Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[O:7][CH2:6][CH2:5][NH:4][CH2:3]1.[CH:9](=O)[CH2:10][OH:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:1][C:2]1([CH3:8])[O:7][CH2:6][CH2:5][N:4]([CH2:9][CH2:10][OH:11])[CH2:3]1
Reactant: CC1(C)CNCCO1
Reactant: O=CCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC1(C)CN(CCO)CCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dissolve 2,2-dimethylmorpholine (151 mg, 1.0 mmol) in 1,2-dichloroethane (3 mL) and add glycolaldehyde (60 mg, 1.0 mmol). Stir at room temperature for 30 min followed by addition of NaBH(OAc)3 (233 mg, 1.1 mmol). Stir 3 h, then quench by adding 30 mL of 1N NaOH. Pour into a separatory funnel and extract with EtOAc (2×50 mL). Wash the combined organic layers with brine (50 mL). The crude alcohol was used as is without further purification. MS (ES+) 160.2 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([NH:19][C@@H:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:21])=[O:18])=[CH:15][C:10]=3[N:9](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:8]=2)=[N:3]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([NH:19][C@@H:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:21])=[O:18])=[CH:15][C:10]=3[NH:9][N:8]=2)=[N:3]1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(-c1ccn(C)n1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(-c3ccn(C)n3)c2cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 55 %

Procedure:
A solution of crude (R)-1-(3-(1-methyl-1H-pyrazol-3-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (36 mg, 0.060 mmol) in DCM (1 mL) was treated with TFA (0.2 mL) and triethylsilane (0.02 mL, 0.125 mmol). The mixture was stirred at room temperature for 5.5 h, evaporated in vacuo and purified on reversed phase HPLC to afford (R)-1-(3-(1-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (15.7 mg, 0.033 mmol, 55%) as a white solid. MS ESI calcd. For C19H20N7O [M+H]+ 362, found 362. 1H NMR (600 MHz, DMSO-d6) δ 13.06 (s, 1H), 9.16 (s, 1H), 9.12 (s, 1H), 7.84-7.79 (m, 1H), 7.78 (d, J=2.2 Hz, 1H), 7.57 (s, 1H), 7.35-7.27 (m, 4H), 7.21 (ddd, J=8.7, 5.8, 2.6 Hz, 1H), 6.68 (d, J=2.2 Hz, 1H), 4.97-4.71 (m, 1H), 3.93 (s, 3H), 1.39 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH:3]=1.C(OO)(=[O:12])C>C(OCC)(=O)C>[CH3:1][C:2]12[O:12][CH:7]1[CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]2
Reactant: CC(=O)OO
Reactant: CC1=CCC(CO)CC1
Solvent: CCOC(C)=O
Product: CC12CCC(CO)CC1O2
Yield: 95 %

