Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]1[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][N:13]1[S:25]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[C:42]3[C:37](=[C:38]([F:46])[C:39]([F:45])=[C:40]([F:44])[C:41]=3[F:43])[NH:36][CH:35]=2)[CH2:30][CH2:29]1)(=[O:27])=[O:26])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][NH:9][C:10]([C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[S:25]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[C:42]3[C:37](=[C:38]([F:46])[C:39]([F:45])=[C:40]([F:44])[C:41]=3[F:43])[NH:36][CH:35]=2)[CH2:30][CH2:29]1)(=[O:27])=[O:26])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)N2CCC(c3c[nH]c4c(F)c(F)c(F)c(F)c34)CC2)[C@@H](C(=O)NOCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NOCc1ccccc1)[C@H]1CNCCN1S(=O)(=O)N1CCC(c2c[nH]c3c(F)c(F)c(F)c(F)c23)CC1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of N-benzyloxy-4-tert-butoxycarbonyl-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (24.40 g, 36.40 mmol) [prepared as described in Step 4 above] in methylene chloride (90 ml) was added trifluoroacetic acid (60 ml). The reaction mixture was stirred for 2 h, concentrated in vacuo, and partitioned between ethyl acetate (500 ml) and sat. sodium bicarbonate (200 ml). The aqueous layer was washed with ethyl acetate and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was dissolved in ethyl acetate (40 ml) and slowly added to hexane (200 ml) with vigorous stirring. The resulting slurry was filtered to afford 20.65 g of N-benzyloxy-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:28]N1C(=O)CCC1=O>ClC(Cl)C>[Br:28][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=2)=[CH:15][C:16]=1[N+:21]([O-:23])=[O:22]
Reactant: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1CBr
Yield: 53.2 %

Procedure:
A solution of 5-(3,5-dichlorophenyl)-3-(4-methyl-3-nitrophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (1.9 g), N-bromosuccinimide (0.9 g) and 2,2′-azobisisobutylonitrile (0.1 g) in dichloroethane was heated to reflux for 3 hours. The reaction solution was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to yield 3-[4-(bromomethyl)-3-nitrophenyl]-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (1.2 g).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:20].O[CH2:22][C:23]1[N:30]2[C:26]([S:27][CH:28]=[CH:29]2)=[CH:25][N:24]=1>CN(C=O)C>[Cl-:20].[S:27]1[CH:28]=[CH:29][N:30]2[C:23]([CH2:22][P+:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:24][CH:25]=[C:26]12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: OCc1ncc2sccn12
Reactant: Cl
Solvent: CN(C)C=O
Product: [Cl-]
Product: c1ccc([P+](Cc2ncc3sccn23)(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 74.8 %

Procedure:
Triphenylphosphine (2.51 g) is added to a solution of 1.23 g of 5-hydroxymethylimidazo[5,1-b]thiazole hydrochloride in 20 ml of DMF, and the mixture is stirred at 100° C. for 12 hr. The solvent is removed by evaporation, and the residue is purified by column chromatography on silica gel (methanol:dichloromethane=5:95) to give 2.1 g of (imidazo[5,1-b]thiazol-5-yl)methyltriphenylphosphonium chloride.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:22]=[CH:21][C:13]3[N:14]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)[CH2:5]1.C(N(CC)CC)C.[Cl:30][C:31]1[S:35][C:34]([C:36](Cl)=[O:37])=[CH:33][CH:32]=1>O1CCCC1>[Cl:30][C:31]1[S:35][C:34]([C:36]([NH:2][CH2:3][C@@H:4]2[O:8][C:7](=[O:9])[N:6]([C:10]3[CH:22]=[CH:21][C:13]4[N:14]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:17])[O:16][C:12]=4[CH:11]=3)[CH2:5]2)=[O:37])=[CH:33][CH:32]=1
Reactant: CC(C)n1c(=O)oc2cc(N3C[C@H](CN)OC3=O)ccc21
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1c(=O)oc2cc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.61 mmol) of 6-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-3-isopropyl-1,3-benzoxazol-2(3H)-one hydrochloride (EP 738726) are suspended in 5 ml of tetrahydrofuran, and 0.26 ml (1.83 mmol) of triethylamine and 132 mg (0.73 mmol) of 5-chlorothiophene-2-carbonyl chloride are added. The reaction mixture is stirred at room temperature overnight and then concentrated. The product is isolated by column chromatography (silica gel, methylene chloride/ethanol=50/1 to 20/1). 115 mg (43% of theory) of the desired compound are obtained.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([C:11]1[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[N:13][N:14]([CH3:16])[CH:15]=1)[N:5]=2.[CH2:24]([NH2:27])[CH2:25][CH3:26]>O1CCOCC1.C(Cl)Cl>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:12]1[C:11]([C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:27][CH2:24][CH2:25][CH3:26])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:15][N:14]([CH3:16])[N:13]=1
Reactant: CCCN
