Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[CH:4]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[CH:14]([C:16]1[C:24]2[O:23][CH2:22][CH:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20]=2[C:19]([CH3:31])=[C:18]([NH:32][C:33](=[O:39])[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:17]=1[CH3:40])=[O:15]>C1COCC1>[OH:15][CH:14]([C:10]1[CH:11]=[CH:12][C:7]([CH:4]([CH3:6])[CH3:5])=[CH:8][CH:9]=1)[C:16]1[C:24]2[O:23][CH2:22][CH:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20]=2[C:19]([CH3:31])=[C:18]([NH:32][C:33](=[O:39])[CH2:34][C:35]([CH3:36])([CH3:37])[CH3:38])[C:17]=1[CH3:40]
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccccc1)CO2
Reactant: CC(C)c1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(O)c1ccc(C(C)C)cc1)OCC2c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of magnesium (119 mg, 4.91 mmol) and a catalytic amount of iodine was added dropwise under an argon atmosphere a solution of 4-isopropyl-1-bromobenzene (978 mg, 4.91 mmol) in THF (10 mL) and the mixture was stirred at room temperature for 20 minutes. To the reaction solution was added dropwise a solution of N-(7-formyl-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (200 mg, 0.547 mmol) obtained in Example 232 in THF (5 mL) and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to ice and the product was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain N-(7-(hydroxy(4-isopropylphenyl)methyl)-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide. To a mixture of the compound and trifluoroacetic acid (5 mL) was added with ice-cooling triethylsilane (0.161 mL, 1.01 mmol), and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, to the residue was added an aqueous saturated sodium bicarbonate solution and the aqueous layer was made alkaline, and the mixture was extracted with ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:23][CH2:22][CH2:21][O:20][CH3:19])[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: COCCN
Solvent: COCCOC
Product: COCCNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and 2-methoxyethylamine in DME. EI-MS m/e (%): 259 (M+, 15), 214 ([M—MeOCH2]+, 100), 201 ([M—MeOCH═CH2]+, 78).
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=2)[N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]2[NH:27][N:26]=[N:25][N:24]=2)[CH:20]=[CH:21][CH:22]=1>>[Cl:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[S:11][C:10]([S:12]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)[CH:18]=3)(=[O:14])=[O:13])=[CH:9][CH:8]=2)[N:3]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2nsc(Cl)n2)s1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2nsc(Cl)n2)s1
Yield: 68.1 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting with 5-(5-chloro-1,2,4-thiadiazol-3-yl)thiophene-2-sulfonyl chloride (16.6 mg, 0.055 mmol) and 5-(3-amino-phenyl)tetrazole (8 mg, 0.05 mmol) affording 14.5 mg (68%) of the title compound. MS (ESI+) calcd for C13H8ClN7O2S3 424.959012, found 424.959022.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:23]=[C:22]([Cl:24])[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[C:13]([O:29][CH3:30])[CH:12]=1)=[O:10])C1C=CC=CC=1.[H][H]>C1COCC1.[OH-].[Pd+2].[OH-]>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:23]=[C:22]([Cl:24])[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[C:13]([O:29][CH3:30])[CH:12]=1)([OH:10])=[O:8]
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1 g (2.284 mmol) 2-(4-benzyloxycarbonyl-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine are dissolved in 50 ml THF and combined with 100 mg palladium hydroxide. The reaction mixture is stirred for 16 h at ambient temperature and 4 bar hydrogen pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:15]([NH:18][CH2:19][CH2:20][CH3:21])[CH2:16][CH3:17]>CN(C)C=O>[CH2:15]([N:18]([CH2:19][CH2:20][CH3:21])[C:2]1[C:3]2[N:4]([CH:12]=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:16][CH3:17]
Reactant: Clc1nc2ccccc2n2cnnc12
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)c1nc2ccccc2n2cnnc12
Yield: 41 %

Procedure:
4-Chloro-[1,2,4]triazolo[4,3-a]-quinoxaline (2.0 g., 0.01 mole), the product of Example 2, and 3.0 g. (0.03 mole) of di-n-propylamine in N,N-dimethylformamide (50 ml.) were stirred for 3 hours at room temperature. The solution was poured over ice to form a precipitate which was separated by filtration and air dried. Recrystallization from cyclohexane (250 ml.) afforded 1.1 g. (41% yield) of 4-di-n-propylamino-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 240°-242° C. Mass spectrum: m/e, 269 (P).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30]I.O>CN(C)C=O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=3)[N:19]=2)[CH3:30])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(-c2csc(NC3CCN(Cc4ccccc4)CC3)n2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1nc(-c2ccc(C#N)cc2)cs1)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.25 h
Yield: 67 %