Procedure:
Epoxidation of 12.6 g (0.1 mol) of (4-methylcyclohex-3-enyl)methanol was performed with a 5 percent by weight solution of peroxyacetic acid in ethyl acetate at 65° C. The epoxidized product was purified by distillation and thereby yielded 12 g of (6-methyl-7-oxabicyclo[4.1.0]hept-3-yl)methanol with a purity of 98%.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:40])[C:15]2[O:21][C:20]3[C:22]([Cl:36])=[CH:23][C:24]([NH:26][CH2:27][CH2:28][NH:29][CH2:30][C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:38])(=[O:37])[C:16]=2[CH:39]=1)=[O:11].[CH:41](=O)[CH3:42].C([BH3-])#N.[Na+]>CO.O>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:40])[C:15]2[O:21][C:20]3[C:22]([Cl:36])=[CH:23][C:24]([N:26]([CH2:2][CH3:3])[CH2:27][CH2:28][N:29]([CH2:41][CH3:42])[CH2:30][C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:38])(=[O:37])[C:16]=2[CH:39]=1)=[O:11]
Reactant: O=C(O)C(F)(F)F
Reactant: CC=O
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNCc3ccco3)cc(Cl)c1O2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(CCN(CC)c1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)OC)cc(C)c1O2)Cc1ccco1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Trifluoroacetic acid (0.03 mL, 0.4 mmol) was added to mixture of Example 84k (0.2 g, 0.40 mmol) and acetaldehyde (0.115 mL, 2 mmol) in dry methanol (10 mL) at 0° C. The reaction mixture was stirred at room temperature in an atmosphere of nitrogen for 1.5 h. It was treated with sodium cyanoborohydride (0.064 g, 1 mmol), stirred for 1.5 h, treated with cold water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and purified using flash chromatography (silica gel, ethyl acetate/pet ether) to obtain the title compound as a white solid. Yield: 0.285 g, (68.69%); 1H NMR (DMSO-d6): δ 1.1 (t, 6H, 2CH3), 2.60-2.69 (m, 4H, 2CH2), 2.70 (s, 3H, CH3), 3.30-3.40 (m, 4H, 2CH2), 3.70 (s, 2H, CH2), 3.95 (s, 3H, OCH3), 4.65 (s, 2H, CH2), 6.25-6.85 (m, 3H, Ar), 6.65 (s, 1H, Ar), 7.45 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.50 (s, 1H, Ar); MS: m/e (CI+) 547 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:17][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1cccc(Br)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NC1CCCCC1)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
After 6-bromopicolinic acid (500 mg, 2.48 mmol) was suspended in acetonitrile (25 ml), cyclohexylamine (0.34 ml, 2.97 mmol), N,N-diisopropylethylamine (0.65 ml, 3.72 mmol), and HBTU (1.13 g, 2.97 mmol) were sequentially added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (30% EtOAc/Hexanes), to obtain 624 mg of colorless oil (94%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].CCN(C(C)C)C(C)C.[C:39]([NH:46][C@@H:47]1[CH2:51][CH2:50][C@H:49]([C:52](O)=[O:53])[CH2:48]1)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:2]([NH:1][C:52]([C@@H:49]2[CH2:50][CH2:51][C@H:47]([NH:46][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:48]2)=[O:53])[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:7][CH2:6]2)=[O:4])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)O)C1
Reactant: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3NS(C)(=O)=O)CC2)C1
Yield: 65 %

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step (f) using (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)-amino]phenyl}piperidyl)propan-1-one (Example 1, Step g) (471 mg, 1.0 mmol), DIEA (Aldrich) (0.20 mL, 1.0 mmol), (+)-(1R, 3S)—N-Boc-aminocyclopentane-3-carboxylic acid (PepTech Corporation) (344 mg, 1.5 mmol), HOAT (Aldrich) (232 mg, 1.70 mmol) and EDC (Aldrich) (544, 2.84 mmol) in DMF (10 mL). Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (421 mg). MS (ESI, pos. ion) m/z: 647 (M+1); MS (ESI, neg ion) m/z: 645 (M−1). Calc'd for C32H43ClN4O6S: 647.23.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40](=[O:42])[CH3:41])[CH:34]=3)=[CH:29][CH:28]=2)=[O:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:26][C:25]([C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40](=[O:42])[CH3:41])[CH:34]=2)=[CH:31][CH:32]=1)([C:23]1[N:22]=[CH:21][N:20]([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)[CH3:43]
Reactant: CC(=O)Nc1cccc(-c2ccc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc2)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(-c2ccc(C(C)(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-[4′-[(1-trityl-1H-imidazol-4-yl)carbonyl][1,1′-biphenyl]-3-yl]acetamide (800 mg) in THF (14 ml) was added dropwise a solution (1.0 M; 4.38 ml) of methylmagnesium bromide in THF at 0° C., and the mixture was stirred at 0° C. for 20 min. Saturated ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate-methanol-hexane to give the title compound (823 mg) as colorless powder crystals.
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+]>CO.O>[N:18]([CH:1]1[CH:6]([OH:7])[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]1)=[N+:19]=[N-:20].[N:18]([CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2][CH:1]1[OH:7])=[N+:19]=[N-:20]
Reactant: O=C(OCc1ccccc1)N1CCC2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NC1CCN(C(=O)OCc2ccccc2)CC1O
Product: [N-]=[N+]=NC1CN(C(=O)OCc2ccccc2)CCC1O
Temperature: 65 °C
Reaction time: 7 h

