Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH2:26][O:27][C:28]4[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=4)[C:31]([OH:33])=[O:32])[N:23]([CH3:37])[C:22]=3[CH:38]=2)=[N:13][C:14]=1[O:15][CH3:16]>C1(C)C=CC=CC=1.CO>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH2:26][O:27][C:28]4[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=4)[C:31]([O:33][CH3:1])=[O:32])[N:23]([CH3:37])[C:22]=3[CH:38]=2)=[N:13][C:14]=1[O:15][CH3:16]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1nc(Oc2ccc3nc(COc4cccc(C(=O)O)c4)n(C)c3c2)ccc1Br
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ccc(Br)c(OC)n4)cc3n2C)c1
Yield: 49 %

Procedure:
Methyl 3-({6-[(5-bromo-6-chloropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoate produced in Example (3a) (0.74 g, 1.47 mmol), sodium methoxide (5.0 M solution in methanol, 2.94 mL, 14.7 mmol), water (10 mL) and 1,4-dioxane (20 mL) were stirred with heating under reflux for three days. After leaving to cool, the reaction mixture was concentrated and water (50 mL) was added. This aqueous solution was neutralized by adding 1 M hydrochloric acid and the precipitated solid was collected by filtration to obtain crude 3-({6-[(5-bromo-6-methoxypyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid. Trimethylsilyldiazomethane (2.0 M solution in hexane) was added to a solution of the crude 3-({6-[(5-bromo-6-methoxypyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid in toluene (20 mL) and methanol (10 mL) until the raw material disappeared. The reaction mixture was concentrated under reduced pressure. Then, the residue was purified by silica gel chromatography (hexane/ethyl acetate, 1:1) to obtain the title compound (0.36 g, 49%) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[Cl-].[S:38]1[CH:42]=[C:41]([CH2:43][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:40]=[CH:39]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:43]\[C:41]4[N:40]=[CH:39][S:38][CH:42]=4)=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: c1ccc([P+](Cc2cscn2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C\c2cscn2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.3 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (1.00 g), [(1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (1.27 g), potassium carbonate (0.44 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:3, v/v) to give 2-(2-furyl)-4-({2-methoxy-4-[({1-phenyl-4-[(Z)-2-(1,3-thiazol-4-yl)ethenyl]-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.40 g, yield 34%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 137-138° C.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23]C)=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:26]1SC(CC)=C(C(C)C)C=1C(OC)=O.C1(S(Cl)(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]([CH2:16][CH3:17])=[C:13]([CH:19]([CH3:26])[CH3:18])[C:12]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Reactant: CCc1sc(N)c(C(=O)OC)c1C(C)C
Agent: O=S(=O)(Cl)c1ccccc1
Product: CCc1sc(NS(=O)(=O)c2ccccc2)c(C(=O)OC)c1C(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from methyl 2-amino-5-ethyl-4-isopropylthiophene-3-carboxylate (Intermediate 25) and benzenesulphonyl chloride
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:22][CH:23]=[O:24])[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-:26].Cl>CCO>[ClH:26].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:22][CH2:23][OH:24])[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Cl-]
Reactant: Cc1csc(Nc2ncc(CC=O)cc2OCc2ccccc2)n1
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Product: Cc1csc(Nc2ncc(CCO)cc2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
A 20 mL vial was charged with 2-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-yl)acetaldehyde (50 mg, 0.15 mmol), NaBH (11 mg, 0.29 mmol), and EtOH (2 mL). The reaction was stirred at room temperature for 10 minutes and aqueous NH4Cl was added. The mixture was extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (1:1 EtOAc:Hexanes) to afford the title compound (37 mg, 66% yield) as a white solid after HCl salt formation. 1H NMR (DMSO-d6) δ 11.03 (bs, 1H), 7.85 (d, 1H), 7.59 (t, 3H), 7.45-7.33 (m, 3H), 6.83 (s, 1H), 5.31 (s, 2H), 3.61 (t, 2H), 2.72 (t, 2H), 2.32 (s, 3H). Mass spectrum (apci) m/z=342.1 (M+H-HCl).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[C@H:30]([OH:43])[CH2:29]1.C(OC([N:51]1[CH2:55][CH2:54][C:53]([C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)([C:56](O)=[O:57])[CH2:52]1)=O)(C)(C)C>C(Cl)Cl>[Cl:65][C:62]1[CH:63]=[CH:64][C:59]([C:53]2([C:56]([N:40]3[CH2:39][CH2:38][N:37]([C:35]4[C:36]5[C@H:28]([CH3:27])[CH2:29][C@@H:30]([OH:43])[C:31]=5[N:32]=[CH:33][N:34]=4)[CH2:42][CH2:41]3)=[O:57])[CH2:54][CH2:55][NH:51][CH2:52]2)=[CH:60][CH:61]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)C1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)C4(c5ccc(Cl)cc5)CCNC4)CC3)c21
Temperature: 25 °C
Reaction time: 10 h
Yield: 80.8 %

