Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][C@H:18]2[CH2:38][CH2:37][C:20]3([O:24][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C@@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:21]3)[CH2:19]2)[C:13](=[O:16])[CH:14]=[CH2:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[O:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[O:45][CH2:46][C:47]1[S:51][C:50]([CH:52]=[O:53])=[N:49][CH:48]=1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][C@H:18]2[CH2:38][CH2:37][C:20]3([O:21][C@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:23]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:24]3)[CH2:19]2)[C:13](=[O:16])[CH2:14][CH2:15][C:52]([C:50]2[S:51][C:47]([CH2:46][O:45][CH:40]3[CH2:41][CH2:42][CH2:43][CH2:44][O:39]3)=[CH:48][N:49]=2)=[O:53])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: C=CC(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: O=Cc1ncc(COC2CCCCO2)s1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)cc1Cl
Temperature: 25 °C
Yield: 56.1 %

Procedure:
To a solution of 4-[3-chloro-4-(methylsulfonyl)phenyl]-5-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]pent-1-en-3-one (525 mg) in ethanol (3 mL) were added 5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole-2-carbaldehyde (259 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (28.3 mg) and triethylamine (57 μL), and the mixture was stirred with heating under reflux for 1.5 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (416 mg, yield 56%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:3])=[O:2].[C:13](Cl)(=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[N+:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)([O-:3])=[O:2]
Reactant: CCCCCCCC(=O)Cl
Reactant: O=[N+]([O-])CCCc1ccccc1
Product: CCCCCCCC(=O)c1ccc(CCC[N+](=O)[O-])cc1

Procedure:
The title compound was prepared from 3-nitropropylbenzene (16) and octanoyl chloride, according to example 2, affording compound (17) with 73% yield, which was used at the next step without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]2[C:6]3[C@@H:7]([NH:19][CH2:20][CH2:21]2)[CH2:8][C:9]2[C:14]([C:5]=3[C:4]=1[O:24][CH3:25])=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2.[CH2:26]=O.[BH4-].[Na+]>CO>[CH3:26][N:19]1[C@H:7]2[CH2:8][C:9]3[C:14](=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=3)[C:5]3[C:6]2=[C:22]([CH:23]=[C:3]([O:2][CH3:1])[C:4]=3[O:24][CH3:25])[CH2:21][CH2:20]1
Reactant: C=O
Reactant: COc1cc2c(cc1OC)-c1c(OC)c(OC)cc3c1[C@H](C2)NCC3
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1OC)-c1c(OC)c(OC)cc3c1[C@H](C2)N(C)CC3
Yield: 90 %

Procedure:
Norglaucine (1.90 g, 5.2 mmol), methanol (50 ml) and 35.5% formaldehyde (6.0 ml) were successively placed in a 250 ml reaction bottle. To the mixture, NaBH4 was added portionwise (total 2.0 g, 52 mmol) at room temperature while stirring. The mixture was then reacted for 6 hours, concentrated under reduced pressure, and fractionated between water (150 ml) and chloroform (150 ml×3). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to produce a solid which was purified by column chromatography (silica gel, with chloroform as the eluant) to obtain solid product glaucine (1.78 g, 90%). Physical data were as follows: mp: 112-114° C. (diethyl ether); [α]D24 +120.0° (c=0.30, MeOH); 1H NMR (CDCl3, 400 MHz) δ 8.06 (1H, s, H-11), 6.75 (1H, s, H-8), 6.56 (1H, s, H-3), 3.91 (3H, s, 9-OMe), 3.88 (3H, s, 10-OMe), 3.86 (3H, s, 2-OMe), 3.64 (3H, s, 1-OMe), 2.54 (3H, s, N-Me).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([NH:21][C:22]([C:24]2[N:25]=[C:26]([CH2:29][N:30]3[CH2:35][C@H:34]([CH3:36])[O:33][C@H:32]([CH3:37])[CH2:31]3)[S:27][CH:28]=2)=[O:23])[CH:3]=1.[CH3:38][O:39][C:40]1[C:45]([NH2:46])=[CH:44][C:43](B2OC(C)(C)C(C)(C)O2)=[CH:42][N:41]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[NH2:46][C:45]1[CH:44]=[C:43]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][N:8]3[S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)(=[O:12])=[O:13])=[C:4]([NH:21][C:22]([C:24]3[N:25]=[C:26]([CH2:29][N:30]4[CH2:35][C@H:34]([CH3:36])[O:33][C@H:32]([CH3:37])[CH2:31]4)[S:27][CH:28]=3)=[O:23])[CH:3]=2)[CH:42]=[N:41][C:40]=1[O:39][CH3:38]
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(NC(=O)c4csc(CN5C[C@@H](C)O[C@@H](C)C5)n4)cc(Br)cc32)cc1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cnn(S(=O)(=O)c4ccc(C)cc4)c3c2)cc1N
Temperature: 80 °C
Yield: 44.3 %

