Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[OH:12][C@H:13]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C@H:15]([CH2:31][N:32]2[C:36](=O)[CH:35]([CH3:38])[NH:34][C:33]2=[O:39])[CH2:14]1.CO>O1CCCC1>[OH:12][C@H:13]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[O:19])[C@H:15]([CH2:31][N:32]2[CH2:36][CH:35]([CH3:38])[NH:34][C:33]2=[O:39])[CH2:14]1
Reactant: CC1NC(=O)N(C[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: CC1CN(C[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1
Reaction time: 0.25 h
Yield: 47.7 %

Procedure:
To a suspension of sodium borohydride (1.81 g) in tetrahydrofuran (50 ml) was dropwise added boron trifluoride etherate (23.4 ml) under ice-cooling and the mixture was stirred at the same temperature for 15 minutes. To this solution was added a solution of (2S,4R)-4-hydroxy-2-(4-methyl-2,5-dioxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (9.37 g) in tetrahydrofuran (50 ml) under ice-cooling and the mixture was stirred at ambient temperature overnight. To the reaction mixture was dropwise added methanol (30 ml) and the mixture was filtered. The filtrate was evaporated in vacuo. The resulting residue was dissolved in methanol (100 ml) and conc. hydrochloric acid (5 ml) and the solution was allowed to stand at ambient temperature for 3 hours. The reaction mixture was evaporated in vacuo and dissolved in ethyl acetate (300 ml). The solution was washed successively with saturated aqueous sodium hydrogen carbonate and aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-hydroxy-2-(4-methyl-2-oxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (4.31 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25](C#N)(=[O:29])[O:26][CH2:27][CH3:28]>C1COCC1>[O:24]=[C:20]1[CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:23][CH2:22][CH:21]1[C:25]([O:26][CH2:27][CH3:28])=[O:29]
Reactant: CCOC(=O)C#N
Reactant: O=C1CCCC1c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1CCC(c2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a solution of diisopropylamine (6.62 mL, 46.8 mmol) in THF (200 mL) at −78° C. was added a 1.6 M solution of n-butyllithium in hexanes (29.3 mL, 46.8 mmol). The solution was stirred for 30 min at −78° C. and treated with a solution of 2-phenylcyclopentanone (5 g, 31.2 mmol) in 50 mL of dry THF. After stirring for 30 min at −78° C., ethyl carbonocyanidate (3.36 mL, 34.3 mmol) was added to the reaction mixture. The resulting solution was warmed to 25° C. with stirring over 3 h. The reaction mixture was quenched with 10 mL of water, washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuum, and purified by column chromatography on silica gel to afford ethyl 2-oxo-3-phenylcyclopentanecarboxylate (5.3 g, 22.82 mmol, 73% yield) as colorless oil. LC-MS (M+K)+=273.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.32-7.39 (2H, m), 7.25-7.31 (1H, m), 7.19-7.25 (2H, m), 4.18-4.32 (2H, m), 3.29-3.55 (2H, m), 1.87-2.62 (4H, m), 1.28-1.39 (3H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].CCCCCC.C(OCC)(=O)C>CN(C)C=O.O.CCCCCC>[CH2:1]([O:8][C:9]([CH2:11][C@H:12]1[CH2:13][CH2:14][C@H:15]([O:18][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:16][CH2:17]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(C[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](CC(=O)OCc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of trans-4-benzyloxycarbonylmethyl-1-hydroxycyclohexane (2.20 g, 8.86 mmol) in dimethylformamide (31 mL) were added imidazole (953 mg, 14.0 mmol) and t-butyldimethylsilyl chloride (1.60 g, 10.6 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 h. The reaction mixture was diluted with water (70 mL) and hexane (200 mL) with stirring under ice cooling to separate the phases. The aqueous layer was extracted again with hexane, and the combined organic layer was concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 50:1) to give 2.96 g of trans-4-benzyloxycarbonylmethyl-1-t-butyldimethylsilyloxycyclohexane as oil (yield: 92%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.CCCCCC>C(Cl)Cl>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[NH:4][C:3]2=[O:20])=[O:27])=[CH:24][CH:23]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (100 mg, 0.37 mmol) and p-chlorobenzoyl chloride (52 μl, 0.41 mmole) were combined at room temperature in 5 ml of methylene chloride. The resulting solution was protected from moisture and stirred at room temperature overnight. The reaction mixture was diluted with 70 ml of methylene chloride and washed with sodium bicarbonate solution (sat.) and brine. The organic extracts were dried (MgSO4) and concentrated to give 150 mg of crude product. Chromatography on silica gel (chloroform - methanol - ammonia, 95:5:0.5 v/v) and trituration with hexane yielded the analytical product as a white powder, m.p. 258°-259° C.