Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH2:26][O:27][CH3:28])[N:9]=2)=[CH:4][CH:3]=1.CC1(C)O[C@H](CO)CO1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@:10]3([CH2:25][C@@H:24]3[CH2:26][O:27][CH3:28])[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Agent: CC1(C)OC[C@@H](CO)O1
Product: COC[C@H]1C[C@@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12

Procedure:
The above employed synthesis scheme was identical to that set forth for Compound 202, except that (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol was used as starting material and the indicated enantiomers were produced at each step. LRMS (M+H)+: 413 m/z. 1H NMR (two conformers detected in ˜1:1 ratio) (400 MHz, DMSO-d6) δ 7.38-7.56 (m, 4H), 3.82 (dd, J=7.32, 10.76 Hz, 0.5H), 3.71 (dd, J=6.87, 10.99 Hz, 0.5H), 3.39 (s, 1.5H), 3.21 (dd, J=6.41, 10.76 Hz, 0.5H), 3.04 (dd, J=7.44, 10.87 Hz, 0.5H), 2.96 (s, 1.5H), 2.60 (s, 3H), 2.39 (s, 1.5H), 2.38 (s, 1.5H), 2.16-2.26 (m, 0.5H), 2.05 (dd, J=5.26, 9.61 Hz, 0.5H), 1.58 (s, 1.5H), 1.54 (s, 1.5H), 1.43-1.52 (m, 0.5H), 1.33-1.39 (m, 0.5H), 1.03 (dd, J=5.26, 9.38 Hz, 0.5H), 0.60 (t, J=6.07 Hz, 0.5H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:13]=2)=[CH:5][CH:6]=1.[OH-].[K+].[I-].[K+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:25]([N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]1[CH:12]=[CH:13][C:8]([N:7]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[CH:9][CH:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1ccc(CN(c2ccccc2)c2ccc(N(Cc3ccccc3)c3ccccc3)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A solution of N,N'-diphenyl-p-phenylenediamine (26 g, 0.1 mol) in toluene (400 ml) is treated sequentially with powdered potassium hydroxide (19.3 g, 0.3 mol), potassium iodide (1.7 g, 0.01 mol) and tetrabutylammonium bromide (1.6 g, 0.005 mol). The resulting mixture is vigorously stirred while benzyl chloride (27.9 g, 0.22 mol) is added dropwise. The mixture is slowly warmed to 90° C. over a one-hour period and then held there for four hours. The mixture is allowed to cool and methylene chloride (100 ml) is added. The resulting mixture is filtered and concentrated to a solid that is washed with water and dried. The title compound is obtained in a yield of 24.8 g (56%) as a tan solid melting at 145°-150° C.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]1([CH2:43]O)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:43][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[C:5]1=[O:13])([CH3:3])=[CH2:2]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: OCc1cccc2ccccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C)n1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a solution of 1-isopropenylbenzimidazolone (1.0 g, 5.7 mmol) in dry THF (80 mL) are added triphenylphosphine (1.8 g, 6.9 mmol) and naphthalen-1-yl-methanol (1.1 g, 6.9 mmol). Then diisopropyl azodicarboxylate (1.4 mL, 6.9 mmol) is added drop wise into the above solution at room temperature. The mixture is stirred for 16 hrs and then the solvent is removed under vacuum. The residue is purified by flash column chromatography using 10% EtOAc in hexanes to give 1.6 g (89%) of 1-isopropenyl-3-naphthalen-1-ylmethyl-1,3-dihydro-benzimidazol-2-one.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:6][C:5]([C:19]2[CH:20]=[C:21]([C:25]([NH:28][S:29]([CH2:32][C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:30])([CH3:27])[CH3:26])[CH:22]=[CH:23][CH:24]=2)=[N:4]1)[CH3:2].C(Cl)Cl.C1C(=O)N([I:47])C(=O)C1>CCOC(C)=O>[CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[C:6]([I:47])[C:5]([C:19]2[CH:20]=[C:21]([C:25]([NH:28][S:29]([CH2:32][C:33]([F:36])([F:34])[F:35])(=[O:30])=[O:31])([CH3:27])[CH3:26])[CH:22]=[CH:23][CH:24]=2)=[N:4]1)[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)c(I)c1Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-[2-(3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)propan-2-yl]-2,2,2-trifluoroethanesulfonamide (560 mg, 10.5 mmol) and DCM (6.97 mL) was cooled to 0° C., treated with NIS (706 mg, 3.14 mmol) in a single portion. The mixture was protected from light and allowed to warm to rt as it was stirred overnight. The reaction was diluted with EtOAc and washed with water 2×, sat. aq. NaHCO3, brine, dried (MgSO4) and concentrated to afford a white solid purified via MPLC, 25 g silica, 10-60% EtOAc in heptanes to afford a white solid: MS: cal'd 662 (MH+), exp 662 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[Cl:11][C:12]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:13]=1[C:14]([N:16]=[C:17]=[O:18])=[O:15]>C(Cl)Cl>[Cl:11][C:12]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:13]=1[C:14]([NH:16][C:17]([NH:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1)=[O:18])=[O:15]
Reactant: Nc1noc2ccccc12
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: ClCCl
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1noc2ccccc12

