Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][NH:7]1.Br[CH2:25][C:26](Br)=[O:27].[CH2:29]([NH:36][CH3:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:25][C:26]([N:36]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:37])=[O:27]
Reactant: O=C(Br)CBr
Reactant: CNCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(F)c(F)c1)NCC2
Product: COc1cc2c(cc1OC)C(Cc1ccc(F)c(F)c1)N(CC(=O)N(C)Cc1ccccc1)CC2

Procedure:
prepared by reaction of 1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with N-benzyl-N-methylamine
Reaction SMILES: O[CH:2]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11].S(Cl)([Cl:19])=O.CCOCC>C(Cl)(Cl)Cl>[ClH:10].[Cl:19][CH:2]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11]
Reactant: O=S(Cl)Cl
Reactant: OC(Cc1ccc(Cl)cc1Cl)n1ccnc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cl
Product: Clc1ccc(CC(Cl)n2ccnc2)c(Cl)c1
Temperature: 25 °C

Procedure:
1-(α-Hydroxy-2,4-dichlorophenethyl)imidazole, 12.85 g (0.05 mole), was dissolved in 100 ml chloroform and 8.33 g (0.07 mole) thionyl chloride was added to cause immediate formation of a solid precipitate. The mixture was refluxed three hours causing total solution of all solids. No precipitate formed on cooling to ambient temperature. A solid precipitate formed on pouring the chloroform solution into 500 ml of ether. The solid was collected and dried, 8.67 g (55.6%), m.p. 165°-167° C. Both ir and H1 nmr spectra supported the chemical structure. DMSO δ TMS 7.4 (m, 6H, aryl/imidazole); 5.78 (t, 1H, CH); 4.1 (d,2H, CH2).
Reaction SMILES: [NH2:1][C:2](=[N:39][C:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:27]2[NH:31][C:30](=[O:32])[N:29]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1.Cl[CH2:49][O:50][C:51](=[O:58])[C:52]([CH3:57])([CH3:56])[CH2:53][O:54][CH3:55].C(=O)([O-])O.[K+].CN(C=O)C>O.C(OCC)(=O)C>[C:18]([O:17][CH2:16][CH2:15][O:14][C:13]1[C:12]([F:26])=[C:11]([CH:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([NH2:1])=[N:39][C:40](=[O:47])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:8][CH:7]=2)[C:27]2[N:31]=[C:30]([O:32][CH2:49][O:50][C:51](=[O:58])[C:52]([CH3:57])([CH3:56])[CH2:53][O:54][CH3:55])[N:29]([C:33]3[N:34]=[CH:35][CH:36]=[CH:37][N:38]=3)[N:28]=2)[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=1)(=[O:20])[CH3:19]
Reactant: COCC(C)(C)C(=O)OCCl
Reactant: COc1cc(OCCOC(C)=O)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC(C)(C)C(=O)OCOc1nc(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2cc(OC)cc(OCCOC(C)=O)c2F)nn1-c1ncccn1
Temperature: 55 °C
Reaction time: 15 h
Yield: 34.1 %

Procedure:
Under nitrogen atmosphere, a mixture of acetic acid 2-{3-[(4-{amino[benzoylimino]methyl}phenylamino)-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy)ethyl ester (441 mg), 3-methoxy-2,2-dimethylpropionic acid chloromethyl ester (Example 4a, 373 mg), potassium hydrogen carbonate (241 mg), and DMF (20 mL) was stirred at 55° C. for 15 hours. The resulting mixture was poured into ethyl acetate (200 mL) and water (50 mL). After shaking the resulting mixture, the organic layer was collected, sequentially washed twice with water (50 mL) and with saturated aqueous sodium chloride solution (50 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (184 mg).