Reactant: Cn1cc(-c2ccc3nc(Br)sc3n2)c(-c2ccccc2F)n1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCNc1nc2ccc(-c3cn(C)nc3-c3ccccc3F)nc2s1
Temperature: 25 °C
Yield: 973.3 %

Procedure:
A solution of 2-bromo-5-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridine (0.0294 g, 0.0755 mmol, 1.0 eq.) and n-propylamine (0.1 mL, 1.22 mmol, 16.1 eq.) in 1,4-dioxane (1.5 mL) was heated at 75° C. for 3 h. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford 5-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-N-propylthiazolo[5,4-b]pyridine-2-amine as a light tan solid (0.270 g, 97% yield). LC/MS (MH)=368.16.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][C:22]([N+:24]([O-:26])=[O:25])=[CH:21][CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)n1S(=O)(=O)c1ccc(Cl)cc1
Yield: 138.3 %

Procedure:
2.90 g (13.3 mmol) of 4-chlorobenzenesulfonylisocyanate and 2.21 g (14.1 mmol) of 2-amino-4-nitrobenzoic acid were treated in the same way as in Example 1 to obtain 7.02 g of the above-identified compound (yield 57.9%). Properties: colorless crystal, Melting point: 258°-260° C., PMR (δppm, DMSO-d6): 7.10 (1H,s), 7.77 (2H,d), 7.92 (1H,d), 8.10 (1H,d), 8.19 (2H,d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][NH:24][C:17]=23)[C:12]([CH3:25])=[CH:11][N:10]=1.[N:26]([CH:29]([CH3:31])[CH3:30])=[C:27]=[O:28]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[N:23][N:24]([C:27]([NH:26][CH:29]([CH3:31])[CH3:30])=[O:28])[C:17]=23)[C:12]([CH3:25])=[CH:11][N:10]=1
Reactant: CC(C)N=C=O
Reactant: Cc1cnc(-c2cc(F)ccc2F)cc1Nc1ccnc2cn[nH]c12
Solvent: CC#N
Product: Cc1cnc(-c2cc(F)ccc2F)cc1Nc1ccnc2cnn(C(=O)NC(C)C)c12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
N-(2-(2,5-Difluorophenyl)-5-methylpyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (100 mg, 0.296 mmol) was suspended in acetonitrile (3 mL). 2-Isocyanatopropane (29.1 μl, 0.296 mmol) was added and the reaction was stirred at 70° C. for 2 hours. The mixture was then cooled to give a solid which was collected by filtration to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (6H, d, J=6.57 Hz) 2.38 (3H, s) 4.05-4.19 (1H, m) 7.26-7.45 (3H, m) 7.76 (1H, ddd, J=9.41, 6.13, 3.16 Hz) 7.93 (1H, s) 8.35-8.44 (1H, m) 8.54 (1H, s) 8.60 (1H, s) 8.82 (1H, d, J=8.34 Hz) 11.01 (1H, s). MS [M+H] found 423.5.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]=O.[CH3:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[N:15]1[C:19]2=[C:20]3[CH:26]=[CH:25][NH:24][C:21]3=[N:22][CH:23]=[C:18]2[NH:17][C:16]1=[O:27]>>[CH3:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[N:15]1[C:19]2=[C:20]3[C:26]([CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:25][NH:24][C:21]3=[N:22][CH:23]=[C:18]2[NH:17][C:16]1=[O:27]
Reactant: C1CCNC1
Reactant: C=O
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Product: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]cc(CN4CCCC4)c3c21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of pyrrolidine (0.0184 mL) in ACOH (0.6 mL) was added paraformaldehyde (7.8 mg), and stirred at ambient temperature for 5 minutes. To the mixture was added 1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (30 mg), and stirred at 85° C. for 8 hours, then stirred at ambient temperature for 14 hours. AcOH was removed in vacuo, and the residue was diluted with tetrahydrofuran, then basified with saturated aqueous sodium hydrogencarbonate. The mixture was extracted with EtOAc, washed with 10% NaCl solution, and brine, dried over MgSO4, evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1 to 10:1) to give 1-[(1S,2R)-2-methylcyclohexyl]-8-(1-pyrrolidinylmethyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (32.7 mg) as a pale yellow amorphous solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13].C(N(CC)CC)C.[C:25]([CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:30]=1)O)#[N:26]>CCOCC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:14][CH:27]([C:25]#[N:26])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:30]=1)=[O:13]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)n1
Reactant: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)n1)c1ccc2ccccc2c1
Reaction time: 18 h

Procedure:
To the acid chloride of 2-(2-naphthyl)-3-methylbutanoic acid (2.5 mmol) in ether is added 1.3 ml of triethylamine followed by the cyano(6-phenoxy-2-pyridyl)methanol in 5 ml of ether, from part A above, over about 2 minutes. The reaction mixture is stirred for about 18 hours and then quenched with saturated aqueous sodium bicarbonate. The organic phase is washed with aqueous sodium bicarbonate, water and brine, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a circular chromatograph eluting with 20% ether/hexane to give cyano(6-phenoxy-2-pyridyl)methyl 2-(2-naphthyl)-3-methylbutanoate, MS m/e 436 (M+).
