Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Zn]CC)C.[Si:6]([O:23][CH2:24][C@@H:25]1[CH2:29][CH:28]=[CH:27][N:26]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.ClCI>C1(C)C=CC=CC=1>[Si:6]([O:23][CH2:24][C@@H:25]1[CH2:29][CH:28]2[CH:27]([CH2:1]2)[N:26]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:19]([CH3:21])([CH3:22])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[Zn]CC
Reactant: CC(C)(C)OC(=O)N1C=CC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: ClCI
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C2CC2C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -25 °C
Reaction time: 18.5 h
Yield: 90.8 %

Procedure:
Diethylzinc (19 mL of ˜1.1 M in toluene, 21 mmol) was added dropwise over 15 min to a cooled (−30° C.) toluene (27 mL) solution of (S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (3.94 g, 9.0 mmol). Chloroiodomethane (stabilized over copper; 3.0 mL, 41 mmol) was added dropwise over 10 min and stirred while maintaining the bath temperature at −25° C. for 1 h and between −25° C. and −21° C. for 18.5 h. The reaction mixture was opened to the air and quenched by the slow addition of 50% saturated NaHCO3 solution (40 mL) and then removed from the cooling bath and stirred at ambient temperature for 20 min. The reaction mixture was filtered through a filter paper and the white cake was washed with 50 mL of toluene. The organic phase of the filtrate was separated and washed with water (40 mL, 2×), dried (MgSO4) and concentrated in vacuo. The crude material was purified using by silica gel chromatography (350 g silica gel; sample was loaded with 7% EtOAc/hexanes; eluted with 7-20% EtOAc/hexanes) to afford (3S)-tert-butyl 3-((tert-butyldiphenylsilyloxy)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (3.69 g, 90.7%) as a mixture of cis/trans-isomers. [Note: the exact cis/trans-isomer ratio was not determined at this stage]. LC-MS: [M+Na]+=474.14. Rt=2.39 min under the following HPLC conditions: Solvent gradient from 100% A: 0% B to 0% A: 100% B (A=0.1% TFA in 1:9 MeOH/water; B=0.1% TFA in 9:1 MeOH/water) over 2 min and hold for 1 min; detection at 220 nm; PHENOMENEX® Luna 3.0×50 mm S10 column. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.62-7.60 (m, 4H), 7.49-7.40 (m, 6H), 3.77/3.67 (overlapping br s, 3H), 3.11-3.07 (m, 1H), 2.23 (app br s, 1H), 2.05-2.00 (m, 1H), 1.56-1.50 (m, 1H), 1.33 (very broad s, 9H), 1.00 (s, 9H), 0.80 (m, 1H), 0.30 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.CI.[C:22](=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([N:12]3[CH2:17][CH2:16][N:15]([CH3:22])[CH2:14][CH2:13]3)[NH:8][S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1
Reactant: O=S1(=O)NC(N2CCNCC2)=Nc2ccc(Cl)cc21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCN(C2=Nc3ccc(Cl)cc3S(=O)(=O)N2)CC1
Reaction time: 2 h
Yield: 38.2 %

Procedure:
To a solution of 1.0 g of 7-chloro-3-(1-piperazinyl)-2H-1,2,4-benzothiadiazine 1,1-dioxide in 15 ml of dimethylformamide is added dropwise at 0° C. 0.56 g of 93% methyl iodide, in the presence of 0.7 g of anhydrous sodium carbonate. The mixture is stirred for 2 hours, while the temperature is kept at 0° C. After removal of dimethylformamide by distillation under reduced pressure, the resulting residue is triturated with 10 ml of water to precipitate the crystals. The collected precipitate is recrystallized from a mixture of dimethylformamide and water to give 0.4 g of the desired product, m.p. above 300° C.
Reaction SMILES: [N:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C>[CH2:25]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]3[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]=2)[CH2:6][CH2:5]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: c1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1O2
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1CCN(C2=Nc3ccccc3Oc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine (0.28 g, 1.00 mmol) in DMF (10 mL) was added sodium hydride (0.056 g, 60% in oil, 1.40 mmol) at 0 ° C. under argon. The mixture was stirred at 0 ° C. for 10 rain at room temperature for 20 minutes, and then treated with 1-bromohexane (2.35 g, 12 mmol). The resulted mixture was stirred at room temperature overnight and quenched with saturated ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography using ethyl acetate/hexane (1/2) as the eluent. The title compound was obtained in 0.167 g (46%) as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:11]([O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cc(O)no1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)no1
Temperature: 50 °C
Reaction time: 16 h
Yield: 20.6 %

