Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH:10]1([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([NH:22][C:23]([C:25]4[CH:29]=[CH:28][S:27][CH:26]=4)=[O:24])[CH:20]=[CH:21][C:16]=3[CH3:15])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
N-Cyclopropylmethyl-6-[2-methyl-5-(thiophen-3-ylcarbonylamino)-phenyl]-nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 14) using General Method B. LCMS: retention time 3.07 min, MH− 392. NMR: δH [2H6]-DMSO 10.11,(1H, s), 9.11,(1H, s), 8.83,(1H, t), 8.35,(1H, s), 8.30,(1H, dd), 7.85,(1H, s), 7.78,(1H, d), 7.67-7.63,(3H, m), 7.31,(1H, d), 3.20,(2H, t), 2.31,(3H, s), 1.06,(1H, m), 0.46,(1H, m), 0.27,(1H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ccnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Yield: 43 %

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (457 mg, 3.0 mmol, prepared generally according to Thibault, C. et al. Org. Lett. 2003, 5, 5023) and 2-fluoro-4-nitrophenol (706 mg, 4.5 mmol), and N,N-diisopropylethylamine (580 mg, 4.5 mmol) in 1-methyl-2-prolidinone (NMP) (3 mL) was heated at 200° C. under microwave irradiation for 1 h. The mixture was diluted with ethyl acetate (150 mL), washed with sat. aq. KH2PO4 solution, and Na2CO3 (aq. 1 M), and dried over Na2SO4. The product was purified by flash column chromatography (silica gel, eluting with CH2Cl2 to 30% EtOAc/CH2Cl2) to afford the desired compound (350 mg, 43%) as a brown solid. MS(ESI+) m/z 274 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH:49]1[CH2:54][CH2:53][CH:52]([N:55]2[C:59]3=[N:60][CH:61]=[N:62][C:63]([NH2:64])=[C:58]3[CH:57]=[N:56]2)[CH2:51][CH2:50]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[NH2:64][C:63]1[N:62]=[CH:61][N:60]=[C:59]2[N:55]([CH:52]3[CH2:53][CH2:54][N:49]([CH2:16][C:13]4[CH:14]=[CH:15][C:10]([C:8]5[C:7]([C:17]6[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=6)=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[N:9]=5)=[CH:11][CH:12]=4)[CH2:50][CH2:51]3)[N:56]=[CH:57][C:58]=12
Reactant: Cc1ccc(-c2nc(Cl)c(C#N)cc2-c2ccccc2)cc1
Reactant: Nc1ncnc2c1cnn2C1CCNCC1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4ncc5c(N)ncnc54)CC3)cc2)nc1Cl
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-6-(4-methylphenyl)-5-phenylnicotinonitrile (4-4) (0.204 g, 0.67 mmol), NBS (0.125 g, 0.70 mmol) and benzoylperoxide (0.032 g, 0.13 mmol) in chloroform (5 mL) was heated to reflux for 24 h. Concentrated in vacuo and the residue was dissolved in MeOH (15 mL) and THF (15 mL). To this solution was added 1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.146 g, 0.67 mmol) and diisopropylethylamine (0.433 g, 3.35 mmol). The mixture was stirred overnight and concentrated. The residue was treated with Na2CO3 (20 mL, 2M) and extracted with CH2Cl2. The combined organic layers was dried, filtered and concentrated in vacuo. The solid was purified by silicon gel chromatography (2-4% MeOH in CH2Cl2) to give the title compound. LRMS m/z (M+H) Calcd: 522.03, found: 521.27.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:3]=1[NH2:4].C(O)C.[H][H]>O.[Ni]>[Cl:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: Nc1c(Cl)cccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Nc1cccc(Cl)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-6-nitroaniline (14.10 g, 81.71 mmol), Raney-nickel (5.02 g of a 50% slurry in water), and ethanol (200 mL) were combined in an autoclave which was pressurized to 15 psig with hydrogen. The resulting mixture was allowed to stir overnight at RT. The mixture was then filtered through a pad of celite, which was subsequently washed with several portions of methanol, and the solvents were removed by rotary evaporation to afford 10.43 g (89%) of a viscous, brown oil, which darkened upon standing. MS (EI): m/z 143.1 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[C:5]([C:11]([OH:13])=[O:12])=[C:4]([CH3:14])[CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>[OH-].[Na+]>[CH2:9]([S:8][C:6]1[C:5]([C:11]([OH:13])=[O:12])=[C:4]([CH3:14])[CH:3]=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:7]=1)[CH3:10]
Reactant: C1COCCN1
Reactant: CCSc1nc(Cl)cc(C)c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCSc1nc(N2CCOCC2)cc(C)c1C(=O)O
Temperature: 105 °C
Yield: 48.9 %

