Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([CH2:8][Br:10])[CH:7]=1
Reactant: Cc1cnc(Cl)c(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncc(CBr)cc1Br
Yield: 34.4 %

Procedure:
3-Bromo-2-chloro-5-methylpyridine (4 g, 19.37 mmol), N-bromosuccinimide (3.79 g, 21.3 mmol) and benzoic peroxyanhydride (0.239 g, 0.969 mmol) were combined in carbon tetrachloride (40 mL), heated under reflux for 24 hours, cooled, and filtered to remove succinimide. The filtrate was concentrated. The resulting residue was purified by chromatography (silica gel, 0-30% ethyl acetate in heptanes) to afford the title compound (1.9 g, 34%).
Reaction SMILES: [CH:1]([CH:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:27])[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])=[N:5][CH2:4]1)=[O:2].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[OH:2][CH2:1][CH:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:27])[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:19])=[O:20])=[N:5][CH2:4]1
Reactant: CN(c1cccc2cc(C3=NCC(C=O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CN(c1cccc2cc(C3=NCC(CO)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a solution of N-[2-(5-formyl-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylpyridine-2-sulfonamide (200 mg) in tetrahydrofurah (2 mL) and ethanol (2 mL) was added sodium tetrahydroborate (38 mg), and the mixture was stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (160 mg, yield 80%) as a white amorphous solid from a fraction eluted with ethyl acetate. MS: 403(MH+).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:24][CH:25]1[CH2:29][CH:28]([N:30]2[CH:38]=[N:37][C:36]3[C:31]2=[N:32][C:33]([NH2:40])=[N:34][C:35]=3[Cl:39])[C:27](=[CH2:41])[CH:26]1[CH2:42][O:43][C:44]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(C)(C)C>O1CCCC1>[NH2:40][C:33]1[N:34]=[C:35]([Cl:39])[CH:36]2[CH:31]([N:32]=1)[N:30]([CH:28]1[CH2:29][CH:25]([OH:24])[CH:26]([CH2:42][O:43][C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:27]1=[CH2:41])[CH:38]=[N:37]2
Reactant: C=C1C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1n1cnc2c(Cl)nc(N)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=C1C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(O)CC1N1C=NC2C(Cl)=NC(N)=NC21
Temperature: 25 °C
Reaction time: 13 h
Yield: 71.7 %

Procedure:
1 M tetrabutyl ammonium fluoride solution in tetrahydrofuran (1.1 L, 1.10 mol) was added to a solution prepared by dissolving the compound of formula (V) obtained in Example 2-9 (426 g, 0.5487 mol) in anhydrous tetrahydrofuran (4 L) and stirred at room temperature for 13 hrs. After completion of the reaction, distilled water (2.0 L) was added to the resulting mixture and extracted with ethyl acetate (2.0 L) twice. The organic layer thus separated was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting material was stirred in methanol (4.0 L) to obtain the title compound (212.6 g, yield: 72%).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][S:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][S:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: CSCOc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCOc1ccc(N)c([N+](=O)[O-])c1

Procedure:
5.7 G. of 1-acetamido-4-methylthiomethoxy-2-nitrobenzene is added to a mixture of 12 ml. 5N NaOH and 60 ml. methanol and the mixture heated for 15 minutes on a steam bath. The mixture is poured into 500 ml. water and is extracted with methylene chloride. The methylene chloride layer is separated, dried over sodium sulfate, and evaporated leaving 1-amino-4-methylthiomethoxy-2-nitrobenzene as a gum. This gum is dissolved in a mixture of 5 ml. acetic acid and 95 ml. methanol. 8 G. of iron powder is added and the mixture is heated at reflux for 2 hours. The methanol and acetic acid are evaporated and the residue is extracted with 200 ml. hot tetrahydrofuran. This solution is filtered and the tetrahydrofuran evaporated to yield 1,2-diamino-4-methylthiomethoxybenzene as a gum. This is purified by column chromatography.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[N:10]=1)[CH2:2]2.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(O)C.C1(C)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].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>[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:13]2[N:14]=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:10]=[C:11]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]3)[N:12]=2)=[CH:32][CH:31]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(N3CC4CCC(C3)O4)n2)CC1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(N)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
A suspension of tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (1.0 g, 2.4 mmol), 4-aminophenylboronic acid, pinacol ester (0.69 g, 3.2 mmol), and tetrakis(triphenylphosphine)palladium (0.28 g, 0.24 mmol) in aqueous 2 M sodium carbonate solution (3 mL) and 1:1 ethanol/toluene (12 mL) was irradiated in the microwave at 120° C. for 1 hour. After cooling, the biphasic mixture was extracted thrice with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[C:6](=[O:7])[O:5][C:4](=[O:8])[NH:3]1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[C:9]([N:3]1[C@@H:2]([CH3:1])[C:6](=[O:7])[O:5][C:4]1=[O:8])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1NC(=O)OC1=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: C[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1
Reaction time: 3 h
Yield: 80.1 %