Procedure:
To a solution of benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (1.0 equiv.) in MeOH and water (0.17M) was added sodium azide (2.0 equiv.) and ammonium chloride (1.0 equiv.). The reaction was stirred at 65° C. in an oil bath for 7 h, then concentrated to remove the methanol. Ethyl acetate was added, the organic phase was separated, dried with Na2SO4, and concentrated under vacuo to give benzyl 3-azido-4-hydroxypiperidine-1-carboxylate and benzyl 4-azido-3-hydroxypiperidine-1-carboxylate as a clear oil in >95% yield. LCMS (m/z): 276.9 (MH+), Rt=2.98 min.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]/[C:3]/1=[CH:11]\[C:12]([OH:14])=[O:13]>CO.O1CCOCC1.[Pd]>[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][CH:3]1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)/C=C1\Cc2ccccc2C1=O
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)CC1Cc2ccccc2C1

Procedure:
A solution of acid 146 (10.0 g, 53.1 mmol) in MeOH (45 mL) and dioxane (150 mL) with Pd/C (10%, 1.0 g) was stirred under H2 (40 psi) for 16 h. The mixture was filtered through Celite and the solvent evaporated to give acid 147 as an off-white solid: mp 85-88° C. [lit. (Nagasawa et al., Japanese Patent 04338358, 1992) 89-91° C.]; 1H NMR δ 8.47 (br s, 1H, OH), 7.08-7.18 (m, 4H, H-4, H-5, H-6, H-7), 2.99-3.06 (m, 2H, H-1, H-3), 2.69-2.74 (m, 1H, H-2), 2.53-2.60 (m, 2H, H-1, H-3), 2.48 (d, J=7.4 Hz, 2H, CH2CO2).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]([CH3:16])[C:5]2[O:9][C:8]([CH2:11][C:12]#N)([CH3:10])[CH2:7][C:6]=2[C:14]=1[CH3:15].[OH-:18].[Na+].Cl.C[OH:22]>O>[OH:1][C:2]1[C:3]([CH3:17])=[C:4]([CH3:16])[C:5]2[O:9][C:8]([CH2:11][C:12]([OH:22])=[O:18])([CH3:10])[CH2:7][C:6]=2[C:14]=1[CH3:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CC(C)(CC#N)O2
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CC(C)(CC(=O)O)O2
Temperature: 0 °C

Procedure:
To a solution of 5-hydroxy-2-cyanomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran in methanol (5 ml) was added a solution of sodium hydroxide (0.5 g) in water (5 ml). The mixture was heated for three hours under reflux under argon atmosphere. The reaction mixture was cooled to 0° C. neutralized with 2N-HCl. The reaction product was extracted with ethyl acetate. The extract solution was washed with water, dried and concentrated, and then crystallized from ethyl acetate - isopropyl ether to afford the desired 2-(5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl)acetic acid (Compound 1) (0.1 g).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]([Cl:20])([Cl:19])[CH:12]([NH2:18])[NH:13][C:14](=[O:17])[CH2:15][Cl:16].C(N(CC)CC)C>CC(C)=O>[Cl:10][C:11]([Cl:19])([Cl:20])[CH:12]([NH:18][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH:13][C:14](=[O:17])[CH2:15][Cl:16]
Reactant: NC(NC(=O)CCl)C(Cl)(Cl)Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(CCl)NC(NC(=O)c1ccccc1)C(Cl)(Cl)Cl
Reaction time: 2 h