Procedure:
1.3 g of 4-{2-[N-(1-benzylpiperid-4-yl)amino]-1,3-thiazol-4-yl}benzonitrile dissolved in 5 ml of N,N-dimethylformamide are added, at room temperature, to 146 mg of sodium hydride (at 60% in dispersion in oil) in suspension in 13 ml of N,N-dimethylformamide and the reaction mixture is stirred for 15 minutes at this temperature. 0.23 ml of methyl iodide is then added, the reaction mixture is stirred for 4 hours at room temperature, and it is poured over water and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and evaporated. The residue is purified by silica gel chromatography, eluting with dichloromethane. Yellow crystals are obtained which melt at 136° C.; yield: 67%.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1)([O-:28])=[O:27]>C(O)C.O>[N+:26]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:11]2[CH2:10][CH2:9][CH:8]([CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:13][CH2:12]2)=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(CN2CCC(C(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 4 h

Procedure:
To a solution of 126 parts of 4-(diphenylmethyl)piperidine in 1200 parts of 95% ethanol is added a solution of 69 parts of sodium carbonate in 1500 parts of water. The resultant mixture is heated at the boiling point under reflux with vigorous stirring while a solution of 112 parts of 4-nitrobenzyl chloride in 800 parts of 95% ethanol is rapidly stirred in, and for 4 hours thereafter. Solvent is then removed by vacuum distillation, and the residue is partitioned between dichloromethane and water. The organic layer is separated, dried over anhydrous potassium carbonate, and stripped of solvent by vacuum distillation. The residue, recrystallized from anhydrous ethanol, affords 1-[(4-nitrophenyl)methyl]-4-(diphenylmethyl)piperidine melting at approximately 130°-131°.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1>CO>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[O:9])=[CH:15][CH:14]=1
Reactant: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Solvent: CO
Product: CN1CCN(C(=O)c2ccc(N)cc2)CC1
Reaction time: 17 h
Yield: 98.4 %

Procedure:
(4-Methylpiperazin-1-yl)(4-nitrophenyl)methanone (31.5 g, 126 mmol) was dissolved in methanol (150 ml) and transferred into a 500-ml PARR flask. The PARR flask was flushed with nitrogen, then 500 mg Pd/C (10% Pd) were added. The flask was flushed with nitrogen, then hydrogen, then shaken under a pressure of 50 psi of hydrogen for 17 hours. The mixture was filtered through CELITE®, the solid washed with MeOH and concentrated to give 27.2 g beige solid ((4-aminophenyl)(4-methylpiperazin-1-yl)methanone. MS (ESI) m/z 220 (M+H). 1H NMR (CDCl3) δ ppm 7.25 (d, 2H, J=7.6), 6.64 (d, 2H, J=7.6), 3.86 (bs, 2H), 3.63 (bs, 4H), 2.40 (bs, 4H), 2.30 (s, 3H).
Reaction SMILES: [CH:1]1([CH:7]=[C:8]([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH3:13][O:12][CH:11]([O:14][CH3:15])[CH:8]([C:9]#[N:10])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COC(OC)C(C#N)=CC1CCCCC1
Agent: [Pd]
Solvent: CO
Product: COC(OC)C(C#N)CC1CCCCC1
Yield: 100 %

Procedure:
3-Cyclohexyl-2-dimethoxymethylacrylonitrile, obtained from Example 3 (8.3 g, 0.04 mol), methanol (100 mL) and 10% palladium on carbon (0.3 g) were shaken together in a Parr bottle under 50 psig hydrogen pressure for 30 minutes. The catalyst was removed by filtration and the methanol was evaporated in vacuo to give the product as a pale-yellow oil (8.3 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42](O)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl.C1C=CC=CC=1>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([O:12][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: COC(=O)c1ccc(F)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 60.8 %

Procedure:
A mixture of methyl 4-fluoro-2-hydroxybenzoate (5.1 g, 30 mmol), triphenylphosphine (9.5 g, 36 mmol), 1-tert-butoxycarbonyl-4-hydroxypiperidine (6 g, 30 mmol), and benzene (10 mL) was heated until all solids dissolved. The solution was cooled to 0° C., then sonicated while adding diethyl azodicarboxylate (6.3 g, 36 mmol) dropwise. After the addition was complete, the reaction mixture was sonicated for an additional 60 min, diluted with CH2Cl2 (25 mL), and purified by flash chromatography, eluting with 10% EtOAc in hexanes to yield the title compound (6.45 g, 61%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([C:18]([CH:20]=[CH:21]N(C)C)=O)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:25][CH3:26])[CH:7]=1)=[O:5])C.Cl.[NH2:28][C:29]([NH2:31])=[NH:30].CC(C)([O-])C.[K+].C(O)(=O)C>C(O)(C)(C)C>[NH2:30][C:29]1[N:31]=[C:18]([C:11]2[CH:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]3[CH2:25][CH3:26])=[CH:13][C:12]=2[F:17])[CH:20]=[CH:21][N:28]=1
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)C=CN(C)C)c(F)cc2c1=O
Reactant: N=C(N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3ccnc(N)n3)cc21
Yield: 35.9 %