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:10][C:9]([F:12])([F:11])[C:5]1[CH:6]=[C:7]([F:8])[C:2]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)=[N:3][CH:4]=1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=Cc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 36.6 g (0.20 mol) of 2,3-difluoro-5-(trifluoromethyl)pyridine in 150 ml of acetonitrile was added 25.6 g (0.21 mol) of p-hydroxybenzaldehyde, 29.0 g (0.21 mol) of powdered potassium carbonate and 50 mL of acetonitrile. The slurry was stirred at ambient temperature for 21 hours and then diluted with 300 mL of water. The organic layer was separated in a separatory funnel and washed twice with 150 mL portions of water followed by washing with 100 mL of a 10 percent potassium carbonate solution. The mixture was then dried over sodium sulfate and the solvent removed in vacuo leaving 48.0 g (84 percent of theoretical) of the above named compound, a light yellow oil, as the product; 1H NMR (CDCl3): 7.3-8.3 (m, 6H, Ar), 10.0 (s, 1H, CH(O).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][C:10]([CH3:14])([CH3:13])[O:11][CH2:12][C:7]=2[CH:6]=1)[OH:4].[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:14][C:10]1([CH3:13])[O:9][C:8]2[CH:15]=[CH:16][C:5]([C@H:3]3[O:4][C:17](=[O:18])[NH:1][CH2:2]3)=[CH:6][C:7]=2[CH2:12][O:11]1
Reactant: CC1(C)OCc2cc([C@@H](O)CN)ccc2O1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (2.53 g, 11.3 mmol) in chloroform (12 mL) was added carbonyldiimidazol (2.75 g, 17 mmol) and triethylamine (2.37 mL, 17 mmol). The mixture was stirred at room temperature overnight.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[CH3:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cccc(-c2csc(N3CCNCC3)n2)c1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cccc(-c2csc(N3CCN(C(=O)Nc4cccnc4)CC3)n2)c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 35.2 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (229 mg, 0.848 mmol), 1-[4-(3-methylphenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.771 mmol) and diisopropylethylamine (0.269 ml, 1.54 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 20 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 103 mg (35.1%) of the desired product as a solid. mp 157-158° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][OH:9].Cl[S:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18])(=[O:13])=[O:12].S(Cl)(Cl)(=O)=O>O.CO.C1COCC1>[OH:9][NH:8][S:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18])(=[O:13])=[O:12]
Reactant: NO
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(=O)(Cl)Cl
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(S(=O)(=O)NO)c1
Yield: 267.3 %

Procedure:
A solution of potassium carbonate (0.43 g, 3.10 mmol) in water (1.2 ml) was added drop wise to a solution of hydroxylamine hydrochloride (0.21 g, 3.10 mmol) in water (0.8 ml) at 0° C. maintaining an internal reaction temperature between 5° C. and 15° C. THF (4 ml) and methanol (1 ml) were added, followed by 3-chlorosulfonyl-benzoic acid (0.34 g, 1.55 mmol) portion wise maintaining a temperature below 15° C. and the reaction mixture was stirred at ambient temperature until complete consumption of the sulfonyl chloride was observed by LCMS. The resulting suspension was concentrated to remove any volatiles and the aqueous suspension was extracted with diethyl ether (2×100 ml), and the combined organic layers were discarded. The aqueous layer was acidified to pH=1, adding a solution of hydrochloric acid (2N) drop wise, then extracted with diethyl ether (2×100 ml). The organic portion was dried over sodium sulphate, filtered and concentrated in vacuo to yield the clean N-hydroxysulphonamide as a yellow solid (0.9 g, 27% yield); 8H (400 MHz, DMSO) 13.52 (1H, br. s.), 9.72-9.74 (2H, m), 8.38 (1H, t, 1.6 Hz), 8.23 (1H, ddd, 7.9, 1.3, 1.2 Hz), 8.06 (1H, ddd, 7.8, 2.0, 1.2 Hz), 7.77 (1H, t, 7.7 Hz); TR=1.10 min.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([N:11]([CH3:35])[CH:12]([C:14]2[CH:15]=[C:16]([C:31]([O:33]C)=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:7]=[C:8]([F:10])[CH:9]=1.CO.Cl>C1COCC1.O>[F:3][C:4]1[CH:5]=[C:6]([N:11]([CH3:35])[CH:12]([C:14]2[CH:15]=[C:16]([C:31]([OH:33])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: COC(=O)c1cc(C(C)N(C)c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