Procedure:
Benzoyl chloride (4.7g) in acetone (5ml) was added dropwise to a solution of 1,1,1-trichloro-2-amino-2-(chloroacetamido)ethane (8g) in acetone (50ml) containing triethylamine (3.4g). The temperature rose to 50°. The mixture was stirred for 2 hours. The salt was filtered off and the filtrate poured into water. The solid formed was collected, washed with water and dried (10g). Recrystallisation from nitromethane gave pure 1,1,1-trichloro-2-benzamido-2-(chloroacetamido)ethane (8.7g. m.p. 211°-213°).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH2:9][CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C.C(OCC)C>C(O)C>[CH2:9]([C:4]1[C:3]([CH2:2][S:18][C:16]2[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:10]
Reactant: CCc1ncccc1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCOCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1ncccc1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
To a 0° C. mixture of 3-(bromomethyl)-2-ethylpyridine (21.9 mmol) and 6-methyl-2-sulfanylpyrimidin-4-ol (2.0 g, 14 mmol) in absolute ethanol (200 mL) was added triethylamine (11 mL, 79 mmol). The mixture was stirred at room temperature overnight. Diethyl ether (300 mL) was added to the clear solution. The precipitate was removed by filtration. The filtrate was recovered, evaporated, and co-evaporated with EtOAc (1×100 mL). The residue was treated with water (300 mL). The solid material was recovered by filtration, washed with water (3×50 mL), diethyl ether (2×50 mL), and hexanes (1×50 mL), and dried in vacuo, affording 2-{[(2-ethylpyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (1.9 g, 52% yield), which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH2:30]([O:37][C:38](=[O:49])[C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:44](=[O:48])[C@H:45]([CH3:47])[NH2:46])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.C(Cl)(Cl)Cl>[CH2:30]([O:37][C:38](=[O:49])[C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:44](=[O:48])[C@H:45]([CH3:47])[NH:46][C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of 0.035 mole of t-butyloxycarbonylalanine in 80 ml of dry tetrahydrofuran which has been cooled to -20° to - 30° is added 4 ml of N-methylmorpholine and then 4.6 ml of isobutylchloroformate. After stirring for 10 minutes there is added 0.035 mole of alanylproline benzylester hydrochloride and 4 ml of N-methylmorpholine in 60 ml of chloroform. The reaction mixture is stirred overnight at room temperature, concentrated in vacuo and the residue taken up between ethyl acetate and 0.25 N hydrochloric acid. The organic layer is separated, washed with saturated sodium bicarbonate, water, dried over magnesium sulfate and concentrated in vacuo to give t-butoxycarbonylalanylalanylproline benzyl ester.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]([CH3:13])[C:11]=1[NH2:12].[C:14](OC(=O)C)(=[O:16])C.C(O)=O>C(N(CC)CC)C.[Cl-].[Na+].O>[NH2:12][C:11]1[N:10]([CH3:13])[N:9]=[CH:8][C:7]=1[NH:6][CH:14]=[O:16]
Reactant: Cn1ncc(N)c1N
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Solvent: CCN(CC)CC
Product: Cn1ncc(NC=O)c1N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of 4,5-diamino-1-methylpyrazole sulfuric acid salt (20 g) in triethylamine (29.2 ml) was stirred at 0° C. for 10 minutes. A mixture of acetic anhydride (9.87 ml) and formic acid (7.96 ml) was stirred at 40° C. for 30 minutes, cooled to 0° C., and added dropwise to the above solution at 0° C. The whole mixture was stirred at 0° C. for 2 hours. To the mixture was added brine, and the whole mixture was extracted with tetrahydrofuran. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give crude N-(5-amino-1-methyl-1H-pyrazol-4-yl)formamide, which was used in the next step without further purification.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:16])=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[CH:31](N(CC)C(C)C)(C)C.CCl.N[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49].O>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:16][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50][CH3:31])=[O:49])=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(N)=O)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Reactant: CCN(C(C)C)C(C)C
Reactant: NCCCCCC(=O)O
Agent: CCl
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCCCCNC(=O)c1ccc2c(c1)[C@H](Nc1ccc(N3CCOCC3)cc1)C[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
81.9 mg of (2S,4R)-1-acetyl-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline-6-carboxamide was dissolved in 2 mL of dichloromethane, and 174.2 μL of N,N-diisopropylethylamine and 124.9 mg of hexafluorophosphate(benzotriazol-1-yloxy)tripyrrolidinophos phonium were added to the solution. The mixture was stirred for one hour at room temperature. Subsequently, 108.9 mg of 6-aminohexanoate methyl-monohydrochloride was added thereto, and the mixture was stirred for one hour at room temperature. After completion of the reaction, water was added to the reaction mixture, and then the mixture was extracted three times with chloroform. The extraction product was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (chloroform:methanol=10:1), and thus 54.0 mg (50.3%, cis-form only) of the title compound was obtained as a pale yellow crystalline powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.[CH:14]1([OH:19])CC=C[CH2:15]1.[N+](=[CH:22][C:23](OCC)=O)=[N-]>[Cu]>[O:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]1[O:7][CH:2]1[CH2:23][CH:22]2[CH:4]([CH:5]2[C:6]([O:19][CH2:14][CH3:15])=[O:1])[CH2:3]1
Reactant: OC1CC=CC1
Reactant: C1CCC(OC2CCCCO2)OC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu]
Product: CCOC(=O)C1C2CC(OC3CCCCO3)CC21
Yield: 55 %