Procedure:
3-Aminobenzisoxazole (300 grams) and 2,6-dichlorobenzoyl isocyanate (600 grams) in 50 ml. methylene chloride were stirred at room temperature for one hour. The solvent was then evaporated and the precipitate recrystallized from ethanol. The identity of the product was determined by NMR and IR analysis, yield 500 mg., m.p.=212°-215° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][S:26][C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CSc3ccc(C)cc3)c(C)o2)cc1
Yield: 77.5 %

Procedure:
A solution of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (6 g, 22.64 mmol, 1.00 equiv), 4-methylbenzenethiol (4.2 g, 33.87 mmol) and cesium carbonate (8.8 g, 26.99 mmol, 1.19 equiv) in N,N-dimethylformamide (120 mL) was stirred under nitrogen overnight at 50° C. The reaction mixture was diluted with 100 mL of water and extracted with 3×150 mL of ethyl acetate. The combined organic layers was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was triturated with 2×50 mL of hexane. The solid was collected by filtration and dried in vacuum to yield 6.2 g (78%) of methyl 4-(5-methyl-4-(p-tolylthiomethyl)oxazol-2-yl)benzoate as a yellow solid. LC-MS: (ES, m/z): 395 [M+CH3CN+H]+, 354 [M+H]+, 271, 203, 126, 120.
Reaction SMILES: OC(O)CCC[C:6](=[N:8][C:9]1[C:10]2[N:11]=[CH:12][N:13]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@H:14]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]1[OH:16])C.CO.O.[C:31]([OH:34])(=[O:33])[CH3:32]>>[OH:33][CH:31]([OH:34])[CH2:32][CH2:6][NH:8][C:9]1[C:10]2[N:11]=[CH:12][N:13]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@H:14]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]1[OH:16]
Reactant: CC(=O)O
Reactant: CC(CCCC(O)O)=Nc1ncnc2c1ncn2[C@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CO
Solvent: O
Product: OC[C@H]1O[C@H](n2cnc3c(NCCC(O)O)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 48 h

Procedure:
The title compound was prepared with material from Example 6, (S)-N6 -[Dihydroxypropylisopropylidene]adenosine (2.3 g, 6 mmol). This was placed in 20% acetic acid in 1:1 methanol:water (100 ml), and stirred at ambient temperature for 22 hours. After removal of solvents, the residue was treated with acetone and the resulting percipitate filtered and dried in vacuo. This was then redissolved in 15% acetic acid, 1:1 water:methanol and stirred another 48 hours. Removal of solvents and vacuum drying at 85° yielded 0.77 g final product. m.p. 231°-5°
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.Cl[C:15]1[N:24]=[C:23]2[C:18]([C:19](=[O:32])[C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][N:22]2C=C)=[CH:17][C:16]=1[F:33].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:15]2[N:24]=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][NH:22]3)=[CH:17][C:16]=2[F:33])[CH2:3]1
Reactant: C=Cn1cc(C(=O)OCC)c(=O)c2cc(F)c(Cl)nc21
Reactant: NC1CCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1c[nH]c2nc(N3CCC(N)C3)c(F)cc2c1=O
Yield: 87 %