Procedure:
N-{6-Bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazol-4-yl}-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamide (4 g), 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine (1.8 g), sodium carbonate (2.8 g) and Pd(dppf)Cl2 (0.48 g) were weighed to a 500 ml round-bottomed flask and 1,4-dioxane (150 ml) and water (150 ml) were added. The reaction was heated to 80° C. for 2 hours. The reaction was cooled then passed through a 10 g silica cartridge, washing with DCM:methanol. The reaction was concentrated to leave only the aqueous phase. DCM was added and the product extracted. The DCM was passed through a hydrophobic frit, then evaporated to dryness. The residue was purified on silica chromatography eluting with 0-6% methanol in DCM over 30 mins. Product containing fractions were combined and evaporated to dryness. The residue was repurified by silica chromatography using a gradient of 1.5-5% methanol in DCM over 30 mins. Product containing fractions were combined and evaporated to dryness to give title compound (1.9 g).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[O:24])=[C:18]([O:33][CH3:34])[CH:17]=2)=[CH:9][N:8]=1)C.[OH-].[Na+]>C(O)C>[CH3:34][O:33][C:18]1[CH:17]=[C:16]([CH2:15][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:36])=[O:3])=[N:8][CH:9]=2)=[O:35])[CH:21]=[CH:20][C:19]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])=[O:24]
Reactant: CCOC(=O)CCc1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CC(=O)Nc2ccc(CCC(=O)O)nc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 50 °C
Reaction time: 7 h
Yield: 54.7 %

Procedure:
A stirred mixture of 3-(5-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}pyrid-2-yl)-propanoic acid ethyl ester [0.62 g, Reference Example 3(a)] and ethanol (40 ml) was treated with 4% aqueous sodium hydroxide solution (3.2 ml) and then heated to 50° C. After stirring at 50° C. for 7 hours, the reaction mixture was cooled and then left to stand at room temperature over night. The reaction mixture was partially concentrated in vacuo, washed with diethyl ether and then acidified to pH 1.0 by addition of hydrochloric acid (1M). The resultant white solid was collected, washed with water and then dried in vacuo. Recrystallisation from aqueous acetonitrile gave the title compound (0.32 g) as a white crystalline solid, m.p. 191-192° C. (with decomposition). MS: MH+ 463.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[C:19](=O)[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:27]1([NH2:30])[CH2:29][CH2:28]1.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCl.C(#N)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[CH:19]([NH:30][CH:27]4[CH2:29][CH2:28]4)[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH:14]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3NC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
A solution of4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-benzoic acid ethyl ester (Intermediate 14, 0.14 g, 0.4 mmol) in 3 mL of dichloromethane and 2 mL of acetonitrile was treated with cyclopropyl amine(1 mL, 14.45 mmol). After 5 minutes, acetic acid (1 mL) was added followed by sodium cyanoborohydride (0.13 g, 2 mmol). The reaction was stirred overnight at ambient temperature. It was then diluted with water and saturated aqueous sodium carbonate solution and extracted with dichloromethane (×2). The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over silica gel (230-400 mesh) using 20% ethyl acetate in hexane as the eluent afforded the title compound (0.1 g, 62%) as a pale yellow solid.
Reaction SMILES: [C:1]([Cl:4])([Cl:3])=[CH2:2].[C:5](Cl)(=[O:9])[CH:6]([CH3:8])[CH3:7]>>[Cl:3][C:1]([Cl:4])=[CH:2][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: C=C(Cl)Cl
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)C=C(Cl)Cl