Procedure:
A mixture of 0.01 M of the tetrahydropyranyl ether of 3-cyclopentenol (VII) and 1 g. of copper powder is stirred vigorously and maintained at 100° C. while 0.07 M (8 g.) of ethyl diazoacetate is added over a period of 8 hours. The reaction mixture is then extracted with hexane and chromatographed over aluminum oxide (activity I). Elution first with hexane, and then benzene, and evaporation of the eluates gives ethyl 3-[(tetrahydropyran-2-yl)oxy]bicyclo[3.1.0]hexane-6-carboxylate (VIII) in 55% yield as a liquid, b.p. 133° at 1.1 mm.; λ max. 195 mmμ (pentane); γ 3100, 3075, 3047, 1725, 1272, 1140 and 1020 cm-1.; δ 3.92 (quartet), 1.07 (triplet) p.p.m.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18](SC)=[CH:17][CH:16]=2)[O:3]1.[CH3:24]O.O.O[O:28][S:29]([O-:31])=O.[K+]>C1COCC1>[CH3:1][C:2]1([CH3:23])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([S:29]([CH3:24])(=[O:31])=[O:28])=[CH:17][CH:16]=2)[O:3]1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(C2=C(c3cccc(F)c3)C(=O)C(C)(C)O2)cc1
Reactant: CO
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2cccc(F)c2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Alternatively, the titled compound was prepared as described in the following procedure: 3.0 g of 2,2-dimethyl-4(3-fluorophenyl)-5-{4-(methylthio)phenyl}-3(2H)-furanone (Example 166) was dissolved in 50 ml THF, 50 ml methanol and 50 ml water along with 10 g of OXONE. The reaction mixture was stirred at room temperature for 2 hours. Then the solution was concentrated in vacuo and the resulting aqueous solution was extracted with 150 ml methylene chloride. The organic layer was washed with brine and then was dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was concentrated in vacuo. The resulting residue was recrystallized from methylene chloride/hexane to afford 3.3 g of 2,2-dimethyl-4-(3-fluorophenyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.C1(C)C=CC=CC=1.[F:25][C:26]1[CH:34]=[C:33]([CH2:35][CH2:36][C@H:37]2[CH2:42][CH2:41][C@H:40]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:39][CH2:38]2)[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>O>[F:25][C:26]1[CH:34]=[C:33]([CH2:35][CH2:36][C@H:37]2[CH2:38][CH2:39][C@H:40]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:41][CH2:42]2)[CH:32]=[CH:31][C:27]=1[C:28]([O:10][C:8]1[CH:9]=[C:2]([F:1])[C:3]([C:4]#[N:5])=[C:6]([F:11])[CH:7]=1)=[O:29]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(C(=O)Cl)c(F)c2)CC1
Reactant: N#Cc1c(F)cc(O)cc1F
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(C(=O)Oc3cc(F)c(C#N)c(F)c3)c(F)c2)CC1
Yield: 95.6 %

Procedure:
Then, 1.1 g (6.4 mmol) of 2,6-difluoro-4-hydroxybenzo-nitrile, 0.8 ml of pyridine, and 2 ml of toluene were mixed. To this mixture, was added dropwise 3 ml of toluene solution containing 6.4 mmol of 2-fluoro-4-(2-(trans-4-pentylcyclohexyl)ethyl)benzoyl chloride at room temperature in 5 minutes. After the dropping was finished, they were reacted at 50° C. for 2 hours. After finishing of the reaction, 10 ml of water was added to the reaction product, and then extracted with 30 ml of toluene. The organic layer thus obtained was washed with 6N-hydrochloric acid thrice, 2N-sodium hydroxide thrice, and water thrice, and then dried over anhydrous magnesium sulfate. Solvent was distilled off at a reduced pressure, and the residue was subjected to a silica gel column chromatography (eluent: toluene) to obtain 2.8 g of a crude 3,5-difluoro-4-cyanophenyl 2-fluoro-4-(2-(trans-4-pentylcyclohexyl)ethyl)benzoate. This product was recrystallized from a mixed solvent of heptane/ether to obtain 2.4 g of (yield: 81.6%) the subject compound.