Procedure:
(S)-4-Methyl-2,5-oxazolidinedione (L-alanine-NCA) (230 mg, 2.0 mmol) was dissolved in ethyl acetate (23 mL), followed by the addition of benzoyl chloride (365 mg, 2.6 mmol) under ice cooling. Further, a solution of 4-dimethylaminopyridine (318 mg, 2.6 mmol) in ethyl acetate (11 mL) was added dropwise under ice cooling over 20 minutes. After the resulting mixture was stirred as was at 0° C. for 3 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in a mixed solvent consisting of ethyl acetate (5 mL) and hexane (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound as white crystals (351 mg, 80%).
Reaction SMILES: [Na+].[I-].C[Si](Cl)(C)C.[CH3:8][C:9]([S:11][C:12]1[C:23]2[O:22][C:21]([CH3:25])([CH3:24])[O:20][C:19]=2[C:18]([C:26]([C:48]2[C:58]3[O:59][C:60]([CH3:63])([CH3:62])[O:61][C:57]=3[C:56]([S:64][C:65]([CH3:67])=[O:66])=[C:50]3[O:51][C:52]([CH3:55])([CH3:54])[O:53][C:49]=23)([C:28]2[C:38]3[O:39][C:40]([CH3:43])([CH3:42])[O:41][C:37]=3[C:36]([S:44][C:45]([CH3:47])=[O:46])=[C:30]3[O:31][C:32]([CH3:35])([CH3:34])[O:33][C:29]=23)O)=[C:17]2[C:13]=1[O:14][C:15]([CH3:69])([CH3:68])[O:16]2)=[O:10].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(#N)C>[CH3:67][C:65]([S:64][C:56]1[C:50]2[O:51][C:52]([CH3:54])([CH3:55])[O:53][C:49]=2[C:48]([CH:26]([C:18]2[C:19]3[O:20][C:21]([CH3:25])([CH3:24])[O:22][C:23]=3[C:12]([S:11][C:9]([CH3:8])=[O:10])=[C:13]3[O:14][C:15]([CH3:68])([CH3:69])[O:16][C:17]=23)[C:28]2[C:38]3[O:39][C:40]([CH3:42])([CH3:43])[O:41][C:37]=3[C:36]([S:44][C:45]([CH3:47])=[O:46])=[C:30]3[O:31][C:32]([CH3:34])([CH3:35])[O:33][C:29]=23)=[C:58]2[C:57]=1[O:61][C:60]([CH3:63])([CH3:62])[O:59]2)=[O:66]
Reactant: CC(=O)Sc1c2c(c(C(O)(c3c4c(c(SC(C)=O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(SC(C)=O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [I-]
Solvent: CC#N
Product: CC(=O)Sc1c2c(c(C(c3c4c(c(SC(C)=O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(SC(C)=O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2
Reaction time: 0.08 h
Yield: 83 %