Procedure:
A mixture of 12.0 g (51.7 mmol) 6-chloro-2-ethylsulfanyl-4-methyl-pyridine-3-carboxylic acid and 33.7 g (387 mmol) morpholine was heated to 105° C. for 5 d. After cooling to RT a 2M aq. NaOH sol. (200 ml) was added, followed by washing with ether (3×200 ml). The aqueous layer was then acidified with a 2M aq. HCl to pH 5 and extracted with EtOAc. In the same manner pH 4 was adjusted followed by extraction with EtOAc. The combined EtOAc extracts were dried over MgSO4 and concentrated in vacuo. Crystallisation (DCM/hexane) of the residue yielded 7.2 g (25.3 mmol, 49%) 2-ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][B:5]([C:7]2[CH:8]=[N:9][NH:10][CH:11]=2)[O:4][C:3]1([CH3:13])[CH3:12].Br[CH2:16][CH:17]([CH3:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:16]([N:9]1[CH:8]=[C:7]([B:5]2[O:6][C:2]([CH3:14])([CH3:1])[C:3]([CH3:13])([CH3:12])[O:4]2)[CH:11]=[N:10]1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
A mixture of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15 mmol, 1.00 equiv), 1-bromo-2-methylpropane (1.05 g, 7.66 mmol, 1.49 equiv) and Cs2CO3 (3.36 g, 10.31 mmol, 2.00 equiv) in acetonitrile (60 mL) was stirred at 80° C. for 4 h. The reaction was cooled to room temperature and the solid material was removed by filtration. The filtrate was diluted with ethyl acetate (30 mL) and then washed with brine (40 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 1.14 g (88%) of 1-iso-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a colorless oil. 1H-NMR (300 MHz, CDCl3): δ 7.78 (s, 1H), 7.65 (s, 1H), 3.91 (d, J=7.2 Hz, 2H), 2.24-2.19 (m, 1H), 1.32 (s, 12H), 0.90 (d, J=7.2 Hz, 6H) ppm. LCMS (method D, ESI): RT=1.51 min, m/z=251.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:30][CH3:31])=[N:20][S:21]([N:24]3[CH2:29][CH2:28]O[CH2:26][CH2:25]3)(=[O:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[CH3:32]O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:30][CH3:31])=[N:20][S:21]([N:24]3[CH2:29][CH2:28][CH2:32][CH2:26][CH2:25]3)(=[O:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: CNC(=NS(=O)(=O)N1CCOCC1)N1C[C@H](c2ccccc2)C(c2ccc(Cl)cc2)=N1
Solvent: CCO
Product: CNC(=NS(=O)(=O)N1CCCCC1)N1C[C@H](c2ccccc2)C(c2ccc(Cl)cc2)=N1

Procedure:
(−)-(4S)-3-(4-Chlorophenyl)-N-methyl-N′-((morpholin-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. ([α25D]=−144°, c=0.01, MeOH). (Chiral stationary phase: Chiralpak AD). The mobile phase consisted of ethanol. Amorphous.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]3[C:29](=[O:30])[C:28]4[C:27]5[C:22](=[CH:23][C:24]([C:31]#[N:32])=[CH:25][CH:26]=5)[NH:21][C:20]=4[C:19]([CH3:34])([CH3:33])[C:18]=3[CH:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]3[C:29](=[O:30])[C:28]4[C:27]5[C:22](=[CH:23][C:24]([C:31]#[N:32])=[CH:25][CH:26]=5)[NH:21][C:20]=4[C:19]([CH3:34])([CH3:33])[C:18]=3[CH:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Reaction time: 19 h