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]([NH2:15])=[O:14])[CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH:19]=1.CS(Cl)(=O)=O.[CH3:40][NH2:41]>COCCOC>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]([NH:24][C:20]2[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=2)[CH2:17][NH:16][C:6]2[C:5]3[C:10](=[C:11]([C:13]([NH2:15])=[O:14])[CH:12]=[C:3]([CH2:2][NH:41][CH3:40])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[O:34])=[CH:27][CH:28]=1
Reactant: COc1ccc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cc(CO)cc34)c2)cc1
Reactant: CN
Agent: CS(=O)(=O)Cl
Solvent: COCCOC
Product: CNCc1cc(C(N)=O)c2ncnc(NCc3cccc(NC(=O)c4ccc(OC)cc4)c3)c2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6-(hydroxymethyl)-4-({3-[(4-methoxybenzoyl)amino]benzyl}amino)quinazoline-8-carboxamide (12.40 mg; 0.03 mmol; 1.00 eq.) in 1,2-dimethoxyethane (1.00 ml) added methanesulfonyl chloride (0.00 ml; 0.04 mmol; 1.50 eq.) (1.0M solution) at 0° C., stirred for 30 min, then added methyl amine (0.07 ml; 2.00 M; 0.14 mmol; 5.00 eq.) and the reaction mixture was stirred at RT overnight. Purified by HPLC to collect the desired product. MS (M+1) 471.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:38][CH3:39])[C:22]([Cl:40])=[CH:21][N:20]=1>>[Cl:40][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:28][C:27]=2[O:38][CH3:39])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine to yield an off-white solid (65%). LCMS: m/z=551.27 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.20 (d, 1H, J=8.8 Hz), 8.04 (s, 1H), 7.79 (bs, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.25 (m, 2H), 6.53 (m, 1H), 6.41 (d, 1H, J=8.8 Hz), 3.91 (s, 3H), 3.88 (m, 4H), 3.74 (m, 2H), 3.14 (m, 4H), 2.33 (m, 2H), 2.04 (m, 2H), 1.33 (s, 6H), 1.21 (t, 3H, J=7.1 Hz).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:20])[NH:12][C@@H:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C=O)C>C1COCC1>[CH2:3]([O:10][C:11](=[O:20])[NH:12][C@@H:13]1[CH2:17][C:16](=[O:18])[N:15]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]1=[O:19])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1C[C@@H](NC(=O)OCc2ccccc2)C(=O)N1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CC(=O)N(Cc2ccccc2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
1.2.2 (via two steps; 2nd step): A suspension of 48.4 mg of 60% NaH in 3 ml of THF was treated with 300 mg of (R)-(2,5-dioxo-pyrrolidin-3-yl)-carbamic acid benzyl ester at 0° C. followed by 161.3 μL of benzyl bromide. After 30 min the resulting precipitate was warmed to rt and treated with 3 ml of DMF to give after 15 min a solution which was stirred for 16 h at rt then quenched with 60 ml of H2O and extracted with 40 ml of toluene. The combined organic layers were dried over MgSO4 and concentrated to give 409 mg (74%) of the (R)-(2,5-dioxo-pyrrolidin-3-yl)-carbamic acid benzyl ester as white crystals; m.p. 145.1-145.5° C. Overall yield for the two step process: 78%.
