Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]2[C:20](=O)[NH:21][N:22]=[C:12]2[C:11]2[CH:24]=[CH:25][CH:26]=[N:27][C:10]1=2)=[O:8])[CH3:5].[CH3:28]I>CN(C)C=O>[CH3:28][N:21]1[CH2:20][N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:9]([C:7](=[O:8])[CH2:6][N:4]([CH3:5])[CH3:3])[C:10]3[N:27]=[CH:26][CH:25]=[CH:24][C:11]=3[C:12]2=[N:22]1
Reactant: CI
Reactant: CN(C)CC(=O)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1c2ccccc2N2CN(C)N=C2c2cccnc21
Temperature: 50 °C
Reaction time: 21 h

Procedure:
Sodium hydride (0.178 g., 4.21 mmoles of a 57% dispersion in mineral oil) is added to a solution of 2,9-dihydro-9-[(dimethylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one (4.21 mmoles) in 50 ml. of dimethylformamide and the mixture is heated at 95° C. for 35 minutes. The mixture is cooled to 50° C., a solution of methyliodide (4.21 mmole) is added and heating is continued at 95° C. for 21 hours. The mixture is evaporated and methylene chloride-water is added to the residue. The organic layer is separated and extracted three times with 10 ml. portions of 10% aqueous hydrochloric acid. The acid extract is cooled, made alkaline with 15% aqueous sodium hydroxide and the basic mixture is extracted with methylene chloride. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. Crystallization of the residue from ether gives 2,9-dihydro-2-methyl-9-[(dimethylamino)acetyl]-3 H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=3[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:35]=[C:34]([O:36][CH3:37])[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:29]=1[C:30]#[N:31].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:27][C:28]1[C:29]([C:30]#[N:31])=[CH:32][C:33]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]4[C:17]([F:26])=[C:18]([F:25])[C:19]([F:24])=[C:20]([F:23])[C:21]=4[F:22])(=[O:14])=[O:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[C:34]([O:36][CH3:37])[CH:35]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Reactant: COc1cc(Cl)c(C#N)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Yield: 79.7 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see EXAMPLE 73, Step 1; 555 mg, 1.355 mmol), 2-chloro-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (INTERMEDIATE UUUU, 477 mg, 1.626 mmol), potassium carbonate (562 mg, 4.06 mmol), and Pd(Ph3P)4 (157 mg, 0.135 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (5080 μl) and water (1693 μl) were added. The flask was lowered into a 50° C. heating bath for 1 h. The reaction mixture was diluted with water and EtOAc. The organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 0-50% EtOAc/Heptane) to give perfluorophenyl 1-(4-chloro-5-cyano-2-methoxyphenyl)isoquinoline-6-sulfonate (583.89 mg, 1.080 mmol, 80% yield) as an off-white foam. m/z (ESI) 540.9 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:32])([C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1)[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C(=O)([O-])[O-].[K+].[K+].[Br:39][CH2:40][CH:41]=[CH:42][CH2:43]Br>CN1C(=O)CCC1>[Br:39][CH2:40][CH:41]=[CH:42][CH2:43][O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:2]([F:32])([F:1])[C:3]([F:23])([F:24])[C:4]([F:21])([F:22])[C:5]([F:19])([F:20])[C:6]([F:17])([F:18])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[CH:26]=1
Reactant: Oc1cccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Reactant: BrCC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)c1cccc(OCC=CCBr)c1
Temperature: 45 °C