Procedure:
condensing vinylidene chloride with isobutyryl chloride in the presence of a Lewis acid to produce 1,1-dichloro-4-methyl-1-penten-3-one,
Reaction SMILES: [CH:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>[Zn]>[OH:7][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCCC=O
Agent: [Zn]
Product: CCCCCC(O)CC(=O)OC(C)(C)C
Yield: 77.2 %

Procedure:
The reaction of hexanal (720 mg) and tert-butyl bromoacetate (2.265 g) was carried out under the presence of zinc (850 mg) according to similar manner to that of Preparation 1-(1) to afford an oil of tert-butyl 3-hydroxyoctanoate (1.2 g).
Reaction SMILES: [F:1][CH:2]([P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[F:3].[Li+].CC([N-]C(C)C)C.[I:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]I>C1COCC1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C>[F:1][C:2]([P:4](=[O:11])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])([F:3])[CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][I:20]
Reactant: ICCOCCOCCI
Reactant: CCOP(=O)(OCC)C(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(F)(F)CCOCCOCCI
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethyl difluoromethylphosphonate (1.0 equiv.) in THF (0.8 M) at −78° C. was slowly added a solution of LDA (2 M, 1.1 equiv.) in heptane/THF/ethylbenzene, and the mixture was vigorously stirred for 30 minutes. In a separate reaction flask, a solution of 1,2-bis(2-iodoethoxy)ethane (1.0 equiv.) in THF (0.8M) was cooled to −78° C. To this solution was transferred, by cannula, the freshly prepared alkyl lithium solution and the reaction mixture was allowed to stir for 1 hour at −78° C. At this point, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was then quenched with a 1 M aqueous solution of HCl. The resulting mixture was transferred to a separatory funnel and washed with CH2Cl2 three times. The combined organic layers were dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using CH2Cl2 to provide diethyl 1,1-difluoro-3-(2-(2-iodoethoxy)ethoxy)propylphosphonate (I-1) as a yellow oil. 1H NMR (CDCl3): δ 4.23-4.31 (m, 4H), 3.75-3.80 (m, 4H), 3.60-3.67 (m, 4H), 3.26 (t, 2H), 2.33-2.50 (m, 2H), 1.38 (t, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl.Cl[CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31].O>CN(C)C=O>[CH2:28]([N:29]([CH2:32][CH3:33])[CH2:30][CH2:31][N:15]([C@@H:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11]1)[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl [(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate (6.0 g) was dissolved in 50 ml of N,N-dimethylformamide and, after addition of sodium hydride (1.1 g), stirred at room temperature for 30 minutes, and subsequently chlorethyldiethylamine hydrochloride (4.1 g) was added. The mixture was subsequently stirred at room temperature with exclusion of moisture for 4 hours. The reaction was stopped by adding water (50 ml), and this was followed by extraction with ethyl acetate (3×50 ml) and drying of the combined organic phases over magnesium sulfate, and removal of the solvent. This resulted in the product with the molecular weight of 406.53 (C21H34N4O4); MS (ESI): 407 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11]O.O=S(Cl)[Cl:15]>C(Cl)Cl>[Cl:15][CH2:11][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: Cn1c(CO)nc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cn1c(CCl)nc2ccccc21

