Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.[ClH:13]>C(Cl)(Cl)Cl>[Cl:13][CH2:3][CH2:2]/[CH:1]=[CH:4]/[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: Cl
Reactant: OC(c1ccc(F)cc1)C1CC1
Solvent: ClC(Cl)Cl
Product: Fc1ccc(/C=C/CCCl)cc1

Procedure:
Dissolve 12.8 g (0.077 mole) of α-cyclopropyl-4-fluorobenzenemethanol in 60 ml of CHCl3, add 20 ml of concentrated HCl and reflux overnight. Separate the two layers, and extract the aqueous layer with methylene chloride. Combine the methylene chloride extracts with the chloroform layer and wash with saturated aqueous sodium bicarbonate, and dry over magnesium sulfate. Evaporate the organic solvents to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:23]([O-:25])=[O:24])=[C:11]([NH:15][S:16]([C:19]([F:20])([F:21])[F:22])(=[O:18])=[O:17])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)(Nc1cccc(Oc2ccc(Cl)nn2)c1)C(F)(F)F
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)nn2)cc1NS(=O)(=O)C(F)(F)F
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
15 g of 1 was added in portions to 200 ml of chilled (4°-5° C.), stirred 90% nitric acid, and the mixture was stirred at 4° C. for 30 minutes. The resulting mixture was poured into ice water and the resulting solid was filtered. The filter cake was washed with water and purified by silica gel column chromatography, using as eluent a 66:30:4 (v:v:v) mixture of hexane, ethyl acetate and tetrahydrofuran, to give 2, as an amber glassy solid.
Reaction SMILES: [CH3:1][C:2](=[CH2:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+].OO.C(OCC)(=[O:19])C>C1COCC1>[CH3:12][CH:2]([CH2:3][NH:4][C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])[CH2:1][OH:19]
Reactant: CCOC(C)=O
Reactant: C=C(C)CNC(=O)OC(C)(C)C
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(CO)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
The tert-butyl N-(2-methylallyl)carbamate (213 mg, 1.24 mmol) was diluted with THF (12 mL) and the mixture was cooled to 0° C. Borane-dimethylsulfide complex (0.9 mL, 1.8 mmol) was added. After 1.5 hours, the reaction was cooled to −40° C. and 1 N NaOH (5 mL) and 30% hydrogen peroxide (5 mL) were carefully added. After 15 minutes, the reaction was warmed slowly until the frozen mixture melted. Ethyl acetate (100 mL) was then added, and the mixture was washed with brine (3×10 mL). The combined aqueous layers were extracted with ethyl acetate (100 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography (about 20 g silica, 10% EtOAc/CH2Cl2 through 15% EtOAc/CH2Cl2) to give the desired product (209 mg, 1.10 mmol, 89%).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:11]([C@@:13]1([CH2:27][F:28])[CH2:17][C:16](=O)[N:15]([C@@H:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14]1)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(=O)(=O)(O)O.Cl.[OH-].[Na+]>O1CCCC1>[CH2:3]([N:10]([CH2:11][C@@:13]1([CH2:27][F:28])[CH2:17][CH2:16][N:15]([C@@H:19]([CH3:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:14]1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@H](c1ccccc1)N1C[C@@](CF)(C(=O)N(Cc2ccccc2)Cc2ccccc2)CC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N1CC[C@](CF)(CN(Cc2ccccc2)Cc2ccccc2)C1