Procedure:
A mixture of methyl 3-hydroxyisoxazole-5-carboxylate (5.0 g, 34.9 mmol), benzyl bromide (6.84 g, 40 mmol) and potassium carbonate (8.3 g, 60 mmol) in N,N-dimethylformamide (100 mL) was stirred at 50° C. for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to purify the residue by NH-silica gel column chromatography (hexane/ethyl acetate 95:5 to 50:50). Solvent was removed to obtain a solid (1.68 g, 21%).
Reaction SMILES: CC(C)(C(=O)CC1CCCCC1)CCCO[C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]([C:24]3[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=3)=[CH:12][C:11]=2[CH:30]=1.FC1C=CC(CCC2C(C3N(C)C=CN=3)=CC3C=C([O:66][CH2:67][CH2:68][CH2:69][C:70]4([C:75](=[O:84])[CH2:76][C:77]5[CH:82]=[CH:81][C:80](F)=[CH:79][CH:78]=5)[CH2:74]CC[CH2:71]4)C=CC=3O2)=CC=1>>[CH3:71][C:70]([CH3:74])([C:75](=[O:84])[CH2:76][CH:77]1[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]1)[CH2:69][CH2:68][CH2:67][O:66][C:8]1[CH:7]=[CH:30][C:11]2[CH:12]=[C:13]([C:24]3[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=3)[CH:14]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:15][C:10]=2[CH:9]=1
Reactant: Cn1ccnc1C1=Cc2cc(OCCCC(C)(C)C(=O)CC3CCCCC3)ccc2OC1CCc1ccccc1
Reactant: Cn1ccnc1C1=Cc2cc(OCCCC3(C(=O)Cc4ccc(F)cc4)CCCC3)ccc2OC1CCc1ccc(F)cc1
Product: Cn1ccnc1C1=Cc2ccc(OCCCC(C)(C)C(=O)CC3CCCCC3)cc2OC1CCc1ccccc1

Procedure:
6-(4,4-dimethyl-6-cyclohexyl-5-oxohexyl)oxy-2-(2-phenylethyl)-3-(1-methyl-1H-imidazol-2-yl)-2H-1-benzopyran, and 1-[3-[2-(2-(4-fluorophenyl)-ethyl)-3-(1-methyl-1H-imidazol-2-yl)-2H-1-benzopyran-6-yl]oxypropyl]-1-[1-oxo-2-(4-fluorophenyl)ethyl]cyclopentane.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][OH:9])[C@@H:4]([CH2:5][CH2:6][CH3:7])[O:3]1.CCN(C(C)C)C(C)C.[Si:19](OS(C(F)(F)F)(=O)=O)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].P([O-])([O-])([O-])=O>C(Cl)Cl.CCOCC>[Si:19]([O:3][C@H:4]([CH2:5][CH2:6][CH3:7])[C@@H:2]([CH3:1])[CH:8]=[O:9])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CCC[C@H]1O[C@]1(C)CO
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CCC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C=O
Temperature: -42 °C
Reaction time: 1.33 h
Yield: 116.2 %