Procedure:
4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Compound B2-22-1, 16.2 g, 34.6 mmol) was dissolved in THF (800 ml) and methanol (230 ml), added with 10 wt % Pd/C (3.2 g), and stirred under hydrogen atmosphere for 19 hr. The solid was filtered through Celite, eluted with a mixture solvent (400 ml; THF/methanol=4/1), and concentrated under reduced pressure. The residues were dissolved in ethyl acetate (400 ml), and then washed with 1% aqueous solution of N-acetylcysteine, saturated aqueous solution of NaHCO3 and saturated brine. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues were concentrated under reduced pressure to obtain the title compound as a crude product (white powder, 14.0 g, 86%).
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=O)[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][S:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][NH:27][NH2:28]>CO>[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][N:27]1[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]2[CH2:9][S:10][CH2:11][C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]2=[N:28]1
Reactant: O=C1C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Reactant: CN(C)CCCNN
Solvent: CO
Product: CN(C)CCCN1N=C2C(=Cc3ccccc3)CSCC2C1c1ccccc1

Procedure:
Tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one (5g) is refluxed with 2.1g of 3-dimethylaminopropylhydrazine in 50ml of methanol for 4 hours. The solvent is evaporated off and the residue is crystallized from 30ml of acetonitrile to yield 3.9g of the title compound, melting point 83°-85°C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[C:15]([Cl:34])=[C:16]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH:17]=[CH:18][C:19]=2[Cl:20])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1.[H-].[Na+].[C:37]([N:41]=[C:42]=[O:43])([CH3:40])([CH3:39])[CH3:38].O>CN(C=O)C>[C:37]([NH:41][C:42](=[O:43])[NH:1][C:2]1[C:3]([C:14]2[C:15]([Cl:34])=[C:16]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH:17]=[CH:18][C:19]=2[Cl:20])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)N=C=O
Reactant: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(N)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(NC(=O)NC(C)(C)C)nc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N—[3-(7-amino-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-6-yl)-2,4-dichloro-phenyl]-3-trifluoromethyl-benzamide (700 mg, 1.34 mmol) in dry DMF (10 ml) at 0° C. is added NaH (60% oil suspension, 64 mg, 1.6 mmol) slowly. The reaction mixture is stirred at room temperature for 30 minutes and then to this reaction mixture t-butyl-isocyanate (0.19 ml, 1.6 mmol) is added. The reaction is stirred at room temperature for 5 hours. The reaction mixture is diluted into 100 ml water, extracted with 80 ml ethyl acetate three times. The organic phase is combined and washed with brine, dried over Na2SO4. The crude product is purified by flash silica gel column to give the title compound as light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][C@@H:11]([CH2:13]I)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=3[NH:23][C:22]2=[O:31])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][C@@H:11]([CH2:13][N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[C:25]5[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=5[NH:23][C:22]4=[O:31])[CH2:19][CH2:20]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: Fc1ccc([C@H]2C[C@@H](CI)CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(C[C@H]2CO[C@@H](c3ccc(F)cc3)C2)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 1.74 g of cis-2-(4-fluorophenyl)-4-(iodomethyl)tetrahydrofuran, 1.5 g of 1-(4-piperidyl)-5-chloro-benzimidazolin-2-one and 0.8 g of potassium carbonate in 20 ml of dimethylformamide is heated with stirring at 70° C. for 16 hours. The reaction mixture is then poured into water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The crystalline residue is recrystallized from ethanol to give 1-[1-(cis-2-(4-fluorophenyl)-tetrahydro-4-furylmethyl)-4-piperidyl]-5-chloro-benzimidazolin-2-one as colorless prisms, melting at 207.5°-208.5° C. The corresponding maleate melts at 207° C. with decomposition.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:22])([CH3:21])[CH:8]1[CH2:12][N:11]([CH:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10](=[O:20])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:22])([CH3:21])[CH:8]1[CH2:12][N:11]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C:10](=[O:20])[CH:9]1[CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CC(=O)N(C2CCCCCC2)C1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1C(=O)N(C2CCCCCC2)CC1C(C)(C)O[SiH2]C(C)(C)C
Reaction time: 2 h

