-2-methyl-2-propanesulfinamide (14.76 g, 122 mmol), and titanium (IV) ethoxide (25.2 mL, 122 mmol) in THF (250 mL) was heated to 70° C. for 24 h. Additional (R)-2-methyl-2-propanesulfinamide (1.0 equiv) and titanium (IV) ethoxide (1.0 equiv) were added and the reaction mixture was heated for additional 24 h. Additional (R)-2-methyl-2-propanesulfinamide (1.0 equiv) and titanium (IV) ethoxide (1.0 equiv) were added and the reaction mixture was heated for additional 8 h. The reaction mixture was quenched with brine (150 mL). The resulting suspension was filtered through celite, and the filter cake was washed with EtOAc. The filtrate was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography (100% hexanes) to afford racemic N-(7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide as an orange solid (15 g, 34.7 mmol, 57.1% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[N:32][CH:33]=2)[CH:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][N:12]3[Si](C(C)C)(C(C)C)C(C)C)[CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[N:32][CH:33]=2)[CH:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(-c3cc(O)cc(Nc4ccc(O)nc4)c3)cccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1cc(Nc2ccc(O)nc2)cc(-c2cccc3[nH]ccc23)c1
Yield: 1.5 %

Procedure:
A solution of 5-[3-hydroxy-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenylamino]-pyridin-2-ol (taken as 0.126 mmol) in TFA/CH2Cl2 (5 mL/5 mL)) was stirred at 0° C. for 1 h. The resulting mixture was concentrated, and saturated aqueous NaHCO3 was added. The pH was adjusted to around 7 and the mixture was extracted with EtOAc (with a small amount of MeOH) several times. After filtering through Celite®, the organic layer was separated, dried and concentrated. Purification by chromatography and further purification by prep-SFC afforded 5-[3-hydroxy-5-(1H-indol-4-yl)-phenylamino]-pyridin-2-ol as a brown solid (0.6 mg, 1.5%). 1H NMR (400 MHz, CDCl3): δ 7.62 (dd, J=9.7, 2.8 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.28 (d, J=2.9 Hz, 1H), 7.23 (d, J=3.3 Hz, 1H), 7.11 (t, J=7.7 Hz, 1H), 7.01 (d, J=7.2 Hz, 1H), 6.63-6.55 (m, 4H), 6.26 (t, J=2.0 Hz, 1H).