Procedure:
HBTU (37 mg, 0.098 mmol) was added to a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (30 mg, 0.098 mmol) and 1-(tert-butoxycarbonyl)-3-(4-chlorophenyl)pyrrolidine-3-carboxylic acid (32 mg, 0.098 mmol) in DCM (5 mL) and TEA (1 mL). The mixture was stirred at room temperature for 10 hours. The solvent was removed, and the residue was subjected to column chromatography, eluted by ethyl acetate-DCM/MeOH (20:1). The product was treated with HCl (4M, 2 mL) in DCM (5 mL) to afford (3-(4-chlorophenyl)pyrrolidin-3-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone as the HCl salt (35 mg, 81%).
Reaction SMILES: [C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@@H:8]1[CH2:10][O:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=2[CH:24]=1>CC#N>[C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@@H:8]([OH:9])[CH2:10][NH:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2
Temperature: 50 °C
Reaction time: 6 h
Yield: 49.5 %

Procedure:
To a solution of tert-butyl-dimethyl-((S)-1-oxiranylmethoxy)-silane (commercial; 13.0 g, 69 mmol) in MeCN (220 mL) was added LiClO4 (22 g, 207 mmol). 6-amino-4H-benzo[1,4]oxazin-3-one (commercial; 11.45 g, 64 mmol) was added and the mixture was stirred at 50° C. for 6 h. The solvent was removed in vacuo and the residue was purified by CC (DCM/MeOH/NH4OH 1000/25/2 to 1000/100/2) to afford the title intermediate as a pale brown foam (11.16 g, 44% yield).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.[NH2:14][C@@H:15]1[C:20]2[CH:21]=[C:22]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH:23]=[CH:24][C:19]=2[O:18][C:17]([CH3:33])([CH3:32])[C@H:16]1[OH:34]>C(N(CC)CC)C>[F:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:2][N:14]([C@@H:15]1[C:20]3[CH:21]=[C:22]([S:25]([C:28]([F:30])([F:31])[F:29])(=[O:27])=[O:26])[CH:23]=[CH:24][C:19]=3[O:18][C:17]([CH3:32])([CH3:33])[C@H:16]1[OH:34])[C:5]2=[O:7]
Reactant: COC(=O)c1cccc(F)c1CBr
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N)[C@@H]1O
Solvent: CCN(CC)CC
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N2Cc3c(F)cccc3C2=O)[C@@H]1O
Yield: 63.9 %

Procedure:
Following the procedure and working up described in Example 12, but using 0.272 g of methyl 2-bromomethyl-3-fluorobenzoate, 0.326 g of trans-4-amino-3,4-dihydro-2,2-dimethyl 6-trifluoromethylsulfonyl-2H-1-benzopyran- 3-ol and 0.15 ml of triethylamine, 0.294 g of the title compound, melting at 259°-261° C., was obtained after purification by column chromatography through silica gel, using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the eluent, followed by recrystallization from a mixture of ethyl acetate and hexane.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[S:8]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)(=[O:10])=[O:9])[CH:4]=[N:3]1.[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.C(O)C>[ClH:38].[CH3:1][N:2]1[CH:6]=[C:5]([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[S:8]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:26](=[NH:46])[NH2:27])=[CH:24][CH:25]=4)=[N:17][C:13]=3[CH:12]=2)(=[O:9])=[O:10])[CH:4]=[N:3]1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(c1cnn(C)c1)S(=O)(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(c1cnn(C)c1)S(=O)(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Yield: 38 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-sulphonic acid-N-(1-methylpyrazol-4-yl)-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 38% of theory, C25H30N8O4S (538.6) Rf value: 0.09 (silica gel; dichloromethane/ethanol=9:1) EKA mass spectrum: (M+H)+ =539
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:13]>O>[Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:13]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: O=S(=O)(O)O
Solvent: O
Product: NC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 82 %