Reaction SMILES: [OH:1][C:2]1[C:9](O)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.CN(C)[CH:24]=[O:25]>O1CCCC1>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:1][C:2]2[C:9]([O:25][CH2:24][C:17]3[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=3)=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:16][CH:15]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CN(C)C=O
Reactant: O=Cc1cccc(O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cccc(OCc2ccc(Cl)cc2)c1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a solution of 2,3-dihydroxybenzaldehyde (61, 2.0 g, 14.5 mmol) in tetrahydrofuran (100 mL) was added sodium hydride (0.52 g, 13.0 mmol) at 0° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warn to room temperature and was stirred at room temperature for 30 minutes. To the reaction mixture was then added 4-chlorobenzyl bromide (22, 2.7 g, 13.0 mmol). The reaction mixture was stirred at room temperature under an atmosphere of nitrogen overnight. N,N-dimethylformamide (50 mL) was added into the reaction mixture and it was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as an off-white solid (62, 2.3 gm, 46%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[H-].[Na+].[C:25](OCC)(=O)C>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]([C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])[CH3:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(F)cc1)C(=O)O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(F)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2-tert-Butoxycarbonylamino-3-(4-fluorophenyl)propionic acid (5.0 g; 17.7 mmol) was dissolved in dry tetrahydrofuran. Iodomethane (8.8 mL; 141 mmol) was added and the reaction mixture was cooled to 0° C. Sodium hydride (2.1 g; 53.0 mmol) was slowly added and the reaction mixture was stirred for 12 hours at room temperature. Ethyl acetate (50 mL) was added and water (20 mL) was added dropwise to the reaction mixture. The ethyl acetate was removed in vacuo and the residue was diluted with diethyl ether (30 mL) and water (100 mL). The organic phase was extracted with a saturated aqueous solution of sodium hydrogen carbonate (50 mL). Citric acid (5%) was added to the combined aqueous phases until pH 3, which were then extracted with ethyl acetate (2×50 mL) and the phases were separated. The organic phase was washed with water (2×50 mL), an aqueous solution of sodium thiosulfate (5%; 2×50 mL) and water (50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was dissolved in diethyl ether (10 mL). Dicyclohexylamine (10 mL) was added. Methylene chloride (30 mL) was added and the mixture was heated until the precipitate was dissolved. Diethyl ether (20 mL) and heptane (20 mL) were added and the reaction mixture was left 12 hours without stirring. The reaction mixture was filtered to afford 5.7 g of (R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(4-fluorophenyl)propionic acid as a dicyclohexylammonium salt.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([F:10])[CH:3]=1.Cl.Cl.BrC1C=CC(CN)=C(F)C=1.[C:23](Cl)(Cl)=[O:24]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:7]=[C:23]=[O:24])=[C:4]([F:10])[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: NCc1ccc(Br)cc1F
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=NCc1ccc(Br)cc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A solution of 4-bromo-2-fluorobenzylamine (20.4 g, 0.10 mol) in toluene (300 ml) is saturated with gaseous hydrochloric acid at 25° C. The resulting suspension of the 4-bromo-2-fluorobenzylamine hydrochloride is heated at 100° C. Phosgene is passed in at this temperature. Stirring of the solution, which has eventually become clear, is continued at 100° C. for 1 hour, and the mixture is then refluxed to remove the gases phosgene and hydrogen chloride. The batch is worked up by distillation. 21.2 g of 4-bromo-2-fluorobenzyl isocyanate (boiling point 109° C. at 4 mbar) are obtained. Yield: 92.1% of theory.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].Br[CH2:15][CH:16]1[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: BrCC1CC1
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CC2)c(C#N)c1
Yield: 47.3 %