Procedure:
To a cooled solution of 3-aminopyrrolidine (3.6 g) and triethylamine (4.2 g) in 100 ml of chloroform was added a solution of ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylate (4.15 g) in 50 ml of chloroform over a period of 40 minutes with stirring. The reaction mixture was kept under ice-cooling for one hour and then stirred for 4 hours at room temperature. To this mixture was added a mixture of water (50 ml) and 2 N sodium hydroxide (20 ml). The chloroform layer was separated from the reaction mixture, washed with water, and dried over anhydrous sodium sulfate. The chloroform was distilled off and the residue was triturated with ethyl acetate (20 ml). The resulting solid was collected and recrystallized from ethyl acetate to give 3.9 g of ethyl 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (ethyl ester of the compound 1) m.p. 139°-141° C.
Reaction SMILES: C1(C)C=CC([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=CC=1.I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[Na])(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:19]1([CH3:20])[CH:18]=[CH:17][CH:22]=[CH:21][C:14]=1[C:11]1[CH:10]=[CH:9][C:8]([NH2:7])=[CH:13][CH:12]=1
Reactant: Ic1ccccc1
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Agent: CC(C)(C)O[Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Cc1ccccc1-c1ccc(N)cc1

Procedure:
10.0 g (50.7 mmols) of N,N-di(p-toluyl)amine (31b), 10.3 g (50.7 mmols) of 4-iodobenzene, 5.85 g (60.8 mmols) of t-BuONa, 300 mg (1.34 mmols) of Pd(CH3CO)2 and 1.50 g (5.71 mmols) of triphenylphosphine were dissolved in xylene and refluxed in an atmosphere of nitrogen for 4 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][N:4]=1.C([Li])CCC.[CH2:23]=[O:24]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:23][OH:24])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][N:4]=1
Reactant: COc1ccc(-c2cnc(OC)cc2C)cc1
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc(OC)cc2CCO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 6.2 %

Procedure:
According to Scheme 30 Step 2: To a stirred solution of 2-methoxy-5-(4-methoxyphenyl)-4-methylpyridine (1 eq, 10.0 mmol, 2.30 g) in anhydrous THF (66 mL) at −78° C. under argon was added dropwise butyl lithium (2.5M, 1.5 eq, 15.1 mmol, 6.0 mL). The reaction mixture was stirred for one hour and then allowed to warm slowly to 0° C. and stirred at 0° C. for a further 30 minutes. The reaction mixture was then cooled to −78° C. and paraformaldehyde (6.07 g) was added. The reaction mixture was then allowed to warm to room temperature and was stirred for 2 hours. The reaction was quenched with saturated aqueous NH4Cl (30 mL), diluted with AcOEt and the aqueous phase was extracted (×3). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure. HCl 3M (15 mL) was added to the solution of the crude residue diluted in acetonitrile (10 mL). The reaction mixture was stirred for 2 hours at 60° C. The aqueous phase was extracted with Et2O, then neutralized with NaHCO3 (40 mL). The aqueous phase was extracted with CH2Cl2. The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 20 g SiO2) using CH2Cl2/AcOEt (99/1) as the eluent to afford 2-(2-methoxy-5-(4-methoxyphenyl)pyridin-4-yl)ethanol (0.62 mmol, 0.16 g, 6%) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[O:33]1[CH2:37][CH2:36][CH:35]([C:38](Cl)=[O:39])[CH2:34]1>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:38]([CH:35]3[CH2:36][CH2:37][O:33][CH2:34]3)=[O:39])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: O=C(Cl)C1CCOC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3CCOC3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, tetrahydrofuran-3-carbonyl chloride (26 mg, 197 μmol, 3 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 250×30 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (21.1 mg, 62% of theory).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:34])[C:18]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:33])[C:28]([O:30]CC)=[O:29])[CH2:23][CH2:22]2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:34])[C:18]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:33])[C:28]([OH:30])=[O:29])[CH2:23][CH2:22]2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N1CCC(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCN(C(=O)C(=O)O)CC2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.6 %