Procedure:
Sodium borohydride (12.2 g) was added to a solution of (R)-N,N-dibenzyl-3-fluoromethyl-1-((S)-α-methylbenzyl)-5-oxopyrrolidine-3-carboxamide (28.6 g) obtained in Preparative Example 10 in tetrahydrofuran (300 ml), and a solution of conc. sulfuric acid (8.6 ml) in tetrahydrofuran (100 ml) was dropwise added at not more than 5° C. over 1 hour. 3N Hydrochloric acid (78 ml) was dropwise added under ice-cooling and the mixture was refluxed for 1 hour with stirring. The reaction mixture was made alkaline by an aqueous solution of sodium hydroxide, and extracted with ethyl acetate, washed with water, dried, concentrated, and purified by silica gel column chromatography to give the object compound as an oil.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][C:27]=2[Cl:28])[NH:24][CH:23]=[C:22]3[C:29]([OH:31])=[O:30])=[CH:15][CH:14]=1)([CH3:12])[CH3:11])(C(C)(C)C)(C)C.[F-].[Cs+].[Cl-].[NH4+]>CN(C=O)C>[Cl:28][C:27]1[CH:26]=[C:25]2[C:21]([C:22]([C:29]([OH:31])=[O:30])=[CH:23][NH:24]2)=[CH:20][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([C:10]([CH3:12])([CH3:11])[CH2:9][OH:8])=[CH:14][CH:15]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(C)(CO)c1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5-[4-(1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropan-2-yl)phenyl]-6-chloro-1H-indole-3-carboxylic acid (76 mg, 0.17 mmol) in DMF (0.55 mL) was treated with solid cesium fluoride (507 mg, 3.32 mmol) and stirred at room temperature for one hour. The reaction mixture was then heated at 60° C. for two hours, then at 50° C. for two hours. The cooled reaction mixture was then poured into saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the title compound as an orange oil. The crude product was dissolved in DMSO (1.8 mL) and 0.9 mL of this solution was purified using reverse-phase chromatography to give the title compound. MS (ES−) 342.0 (M−H)−. Retention time: 1.61 min; Waters Xbridge dC18 5 μm 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.03% NH4OH). Flow: 2.0 mL/min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1>C(Cl)Cl.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(-n2cccn2)c(F)c1
Agent: [Pd]
Solvent: ClCCl
Product: Nc1ccc(-n2cccn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of 1-(2-fluoro-4-nitrophenyl)-1H-pyrazole (3.31 g, 16 mmol) in CH2Cl2 (60 mL) was added catalyst Pd/C (0.33 g). The reaction mixture was stirred at rt under H2 overnight, and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/CH2Cl2 (V/V)=1:1) to give the title compound as a white solid (1.30 g, 46%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:9][N:8]=[C:7]([CH2:10][S:11]([OH:14])(=[O:13])=N)[C:5]=2[CH:6]=1.BrCC1C2C=CC=CC=2[O:19]N=1.S([O-])([O-])=O.[Na+:30].[Na+]>>[Na+:30].[O:9]1[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[C:7]([CH2:10][S:11]([O-:14])(=[O:19])=[O:13])=[N:8]1
Reactant: N=S(=O)(O)Cc1noc2ccccc12
Reactant: BrCc1noc2ccccc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: O=S(=O)([O-])Cc1noc2ccccc12

Procedure:
A process for the preparation of zonisamide, disclosed in U.S. Pat. No. 4,172,896, comprises the sulfonation of 3-bromomethyl-benzo[d]isoxazole (1) with sodium sulfite to obtain benzo[d]isoxazol-3-yl-methanesulfonic acid sodium salt (2) which is then transformed into the corresponding sulfonyl chloride (3) by treatment with phosphorous oxychloride. The reaction of the latter with gas ammonia yields zonisamide (4), as reported hereinbelow.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[F:21][C:22]1[CH:23]=[C:24]([NH:25][C:16]2[CH:17]=[N:18][CH:19]=[C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[N:15]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Reactant: Nc1cccc(F)c1
Product: COc1cc(Nc2cncc(Nc3cccc(F)c3)n2)cc(OC)c1OC
Yield: 23 %

Procedure:
Using Method R, with 200 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine (all amounts scaled accordingly) and 3-fluoroaniline, 60 mg of title compound were obtained. Yield: 23%. 1H NMR (250 MHz, DMSO-d6) δ 3.62 (s, 3H), 3.65 (s, 6H), 6.65-6.72 (m, 1H), 6.81 (s, 2H), 7.24 (m, 2H), 7.56 (s, 1H), 7.58 (s, 1H), 7.67 (d, 1H, J=13.0 Hz), 9.12 (s, 1H), 9.41 (s, 1H). 13C NMR (62.5 MHz, DMSO-d6) δ 55.45, 60.07, 97.24, 106.71, 107.05, 114.04, 122.16, 122.49, 130.14, 132.43, 136.55, 142.71, 142.89, 149.52, 150.10, 152.89.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9].C[N:11]1C=CC=C1.N#CC#N.[ClH:20]>>[ClH:20].[NH:11]=[C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[C:8]#[N:9]
Reactant: Cn1cccc1
Reactant: Cn1cccc1CC#N
Agent: Cl
Agent: N#CC#N
Product: Cn1cccc1C(=N)C#N