Procedure:
A mixture of 3-(perfluoro-n-octyl)phenol (10.24 g), potassium carbonate (4.2 g), NMP (30 mL) and 1,4-dibromo-2-butene (12.8 g) is heated to 45° C. for 2 hr. Extraction in the normal fashion and Kugelrohr distillation of the excess dibromide (0.1 mm Hg, 80° C.) gives 1-bromo-4-[3-(perfluoro-n-octyl)phenoxy]but-2-ene.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.[CH2:35]([N:42]1[C:46]([CH2:47]Br)=[CH:45][C:44]([CH3:49])=[N:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:35]([N:42]1[C:46]([CH2:47][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])=[CH:45][C:44]([CH3:49])=[N:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: Cc1cc(CBr)n(Cc2ccccc2)n1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cc(C)nn3Cc3ccccc3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a stirring solution of 300 mg (0.66 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 5 mL of DMF at 0° C. is added 1.57 mL (0.79 mmol, 1.2 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 5 min, and a solution of 190 mg (0.72 mmol, 1.1 equiv.) of 1-Benzyl-5-bromomethyl-3-methyl-1H-pyrazole, prepared as in Intermediate 56, in 2 mL of DMF is added. The resulting solution is stirred for 18 h at RT then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/2 as eluent afforded 254 mg of the title compound as a white solid: mp 117°-120° C.; 1H NMR (CDCl3, 400 MHz) δ7.37-7.02 (m, 15H), 6.94 (m, 2H), 6.85 (d, 1H, J=7.4), 5.80(s, 1H), 5.30 (dd, 2H, J=16.1, 30.9), 4.98 (m, 1H), 4.19 (dd, 2H, J=15.6, 76.0), 3.83 (s, 3H), 3.43 (t, 1H, J=6.7), 3.25 (ddd, 1H, J=7.1, 16.0, 40.5), 2.20 (s, 3H), 1.06 (m, 6H); low resolution MS (FAB)m/e 642 (MH+), 641 (M+); Anal. (C39H39N5O4) Calcd. C, 72.99; H, 6.13; N, 10.91 Found C, 72.86; H, 6.11; N, 10.96.
Reaction SMILES: [C:1]([O:5][C:6]1[C:11]([OH:12])=[C:10]([F:13])[N:9]=[C:8]([F:14])[C:7]=1[F:15])([CH3:4])([CH3:3])[CH3:2].[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]1[C:11]([O:12][CH3:16])=[C:10]([F:13])[N:9]=[C:8]([F:14])[C:7]=1[F:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)Oc1c(O)c(F)nc(F)c1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(F)nc(F)c(F)c1OC(C)(C)C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
To a solution of 237 mg (1.07 mmol) of 4-t-butoxy-2,3,6-trifluoro-5-hydroxypyridine, from step 275a above, in 3 mL of anhydrous THF was added 335 mg (1.277 mmol) of triphenyl phosphine and 0.060 mL (1.48 mmol) of methanol. To this solution was added 0.200 mL (1.270 mmol) of DEAD dropwise at room temperature. The reaction was complete in 10 min, so the solvents were removed under vacuum and the residue was purified by flash chromatography on silica gel, eluting with 1:16 ethyl acetate:hexane to give 215.6 mg of the title product as a colorless liquid after removal of the solvent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][N:13](C(OC)OC)C.CO>CN(C=O)C>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][N:11]2[N:13]=[CH:12][N:1]=[C:2]2[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccn2ncnc2c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of methyl 2-aminoisonicotinate (28.8 g, 191 mmol) in DMF (97.5 mL) was added DMF-DMA (70.6 mL, 496 mmol) and the mixture heated to 130° C. for 12 hours. The mixture was then concentrated to give a residue. To the residue was added MeOH (381 mL), followed by NH2OHSO4 (31.9 g, 248 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to give methyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate in 18% yield, 6 g. To a solution of methyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3 g, 16 mmol) in methanol was added 1M aq. LiOH (70 mL) and the resulting mixture stirred for 10 hours at room temperature. The pH was adjusted to 5-6 using aq. HCl and the whole mixture extracted with EtOAc (30 mL×3). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid in 38% yield, 1.05 g 1H NMR (400 MHz, DMSO-d6) δ: 7.56-7.58 (m, 1H), 8.32 (m, 1H), 8.66 (m, 1H), 9.04-9.06 (m, 1H), 13.5-14.0 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:10]3[N:15]=[CH:14][C:13]4[CH:16]=[N:17][N:18]([C:19]5[CH:24]=[CH:23][CH:22]=[C:21](F)[N:20]=5)[C:12]=4[CH:11]=3)[CH:7]=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH:26]1[CH2:32][CH:31]([OH:33])[CH2:30][NH:29][CH2:28][CH2:27]1>>[CH:1]1([C:4]2[CH:5]=[C:6]([C:10]3[N:15]=[CH:14][C:13]4[CH:16]=[N:17][N:18]([C:19]5[N:20]=[C:21]([N:26]6[CH2:32][CH:31]([OH:33])[CH2:30][NH:29][CH2:28][CH2:27]6)[CH:22]=[CH:23][CH:24]=5)[C:12]=4[CH:11]=3)[CH:7]=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Fc1cccc(-n2ncc3cnc(-c4cncc(C5CC5)c4)cc32)n1
Reactant: OC1CNCCNC1
Product: OC1CNCCN(c2cccc(-n3ncc4cnc(-c5cncc(C6CC6)c5)cc43)n2)C1
Yield: 17 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 6-(5-cyclopropylpyridin-3-yl)-1-(6-fluoropyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine and 1,4-diazepan-6-ol, 115 was obtained as an off-white solid (25.1 mg, 17%). 1H NMR (400 MHz, DMSO) δ 9.31-9.27 (s, 1H), 9.07-9.00 (dd, J=16.3, 6.5 Hz, 2H), 8.65-8.59 (d, J=5.6 Hz, 1H), 8.48-8.44 (t, J=2.8 Hz, 1H), 8.09-8.03 (t, J=2.0 Hz, 1H), 7.73-7.67 (t, J=8.1 Hz, 1H), 7.20-7.14 (d, J=7.7 Hz, 1H), 6.73-6.68 (d, J=8.5 Hz, 1H), 4.82-4.73 (s, 1H), 4.03-3.87 (m, 3H), 3.74-3.57 (m, 2H), 3.02-2.93 (t, J=5.4 Hz, 2H), 2.87-2.75 (dd, J=13.8, 3.8 Hz, 1H), 2.70-2.60 (dd, J=13.8, 5.9 Hz, 1H), 2.15-2.03 (m, 1H), 1.10-1.02 (m, 2H), 0.92-0.82 (m, 2H); MS (ESI) m/z: 428.2 [M+H]+
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][CH:20]([CH3:22])[CH3:21])=[N:8][CH:9]=[N:10][CH:11]=1)=O)C.[OH-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>O1CCOCC1>[CH:20]([N:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:7]2[N:8]=[CH:9][N:10]=[CH:11][C:6]=2[C:4]1=[O:3])([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1cncnc1Nc1ccccc1NC(C)C
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)N1C(=O)c2cncnc2Nc2ccccc21
Temperature: 80 °C
Reaction time: 5 h