2N NaOH (6.54 mL, 13.1 mmol), was added dropwise to a stirred suspension of methyl 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (3 g, 6.54 mmol), in THF (30 mL)/MeOH (30 mL). The resulting solution was stirred at RT overnight. The reaction mixture was diluted with water, the pH was adjusted to 3 with a 2M aq. sol. HCl. The solvents were removed and the white precipitate was collected by filtration, washed with water and dried then washed with ethyl acetate and ether to afford 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (2.5 g, 86%) which was used without further purification. Mass Spectrum: M+H+ 445.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].O>O1CCCC1>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[NH:1][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc2ccccc2n1
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc2ccccc2n1)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 2-aminoquinoline (1.00 g, 6.94 mmol) and pyridine (0.673 ml, 8.32 mmol) in tetrahydrofuran (23 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.15 ml, 8.32 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 908 mg (40.9%) of the desired product as a solid was separated by filtration.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:10][C:4]1[CH:3]=[C:2]([C:15]2[CH:14]=[CH:13][C:12]([F:11])=[C:17]([O:18][CH3:19])[CH:16]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: COc1cc(B(O)O)ccc1F
Reactant: Nc1c(F)cc(Br)cc1F
Product: COc1cc(-c2cc(F)c(N)c(F)c2)ccc1F
Yield: 197.5 %

Procedure:
The title compound (480 mg) was prepared from 4-bromo-2,6-difluoroaniline (200 mg, 0.96 mmol) and 4-fluoro-5-methoxyphenylboronic acid (210 mg, 1.24 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.39-7.29 (m, 3H), 7.21-7.12 (m, 2H), 5.33 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: I[CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@:14]2([O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]([OH:19])[C@H:16]2[OH:17])[OH:15])=[CH:10][C:9]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[Na+]>CN(C)C=O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@:14]2([O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]([OH:19])[C@H:16]2[OH:17])[OH:15])=[CH:10][C:9]=1[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:31][CH:32]=1
Reactant: IC1CCCC1
Reactant: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(OC4CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
0.16 ml iodocyclopentane are added to a mixture of 0.25 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene and 0.4 g caesium carbonate in 2.5 ml of dimethylformamide. The mixture is stirred for 4 h at 45° C., before another 0.1 g caesium carbonate and 0.05 ml iodocyclopentane are added. After another 14 h stirring at 45° C. aqueous sodium chloride solution is added and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulphate, the solvent is removed and the residue is purified using silica gel (dichloromethane/methanol 1:0->5:1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[I-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(N(C(C)C)C(C)C)C>C(#N)C>[N:1]1([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][NH:7][C:8]3=[O:11])=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1ccc2c(c1)C(=O)NC2
Reactant: BrCCCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1NCc2ccc(N3CCCCC3)cc21
Temperature: 75 °C
Reaction time: 20 h

Procedure:
6-Amino-2,3-dihydro-isoindol-1-one (0.810 g, CAS 675109-45-2) was dissolved in 12 ml of acetonitrile and treated successively with sodium iodide (2.458 g, 3 eq.), 1,5-dibromopentane (1.11 ml, 1.5 eq.), and N-ethyl-diisopropylamine (2.88 ml, 3.1 eq.), and the mixture was stirred at 75° C. for 20 h. Pouring onto crushed ice, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by crystallization from hexane/ethyl acetate yielded 6-piperidin-1-yl-2,3-dihydro-isoindol-1-one (0.669 g) as light brown crystals, MS 217.3 ([M+H]+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=1.NC1C=C(O)C(C)=CC=1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17]([NH:33][C:34]3[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=3)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Reactant: Cc1cccc(N)c1