Procedure:
A solution of (1-methyl-1H-benzoimidazol-2-yl)-methanol (500 mg, 3.08 mmol) and SOCl2 (1.1 mL) in DCM (2 mL) was stirred at room temperature for 3 hours. After evaporation of the solvents, 2-chloromethyl-1-methyl-1H-benzoimidazole (556 mg, 3.08 mmol) was obtained and was used without any purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1.C(=O)(O)[O-].[K+].[C:33](OCC)(=[O:35])[CH3:34]>C(OC(=O)C)(=O)C.Cl(O)(=O)(=O)=O>[C:33]([N:11]1[C:10]2[CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:20]3[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=3[C:18]=2[C:17]2[CH:16]=[C:15]([O:26][CH3:27])[CH:14]=[CH:13][C:12]1=2)(=[O:35])[CH3:34]
Reactant: COc1ccc2[nH]c3cc(-c4ccccc4Cl)c4c(c3c2c1)C(=O)NC4=O
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2C(C)=O)C(=O)NC3=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of carbazole (33) (45 mg, 0.12 mmol) prepared as described in example 79 in acetic anhydride (4.0 mL) was added 35% perchloric acid (2 drops). The resulting solution was stirred at room temperature for 30 minutes before being poured onto ice water, basified by the addition of solid potassium bicarbonate and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (2:3), followed by trituration from ethyl acetate gave acetamide (338) (40 mg, 80%) as a pale yellow powder, mp 277–280° C. 1H NMR δ [(CD3)2SO] 11.46 (br s, 1H), 8.74 (d, J=2.8 Hz, 1H), 8.53 (s, 1H), 8.17 (d, J=9.2 Hz, 1H), 7.60 (m, 1H), 7.54–7.47 (m, 3H), 7.32 (dd, J=9.2, 2.8 Hz, 1H), 3.93 (s, 3H), 2.91 (s, 3H). Found: C, 65.50; H, 3.49; N, 6.61. C23H15ClN2O4.1/4H2O requires: C, 65.26; H, 3.69; N, 6.62.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH3:22])[CH2:5]1)(=[O:3])[NH2:2].Br[CH:24]([CH3:34])[C:25](=O)[C:26]([O:28][CH2:29][CH2:30]CC)=[O:27].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[O:3][C:24]([CH3:34])=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH3:22])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: CCCCOC(=O)C(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)oc1C
Yield: 78.2 %

Procedure:
The same operation as in Example (103c) was performed using cis(±)-benzyl (1-carbamoyl-3-methoxypiperidin-4-yl)carbamate obtained in Example (103b) (1.97 g, 6.4 mmol), butyl 3-bromo-2-oxobutanoate obtained in Example (106a) (10 g, 42.3 mmol), sodium bicarbonate (1.26 g, 15 mmol) and THF (40 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/10, 1/2, 1/1, 2/1, 4/1) to obtain 2.09 g of the title compound as a yellow oily substance (73%).
Reaction SMILES: [CH:1]1([CH:7](O)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1C(C)=CC=CC=1C.C(N(C(C)C)CC)(C)C.Cl.Cl.[F:53][C:54]1[CH:55]=[C:56]([C:60]2([CH2:66][CH2:67][N:68]3[C@H:73]4[CH2:74][CH2:75][C@@H:69]3[CH2:70][CH:71]([N:76]3[C:80]5[CH:81]=[CH:82][CH:83]=[CH:84][C:79]=5[N:78]=[C:77]3[CH3:85])[CH2:72]4)[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)[CH:57]=[CH:58][CH:59]=1>C(Cl)Cl>[CH:1]1([CH:7]([N:63]2[CH2:62][CH2:61][C:60]([C:56]3[CH:57]=[CH:58][CH:59]=[C:54]([F:53])[CH:55]=3)([CH2:66][CH2:67][N:68]3[C@H:69]4[CH2:75][CH2:74][C@@H:73]3[CH2:72][CH:71]([N:76]3[C:80]5[CH:81]=[CH:82][CH:83]=[CH:84][C:79]=5[N:78]=[C:77]3[CH3:85])[CH2:70]4)[CH2:65][CH2:64]2)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)C(O)C1CCCCC1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCNCC1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1cccc(C)n1
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(C(=O)OCc2ccccc2)C2CCCCC2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 19.5 %