Procedure:
A mixture of ethyl [4-({[4-(2-tert-butylphenyl)piperazin-1-yl](oxo)acetyl}amino)piperidin-1-yl](oxo)acetate (Example 185, 0.24 g, 0.51 mmol) and 1 M LiOH solution (5 mL, 5.0 mmol) in tetrahydrofuran (5 mL) was stirred at 0° C. for 1.5 h. The reaction mixture was acidified with 1 M HCl solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.21 g, 91%) as a white powder.
Reaction SMILES: [CH2:1]([C:3]([O:9][CH3:10])([CH2:7][CH3:8])[C:4]([OH:6])=[O:5])[CH3:2].[Si:11]([O:18][C@H:19]1[CH2:28][C@H:27](O)[C@H:26]2[C:21]([CH:22]=[CH:23][C@H:24]([CH3:47])[C@@H:25]2[CH2:30][CH2:31][C@H:32]2[O:37][C:36](=[O:38])[CH2:35][C@H:34]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:33]2)=[CH:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>>[Si:11]([O:18][C@H:19]1[CH2:28][C@H:27]([O:5][C:4](=[O:6])[C:3]([CH2:7][CH3:8])([O:9][CH3:10])[CH2:1][CH3:2])[C@H:26]2[C:21]([CH:22]=[CH:23][C@H:24]([CH3:47])[C@@H:25]2[CH2:30][CH2:31][C@H:32]2[O:37][C:36](=[O:38])[CH2:35][C@H:34]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[CH2:33]2)=[CH:20]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: CCC(CC)(OC)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCC(CC)(OC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 45.3 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 1.28 g of 2-ethyl-2-methoxybutyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 558 mg of the title compound as a colorless foam.
Reaction SMILES: O.[CH3:2][C:3]1([CH3:30])[O:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[C:16]([CH3:17])=[CH:15][N:14]=[C:13]([CH2:18][S:19][C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)[C:12]=2[CH3:29])[CH2:5][O:4]1.C(N(CC)C(C)C)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1.C(=O)([O-])[OH:52].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C1(C)C=CC=CC=1>[CH3:2][C:3]1([CH3:30])[O:4][CH2:5][CH:6]([CH2:9][O:10][C:11]2[C:16]([CH3:17])=[CH:15][N:14]=[C:13]([CH2:18][S:19]([C:20]3[NH:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)=[O:52])[C:12]=2[CH3:29])[CH2:7][O:8]1
Reactant: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Reactant: O=C([O-])O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)c1ccccc1
Solvent: O
Product: Cc1cnc(CS(=O)c2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 81.1 %