Procedure:
12.7 g (0.03 mol) of 5-ethoxycarbonyl-4-(2-isopropylaminoanilino)pyrimidine in 42.2 ml of a 0.1 N. aqueous sodium hydroxide solution are heated for 1 hour under reflux. The solvent is removed on a rotary evaporator and the crystalline residue is dried in vacuo at 60° C. 28.9 g (0.11 mol) of triphenylphosphine and 16.9 g (0.11 mol) of carbon tetrachloride are added to the dry product, dissolved in 150 ml of absolute dioxan, and the mixture is stirred for 5 hours at 80° C. The solvent is removed on a rotary evaporator, and the oily residue which remains is chromatographed on neutral silica gel using 99:1 methylene chloride/methanol as the eluant; yield: 6.3 g, with m.p. 204° to 206° C. (from isopropanol).
Reaction SMILES: C1C=CC=CC=1.[C:7]1([CH:13]2[NH:17][C:16]([CH3:19])([CH3:18])[CH2:15][O:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(N(CC)CC)C>[C:7]1([CH:13]2[N:17]([C:22](=[O:23])[CH2:21][Cl:20])[C:16]([CH3:19])([CH3:18])[CH2:15][O:14]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC1(C)COC(c2ccccc2)N1
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)COC(c2ccccc2)N1C(=O)CCl
Reaction time: 0.5 h

Procedure:
Twenty-one and three tenths (21.3) ml. of a benzene solution containing 5.3 g. of 2-phenyl-4,4-dimethyl oxazolidine was mixed with 50 ml. of benzene and 3.4 g. of chloroacetyl chloride. To this solution was added 3.1 g. of triethylamine, dropwise with stirring in an ice bath. The mixture was stirred for about 30 minutes after addition was complete and then washed with water, separated and dried over magnesium sulfate and the solvent stripped. There was obtained a yield of 6.5 g. of an oil, the title compound, ND30 =1.5364.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.O.[OH-].[Na+].[H][H]>[Pd].C(O)CCC>[Cl:1][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: Clc1ccccc1N(Cl)Nc1ccccc1
Yield: 78.2 %