Procedure:
NaI (0.15972 g, 1.1256 mmol) and trimethylsilyl chloride (0.142 mL, 1.1256 mmol) were stirred in acetonitrile (50 mL). Tris(8-methylcarbonylthio-2,2,6,6-tetramethylbenzo-[1,2-d:4,5-d']bis(1,3)dioxole-4-yl)methanol (0.1286 g, 0.1407 mmol, Example 49) was added in solid form and the color of the solution became brownish. Na2S2O4 (20 mL, sat.) was added after 60 minutes and the mixture was stirred 5 minutes before separation of the phases. The aqueous phase was extracted with diethyl ether (50 mL), and the combined organic phase was dried (MgSO4) and evaporated, yielding 0.105 g (0.1168 mmol, 83%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([Cl:16])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a suspension of 3-nitrobenzoic acid (6.5 g, 38.9 mmol) in DCM (50 ml) was added oxalyl chloride (5 ml, 58.1 mmol) and DMF (0.5 ml, 6.46 mmol), respectively. The resulting mixture was stirred at room temperature until a clear solution was formed. The solvent was removed under vacuum. 3-Nitrobenzoyl chloride thus obtained was dissolved in DCM (50 ml), Et3N (10.13 ml, 72.7 mmol) and thiomorpholine (5 g, 48.5 mmol) were added at 0° C. Reaction mixture was gradually allowed to reach to room temperature and stirred for 2 hrs. The reaction mixture was concentrated under vacuum and cold water was added to the residue, the solid obtained was filtered and dried under vacuum to give the product (9.2 gm).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2].N1C2C(=CC=CC=2)[CH:17]=N1.CO.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:17])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c2cc(C(=O)O)ccc12
Reactant: c1ccc2[nH]ncc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCc1n[nH]c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.35 g (7.1 mmol) of 3-ethyl-1H-indazol-6-yl-carboxylic acid, [Marfat, A., et al., “Indazole Derivatives and Their Use as Inhibitors of Phosphodiesterase Type IV and the Production of Tumor Necrosis Factor TNF, U.S. Pat. No. 6,262,040], 2.9 mL (71 mmol) of methanol, and 0.95 g (7.8 mmol) of DMAP in 60 mL of CH2Cl2 was added 1.5 g (7.8 mmol) of EDCI-HCl. This mixture was stirred at room temperature overnight, concentrated and the residue dissolved in 50 ML of ethyl acetate. The organic layer was successively washed with 40 mL of 1N HCl, 40 mL of water and 40 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography over silica gel using a gradient of 35% to 50% ethyl acetate in hexanes over 20 minutes as eluant to yield 860 mg (4.2 mmol) of methyl 3-ethyl-1H-indazol-6-yl-carboxylate. 1H-NMR (CDCl3) δ 11.7 (s, 1H), 8.18 (s, 1H), 7.73. (apparent q, 9.0 Hz, 2H), 3.94 (s. 3H), 3.03 (q, 7.5 Hz, 2H), 1.42 (t, 7.5 Hz, 3H).
Reaction SMILES: ClC1C=C(NN=C(Cl)S(C)(=O)=O)C=CC=1.IC1C=CC(N2CCC=C(N3CCOCC3)C2=O)=CC=1.C(N(CC)CC)C.[Cl:43][C:44]1[CH:45]=[C:46]([N:50]2[C:54]3(N4CCOCC4)[C:55](=[O:66])[N:56]([C:59]4[CH:64]=[CH:63][C:62]([I:65])=[CH:61][CH:60]=4)[CH2:57][CH2:58][CH:53]3[C:52]([S:73]([CH3:76])(=[O:75])=[O:74])=[N:51]2)[CH:47]=[CH:48][CH:49]=1>C1(C)C=CC=CC=1>[Cl:43][C:44]1[CH:45]=[C:46]([N:50]2[C:54]3[C:55](=[O:66])[N:56]([C:59]4[CH:60]=[CH:61][C:62]([I:65])=[CH:63][CH:64]=4)[CH2:57][CH2:58][C:53]=3[C:52]([S:73]([CH3:76])(=[O:75])=[O:74])=[N:51]2)[CH:47]=[CH:48][CH:49]=1
Reactant: CS(=O)(=O)C1=NN(c2cccc(Cl)c2)C2(N3CCOCC3)C(=O)N(c3ccc(I)cc3)CCC12
Agent: CS(=O)(=O)C(Cl)=NNc1cccc(Cl)c1
Agent: O=C1C(N2CCOCC2)=CCCN1c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1nn(-c2cccc(Cl)c2)c2c1CCN(c1ccc(I)cc1)C2=O
Temperature: 70 °C
Reaction time: 14 h
Yield: 64 %