Procedure:
This is a representative procedure for the rearrangement of epoxy alcohols with trialkylsilyl trifluoromethanesulfonates. Epoxy alcohol 15 (74.3 mg, 0.4647 mmol) was dissolved in 4.0 ml of CH2Cl2, treated with 100 mg of 4 Å powdered molecular sieves, DIPEA (129 μl, 0.7419 mmol, 1.3 eq) and cooled to -42° C. TBSOTf (157.2 μl, 0.6849 mmol, 1.3 eq) was then added drop wise and stirred for 80 min at which time the solution was poured onto 20 ml of Et2O and shaken with 5 ml of pH 5.5 phosphate buffer. The layers were separated and the aqueous phase extracted with Et2O (2×5 ml ). The combined organic phases were washed with H2O (3×2 ml), 5% NaHCO3 (2×2 ml), brine (1×2 ml), dried over MgSO4 and the solvent evaporated to yield 132.0 mg of aldehyde 16 (slight contamination of silanol, 95%+yield). 1H NMR (CDCl3, 360. 134 MHz) δ:9.67 (1H, d, J=2.35 Hz), 3.89 (1H, q, J=5.40 Hz), 2.44 (1H, qdd, J=7.02, 5.40, 2.35 Hz), 1.5-1.3 (4H, m), 1.02 (3H, d, J=7.02 Hz), 0.86 (3H, t, J=7.31 Hz), 0.82 (9H, s), 0.01 (3H, s,), and -0.01 (3H, s). 13C NMR (CDCl1 90.55 MHz) δ:205.0, 73.2, 51.1, 37.0, 25.6, 18.01, 17.99, 14.2, 10.3, -4.3 , and -4.8. IR (thin film): 2959 (s), 2934 (s), 2859 (s), 1727 (s), 1472 (s), 1464 (s), 1362 (m), 1256 (s), 1125 (s), 1090 (s), 1074 (s), 1038 (s), 1007 (m), 889 (w), 837 (s), and 775 (s) cm-1. High resolution MS (m/z): 187.1161, calcd for C9H19O2Si 187.1154 (M-C4H9). [α]D =-18.4° (c=1.43, CH2Cl2). 1H NMR integration of δ 3.89 and the contaminating diastereomer at δ 3.89 and the contaminating diastereomer at δ 4.05 indicated a 20:1 ratio.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][C:7]1=2)=[O:4].[ClH:26]>CO.O1CCOCC1>[ClH:26].[CH3:1][O:2][C:3]([CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][NH:16][CH2:17][CH2:18][C:7]1=2)=[O:4].[ClH:26]
Reactant: COC(=O)Cn1c2c(c3ccccc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)Cn1c2c(c3ccccc31)CNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 5-methoxycarbonylmethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (377 mg, 1.09 mmol) was dissolved in methanol (15 mL). 4N HCl in 1,4-dioxan (1.5 mL) was added and the mixture stirred at room temperature overnight. The solution was concentrated in vacuo, azeotroped once with toluene and dried under vacuum to give 5-methoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride as an off white solid (314 mg, 100% assuming HCl salt).
Reaction SMILES: C([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]([O:23]CC)=[O:22])=[CH:14][C:13]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:12][CH:11]=2)C1C=CC=CC=1.[OH-].[K+]>C(O)C.O>[CH2:16]([N:9]1[C:10]2[C:15](=[CH:14][C:13]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:12][CH:11]=2)[C:16]([CH:17]=[CH:18][CH:19]=[CH:20][C:21]([OH:23])=[O:22])=[CH:8]1)[C:15]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=CC=Cc1c(Cc2ccccc2)[nH]c2ccc(OCc3ccccc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C=CC=Cc1cn(Cc2ccccc2)c2ccc(OCc3ccccc3)cc12