Procedure:
A process of preparing 1-methylpyrrole-2-acetonitrile which comprised the steps of interacting N-methylpyrrole and cyanogen in the presence of hydrogen chloride in an inert organic solvent to form an α-imino-1-methypyrrole-2-acetonitrile HCl salt, treating the latter salt with at least an equivalent amount of an acid-neutralizing base, and reducing the thus-obtained α-imino-1-methylpyrrole-2-acetonitrile to said 1-methylpyrrole-2-acetonitrile by the action of hydrogen sulfide as the reducing agent in an inert organic solvent at a temperature from about -20° to about 50° C and a pressure from atmospheric pressure to about 60 p.s.i. pressure.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Br:18])[CH:14]=3)[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>[Cu].C1C(Cl)=CC=C(Cl)C=1>[C:1]1([N:7]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Br:18])[CH:14]=3)[CH:9]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Ic1ccccc1
Reactant: Brc1ccc2cc(Nc3ccccc3)ccc2c1
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: Clc1ccc(Cl)cc1
Product: Brc1ccc2cc(N(c3ccccc3)c3ccccc3)ccc2c1
Yield: 77 %

Procedure:
A mixture of N-phenyl-6-bromo-2-naphthylamine (29.8 g. 0.10 moles), iodobenzene (50 g. 0.245 mol.), potassium carbonate (60 g. 0.434 mol.), copper bronze (4.0 g. 0.063 g. atoms), 18-crown-6 (3.7 g. 0.014 mol.) and dichlorobenzene (100 ml) was kept under reflux for 3 hours under nitrogen, cooled and filtered. The residue remaining after concentration of the filtrate, was chromatographed over 600 g of silica gel. Elution with toluene-heptane (1:9), gave the product, 28.65 g., m.p. 135.8-137.4° C., in 77% yield. Mass Spec: m/z 373, 375 (M+), 421 (M+ iodo). The product was contaminated with a small amount of the corresponding iodo compound. A sample recrystallized from heptane, m.p. 137.9-139.2° C. was analyzed. Analysis calculated for C22H16NBr: C, 70.59; H, 4.31; N, 4.09; Br, 21.35. Found: C, 69.23; H, 4.22; N, 3.61; Br, 20.56.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[NH:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[NH:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1
Reactant: O=CCCCC(=O)NC1Cc2ccccc2C1
Reactant: CCCNC1CCc2ncsc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCN(CCCCC(=O)NC1Cc2ccccc2C1)C1CCc2ncsc2C1
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of 395 mg (2 mmol) propyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-amine and 694 mg (3 mmol) N-(2,3-dihydro-1H-inden-2-yl)-5-oxopentanamide in 1,2-dichloroethane (20 mL) is stirred for about 30 minutes. Then 0.75 g (3 mmol) of sodium triacetoxyborohydride is added and the mixture is stirred overnight. After hydrolysation with 30 mL of 1N aqueous NaOH solution the organic phase is separated, dried over sodium sulfate and concentrated in vacuum. The crude product obtained is purified via column chromatography on silica gel.
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[C:3]1[CH:4]=[C:5]([CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:27]=1[C:36]1[CH:41]=[C:40]([CH:42]([CH3:44])[CH3:43])[C:39]([F:45])=[CH:38][C:37]=1[O:46][CH3:47])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:10][N:9]=1.Cl.O1CCOCC1.[OH-].[Na+]>C(OCC)(=O)C>[F:55][C:2]([F:1])([F:56])[C:3]1[CH:4]=[C:5]([CH:48]=[C:49]([C:51]([F:52])([F:54])[F:53])[CH:50]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:27]=1[C:36]1[CH:41]=[C:40]([CH:42]([CH3:43])[CH3:44])[C:39]([F:45])=[CH:38][C:37]=1[O:46][CH3:47])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][N:9]=1
Reactant: COc1cc(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)OC(C)(C)C)cn2)c(-c2cc(C(C)C)c(F)cc2OC)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)O)cn2)c(-c2cc(C(C)C)c(F)cc2OC)cc1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 83.4 %