Procedure:
A solution of Example 1B (1.09 g, 3.07 mmoles) in tetrahydrofuran (3.5 mL) was added drop wise to a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (3.7 mL, 3.7 mmoles) at room temperature and stirred for two hours at that temperature. A solution of methyl iodide (0.54 g, 3.83 mmoles) in tetrahydrofuran (1 mL) was added drop wise to the reaction mixture at room temperature and stirred for another two hours. The reaction was quenched with 10% NH4Cl (25 mL) and extracted with ethyl acetate. The organic layer was washed with brine (25 mL), dried with MgSO4, filtered, and solvent evaporated in vacuo. The crude product was purified by flash column chromatography (hexanes:ethyl acetate 95:5 to 60:40) to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].O.[S-2:13].[Na+].[Na+].O>C(O)C>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[SH:13]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: [S-2]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc(Cl)c1S
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.7 %

Procedure:
Twenty grams of 2,3-dichloronitrobenzene was dissolved in 200 ml of absolute ethanol and the resulting solution added dropwise over three hours to a mixture of 40.0 g of sodium sulfide hydrate in 225 ml of absolute ethanol. The reaction temperature did not exceed 30° C. during the addition. The reaction was allowed to stir for 48 hours at room temperature. Since some of the 2,3-dichloronitrobenzene was still present, as indicated by GLC, an additional 9.0 g of the sodium sulfide hydrate was added at once and the reaction was allowed to stir overnight at room temperature. The ethanol was removed and the concentrate was partitioned between 300 ml of water and 250 ml of ether, the ether extract was discarded, and the aqueous phase made acidic by the dropwise addition of 50 ml of concentrated hydrochloric acid with the evolved gas being scrubbed through a bleach trap. A large amount of solid formed. Water, 100 ml, was added and the aqueous phase extracted with 350 ml of methylene chloride. The organic phase was dried with magnesium sulfate, filtered and concentrated to yield 11.8 g of a tan solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=3)[CH2:4][C@H:3]2[O:18][CH3:19])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccn1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccnc(C(=O)OC)c3)C[C@H]2OC)nc1Cl

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-4-(4-amino-3-methoxypiperidin-1-yl)pyridine-2-carboxylate obtained in Example (160c) (21.2 mg, 0.08 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (14 mg, 0.08 mmol), WSC hydrochloride (45.98 mg, 0.24 mmol) and HOBt (10.81 mg, 0.08 mmol), to obtain 13.8 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:17]([OH:26])[C:16]([Br:27])=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:12][C:13]1[C:18]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[C:17]([O:26][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:16]([Br:27])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1c(N)ccc(Br)c1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2c(Br)ccc(N)c2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 80.2 %