Procedure:
To a −78° C. solution of benzyl cyclohexyl(hydroxy)acetate (61 mg, 0.25 mmol) and 4A molecular sieves in 1.2 mL CH2Cl2 was added trifluoromethanesulfonic anhydride (0.05 mL, 0.30 mmol). After stirring for 10 min at this temperature, 2,6-lutidine (0.06 mL, 0.49 mmol) was added. After 15 min, diisopropylethylamine (0.09 mL, 0.49 mmol) was added and after another 15 min, a solution of 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (153 mg, 0.30 mmol) in 1 mL CH2Cl2 was added. The reaction mixture was stirred at −78° C., then allowed to warm to room temperature overnight, washed with saturated aqueous NaHCO3, and purified by preparatory TLC using 5% MeOH in CHCl3 to afford benzyl cyclohexyl(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetate (33 mg, 20%) as an oil. 1H NMR (400 MHz, CDCl3), δ 7.68-7.64 (m, 1H), 7.33-7.23 (m, 7H), 7.20-7.12 (m, 2H), 7.05 (m, 1H), 6.97 (m, 1H), 6.89 (m, 1H), 5.05 (ABq, 2H, J=12.3 Hz), 4.61 (m, 1H), 3.26-3.18 (m, 2H), 2.92 (d, 1H, J=10.4 Hz), 2.70 (m, 1H), 2.64-2.50 (m, 2H), 2.57 (s, 3H), 2.46-2.30 (m, 3H), 2.12-0.81 (m, 25H); ESI-MS 677 (M+H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Sn:13](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17]>CCOC(C)=O>[CH2:22]([Sn:13]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:18][CH2:19][CH2:20][CH3:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Temperature: -78 °C
Yield: 59.8 %

Procedure:
n-BuLi (200 mL, 0.5 mol) was added dropwise to 2-bromopyridine (79 g, 0.5 mol) under N2 with continuous stirring at −78° C. This solution was stirred at −78° C. for 1 h and (Bu)3SnCl (178.8 g, 0.55 mol) was added dropwise to the reaction solution. After addition, the reaction solution was stirred at −78° C. for 1 h and room temperature for 1 h. TLC (petroleum:EtOAc=10:1) indicated the reaction was complete. The reaction solution was quenched with sat. NH4Cl and extracted with EtOAc (350 mL×3). The combined extracts were washed with water, dried over Na2SO4, concentrated and purified by chromatography, eluted with (petroleum:EtOAc=10:1) to give title compound (110 g, 60%) as a yellow liquid.
Reaction SMILES: [CH:1]([C:3]1[CH:34]=[CH:33][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16](=[O:32])[C@@H:17]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:18][C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH2:12][CH2:11]3)[S:9][C:5]=2[CH:4]=1)=O.[CH:35]1([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:35]1([NH:40][CH2:1][C:3]2[CH:34]=[CH:33][C:6]3[N:7]=[C:8]([N:10]4[CH2:11][CH2:12][N:13]([C:16](=[O:32])[C@@H:17]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:18][C:19]5[S:20][CH:21]=[CH:22][CH:23]=5)[CH2:14][CH2:15]4)[S:9][C:5]=3[CH:4]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(C=O)cc3s2)CC1
Reactant: NC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(CNC4CCCC4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-Butyl 1-(4-(6-formylbenzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (45 mg), cyclopentylamine (12 mg), and sodium triacetoxyborohydride (29 mg) were combined in DCM (1 mL), and the resulting mixture stirred at room temperature overnight, then heated to reflux for 24 hours. The resulting mixture was then cooled to room temperature, quenched with saturated aqueous sodium bicarbonate, extracted with DCM, and chromatographed (0 to 5% MeOH in DCM) to yield (S)-tert-butyl 1-(4-(6-((cyclopentylamino)methyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate as a colorless oil.