Agent: Cc1ccc(N)cc1O
Product: COc1ccc(Sc2ccc(C(=O)Nc3cccc(C)c3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
The product from Example 137B was reacted with m-toluidine according to the procedure from Example 137C substituting m-toluidine for 5-amino-o-cresol to provide the title compound as an off white solid after silica gel chromatography (56 mg, 70%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6H), 2.21 (s, 3H), 3.15-3.29 (m, 1H), 3.78 (s, 3H), 7.00 (d, J=8.82 Hz, 2H), 7.12-7.37 (m, 4H), 7.40 (d, J=8.82 Hz, 2H), 7.64 (d, J=8.46 Hz, 1H), 7.84 (d, J=11.40 Hz, 1H), 7.99 (s, 1H), 8.59 (s, 1H), 8.86 (d, J=8.46 Hz, 1H), 9.87 (s, 1H), 10.21 (s, 1H); MS (APCI) m/z 536 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([N:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)[CH:40]=[CH:41][CH:42]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cl-].[Na+].O.CCOC(C)=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>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([C:37]3[CH:38]=[C:39]([N:43]4[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]4)[CH:40]=[CH:41][CH:42]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
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: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 105 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (193 mg, 0.40 mmol) and tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (217 mg, 0.56 mmol) in 1,4-dioxane (3 mL) was added potassium carbonate solution (0.80 mL, 1.6 mmol, 2 M aqueous solution) and Pd(PPh3)4 (23 mg, 0.02 mmol). The reaction mixture was stirred at 105° C. for 3 h. The mixture was diluted with brine (5 mL) and EtOAc (5 mL). The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo and used without further purification. LCMS-ESI+: calc'd for C36H43ClN3O5S: 664.3 (M+H+); Found: 664.3 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.[CH2:16]([N:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21]Cl)[CH3:17].[I-].[K+].C(=O)(O)[O-].[Na+].[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(O)CCC.C(#N)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[CH2:16]([N:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:5][CH2:6]1)[CH3:17]
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: CCN(CC)CCCCl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCCCO
Solvent: CC#N
Product: CCN(CC)CCCN1CCC(c2noc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
A suspension of 4.0 g of 3-(4-piperidyl)-1,2-benzisoxazole, 3.2 g of 3-diethylaminopropyl chloride, 3.0 g of potassium iodide and 5.0 g of sodium bicarbonate in 100 ml of butanol was heated under reflux for 2 hrs, cooled to room temperature and filtered. The filitrate was washed with water and extracted with ether (3 times). The ether extracts were dried over anhydrous sodium sulfate, filtered and evaporated to give an oil. The oil was dissolved in 10 ml of acetonitrile and 4.2 g of fumaric acid was added. The mixture was stirred for 2 hrs, filtered and the filter cake was recrystallized three times from ethanol-ether to give 2.8 g (26%) of product, mp 174°-176°.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.C(O)(=O)C.[O-:15][C:16]#[N:17].[K+]>O>[NH:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[NH:17][C:16]1=[O:15]
Reactant: N#C[O-]
Reactant: COC(=O)c1sccc1N
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2sccc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.7 %

Procedure:
To a mixture of methyl 3-amino-thiophenecarboxylate 1 (850 g, 5.41 mol, 1.0 equiv.), acetic acid (6 L) and water (5 L), a solution of potassium cyanate (KOCN, 1316 g, 16.22 mole, 3.0 equiv.) in water (3.2 L) was added slowly over a period of 1 hour. The resulting mixture was stirred at the ambient temperature for 20 hour, filtered and rinsed with water (4 L). The cake was charged to a suitably sized reactor and 2 M aqueous sodium hydroxide solution (14 L) was added. The slurry was stirred for 2 hours and LCMS confirmed the formation of the desired product. The mixture was cooled to 10° C. and 3 M aqueous hydrochloric acid (˜11 L) was added until pH=5.0-6.0 (by pH paper). The slurry was filtered, rinsed with water (6 L), dried in vacuum oven at 50° C. for 24 hours to afford thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione 2 as an off-white solid (834 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 6.90 (d, J=5.2 Hz, 1H), 8.10 (d, J=5.2 Hz, 1H), 5.40-5.55 (br s, 2H). LCMS (ESI pos) m/e 169 (M+1).