Procedure:
The methanehydrazonoyl chloride (8.47 g, 31.7 mmol) and 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (12.17 g, 31.7 mmol) were combined in anhydrous toluene. The solution heated to 70° C. and triethylamine (13.2 mL, 95.1 mmol) was added dropwise. After the addition was complete the reaction was warmed to 90° C. and stirred at this temperature for 14 h. Analysis by LC/MS indicated formation of 1-(3-chloro-phenyl)-6-(4-iodo-phenyl)-3-methanesulfonyl-7a-morpholin-4-yl-1,3a,4,5,6,7a-hexahydro-pyrazolo[3,4-c]pyridin-7-one complete with less than 5% of 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one remaining. The solvent was removed in vacuo. To the viscous oil was added dichloromethane (50 mL) then Trifluoroacetic acid (30 mL) and heated to reflux for 4 h. The solvent was evaporated and the residue purified by flash column chromatography eluting with a gradient of hexane to 40% ethylacetate/hexane to give 10.65 g (64%) of 1-(3-chloro-phenyl)-6-(4-iodo-phenyl)-3-methanesulfonyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.[CH2:14]([O:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[CH3:15].Br[CH2:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29].Cl>C1COCC1.C(OCC)(=O)C>[CH2:14]([O:16][C:17]([C:19]1([CH2:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[CH3:15]
Reactant: CCC(CC)CBr
Reactant: CCOC(=O)C1CCCCC1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC(CC)CC)CCCCC1
Temperature: -65 °C
Reaction time: 0.33 h
Yield: 76.7 %

Procedure:
To a solution of diisopropylamine (2.37 g, 23.4 mmol) in THF (12 mL) 1.6 M n-BuLi in hexane (13.2 mL, 21.09 mmol) was added with stirring over 20 min at −65° C. The suspension was warmed up to −40° C. and then added via a teflon tube over 20 min to a stirred solution of cyclohexanecarboxylic acid ethyl ester (2.196 g, 14.1 mmol) in THF (20 mL) at −65° C. The resulting solution was stirred 1 h at −65° C., then 1-bromo-2-ethylbutane (3.714 g, 22.5 mmol) in THF (10 mL) was added at −65° C. over 20 min. The solution was stirred 1.5 h at −65° C. and then overnight without a cooling bath while slowly warming up to room temperature. At 5° C. ice-water (15 mL) was added, followed by 2N HCl (30 mL). The organic phase was diluted with ethyl acetate and washed with sat. aq. NaHCO3 and with aq. NaCl. The aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The crude product (3.4 g) was distilled at 50° C. (0.01 mbar) to give 2.6 g (77%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid ethyl ester as a colorless oil, purity 92.6% (GC area) (cyclohexanecarboxylic acid diisopropylamide as impurity: 3.8% in dist. product and 3.1% in crude product)
Reaction SMILES: BrCBr.Cl[Si](C)(C)C.[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18](I)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[Cl:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][N:23]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C=O)C.[Zn]>[Cl:21][C:22]1[N:23]=[CH:24][C:25]([CH:18]2[CH2:19][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:17]2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Clc1cc(I)ccn1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: BrCBr
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(c2ccc(Cl)nc2)C1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with zinc (2.54 g, 38.9 mmol), DMF (32 mL), and dibromomethane (736 mg, 4.24 mmol). After stirring at 70° C. for 10 min, the reaction mixture was cooled to room temperature, and chlorotrimethylsilane (423 mg, 3.89 mmol) was added. The resulting mixture was stirred at room temperature for 30 min, and a solution of 1-(tert-butoxycarbonyl)-3-iodoazetidine (9.31 g, 38.9 mmol) in DMF (32 mL) was added. After stirring at 40° C. for 1 h, a solution of 2-chloro-4-iodo-pyridine (10.0 g, 35.3 mmol) in DMF (16 mL) was added, followed by a solution of (dibenzylideneacetone)dipalladium(0) (1.62 g, 1.77 mmol) and tri(2-furyl)-phosphine (820 mg, 3.53 mmol) in DMF (16 mL). After stirring at 70° C. for 16, the reaction mixture was partitioned between saturated aqueous ammonium chloride (200 mL) and diethyl ether (200 mL). The layers were separated, and the aqueous phase was extracted with diethyl ether (200 mL). The organic extracts were combined, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford a 54% yield (5.42 g) of 117a as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 8.29 (d, 1H, J=2.5 Hz), 7.70 (dd, 1H, J=8.5, 2.5 Hz), 7.35 (d, 1H, J=8.5 Hz), 4.37 (t, 2H, J=8.5 Hz), 3.91 (dd, 2H, J=8.5, 4.5 Hz), 3.73 (m, 1H), 1.46 (s, 9H); MS (ESI+) m/z 269.0 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1 mL, 13.5 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (120 mg, 0.27 mmol) in dichloromethane (2 mL). After 1 h, the mixture was concentrated and saturated sodium bicarbonate was added. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 346.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:13][CH:12]3[C:10]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)([CH2:11]3)[CH2:9]2)=O)=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:8]2[CH2:13][CH:12]3[C:10]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)([CH2:11]3)[CH2:9]2)=[CH:21][CH:22]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CC2CC2(c2ccc(Cl)cc2)C1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Clc1ccc(CN2CC3CC3(c3ccc(Cl)cc3)C2)cc1