Procedure:
To 900 mg (2.5 mmol) of the 7-(2'-dimethylaminoethenyl)carbonyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester in 15 ml of t-butanol at 50° C. was added 580 mg (2.5 eq) of guanidine hydrochloride that had been previously treated with 1.35 g (5 eq) of potassium t-butoxide at 50° C. in t-butanol for 30 minutes. The final mixture was stirred for 24 hours at 60° C. It was poured into 8% aqueous acetic acid and extracted into chloroform. The chloroform was extracted three times with water. The chloroform was dried magnesium sulfate and concentrated. The residue was purified by column chromatography and gave 295 mg of 7-(2-amino-4-pyrimidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 245°-247° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([NH:13][CH2:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18])=[O:12].Cl[Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1C=CN=C1.Cl>CN(C)C=O.O>[Si:26]([O:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])=[O:12])=[C:2]([Cl:1])[CH:7]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: COC(=O)c1ccccc1CNC(=O)CCc1ccc(O)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CNC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of methyl 2-({[3-(2-chloro-4-hydroxyphenyl)propanoyl]amino}methyl)benzoate (380 mg) in N,N-dimethylformamide (4.00 mL) were added chloro tert-butyl dimethylsilane (215 mg) and imidazole (114 mg), followed by stirring at room temperature for 4 hours. To the reaction mixture were added water and 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 2-({[3-(4-{[tert-butyl(dimethyl)silyl]oxy}-2-chlorophenyl)propanoyl]amino}methyl)benzoate (500 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][OH:11].Br[CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:16][C:15]([CH3:17])=[CH:14][CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][OH:11]
Reactant: OCc1nc2ccccc2[nH]1
Reactant: CC(C)=CCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCn1c(CO)nc2ccccc21
Yield: 36.1 %

Procedure:
To a solution of (1H-benzoimidazol-2-yl)-methanol (457 mg, 3.09 mmol) and 4-bromo-2-methyl-2-butene (0.36 mL, 3.09 mmol) in DMF (10 mL) was added DIPEA (0.69 mL, 3.70 mmol) at 60° C. overnight and in the morning, the mixture was cooled and concentrated. The residue was dissolved in saturated NaHCO3 (20 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to afford a brown oil. Purification by flash column chromatography on silica gel using 2% MeOH/CH2Cl2 afforded [1-(3-methyl-but-2-enyl)-1H-benzoimidazol-2-yl]-methanol as a pale yellow solid (241 mg, 36%). 1H NMR (CDCl3) δ 1.72 (s, 3H), 1.87 (s, 3H), 4.80 (d, 2H, J=6.6 Hz), 4.86 (s, 2H), 5.21 (td, 1H, J=6.0, 1.2 Hz), 7.19-7.23 (m, 3H), 7.65-7.68 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([CH:24]1[C:28]2[S:29][CH:30]=[CH:31][C:27]=2[C:26](=O)[O:25]1)C.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:26]1[O:25][CH:24]([CH3:22])[C:28]2[S:29][CH:30]=[CH:31][C:27]1=2
Reactant: CCC1OC(=O)c2ccsc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1OC(=C2C(=O)Nc3ccc(F)cc32)c2ccsc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (453 mg, 3.0 mmol.) in THF (3 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (6.0 mL of a 1 M solution in THF, 6.0 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed to room temperature. A solution of 6-ethyl-6H-thieno[2,3-c]furan-4-one, (310 mg, 2.0 mmol) in THF (5 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (50 mL). The resulting mixture is heated to 90° C. for 45 min and stirred at room temperature for 36 h. The precipitate which formed is collected by filtration and dried. The solid obtained is purified by chromatography (silica gel, ethyl acetate/hexanes) to give the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:24][CH:25]=[CH2:26])[C:9](=[N:17][S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][Li]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:24][CH:25]=[CH2:26])[C@:9]([NH:17][S@@:18]([C:20]([CH3:21])([CH3:22])[CH3:23])=[O:19])([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH3:27])[CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: C=CC[C@@H](C(=N[S@](=O)C(C)(C)C)c1ccc(Cl)cc1)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: C=CC[C@H](c1cccc(Cl)c1)[C@](C)(N[S@](=O)C(C)(C)C)c1ccc(Cl)cc1