Procedure:
A mixture of methyl 3-cyano-4-hydroxybenzoate (D22; 120 mg, 0.677 mmol), (bromomethyl)cyclopropane (Aldrich; 0.099 ml, 1.016 mmol), and potassium carbonate (140 mg, 1.016 mmol) in dry N,N-dimethylformamide (DMF) (2 ml) was heated under microwave irradiation at 150° for 90 mins. The cooled mixture was partitioned between water (30 ml) and ethyl acetate (3×25 ml), and the organic layer was washed with 50:50 brine:water and brine, dried (MgSO4) and evaporated in vacuo to give a light brown crystalline solid which was purified by flash chromatography on silica gel, eluting with 0-30% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (74 mg)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[H][H].Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:41])([F:40])[F:39])(=[O:31])=[O:30])=[N:24][CH:25]=[CH:26][N:27]=2)=[CH:18][CH:17]=1>CN(C)C=O.O>[N:1]1([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([NH:28][S:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:40])([F:39])[F:41])(=[O:30])=[O:31])=[N:24][CH:25]=[CH:26][N:27]=3)=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: [H][H]
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccnc1-c1ccc(Cn2ccc3ccccc32)cc1)c1ccccc1C(F)(F)F
Yield: 62 %

Procedure:
To a solution of 1H-Indole (234 mg, 2.0 mmol, 1 eq) in dimethylformamide (10 mL) was added sodium hydride (80 mg, 2 mmol, 1 eq). After the evolution of hydrogen ceased, N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzene sulfonamide (intermediate 26) (854 mg, 2 mmol, 1 eq) in dimethylformamide (5 mL) was added and the reaction mixture heated to 80 degrees over 3 hours. The reaction was cooled, diluted with 30 mL of water and extracted with diethyl ether. The organic layer was dried over MgSO4, evaporated and purified by flash chromatography on silica gel eluting with AcOEt and cyclohexane to give pure N-{3-[4-(1H-indol-1-ylmethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide as a yellow solid (630 mg, 1.24 mmol, yield: 62%, 97% HPLC purity).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Br:18][C:19]1[CH:24]=[C:23]([O:25]C)[CH:22]=[C:21]([Br:27])[C:20]=1[N:28]=[C:29]=[S:30]>CN(C)C1C=CN=CC=1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:29](=[S:30])[NH:28][C:20]1[C:21]([Br:27])=[CH:22][C:23]([OH:25])=[CH:24][C:19]=1[Br:18]
Reactant: COc1cc(Br)c(N=C=S)c(Br)c1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Agent: CN(C)c1ccncc1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(Br)cc(O)cc2Br)c1NCCCO
Temperature: 80 °C
Reaction time: 16 h
Yield: 24.9 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (1.00 g, 3.87 mmol), 1,3-dibromo-2-isothiocyanato-5-methoxybenzene (1.50 g, 4.64 mmol) and catalytic amount of 4-dimethylaminopyridine was stirred at 80° C. for 16 h and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a brown oil (560 mg, 0.963 mmol, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[CH2:35]Br>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:13][N:12]([CH2:35][C:34]3[CH:37]=[C:38]([O:42][CH3:43])[C:39]([O:40][CH3:41])=[C:32]([O:31][CH3:30])[CH:33]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(CBr)cc(OC)c1OC
Reactant: Clc1ccc(C2(CCCOC3CCCCO3)CCNC2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CN2CCC(CCCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 16 h

Procedure:
Combine 4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidine (10 mmol), K2CO3 (30 mmol), and 3,4,5-trimethoxy-benzyl bromide (10 mmol) in THF/H2O (4/1, 200 mL). Heat to reflux and stir for 16 h. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with H2O. Separate the layers, dry the organic layer over MgSO4, filter, and concentrate in vacuo. Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[F:7][C:8]1[CH:9]=[C:10]([OH:16])[CH:11]=[C:12]([F:15])[C:13]=1[F:14].[O-]C1C=CC=CC=1.Cl[C:25]1[N:26]([C:35]2[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[C:27](=[O:34])[C:28]2[N:29]=[CH:30][NH:31][C:32]=2[N:33]=1>C(O)(C)C.CC(N(C)C)=O>[Cl:41][C:38]1[N:37]=[CH:36][C:35]([N:26]2[C:27](=[O:34])[C:28]3[N:29]=[CH:30][N:31]([CH3:1])[C:32]=3[N:33]=[C:25]2[O:16][C:10]2[CH:9]=[C:8]([F:7])[C:13]([F:14])=[C:12]([F:15])[CH:11]=2)=[CH:40][CH:39]=1