Procedure:
A 16.60 g portion of 3-(p-chlorobenzoyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane (prepared above) is dissolved in 160 ml of benzene and 55.5 g of sodium bis(2-methoxyethoxy)aluminum hydride (70% benzene solution) is added dropwise. The mixture is refluxed for 2 hours, cooled and quenched slowly with 10N sodium hydroxide. Water is added, the organic layer is separated and washed 3 times with water and then dried over sodium magnesium sulfate. Removal of the solvent yields an off-white solid, mp 88°-92° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>>[CH3:39][S:40]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCNCC4)CC3)cccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCN(S(C)(=O)=O)CC4)CC3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
2-Isopropyl-1H-benzoimidazole-4-carboxylic acid (1-piperidin-4-ylmethylpiperidin-4-ylmethyl)amide (40 mg, 0.1 mmol) was dissolved in N,N-dimethylforinamide (1.0 mL) at room temperature. To this solution was added N,N-diisopropylethylamine (0.175 mL, 1 mmol) followed by methanesulfonyl chloride (11.5 mg, 0.1 mmol). The mixture was stirred at room temperature for 16 h, then concentrated in vacuo and the residue purified by preparative reverse-phase HPLC to afford the bis trifluoroacetate salt of the title compound as a white solid (27.2 mg, 0.04 mmol, 40%). (m/z): [M+H]+ calcd for C24H37N5O3S 476.27; found 476.2. Retention time (anal. HPLC: 2-65% MeCN/H2O over 4 min)=1.66 min.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:16](OC)(=[O:27])[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.CC(C)([O-])C.[K+].Cl>CO.CN(C)C=O>[CH3:24][O:23][C:21]([C:20]1[CH:25]=[CH:26][C:17]([C:16](=[O:27])[CH2:14][C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:11]=2)=[O:15])=[CH:18][CH:19]=1)=[O:22]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: CCCCCOc1ccc(C(C)=O)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Reaction time: 3.5 h
Yield: 91.7 %

Procedure:
Dimethylformamide (485 l), p-pentyloxyacetophenone (30.3 kg) and dimethyl terephthalate (45.6 kg) were charged in 2000-liter reactor and stirred. To this mixture was added potassium tert-butoxide (24.7 kg) in several portions and, after that, a reaction was carried out at the inner temperature of 20 to 25° C. for 3.5 hours. After completion of the reaction, methanol (1210 l) was added to the reaction solution at 20 to 30° C. and then 6N hydrochloric acid (49 l) at 5 to 15° C. The mixture was stirred at room temperature for 1 hour, and the resulting appeared crystals were filtered and washed with methanol (152 l) and then water (152 l). The crystals were dried overnight in vacuo to give 1-(4-methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione (49.6 kg).