Procedure:
In a manner similar to Example 2, 1 g (2.4 mmol) of ethyl 5-(benzyl-5-benzyloxyindol-3-yl)-2,4-pentadienoate was treated with 0.5 g (8.6 mmol) of potassium hydroxide in ethanol-water to give, after powders, m.p. 202-203. MS(EI): 365 (M+--CO2), 274 (M+--CO2 --CH2C6H5); NMR (DMSO-d6): δ5.14 (s, 2), δ5.36 (s, 2), δ5.89 (d, J=15 Hz, 1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6](Cl)=[O:7].[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>CCOCC>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: O=C(Cl)C1CCCO1
Reactant: OCc1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)C1CCCO1
Reaction time: 0.67 h

Procedure:
Tetrahydrofuroyl chloride (15.0 g, 112 mmol) was added dropwise to a cold solution of benzyl alcohol (10.9 g, 101 mmol) and pyridine (20.0 g, 253 mmol) in Et2O (200 mL). The solution was stirred at 0° for 40 minutes, then filtered to remove the side product pyridine hydrochloride. The filtrate was washed with 0.1M HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), and then dried over MgSO4. Filtration and evaporation of the solvent gave a yellow oil, which was distilled. Benzyl tetrahydrofuroate was obtained as a colorless oil (21.1 g), b.p. 118° to 120° at 0.5 mm Hg. Microanalysis calc'd for C12H14O3 (206.2): C, 69.89; H, 6.84; O, 23.27; Found: C, 69.62; H, 6.89.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:18]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl.[OH-].[Ca+2].[OH-]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8](=[O:27])[C:7]=2[CH:18]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1CC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)S(=O)c1ccccc1CC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.63 G. 3-cyano-10,11-dihydro-11-oxodibenzo[b,f]thiepin is dissolved in 100 cc. methylene chloride and 1.12 g. m-chloroperbenzoic acid is added and the solution stirred for one hour at room temperature. The reaction mixture is diluted with methylene chloride, excess powdered calcium hydroxide is added, and the mixture stirred for five minutes and filtered through celite. The organic filtrate is evaporated to dryness and the residue chromatographed on silica gel and eluted with a 1:1 mixture of benzene: chloroform to yield 937 mg. (54%) of the desired pure sulfoxide, m.p. 219°-221° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH:18]([CH3:20])[CH3:19])[C:14]([NH:16][CH3:17])=[O:15])[C:7]2=[O:12].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([CH3:32])[C:29](O)=[O:30])=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C@H:28]([CH3:32])[C:29]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([C@H:13]([CH:18]([CH3:20])[CH3:19])[C:14]([NH:16][CH3:17])=[O:15])[C:7]3=[O:12])=[O:30])=[CH:26][CH:27]=1
Reactant: C[C@H](C(=O)O)c1ccc(Cl)cc1
Reactant: CNC(=O)[C@@H](C(C)C)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](C(C)C)n1ccc2c(NC(=O)[C@@H](C)c3ccc(Cl)cc3)cccc2c1=O