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[C:10]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][C:12]2[N:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:13]=2[CH:23]=1.[Cl:31]N1C(=O)CCC1=O.[NH4+].[Cl-]>C1COCC1>[Cl:31][C:15]1[N:14]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:13]2[CH:23]=[C:9]([Cl:8])[C:10]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:11][C:12]=2[N:16]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCCOCn1cnc2cc(Oc3ccccc3)c(Cl)cc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCCOCn1c(Cl)nc2cc(Oc3ccccc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of diisopropylamine (260 L, 1.85 mmol) in dry THF (2 mL) cooled in −78° C. bath was added n-buthyllithium in hexanes (1.16 mL of a 1.6 M solution). After 45 min, the contents of the flask were added via syringe to a −78° C. solution of 6-chloro-1-(2-methoxy-ethoxymethyl)-5-phenoxy-1H-benzoimidazole (0.560 g, 1.68 mmol) in dry THF (2 mL). After 60 min, N-chlorosuccinimide (0.247 g, 1.85 mmol) in THF (3 mL) was added via syringe to the dark solution at which time the color changed to light brown. The reaction mixture was allowed to warm to ambient temperature then was added to saturated aq. NH4Cl and extracted with EtOAc. The combined organic layers were washed with 0.5 M citric acid, 5% aq. NaHCO3, brine, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) to yield the titled compound as a mixture of regioisomers (0.251 g, 41%; orange oil). MS (ESI/CI): mass calcd. for C17H16Cl2N2O3, 366; m/z found, 367 [M+H]+. 1H NMR (400 MHz, CDCl3) δ7.80 (s, 1H), 7.62 (s, 1H), 7.37 (s, 1H), 7.36-7.29 (m, 4H), 7.18 (s, 1H), 7.14-7.04 (m, 2H), 6.98-6.90 (m, 4H), 5.63 (s, 2H), 5.54 (s, 2H), 3.72-3.63 (m, 2H), 3.63-3.57 (m, 2H), 3.57-3.50 (m, 2H), 3.49-3.42 (m, 2H), 3.38 (s, 3H), 3.28 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[C:18](Cl)(=[O:24])[CH2:19][CH2:20][C:21](Cl)=[O:22]>>[CH2:9]([O:8][C:6]([C:5]1[CH:16]=[CH:17][C:2]([O:1][C:18](=[O:24])[CH2:19][CH2:20][C:21]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:7])=[CH:16][CH:17]=2)=[O:22])=[CH:3][CH:4]=1)=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: O=C(Cl)CCC(=O)Cl
Product: O=C(CCC(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1)Oc1ccc(C(=O)OCc2ccccc2)cc1

Procedure:
A similar procedure to Example 1 is carried out by using 22.8 g of benzyl p-hydroxybenzoate and 7.7 g of succinic acid dichloride to yield di(p-benzyloxycarbonylphenyl)succinate, m.p. 106°-107° C., as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N+:14]([O-])=O)[C:8]=2[N:7]=[C:6]1[C:17]1[C:22](OC)=[CH:21][CH:20]=[CH:19][C:18]=1[F:25].[C:31](O)(=[O:33])C>Cl>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([NH2:14])[C:8]=2[N:7]=[C:6]1[C:17]1[CH:22]=[CH:21][C:20]([O:33][CH3:31])=[CH:19][C:18]=1[F:25]
Reactant: COc1cccc(F)c1-c1nc2c([N+](=O)[O-])cccc2n1Cc1c(F)cccc1F
Reactant: CC(=O)O
Agent: Cl