Procedure:
630 g o-chloronitrobenzene, 615 g water and 185 g sodium hydroxide (corresponding to a 23.1 wt. % aqueous solution), 0.9 g naphthalenediol-1,4, 535 g n-butanol and 1.0 g palladium on alumina (5% Pd) (the quantitative ratio of palladium metal to o-chloronitrobenzene used being 0.00008:1) are hydrogenated at a hydrogen pressure of 6 bars and at 55° to 65° C. for 4 hours and worked up as described in Example 1. 396 g pure 2,2'-dichlorohydrazobenzene of a purity of better than 98% is obtained in a yield of 78% of theory. In addition, 37 g o-chloroaniline is obtained which after the n-butanol has been drawn off is distillable under vacuum and thus may be recovered pure. When the distillation residue is mixed with 65 g n-butanol of 60° C., a second fraction of 61 g 2,2'-dichlorohydrazobenzene of a purity of from 97 to 98% crystallizes out on cooling. The total hydrazobenzene yield thus is 89.8%. In addition, 7.3 wt. % o-chloroaniline is obtained.
Reaction SMILES: C(N(CC)CC)C.[Si:8]([O:15][CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=1)[OH:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:18][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=1)[CH2:16][O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1ccc(Cl)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(OS(C)(=O)=O)c1ccc(Cl)c(F)c1
Reaction time: 1 h
Yield: 95.8 %

Procedure:
Triethylamine (“TEA”) (0.741 mL, 5.31 mmol; d. 0.726) was added to a cold (0° C.) solution of 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanol (1.08 g, 3.54 mmol) in DCM (10 mL), followed by addition of methanesulfonyl chloride (0.329 mL, 4.25 mmol). After 1 hour, the reaction mixture was diluted with DCM, and the organic layer was washed with saturated aqueous NaHCO3, dried, filtered and concentrated to afford 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (1.30 g, 3.39 mmol, 95.8% yield). 1H NMR (400 MHz, CDCl3) δ 7.33 (m, 1H), 7.18 (m, 1H), 7.10 (m, 1H), 6.63 (m, 1H), 5.74 (d, 1H), 5.32 (d, 1H).
Reaction SMILES: [CH3:1][C:2]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:3][CH:4]=[O:5].[OH-:14].[Na+]>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][C:2]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:3][C:4]([OH:14])=[O:5]
Reactant: CC(C=Cc1ccccc1)=CC=O
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C=Cc1ccccc1)=CC(=O)O
Reaction time: 5 h
Yield: 14.7 %

Procedure:
To a stirred solution of 3-methyl-5-phenyl-2,4-pentadienal (16.5 g) in ethanol (330 mL) was added dropwise a solution of silver nitrate (19.28 g) in water (160 mL) followed by dropwise addition of an aqueous sodium hydroxide (25 g, 80 mL) solution. The resulting mixture was allowed to stir for an additional five hours and then filtered. The solid was washed with ethanol. The combined filtrate was concentrated in vacuum. The residue was dissolved in water (200 mL). The aqueous solution was extracted with ether (300 mL) twice and acidified with 6 N hydrochloric acid (74 mL). The solid formed was filtered and recrystallized from methanol (40 mL) to yield 2.65 g of the desired 3-methyl-5-phenyl-2,4-pentadienoic acid. 1H NMR (acetone-d6, 300 MHz), δ(ppm) 7.60 (d, 2H), 7.35 (m, 3H), 7.06 (m, 2H), 6.02 (broad s, 1H), 2.50 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([O:10][C:11](=[O:23])[CH:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13](C)=O)[CH3:9].C=O>O1CCCC1>[C:17]1([CH2:16][C:12]([C:11]([O:10][CH2:8][CH3:9])=[O:23])=[CH2:13])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Agent: C=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=C(Cc1ccccc1)C(=O)OCC
Reaction time: 0.33 h
Yield: 135.7 %