Procedure:
To tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4′-fluoro-5′-isopropyl-4,5,2′-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (129 mg) is added a 4N-hydrogen chloride/dioxane solution (3 ml) and the mixture is stirred at room temperature for 7 hours. To the reaction solution are added a saturated aqueous sodium hydroxide solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4′-fluoro-5′-isopropyl-4,5,2′-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid (100 mg). MS (m/z): 740 [M+H]+
Reaction SMILES: CN(C)C=O.Cl[C:7]1[N:8]=[CH:9][C:10]([CH:13]=[O:14])=[N:11][CH:12]=1.[CH3:15][C:16]([CH3:39])([CH2:21][O:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1)[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[CH:13]([C:10]1[N:11]=[CH:12][C:7]([C:26]2[C:27]([CH3:29])=[CH:28][C:23]([O:22][CH2:21][C:16]([CH3:15])([CH3:39])[C:17]([O:19][CH3:20])=[O:18])=[N:24][CH:25]=2)=[N:8][CH:9]=1)=[O:14]
Reactant: COC(=O)C(C)(C)COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=Cc1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)COc1cc(C)c(-c2cnc(C=O)cn2)cn1
Temperature: 65 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
N,N-dimethylformamide (10 mL) was added to 5-chloropyrazine-2-carbaldehyde (500 mg), methyl 2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}propanoate (1410 mg) and 2N aqueous sodium carbonate solution (5.26 mL), and after replacing the atmosphere with nitrogen, palladium chloride (dppf) methylene chloride complex (143 mg) was added to the mixture and the resulting mixture was stirred at 65° C. for 2 hours. To the reaction mixture were added ethyl acetate and water, and the liquids were separated. After filtration with Celite, the organic layer was separated, washed with water and then with a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 70:30) to obtain methyl 3-{[5-(5-formylpyrazin-2-yl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate (855 mg).
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)[CH2:2][CH3:3].[Li]CCCC.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16]>C1COCC1>[CH2:1]([C:4]1[S:5][C:6]([Sn:15]([CH3:17])([CH3:16])[CH3:14])=[CH:7][CH:8]=1)[CH2:2][CH3:3]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc([Sn](C)(C)C)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
2-propylthiophene (5.0 g, 39.6 mmol) was dissolved in 160 ml THF and n-BuLi (27 ml, 1.6 M in hexanes, 43.6 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 1 h and then cooled down to −78° C. A solution of trimethyltin chloride (8.679 g, 43.6 mmol) in 50 ml THF was added dropwise. The mixture was allowed to warm slowly to room temperature and stirred for 2 h. After quenching with ice water and aqueous work-up, the product was obtained as a light brown liquid (10.1348 g, 88.6% yield).
Reaction SMILES: [OH-].[K+].C([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][N:37]2[C:42]([CH3:44])([CH3:43])[CH2:41][CH:40]([O:45]C(=O)CCCCCCCCCCCCCCCCC)[CH2:39][C:38]2([CH3:66])[CH3:65])[C:25]([CH3:68])([CH3:67])[CH2:24]1)(=O)CCCCCCCCCCCCCCCCC>C(O)C>[OH:45][CH:40]1[CH2:41][C:42]([CH3:44])([CH3:43])[N:37]([O:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][N:26]2[C:25]([CH3:68])([CH3:67])[CH2:24][CH:23]([OH:22])[CH2:28][C:27]2([CH3:30])[CH3:29])[C:38]([CH3:66])([CH3:65])[CH2:39]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(OCCCCON2C(C)(C)CC(OC(=O)CCCCCCCCCCCCCCCCC)CC2(C)C)C(C)(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(O)CC(C)(C)N1OCCCCON1C(C)(C)CC(O)CC1(C)C

Procedure:
The title compound is prepared by the basic hydrolysis (potassium hydroxide in ethanol) of the compound prepared in Example 29A.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[O:31].O>C(#N)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:30](=[O:31])[CH2:29][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:33][CH:34]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2CC(=O)c2ccc(Cl)cc2)CC1
Yield: 13.1 %

Procedure:
K2CO3 (0.129 mol) was suspended in a solution of ethyl 4-(1H-benzimidazol-2-yl-amino)-1-piperidinecarboxylate (0.0347 mol) and 2-bromo-1-(4-chlorophenyl)ethanone (0.0647 mol) in acetonitrile (150 ml). The mixture was stirred and refluxed for 8 hours, then cooled, poured out into H2O and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97.5/2.5/0.1). The pure fractions were collected and the solvent was evaporated. Part of this fraction (3 g) was taken up in 2-propanone and diethyl ether. The precipitate was filtered off and dried, yielding 2 g of ethyl 4-[[1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (interm. 1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:19]([F:24])([F:23])C([O-])=O.[Na+]>CN(C)C=O.O>[F:23][CH:19]([F:24])[O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.1 %