Procedure:
A 12-L 3-neck round bottom flask equipped with overhead stirrer, refluxing condenser, and N2 inlet/outlet was charged with 2,6-dichloro-5-fluoronicotinonitrile (2.0 kg, 1.0 eq). Concentrated sulfuric acid (4.93 L) was added and the mixture was stirred at RT until most of the brown solids had dissolved. Next, the reaction mixture was stirred at 65° C. for 1 h. The dark-brown solution was cooled to a temperature <10° C. using an ice bath. The reaction mixture was added to a 50-L round bottom flask, which contained de-ionized water (24.7 L) that had been cooled to a temperature <10° C., using a peristaltic pump. The reaction mixture was added to the water quench over a 2.3 h period, which kept the internal temperature of the mixture below 21° C. The resulting slurry was filtered through a Buchner funnel fitted with a Sharkskin filter paper. The 50-L RBF was rinsed with water (3×4 L) and the rinses were used to wash the filter cake. The filter cake was conditioned for 50 min, transferred to a drying tray, and was dried under high vacuum at 40-50° C. for 24 h and then at 20-25° C. for 18 h to give the title compound as a beige solid (896.4 g, 82%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.94 (s, 1H), 8.10 (s, 1H), 8.24 (d, 1H). [M+H] calc'd for C6H3Cl2FN2O, 209. found, 209.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][CH2:11][C:12]([NH2:14])=[O:13].[C:15](=O)([O-])[O-].[K+].[K+].CI>CO>[CH3:15][N:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH2:11][C:12]([NH2:14])=[O:13]
Reactant: NC(=O)CNC1Cc2ccccc2C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CO
Product: CN(CC(N)=O)C1Cc2ccccc2C1
Reaction time: 0.25 h

Procedure:
2-(2-indanylamino)acetamide (0.016 moles, 3.00 g) is dissolved in methanol (60 ml), and potassium carbonate (0.016 moles, 2.18 g) is added under stirring. Methyl iodide (0.028 moles, 4.14 g) is dropped therein at r.t. in 15 minutes. The mixture is reacted for 4 hours at r.t., then evaporated under vacuum. The resulting solid is taken up into water (100 ml), the aqueous solution is extracted with ethyl acetate (3×150 ml). The organic solution is dried over sodium sulfate, then evaporated under vacuum to obtain an oil which is chromatographed under medium pressure through silica gel (eluent chloroform:methanol=90:10) Yield: 1.31 g (40%)--m.p.=122-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:15]([CH3:17])[CH3:16])=[C:11]([CH2:13]I)[N:12]=1.[C-:18]#[N:19].[Na+].O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:15]([CH3:17])[CH3:16])=[C:11]([CH2:13][C:18]#[N:19])[N:12]=1
Reactant: [C-]#N
Reactant: CC(C)c1oc(-c2ccccc2Cl)nc1CI
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)c1oc(-c2ccccc2Cl)nc1CC#N
Temperature: 25 °C
Yield: 8.7 %

Procedure:
In acetone (2 mL) was dissolved 2-(2-chlorophenyl)-4-iodomethyl-5-isopropyloxazole (590 mg, 1.63 mmol). Sodium cyanide (88 mg, 1.63 mmol) was added, and the resulting mixture was heated under reflux for 22 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated brine, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography on silica gel (hexane/ethyl acetate=5/1), to obtain the desired compound (37 mg, 82%).
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].F[C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].C(N(CC)CC)C>CN(C=O)C>[CH:2]([S:4][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])([CH3:3])[CH3:1]
Reactant: CC(C)S
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
Isopropylthiol (3.06 mL, 32.8 mmol) was added to a solution of 2-fluoro-5-nitrobenzoic acid (5.06 g, 27.3 mmol) and triethylamine (8.4 mL, 60.3 mmol) in DMF (86 mL). The reaction mixture was stirred overnight at rt and then most of the DMF was removed in vacuo. The residual solution was poured into ice water (500 mL) and the resulting yellow solid was isolated by filtration to give 16A (6.5 g, 100%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:40](C#N)=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.Cl.[C:46]([O:49][CH2:50][CH3:51])(=[O:48])C>C(O)C.O>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:37]4[CH:42]=[CH:41][C:40]([C:46]([O:49][CH2:50][CH3:51])=[O:48])=[CH:39][CH:38]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C#N)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)cc1

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene obtained in Example 128-(4) and 4-cyanophenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene as colorless powder. APCI-Mass m/Z 657/659 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene (128 mg) was suspended in ethanol (2 ml) and added thereto was a concentrated hydrochloric acid aqueous solution (1 ml). The mixture was heated reflux for 8.5 hours. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was washed with water and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-ethoxycarbonylphenyl)-2-thienylmethyl)benzene (39 mg) as pale yellow foam. APCI-Mass m/Z 536/538 (M+NH4).
Reaction SMILES: [Cl:1][CH:2]([Cl:21])[C:3]([F:20])([F:19])[O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([S:14](Cl)(=[O:16])=[O:15])=[C:7]([CH3:18])[CH:6]=1.[C:22](#[N:25])[CH:23]=[CH2:24].Cl.C(N(CC)CC)C>C(#N)C>[Cl:1][CH:2]([Cl:21])[C:3]([F:20])([F:19])[O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([S:14]([CH:24]=[CH:23][C:22]#[N:25])(=[O:16])=[O:15])=[C:7]([CH3:18])[CH:6]=1
Reactant: C=CC#N
Reactant: Cc1cc(OC(F)(F)C(Cl)Cl)c([N+](=O)[O-])cc1S(=O)(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OC(F)(F)C(Cl)Cl)c([N+](=O)[O-])cc1S(=O)(=O)C=CC#N
Yield: 10.4 %