Procedure:
A solution of (R)—N—((R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)pent-4-enylidene)-2-methylpropane-2-sulfinamide (Example 418, Step B, 9.97 g, 24.41 mmol) in THF (98 ml) was cooled to −78° C. Methyllithium (1.6M in ether, 16.78 ml, 26.9 mmol) was added over a period of six min. The reaction was removed from the cold bath and diluted with 500 mL ether and quenched with 150 mL of saturated aqueous ammonium chloride solution. The organic layer was separated and washed with brine, then dried with anhydrous magnesium sulfate and concentrated to afford a colorless oil. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through (3×80 g) RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.), eluting with 30% ethyl acetate in hexane. Fractions containing the desired product, eluting as the bottom spot on silica gel TLC in hexane/ethyl acetate, were combined and concentrated under reduced pressure to provide the title compound as a glass.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O>CS(C)=O>[N:15]1([C:6]2[N:5]=[C:4]([NH2:8])[CH:3]=[CH:2][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: Nc1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cccc(N2CCCC2)n1
Temperature: 190 °C
Reaction time: 10 h
Yield: 36.8 %

Procedure:
A mixture of 4-chloro-2-aminopyridine (19.3 g, 0.150 mol), K2CO3 (41.7 g, 0.30 mol) and pyrrolidine (32.0 g, 0.45 mol) in DMSO (150 mL) was stirred at 190° C. for 10 hours. After cooling to room temperature, water (300 mL) was added and extracted with ethyl acetate (150 mL×4). The combined organic layers were washed with water (25 mL×3), dried over Na2SO4 and concentrated in vacuo, the residue was purified by silica gel chromatography (10:1 ethyl acetate/petroleum ether) to obtain 6-(pyrrolidin-1-yl)pyridin-2-amine (9.0 g, 37% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:33]=[CH:32][C:6]2[CH:7]=[C:8]([S:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:16](=[O:31])[CH2:15]3)(=[O:13])=[O:12])[CH2:9][O:10][C:5]=2[CH:4]=1.Cl.Cl[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C(N(CC)CC)C>C(O)C>[Cl:2][C:3]1[CH:33]=[CH:32][C:6]2[CH:7]=[C:8]([S:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][N:24]([C:40]5[CH:39]=[CH:38][N:37]=[CH:36][CH:41]=5)[CH2:23][CH2:22]4)[C:16](=[O:31])[CH2:15]3)(=[O:13])=[O:12])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: Clc1ccccn1
Reactant: COC(=O)C1(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)C1(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CCN(c2ccncc2)CC1
Yield: 51.3 %

Procedure:
To 1-[1-(tert-butoxycarbonyl)-4-methoxycarbonylpiperidin-4-ylmethyl]-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone (260 mg) was added 4N hydrochloric acid in ethyl acetate (10 ml) and methanol (4 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give colorless solid of 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-(4-methoxycarbonylpiperidin-4-ylmethyl)-2-piperazinone hydrochloride (228 mg). A solution of 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-(4-methoxycarbonylpiperidin-4-ylmethyl)-2-piperazinone hydrochloride (228 mg), chloropyridine hydrochloride (80 mg) and triethylamine (225 mg) in ethanol (14 ml) was allowed to react in a sealed tube at 150% for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution=20:1) to give colorless solid of the title compound (126 mg).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:7]=[CH:6]2.C(Cl)[Cl:21].N1C=CC=CC=1.CS(Cl)(=O)=O>>[Cl:21][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:7]=[CH:6]2
Reactant: CC(C)(C)OC(=O)n1ncc2cc(CO)c(F)cc21
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1ncc2cc(CCl)c(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
A solution of tert-butyl 5-(hydroxymethyl)-6-fluoro-1H-indazole-1-carboxylate (22F, 3.0 g, 11.27 mmol) in methylene chloride (50.00 mL, 780.0 mmol) at rt. was treated with pyridine (4.56 mL, 56.33 mmol) and methanesulfonyl chloride (1.31 mL) and stirred at rt. for 16 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (300 mL) washed with aq HCl (100 mL), brine (100 mL), dried (MgSO4), filtered, concentrated in vacuo, and purified by chromatography (SiO2, EtOAc/Hexanes) to yield tert-butyl 5-(chloromethyl)-6-fluoro-1H-indazole-1-carboxylate (22G, 1.9 g; Yield=59%)
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[N:7]([CH3:10])[CH:8]=[O:9])=[O:4].[C:15]([OH:23])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([O:23][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[N:7]([CH3:10])[CH:8]=[O:9])=[O:4])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccccc1
Reactant: CN(C=O)c1ccccc1C(=O)CCl
Product: CN(C=O)c1ccccc1C(=O)COC(=O)c1ccccc1

Procedure:
The solution of 2'-(2-chloroacetyl)-N-methylformanilide may be reacted with benzoic acid by a method analogous to that of Example 2(d) to give the novel compound 2-[2-(N-methylformamido)phenyl]-2oxoethyl benzoate.