Procedure:
4-Methylbenzenesulfonyl chloride (2.26 g) was added to a solution of tert-butyl 6-amino-3-bromo-2-hydroxybenzoate (Intermediate 51, 2.85 g), DMAP (1.21 g), and triethylamine (1.5 g) in DCM (40 mL) and left at room temperature for 1 hour. The resulting solution was washed with water, filtered through a phase separator and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15% to give tert-butyl 6-amino-3-bromo-2-(4-methylbenzenesulfonyloxyl)benzoate (3.51 g) as an off-white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH:66]([CH3:68])[CH3:67])[C:3]([NH:5][C@@H:6]([CH3:65])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][C@H:18]3[CH:24]=[N:23][C:22]4[CH:25]=[C:26]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]5[C:37]([O:61][CH3:62])=[CH:38][C:39]6[C:45](=[O:46])[N:44]7[CH:47]=[C:48]([C:50]8[CH:59]=[CH:58][C:53]([C:54]([O:56]C)=[O:55])=[CH:52][CH:51]=8)[CH2:49][C@H:43]7[CH:42]=[N:41][C:40]=6[CH:60]=5)[C:27]([O:29][CH3:30])=[CH:28][C:21]=4[C:20](=[O:63])[N:19]3[CH:64]=2)=[CH:12][CH:11]=1)=[O:8])=[O:4].[OH-].[Li+]>C1COCC1.CO>[NH2:1][C@@H:2]([CH:66]([CH3:68])[CH3:67])[C:3]([NH:5][C@@H:6]([CH3:65])[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH2:17][C@H:18]3[CH:24]=[N:23][C:22]4[CH:25]=[C:26]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]5[C:37]([O:61][CH3:62])=[CH:38][C:39]6[C:45](=[O:46])[N:44]7[CH:47]=[C:48]([C:50]8[CH:51]=[CH:52][C:53]([C:54]([OH:56])=[O:55])=[CH:58][CH:59]=8)[CH2:49][C@H:43]7[CH:42]=[N:41][C:40]=6[CH:60]=5)[C:27]([O:29][CH3:30])=[CH:28][C:21]=4[C:20](=[O:63])[N:19]3[CH:64]=2)=[CH:14][CH:15]=1)=[O:8])=[O:4]
Reactant: COC(=O)c1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccc(NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)cc7)C[C@H]5C=N6)cc4N=C[C@@H]3C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(C(=O)O)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(c3ccc(NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)cc3)=CN1C2=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 9 (20 mg) in THF/CH3OH (2 mL) was added a lithium hydroxide solution (1 mL of a 0.1 M solution). The reaction mixture was stirred at an ambient temperature. At 5 hours, LC-MS revealed approximately a 30% conversion to desired product with significant decomposition. The reaction mixture was cooled to −80° C. for 16 hours. LC-MS showed a ˜1:1 mixture of 10 and 9. The reaction mixture was neutralized with 0.1N HCl (˜1 mL) and was concentrated to approximately 1 mL. DMSO (1 mL) and CH3CN (1 mL) were added, and the mixture was purified by preparatory reverse-phase HPLC. Product containing fractions were combined, frozen and lyophilized. This resulted in 1.7 mg (9%) of 10 as a yellow film: MS (ES+) m/z 938 [M+H]+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A mixture of benzyl bromide (1.4 g; 8.2 mmol), 3-hydroxybenzaldehyde (1.0 g; 8.2 mmol) and Cs2CO3 (2.67 g; 8.2 mmol) in anhydrous DMF (5 ml) was stirred overnight at room temperature under N2. After evaporation of solvent in vacuo, the residue was diluted to 20 ml with CH2Cl2, washed with H2O, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness to give the title compound (1.33 g; 76%) as creamy foam. 1H-NMR (CDCl3) 5.11 (s, 2H); 7.2-7.48 (m, 9H); 9.96 (s, 1H).
Reaction SMILES: Br[CH:2]([C:6]1[S:7][C:8]([C:17]2[N:21]=[CH:20][N:19](C3CCCCO3)[N:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)[C:3]([CH3:5])=O.[NH2:28][C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1.Cl.[OH-].[Na+]>C1COCC1.CC(O)C>[CH3:34][C:32]1[N:33]2[C:2]([C:6]3[S:7][C:8]([C:17]4[N:21]=[CH:20][NH:19][N:18]=4)=[C:9]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:10]=3)=[C:3]([CH3:5])[N:28]=[C:29]2[S:30][CH:31]=1
Reactant: Cc1csc(N)n1
Reactant: CC(=O)C(Br)c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1nc2scc(C)n2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Temperature: 80 °C
Reaction time: 4 h
Yield: 9.3 %

Procedure:
To a mixture of 1-bromo-1-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}acetone (1.15 g, 2.5 mmol) obtained by similar manner with Example 116-B(vi) in THF (12.5 mL) and 2-propanol (12.5 mL), was added 2-amino-4-methylthiazole (1.43 g, 12.5 mmol), the mixture was stirred at 80° C. for 4 h. The reaction mixture was allowed to cool to 50° C., 2N hydrochloric acid (12.5 mL) was added, and the mixture was stirred for 12 h. The reaction mixture was allowed to cool to rt, and then neutralized by the addition of 2N aqueous sodium hydroxide solution (12.5 mL). The mixture was extracted with EtOAc (50 mL×2), and the combined organic layers were dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (EtOAc/hexane=50/50→100/0; then MeOH/EtOAc=30/70) followed by silica gel column chromatography (EtOAc/hexane=30/70→100/0) to give the title compound (88 mg, 9%) as a yellow solid.