Procedure:
A toluene (dehydrated) (2.96 ml)-water (3.09 μl, 0.172 mmol) solution of the 2-(((4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (591 mg, 1.43 mmol) separately obtained in the same manner as described in the steps (11a) to (11g) of Example 11 and L-(+)-diethyl tartrate (108 μl, 0.629 mmol) was stirred at 50° C. for 5 minutes in a nitrogen atmosphere. Titanium (IV) isopropoxide (84.4 μl, 0.286 mmol) was added and the resultant mixture was stirred for one hour in the same conditions. After the mixture was cooled to room temperature and N,N-diisopropylethylamine (79.7 μl, 0.458 mmol) was added, the resultant mixture was cooled to 0° C. After cumene hydroperoxide (816 μl, 4.42 mmol as the content was regarded as 80%) was added dropwise for 10 minutes at 0° C. to 1° C., the mixture was stirred for 3 hours and 10 minutes in the same conditions. After a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 20 g, elution solvent: dichloromethane, dichloromethane/methanol=20/1). The fractions containing the title compound were collected with ethyl acetate and concentrated to obtain the title compound (498 mg, yield: 81.1%) as a colorless foam.
Reaction SMILES: Cl[C:2]([O:5]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.N1C=CC=CC=1.Cl.C(OCCNC)(=O)C1C=CC=CC=1.[C:33]([O:41][CH2:42][CH2:43][N:44]([C:46]([N:48]1[C:52]2[CH:53]=[C:54](OC)[CH:55]=[CH:56][C:51]=2[N:50]=[C:49]1[S:59]([CH2:61][C:62]1[C:67]([CH3:68])=[C:66]([O:69][CH3:70])[C:65]([CH3:71])=[CH:64][N:63]=1)=[O:60])=[O:47])[CH3:45])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.C(N(CC)CC)C>[C:33]([O:41][CH2:42][CH2:43][N:44]([C:46]([N:48]1[C:52]2[CH:53]=[CH:54][C:55]([O:5][CH3:2])=[CH:56][C:51]=2[N:50]=[C:49]1[S:59]([CH2:61][C:62]1[C:67]([CH3:68])=[C:66]([O:69][CH3:70])[C:65]([CH3:71])=[CH:64][N:63]=1)=[O:60])=[O:47])[CH3:45])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)n(C(=O)N(C)CCOC(=O)c3ccccc3)c2c1
Agent: CNCCOC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc2c(c1)nc(S(=O)Cc1ncc(C)c(OC)c1C)n2C(=O)N(C)CCOC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of bis(trichloromethyl)carbonate (0.344 g) in tetrahydrofuran (10 mL) was added dropwise a solution of pyridine (0.281 mL) in tetrahydrofuran (5 mL) under ice-cooling, and stirred for 30 minutes at 0° C. To the reaction solution was added 2-(methylamino)ethyl benzoate hydrochloride (0.750 g) obtained in Reference Synthetic Example 5. A solution of triethylamine (0.485 mL) in tetrahydrofuran (5 mL) was added, and stirred at 0° C. for 1 hr, and further at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and to the residue was added water (30 mL), and then extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate, followed by concentrating under reduced pressure. The resulting oil was dissolved in tetrahydrofuran (5 mL), and the solution was added to a solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (1.0 g), triethylamine (0.808 mL) and 4-dimethylaminopyridine (0.071 g) in tetrahydrofuran (10 mL), and stirred at 40° C. for 18 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (30 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate, followed by concentrating under reduced pressure. The residue was purified with silica gel column chromatography (eluted with ethyl acetate:hexane=1:1, then ethyl acetate) to give a mixture of 1:1 of title compound and 2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl benzoate as pale yellow amorphous solid (1.50 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][CH2:17][C:18]([O:20]CC)=O)=[CH:7][CH:6]=[CH:5][N:4]=1.[OH-].[Na+].Cl>CO>[CH2:3]([N:4]([CH2:5][C:6]#[CH:7])[C:18](=[O:20])[CH2:17][CH2:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][N:10]1[CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:8]#[CH:9]
Reactant: CCOC(=O)CCC1CCCCN1Cc1cccnc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCN(CC#C)C(=O)CCC1CCCCN1Cc1cccnc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 104 %

Procedure:
500 mg of ethyl 3-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]propanoate, 2 ml of a 2N aqueous sodium hydroxide and 2 ml of methanol were stirred at 60° C. for 2 hours. After cooling to room temperature, 4 ml of a 1N aqueous hydrochloric acid was added thereto and the solvent was evaporated. Ethanol was added to the residue, the insoluble matters were filtered off and the solvent was evaporated. The resulting oil (500 mg), 170 mg of dipropargylamine, 450 mg of WSC and 240 mg of HOBt were dissolved in DMF, followed by stirring under room temperature for 3 hours. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1to 1:1, subsequently ethyl acetate), to give 300 mg of an oil.