Procedure:
To a solution of 2-methyl-4-nitrophenol (14 g, 91.50 mmol) in dimethylformamide (120 mL) and water (25 mL) was added Cs2CO3 (41.8 g, 128.22 mmol), and sodium 2-chloro-2,2-difluoroacetate (32 g, 209.84 mmol). The resulting solution was stirred for 20 minutes at room temperature, then for an additional 3 hours at 100° C. The reaction solution was cooled to room temperature before the addition of 100 ml of H2O. The resulting solution was extracted with EtOAc (4×100 ml) and the combined organic layers were washed with H2O (2×150 mL), dried over Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography to provide 16 g (86%) of 1-(difluoromethoxy)-2-methyl-4-nitrobenzene.
Reaction SMILES: C(C1C=CC(C2C=CC=CC=2)=C(C(C)C)C=1C(C)C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:30]([O:37][CH2:38][CH2:39][C@@H:40]1[C:44]2[NH:45][C:46](B3OC(C)(C)C(C)(C)O3)=[CH:47][C:43]=2[C:42](=[O:57])[NH:41]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:58]([NH:62][C:63]1[N:72]([CH3:73])[C:71](=[O:74])[C:70]2[C:65](=[C:66](I)[CH:67]=[CH:68][CH:69]=2)[N:64]=1)([CH3:61])([CH3:60])[CH3:59].[OH-].[Na+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[CH2:30]([O:37][CH2:38][CH2:39][C@@H:40]1[C:44]2[NH:45][C:46]([C:66]3[CH:67]=[CH:68][CH:69]=[C:70]4[C:65]=3[N:64]=[C:63]([NH:62][C:58]([CH3:59])([CH3:60])[CH3:61])[N:72]([CH3:73])[C:71]4=[O:74])=[CH:47][C:43]=2[C:42](=[O:57])[NH:41]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC1(C)OB(c2cc3c([nH]2)[C@@H](CCOCc2ccccc2)NC3=O)OC1(C)C
Reactant: Cn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Agent: [Pd]
Agent: CC(C)c1ccc(-c2ccccc2)c(C(C)C)c1C(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)[C@@H](CCOCc3ccccc3)NC4=O)cccc2c1=O
Temperature: 80 °C
Yield: 49.1 %

Procedure:
A mixture of 2-(dicyclohexylphosphino)-2′,4′,6%-tri-isopropyl1,1′-biphenyl(Strem Chemicals, Newburyport, Mass., 110 mg, 0.23 mmol), tris(dibenzylideneacetone)dipalladium (0) (Strem Chemicals, Newburyport, Mass., 105 mg, 0.115 mmol), potassium phosphate tribasic (1.83 g, 8.63 mmol), (R)-6-(2-(benzyloxy)ethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (503a, 1.10 g, 2.88 mmol) and 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (701) (830 mg, 2.32 mmol) in 1,4-dioxane (12 mL), water (3.60 mL) in a sealed glass tube was heated in a heating block at 80° C. for 2 h. The reaction mixture was treated with 1 N NaOH and extracted with EtOAc (2×50 mL), washed with brine and dried over MgSO4, filtered and concentrated. The crude reaction mixture was chromatographed on an ISCO Combiflash RF (40 g Thomson SingleStep column, using a gradient of 20-100% EtOAc in hexanes then 0-10% MeOH in DCM) affording (R)-8-(6-(2-(benzyloxy)ethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-(tert-butylamino)-3-methylquinazolin-4(3H)-one (503b, 555 mg, 1.14 mmol, 40% yield) as a dark brown oil. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.01 (1H, dd, J=7.9, 1.5 Hz), 7.89 (1H, dd, J=7.5, 1.5 Hz), 7.19-7.28 (3H, m), 7.08-7.17 (3H, m), 6.69 (1H, s), 4.75 (1H, dd, J=6.7, 5.1 Hz), 4.45 (2H, q, J=11.3 Hz), 3.70-3.77 (1H, m), 3.62-3.70 (1H, m), 3.55 (3H, s), 2.19-2.31 (1H, m), 1.98-2.09 (1H, m), 1.54 (9H, s). m/z (ESI, +ve) 486.0 (M+1)′.