Reactant: Oc1cc(F)c(F)c(F)c1
Reactant: CC(C)(C)[O-]
Reactant: O=c1c2nc[nH]c2nc(Cl)n1-c1ccc(Cl)nc1
Agent: [K+]
Agent: [O-]c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CC(C)O
Product: Cn1cnc2c(=O)n(-c3ccc(Cl)nc3)c(Oc3cc(F)c(F)c(F)c3)nc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.0 M KOtBu in isopropanol (2 mL) is added to the solution of 3,4,5-trifluorophenol (0.29 g, 1.86 mmol) and stirred for 20 minutes at RT. To the resulting phenoxide solution is added a solution of 2-chloro-1-(6-chloropyridin-3-yl)-1,9-dihydro-6H-purin-6-one (0.5 g, 1.69 mmol) in dimethylacetamide (3 mL) and the resulting mixture is stirred overnight at 50° C. The resulting reaction mixture is cooled, quenched with saturated NH4Cl solution, extracted with DCM (2×50 mL) and dried (Na2SO4). The organic layer is filtered and concentrated under vacuum to afford the crude product as a light brown solid. The crude product is further purified by flash column chromatography using 5% MeOH/CH2Cl2 to afford the title compound as white solid. 1H NMR (300 MHz, CDCl3) δ 8.41 (s, 1H), 7.55-7.81 (m, 2H), 7.4 (brs, 1H), 6.71-7.02 (m, 2H), 3.85 (s, 3H). MS (M+1): 408.04; RT=1.48 min. The IC50 determined as described in Example 6 is 100 nanomolar or less.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[C:10]([CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl:37][C:38]1[CH:39]=[C:40]([NH2:45])[CH:41]=[CH:42][C:43]=1[Cl:44]>C(Cl)Cl.CN(C=O)C>[Cl:37][C:38]1[CH:39]=[C:40]([NH:45][C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:22]=[CH:23][C:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:30])=[CH:9][C:10]=3[CH2:24][NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:21][CH:20]=2)=[O:19])[CH:41]=[CH:42][C:43]=1[Cl:44]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)O)cc2)c(CNS(C)(=O)=O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)Nc3ccc(Cl)c(Cl)c3)cc2)c(CNS(C)(=O)=O)c1
Reaction time: 0.5 h
Yield: 37 %

Procedure:
The product of step D (62 mg, 0.14 mmol) was diluted with methylene chloride (1 mL) followed by the addition of oxalyl dichloride (0.093 mL, 0.19 mmol) and 1 drop of DMF. The reaction was stirred for 30 minutes followed by the addition of 3,4-dichlorobenzenamine (46 mg, 0.28 mmol). The reaction was allowed to stir for 1 hour. The reaction mixture was loaded directly onto a 12i sim and purified on the horizon eluting with methylene chloride:MeOH (99.5-0.5 to 95:5) to yield 30 mg of tert-butyl 2-(4-(4-((3,4-dichlorophenyl)carbamoyl)phenoxy)-3-(methylsulfonamidomethyl)phenyl)acetate as a clear oil.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C[Al](C)C.C1(C)C=CC=CC=1.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[C:22]([C:27](=[O:44])[NH:28][CH:29]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=3)[C:30]([F:33])([F:32])[F:31])[N:23]2[CH3:26])=[CH:19][C:18]=1[C:45](OCC)=[O:46]>ClCCl.O>[CH2:1]([NH:4][C:45]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:17]=1[Cl:16])[N:23]([CH3:26])[C:22]([C:27]([NH:28][CH:29]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=1)[C:30]([F:31])([F:32])[F:33])=[O:44])=[CH:21]2)=[O:46])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)n(C)c2cc1Cl
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCNC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)n(C)c2cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Allylamine (156 mg, 2.73 mmol) was dissolved in 3 ml of dichloromethane and admixed dropwise under argon with a solution of trimethylaluminium in toluene (2 M, 1.37 ml, 2.73 mmol). The mixture was stirred for 30 min, and then ethyl 6-chloro-1-methyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate (165 mg, 0.27 mmol) dissolved in 3 ml of dichloromethane was added dropwise. The mixture was heated under reflux overnight and, after cooling to room temperature, water was added cautiously. The mixture was extracted with ethyl acetate, the organic phase washed with potassium sodium tartrate solution, dried over magnesium sulphate and filtered, and the filtrate concentrated under reduced pressure. The purification was effected by means of silica gel chromatography with the eluent cyclohexane/ethyl acetate (EA) (0% EA to 30% EA).