Procedure:
(R)-2-(5-Amino-1-oxoisoquinolin-2(1H)-yl)-N,3-dimethylbutanamide (0.2 g, 0.0007 mol), (S)-2-(4-chlorophenyl)propanoic acid (0.16 g, 0.00088 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.56 g, 0.0015 mol), N,N-diisopropylethylamine (0.4 g, 0.003 mol) were stirred in methylene chloride (3 mL, 0.05 mol) and N,N-dimethylformamide (1 mL, 0.01 mol) at room temperature over a weekend. The reaction mixture was diluted with CH2Cl2 (100 mL), washed with NaHCO3 (20 mL×3), dried over Na2SO4, purified via flash chromatography (12 g of silica gel, 0-90% EtOAc/Hexane), and then prep. HPLC yielded a white solid. 1H NMRδ (CDCl3) δ: 9.23 (d, J=8.1 Hz, 1H), 8.00 (t, J=7.5 Hz, 1H), 7.52-7.36 (m, 6H), 7.04 (br, 1H), 6.17 (br, 1H), 6.03-6.00 (m, 1H), 5.07 (d, J=11.4 Hz, 1H), 3.82 (q, J=7.0 Hz, 1H), 2.76 (d, J=4.8 Hz, 3H), 2.56-2.48 (m, 1H), 1.65 (dd, J=1.8, 7.1 Hz, 3H), 1.06 (d, J=6.4 Hz, 3H), 0.75 (dd, J=2.6, 6.6 Hz, 3H). MS m/z 440.0 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([S:4]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH3:3].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH:24]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:23]([C:32](Cl)=[O:33])[C:22]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=3[O:45][CH2:46][CH3:47])=[N:21]2)=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH:24]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[N:23]([C:32]([N:10]3[CH2:9][CH2:8][N:7]([S:4]([CH:2]([CH3:1])[CH3:3])(=[O:5])=[O:6])[CH2:12][CH2:11]3)=[O:33])[C:22]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:37][C:36]=3[O:45][CH2:46][CH3:47])=[N:21]2)=[CH:16][CH:15]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)S(=O)(=O)N1CCNCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(S(=O)(=O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(Propane-2-sulfonyl)-piperazine (0.0286 mmol) was dissolved in 0.25 mL of methylene chloride and added to a solution of 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (0.024 mmol, example 3) and diisopropylethylamine (0.072 mmol) in. 25 mL of methylene chloride in a 4 mL vial. The vial was capped and shaken overnight at room temperature. The reaction mixture was diluted with 1 mL of methylene chloride and 1 mL of water. The vial was agitated and centrifuged. The organic layer was transferred to a 4 mL vial and concentrated in vacuo to give [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(propane-2-sulfonyl)-piperazin-1-yl]-methanone. LR-MS (M+H)+=697.4.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH:12]([O:14][C:15]([C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]#[N:24])[CH2:19][CH2:18]2)=[O:16])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C(Cl)(Cl)[Cl:26]>C(O)C.[Pt]=O>[ClH:26].[ClH:26].[NH2:2][CH2:1][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH:12]([O:14][C:15]([C@H:17]2[CH2:18][CH2:19][C@H:20]([CH2:23][NH2:24])[CH2:21][CH2:22]2)=[O:16])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(OC(=O)[C@H]1CC[C@H](C#N)CC1)OC(=O)[C@H]1CC[C@H](C#N)CC1
Reactant: ClC(Cl)Cl
Agent: O=[Pt]
Solvent: CCO
Product: CC(OC(=O)[C@H]1CC[C@H](CN)CC1)OC(=O)[C@H]1CC[C@H](CN)CC1
Product: Cl
Reaction time: 15 h

Procedure:
1,1-Ethandiol bis-(trans-4-cyanocyclohexanecarboxylate) (6 g) was dissolved in a mixture of anhydrous ethanol and chloroform. Platinum oxide (1 g) was added and the mixture was hydrogenated at 3.1 MPa at 22° C. for 15 h. The catalyst was filtered off and the solvent evaporated. The product was crystallized from a mixture of 2-propanol and methanol. Yield 5.5 g, m.p. 260° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[CH2:11][C:10](=[O:14])[NH:9][C:8]2[C:15]3[C:20]([CH:21]=[CH:22][C:7]1=2)=[CH:19][CH:18]=[CH:17][CH:16]=3.[Cl:23][C:24]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].CC1C(C)=CC=CC=1C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1OC)=O>>[O:14]=[C:10]1[NH:9][C:8]2[C:15]3[C:20]([CH:21]=[CH:22][C:7]=2[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:24]=2[Cl:23])[C:12](=[O:13])[CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: COc1cccc(C(=O)Cl)c1Cl
Reactant: NCCCCN1C(=O)CC(=O)Nc2c1ccc1ccccc21
Agent: COc1cc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)ccc1NC(=O)c1cccc(C)c1C
Product: COc1cccc(C(=O)NCCCCN2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1Cl
Yield: 55.8 %