Procedure:
N-butyl lithium (201 ml of 1.6M) was added dropwise to diisopropyl amine (45 ml) in dry tetrahydrofuran (870 ml) at -78° C. After stirring at this temperature for 0.5 hours ethyl-2-benzylacetoacetate (39.6 g, 0.18M) in THF (250 ml) was added dropwise at 0° C. After stirring for 20 minutes, paraformaldehyde (35.42 g) was added at room temperature followed by stirring for one hour and refluxing for 4 hours. The reaction mixture was filtered and the liquid evaporated to dryness. The residue was dissolved in a mixture of KHCO3 /H2O and methylene chloride (1:1) and stirred for 0.5 hours. The layers were separated and the methylene chloride layer was dried over K2CO3 and then evaporated to dryness to yield 46.4 g of named product. This product was purified with a Prep-500 chromatograph eluting with hexane to 5% ethyl acetate/hexane gradient to yield 30 g of a clear liquid. ms (fd)= 190M+
Reaction SMILES: [CH2:1]([C:5]1[NH:9][C:8]2=[CH:10][S:11][CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:15]([O:19][C:20]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.[Cl-].[Na+].O>[C:15]([O:19][C:20]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:9]3[C:8]4=[CH:10][S:11][CH:12]=[C:7]4[N:6]=[C:5]3[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:30][CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc2cscc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc2cscc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
To a stirred solution of 2-butyl-1H-thieno-[3,4-d]imidazole (38 mg, 0.211 mmol) in DMF (1.6 mL) at room temperature was added NaH (316 mmol). After 30 minutes, tert-butyl-4'-bromomethylbiphenyl-2-carboxylate (80.5 mg, 0.232 mmol) was added in one portion. The reaction mixture was stirred for 2 hours and brine (5 mL) was added. Extractive workup (EtOAc) and purification by flash chromatography (SiO2, 40% EtOAc/hexane) gave 64 mg (68%) of 4'-[(2-butyl-1H-thieno[3,4-d]imidazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid t-butyl ester as a thick oil: 1H NMR (300 MHz, CDCl3) δ 7.78 (dd, 1H, J=7.5 and 1 Hz), 7.48 (td, 1H J=7.5 and 1 Hz), 7.40 (td, 1H, J=7.5 and 1 Hz) 7.32-7.26 (m, 3H), 7.19 (d, 2H, J=8 Hz), 6.99 (d, 1H, J=2.5 Hz), 6.28 (d, 1H, J=2.5 Hz), 5.17 (s, 2H), 2.78 (t, 2H, J=8 Hz), 1.91-1.81 (m, 2H), 1.54-1.41 (m, 2H), 1.23 (s, 9H), 0.96 (t, 3H, J=7 Hz).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:6][CH2:7]1)(=[O:30])[CH3:29]
Reactant: O=C(O)CCCCCC[C@H]1CC[C@H](O)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)O[C@H]1CC[C@H](CCCCCCC(=O)O)CC1
Reaction time: 72 h

Procedure:
trans-7-(4-Hydroxycyclohexyl)heptanoic acid (6.5 g) and p-toluenesulfonic acid (15 mg) are stirred in acetic anhydride (32.5 ml) at 60°-70° C. for 1.5 hours. The excess acetic anhydride is distilled off under reduced pressure, followed by addition of water (90 ml), and the mixture is stirred for 3 days. The resulting crystalline precipitate is collected by filtration and recrystallized from ethyl acetate-hexane to give 6.5 g of trans-7-(4-acetoxycyclohexyl)heptanoic acid as colorless needless, m.p. 66°-68° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:7][C:6]2=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:7][C:6]2=[S:30]
Reactant: COc1ccc2c(c1)c(=O)nc(-c1ccccc1)n2C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)c(=S)nc(-c1ccccc1)n2C
Reaction time: 3 h

Procedure:
1.20 g (4.51 mmol) 6-Methoxy-1-methyl-2-phenyl-1H-quinazolin-4-one and 1.82 g (4.50 mmol) Lawesson's reagent (C14H14O2P2S4, Fluka) were dissolved in 20 ml toluene. The reaction mixture was boiled for 3 h. After evaporation the residue was further purified by column chromatography with silica, eluent dichloromethane/acetone 95/5.
Reaction SMILES: [CH3:1][C:2]1[N:3](CC(OC(C)(C)C)=O)[C:4]2[C:9]([C:10]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[C:8](C1SC=CC=1)[CH:7]=[CH:6][CH:5]=2.Cl.[Br:36]C1C=CC(NN)=CC=1>>[Br:36][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[C:10]2[S:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: NNc1ccc(Br)cc1
Reactant: Cc1c(Sc2ccc(S(C)(=O)=O)cc2)c2c(-c3cccs3)cccc2n1CC(=O)OC(C)(C)C
Agent: Cl
Product: Cc1[nH]c2ccc(Br)cc2c1Sc1ccc(S(C)(=O)=O)cc1

Procedure:
The sub-title compound was prepared by the method of Example 3 part (i) using the product from Example 26 part (i) (2.5 g) and 4-bromophenyl hydrazine hydrochloride (2.3 g). The reaction mixture was evaporated to half volume and the resulting precipitate filtered off, washed with ether and dried to yield the sub-title compound (2.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29]S(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:36]=[C:37](O)[CH:38]=[CH:39][CH:40]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:34])[CH:40]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2cccc(Cl)c2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 85.2 %

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (401 mg) was reacted with 3-chlorophenol (198.7 mg) and was recrystallized from hexane-ethyl acetate to obtain (RS)-2-(4-chlorobenzenesulfonyl-amino)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl) propanamide (363.2 mg).