Product: COc1ccc(-c2nc3c(N)cccc3n2Cc2c(F)cccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2-fluoro-4-methoxylphenyl)-4-nitrobenzimidazole (Example 50) (2.00 g, 4.98 mmol) dissolved in acetic acid (20 mL) was added SnCl2x2H2O (9.02 g) dissolved in concentrated HCl (8 mL). After stirring for 30 min at room temperature, the mixture was concentrated. The residue was diluted with CH2Cl2 and washed with NaHCO3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na2SO4), filtered, and evaporated. The crude product was recrystallized from methanol to give 3.26 g of white crystals, (8.78 mmol, 70% yield). M.p. 200-202° C. 1H-NMR (200 MHz, CD2Cl2) δ7.45 (m, 1H, H4′), 7.22 (m, 1H, H4″), 7.05 (dd, J=7.8, 7.6 Hz, 1H, H6), 6.85-6.72 (m, 5H, H3″,5″), 6.50 (dd, J=7.7, 1.0 Hz, 1H, H5), 5.21 (d, J=5.4 Hz, 2H, CH2PhF2 (rotamers)), 4.34 (br, 2H, NH2), 3.72 (s, 3H, OCH3).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][C:26](C=O)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)=O)(C)(C)C.[CH3:34][NH:35][CH2:36][CH:37]1[O:41][CH2:40][CH2:39][CH2:38]1.[C:42](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O>O1CCCC1.ClCCl>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][C:26]([CH2:34][N:35]([CH3:42])[CH2:36][CH:37]3[CH2:38][CH2:39][CH2:40][O:41]3)=[CH:25][N:24]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(C=O)cc2C#N)cc1
Reactant: CNCC1CCCO1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(Cc1cnc(-c2ccc(C(=O)Nc3ccccc3N)cc2)c(C#N)c1)CC1CCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyano-5-formylpyridin-2-yl)benzamide (0.20 g, 0.45 mmol; prepared as described in Method 15 below), N-methyltetrahydrofurfurylamine (81 mg, 0.7 mmol) and acetic acid (26 μl, 0.45 mmol) were dissolved in tetrahydrofuran (5 ml). The mixture was stirred at ambient temperature for 1 hour. Sodium triacetoxyborohydride (144 mg, 0.7 mmol) was then added and the mixture stirred for a further 3 hours. The mixture was concentrated and the residue purified by flash chromatography eluting with 100% ethyl acetate. Concentration of the solvent gave product as a gum. This was dissolved in dichloromethane (6 ml), trifluoroacetic acid (1.2 ml) was added and the solution then stirred at ambient temperature for 2 hours. The resulting solution was absorbed onto an SCX-2 column, which was washed with methanol (3 column volumes) and the product eluted with a 2M solution of ammonia in methanol (3 column volumes) then concentrated to give the product as a gum. This was re-precipitated by stirring in diethyl ether (3 ml) to give the title compound as a foam/gum (43 mg, 22%). NMR Spectrum: (DMSO-d6, 373K) 1H NMR 1.53 (m, 1H), 1.82 (m, 2H), 1.98 (m, 1H), 2.37 (s, 3H), 2.64 (m, 2H), 3.00 (br s, 2H), 3.66 (q, 1H), 3.77 (q, 1H), 3.84 (m, 2H), 4.04 (m, 1H), 6.63 (m, 1H), 6.82 (d, 1H), 6.98 (m, 1H), 7.27 (d, 1H), 8.00 (d, 2H), 8.14 (d, 2H), 8.29 (s, 1H), 8.89 (s, 1H), 9.50 (br s, 1H); Mass Spectrum: M+H+ 442.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:25][C:24]1[C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: Cc1cccnc1CCl
Agent: Cl
Product: Cc1cc(C#Cc2cn(Cc3ncccc3C)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=303.2 (M+H30), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloromethyl-3-methyl-pyridine hydrochloride.