Procedure:
By using N-(tert-butoxycarbonyl)-1,4-diaminobutane as the starting material, 5-(4-aminobutyl)-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione was obtained in the same manner as that of Example 42, (1) and (2). By using 5-(4-aminobutyl)-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.1 mmol), and 2-chloro-3-methoxybenzoyl chloride (0.15 mmol), the title compound (26 mg, yield 56%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[B:20]1[O:24]C(C)(C)C(C)(C)[O:21]1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl>C(OCC)(=O)C.O.O1CCCC1>[CH2:15]([O:14][C:12]([C:11]1[CH:17]=[CH:18][C:19]([B:20]([OH:21])[OH:24])=[C:9]([O:8][CH3:7])[CH:10]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(B(O)O)c(OC)c1
Yield: 89.3 %

Procedure:
Sodium meta periodate (0.157 g) was added to a mixture of ethyl 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.075 g), water (1 mL) and tetra hydrofuran (4 mL) at room temperature with stirring, and the mixture was stirred at that temperature for 10 min. 2 mol/L hydrochloric acid (0.082 mL) was added, and the resulting mixture was stirred at that temperature for additional 2 hrs, then water and ethyl acetate were added. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4-ethoxycarbonyl-2-methoxyphenylboronic acid (0.049 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH:17]2[CH:19]([C:20](N)=O)[CH2:18]2)=[CH:11][CH:10]=1)#[N:2].Br[C:24]1[C:25]([CH3:30])=[CH:26][CH:27]=[N:28][CH:29]=1.C(O)=O.C([N:36](CC)CC)C>C1(C)C=CC=CC=1>[CH:19]1([C:17]2[N:16]([CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[CH:14][CH:13]=3)[C:29]3=[N:28][CH:27]=[CH:26][C:25]([CH3:30])=[C:24]3[N:36]=2)[CH2:18][CH2:20]1
Reactant: N#Cc1ccccc1-c1ccc(CNC2CC2C(N)=O)cc1
Reactant: Cc1ccncc1Br
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O=CO
Product: Cc1ccnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Yield: 83 %

Procedure:
Toluene (30 ml) was added to 2.0 g (4.3 mmol) of 2-(2'-cyanobiphenyl-4-yl)methylamino-3-cyclopropanecarboxamide-5-bromo-4-methyl-pyridine, 1.0 g (21.7 mmol) of formic acid, 3.5 g (34.6 mmol) of triethylamine and 10% Pd--C (300 mg), followed by heating under reflux for 6 hours. After the reaction liquid was brought to room temperature and filtered to remove the catalyst, vacuum concentration was effected. Chloroform (100 ml) and water (50 ml) were added to the residue and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (50 ml) twice. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 1.3 g of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine (yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC(OC1C=CC=CC=1)=O>C(Cl)Cl.S(=O)(=O)(O)O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCN(Cc2ccccc2)C1
Agent: O=C(Cl)Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cl
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCNC1

Procedure:
A solution of 8.31 g (0.0248 mole) of 3-[(4-chlorophenyl)sulfonyl]-1-(phenylmethyl)pyrrolidine (free base) and 7.1 g (0.0455 mole) of phenyl chloroformate in 300 ml of methylene chloride was stirred at room temperature for 20 hr. The solution was extracted several times with dilute aqueous sodium hydroxide solution and the organic layer was separated and dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. The oil was suspended in 300 ml of 60% sulfuric acid and the mixture poured over ice. The resulting acidic mixture was extracted with methylene chloride and the methylene chloride layer was discarded. The acidic aqueous layer was made basic with 50% sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extract of the basic solution was dried over magnesium sulfate and the solvent removed in vacuo to give an oil, the free base of the title compound. The hydrochloride salt was prepared using ethereal hydrogen chloride added to a methanol solution of the free base and recrystallized from methyl alcohol-diethyl ether to give 4.11 g (58.9%) of white crystalline solid, m.p. 202°-203° C.