Procedure:
In a 100 ml Fisher-Porter pressure vessel were placed 9.0 g (0.024 mol) of 4-(2,2-dichloro-1,1-difluoroethoxy)-2-methyl-5-nitrobenzenesulfonyl chloride, 2.4 g (0.048 mol) acrylonitrile, 2 ml acetonitrile, 0.07 g cupric chloride and 0.12 g triethylamine hydrochloride. After cooling and evacuating the vessel to 5 mm mercury pressure, it was sealed and heated in an oil bath at 105°-110° C for 38 hours. The vessel was opened and the reaction medium was filtered with the aid of benzene. The insolubles were discarded and the filtrate was treated with 5.0 g of triethylamine, refiltered, and washed with water. After decolorizing wth charcoal and drying over MgSO4, removal of the solvent under reduced pressure afforded a dark amber oil. Recrystallization from methanol provided 1.0 g of the title compound as a white solid, m.p. 109° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](O)[C:5]2[C:6](=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:9]([CH3:11])[N:10]=2)[N:7]=1.P(Cl)(Cl)([Cl:23])=O>>[CH3:1][C:2]1[CH:3]=[C:4]([Cl:23])[C:5]2[C:6](=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:9]([CH3:11])[N:10]=2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c2nn(C)c(-c3ccc(Cl)cc3Cl)c2n1
Product: Cc1cc(Cl)c2nn(C)c(-c3ccc(Cl)cc3Cl)c2n1

Procedure:
Intermediate (4) (400 mg) was suspended in phosphorous oxychloride (2 ml) and refluxed for 2 hours. The reaction mixture was concentrated, yielding 5-methyl-7-chloro-2-methyl-3-(2,4-dichlorophenyl)pyrazolo[4,3-b]pyridine (intermediate 5).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)#[N:16].CC(C)([O-])C.[K+].Cl>CN(C)C=O>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH:7]=1)[NH:21][C:20]1[CH:22]=[CH:23][C:17]([C:15]#[N:16])=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Nc2cc(Cl)c([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,4-Dichloro-1,5-dinitrobenzene (II-1, 1.2 g, 5 mmol) and p-cyanoaniline (III-1, 0.59 g, 5 mmol) were dissolved in N,N-dimethylformamide (DFM, 10 ml). To the solution was added potassium tert-butoxide (1.4 g, 12.5 mmol) in batches in ice water bath. The mixture was allowed to react at room temperature for 45 minutes. The reaction liquid was poured into ice water. The pH value was adjusted to about 6 with dilute hydrochloric acid. The mixture was stirred for 30 minutes to precipitate a solid. The solid was filtered, washed with water to neutrality, dried, and separated on silica gel column (eluted with ethyl acetate: petroleum ether) to obtain a compound VI-1 (1.44 g, faint yellow solid). 1H NMR (CDCl3) δ ppm 7.41 (1H, s, ArH-6), 7.57 (2H, d, J=8.7 Hz, ArH-3′, 5′), 7.91 (2H, d, J=8.7 Hz, ArH-2′, 6′), 8.90 (1H, s, ArH-3), 10.07 (1H, s, NH).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][NH:39][CH3:40]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:39]([CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])[CH3:40])=[O:26])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CNCCN(C)C
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccc(C(=O)N(C)CCN(C)C)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50B starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50B, Step 1) and N,N,N′-trimethylethylenediamine (Aldrich, Cat. No. 127124). LCMS (M+H)+: m/z=544.3.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[CH2:10][C@@H:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C@@:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])([C:16]#[N:17])[C@H:7]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[F:33])C.[Li+].[OH-]>C1COCC1.O>[Cl:32][C:28]1[C:27]([F:33])=[C:26]([C@@H:7]2[C@:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[F:25])([C:16]#[N:17])[C@H:9]([CH2:11][C:12]([CH3:14])([CH3:15])[CH3:13])[CH2:10][N:6]2[CH2:5][C:4]([OH:34])=[O:3])[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CN1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@@H]1CN(CC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 22 h
Yield: 102.4 %

Procedure:
To a mixture of rac [(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid ethyl ester (14.7 mg, 0.0288 mmol, Example C1) in THF (1.8 mL) was added a solution of LiOH (Aldrich, 8.5 mg, 0.02 mmol) in water (1.2 mL) and the reaction mixture was stirred at rt for 22 hrs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 4-5), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid (14.2 mg, 102%). HRMS (ES+) m/z Calcd for C24H24Cl2F2N2O2+H [(M+H)+]: 481.1256; Found: 481.1255.