Reaction SMILES: [H-].[Na+].C(S)C.[CH2:6]([C:8]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([OH:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:21]([CH3:33])[CH:20]=1)([C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1)[CH2:9][CH3:10])[CH3:7]>CN(C=O)C>[CH2:6]([C:8]([C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([OH:32])[C:28]([CH3:30])([CH3:31])[CH3:29])=[C:21]([CH3:33])[CH:20]=1)[CH2:9][CH3:10])[CH3:7]
Reactant: CCC(CC)(c1ccc(OC)cc1)c1ccc(CCC(O)C(C)(C)C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: CCC(CC)(c1ccc(O)cc1)c1ccc(CCC(O)C(C)(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 37.6 %

Procedure:
A stirred suspension of NaH (60% dispersion in mineral oil, 80 mg, 2.0 mmol) in anhyd DMF (0.5 mL) was chilled to 0° C. and charged dropwise with ethanethiol (74 μL, 1.0 mmol). The reaction mixture was removed from the ice-bath and stirred at ambient temperature. After 10 min, additional DMF (0.5 mL) was added to facilitate stirring. To the resulting mixture was added dropwise a solution of 1-{4-[1-ethyl-1-(4-methoxyphenyl)-propyl]-2-methylphenyl}-4,4-dimethylpentan-3-ol (0.10 g, 0.26 mmol) in anhyd DMF (0.7 mL). The reaction mixture was transferred to an oil bath and heated at reflux. After 3 h the mixture was cooled, quenched with satd NH4Cl (50 mL), extracted with Et2O (2×50 mL). The combined extracts were washed with H2O (2×50 mL) and brine, then dried (Na2SO4), concentrated under reduced pressure and chromatographed (silica, EtOAC/Hex, 0:100 to 25:75) to give the title compound (36 mg, 37% non-optimized) as a tacky white solid: 1H-NMR (CD2Cl2) δ 7.00-7.06 (3H, m), 6.90-6.94 (2H, m), 6.71 (2H, d), 4.95 (1H, br s), 3.24 (1H, dd, J=1.8, 10.6), 2.85 (1H, ddd, J=5.1, 10.6, 13.9), 2.54 (1H, ddd, J=6.1, 10.4, 13.9), 2.24 (3H, s), 2.05 (4H, q, J=7.3), 1.72-1.84 (1H, m), 1.42-1.54 (1H, m), 0.88 (9H, s), 0.59 (6H, t, J=7.3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([CH:17]=[CH2:18])[CH2:9][C:10](=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=1.C(NC1C=CC(S([N:32]=[N+:33]=[N-])(=O)=O)=CC=1)(=O)C.[N-]=[N+]=[N-].C(NC1C=CC(S([NH-])(=O)=O)=CC=1)(=O)C>C(N(CC)CC)C.ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]([CH:17]=[CH2:18])[CH2:9][C:10](=[O:16])[C:11](=[N+:32]=[N-:33])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: C=C[C@H](CC(=O)CC(=O)OC)c1cccc(F)c1
Agent: CC(=O)Nc1ccc(S([NH-])(=O)=O)cc1
Agent: [N-]=[N+]=[N-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C=C[C@H](CC(=O)C(=[N+]=[N-])C(=O)OC)c1cccc(F)c1
Temperature: 21 °C
Reaction time: 9 h

Procedure:
A 50 L, 4-necked round bottom flask, equipped with mechanical stirrer, thermocouple, addition funnel, nitrogen inlet, and steam pot, was charged with a solution of methyl (5S)-5-(3-fluorophenyl)-3-oxohept-6-enoate 8 (8823 g of solution, 1300 g of ketoester in 1,2-dichloroethane). Additional 1,2-dichloroethane (7 L) was charged to the flask, followed by 4-acetamidobenzenesulfonyl azide (1.25 kg). The solution was heated from about 18° C. to 21° C. with steam. (Note: the dissolution of azide was endothermic.) Triethylamine (2.17 L) was added over 40 min with water bath cooling to maintain a temperature of 19-23° C. The reaction was stirred at 18-23° C. for approximately 9 h. The reaction was mildly exothermic. The reagent product, 4-acetamidobenzenesulfonyl amide, began to precipitate from the reaction during the addition of triethylamine and eventually formed a thick slurry. The reaction was followed by HPLC and was judged complete when the amount of starting material was <0.5%. When completed, the reaction mixture was filtered, and the cake was washed four times with 1,2-dichloroethane (3×2 L displacement washes, 1×1 L slurry wash). The filtrate and washes were combined and extracted with cold (5-10° C.) 2N HCl (7.4 L). The extraction was exothermic and was done in a 50 L extractor with cooling to maintain a temperature of 20-22° C. The pH of the aqueous phase was 1.0. The organic layer was extracted twice with water (2×7 L). The organic extract was charged to a 50 L, 4-necked round bottom flask, equipped with mechanical stirrer, thermocouple, nitrogen inlet, and stopper. The solution was dried for 4 h with sodium sulfate (1 kg). The organic solution was passed through a 5 μ inline filter. The final weight of organic solution was 25.6 kg. Final yield of 9 was >95%.