Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl.C([N:53]1[CH:57]=[CH:56][N:55]=[C:54]1[CH2:58]Cl)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[N:30]([CH2:58][C:54]4[NH:53][CH:57]=[CH:56][N:55]=4)[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reactant: ClCc1nccn1Cc1ccccc1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ncc[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 38.1 using 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-phenyl-pyrrolidine and 1-benzyl-imidazol-2-ylmethylchloride hydrochloride to give the title compound.
Reaction SMILES: [O:1]=[C:2]([N:12]1[CH2:15][CH:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:13]1)/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C([O-])(O)=O.[Na+]>C1COCC1>[O:1]=[C:2]([N:12]1[CH2:13][CH:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH2:15]1)/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:24](=[O:26])[CH3:25])=[N:9][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(/C=C/C(=O)N2CC(OCc3ccncc3)C2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(/C=C/C(=O)N2CC(OCc3ccncc3)C2)cn1
Temperature: 60 °C
Reaction time: 40 h
Yield: 13.1 %

Procedure:
To a solution of 5-{(1E)-3-oxo-3-[3-(pyridin-4-ylmethoxy)azetidin-1-yl]prop-1-en-1-yl}pyridin-2-amine (16 mg, 0.05 mmol) and acetic anhydride (6 μL, 0.06 mmol) in THF (2.4 mL) was added NaHCO3 (5.5 mg, 0.065 mmol). The reaction mixture was warmed at 60° C. and stirred for 40 h. LCMS showed that some starting material was remaining. Another portion of acetic anhydride (6 μL) and NaHCO3 (5.5 mg) were added and the mixture was stirred at 60° C. for 24 h. These additions were repeated twice over 48 h. The mixture was then concentrated, partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to give an oil. The crude was purified on preparative TLC (eluent: 90/10 DCM/MeOH) to give the title compound (2.3 mg, 12%) as a pale yellow solid.
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:29]([N:36]1[CH2:43][CH2:42][CH2:41][C@H:37]1[C:38]([OH:40])=O)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].[CH:44]1[C:52]2[C:51]3[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:50]=3[O:49][C:48]=2[CH:47]=[CH:46][C:45]=1[NH2:58]>>[CH:44]1[C:52]2[C:51]3[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:50]=3[O:49][C:48]=2[CH:47]=[CH:46][C:45]=1[NH:58][C:38]([C@@H:37]1[CH2:41][CH2:42][CH2:43][N:36]1[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 37.6 %

Procedure:
Following the procedure of Example 30, triethylamine (0.43 mL, 3.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.31 g, 1.6 mmol), N-hydroxybenzotriazole (0.22 g, 1.6 mmol), N-Boc-L-proline (0.29 g, 1.4 mmol), and 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.25 g, 1.2 mmol) provided tert-butyl (2S)-2-[(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylamino)carbonyl]pyrrolidine-1-carboxylate (0.18 g). MS (ESI) m/z 399 ([M+H]+); MS (ESI) m/z 397.3 ([M−H]−).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:12]([CH2:33][CH3:34])[C:13]([N:15]1[CH:19]=[C:18]([CH2:20]O)[C:17]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[CH3:32])(=[O:24])=[O:23])=[N:16]1)=[O:14])[CH3:11].O>C(Cl)Cl>[CH2:10]([N:12]([CH2:33][CH3:34])[C:13]([N:15]1[CH:19]=[C:18]([CH2:20][F:7])[C:17]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[CH3:32])(=[O:24])=[O:23])=[N:16]1)=[O:14])[CH3:11]
Reactant: CCN(CC)C(=O)n1cc(CO)c(S(=O)(=O)c2cccc(Cl)c2C)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(=O)n1cc(CF)c(S(=O)(=O)c2cccc(Cl)c2C)n1
Reaction time: 1 h
Yield: 95 %

Procedure:
20 μl of diethylaminosulfur trifluoride were added at 0° C. to a solution of 54 mg of 1-(diethylcarbamoyl)-3-(2-methyl-3-chlorophenylsulfonyl)-4-hydroxymethylpyrazole (prepared as described in Example 10) in 1.8 ml of methylene chloride, and the resulting mixture was stirred for 1 hour. At the end of this time, the reaction mixture was poured into water and extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, eluted with an 8:1 by volume mixture of hexane and ethyl acetate, to afford 51 mg (yield 95%) of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](=O)(O)[O-].[Na+].IC>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C([O-])O
Reactant: Cc1c(Br)cccc1C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccc(Br)c1C
Temperature: 60 °C
Yield: 103.3 %

Procedure:
A mixture of 3-bromo-2-methylbenzoic acid (16 g, 74.4 mmol), sodium bicarbonate (12.5 g, 148.8 mmol) and iodomethane (21.2 g, 148.8 mmol) in DMF (160 mL) was heated at 60° C. for 2 hours. The mixture was cooled to room temperature and poured into ice water (400 mL). The mixture was extracted with ethyl acetate (4×100 mL). The EtOAc solution was washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Solvent was removed to give methyl 3-bromo-2-methylbenzoate (17.6 g, 100%) as an oil: 1H NMR (CDCl3) δ 7.70 (t, J=7.6 Hz, 2H), 7.08 (t, J=7.9 Hz, 1H), 3.90 (s, 3H), 2.67 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]([O:16][CH3:17])=[S:15].[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(O)(=O)C>[C:18]([NH:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]([O:16][CH3:17])=[S:15])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=S)c1c(Cc2ccccc2)n[nH]c1N
Solvent: CC(=O)O
Product: COC(=S)c1c(Cc2ccccc2)n[nH]c1NC(C)=O

Procedure:
70.5 g (0.27 mol) Methyl 5-amino-3-benzylthiopyrazole-4-carboxylate was dissolved at 80° C. in 135 ml glacial acetic acid and treated with 27.75 g (0.27 mol) acetic anhydride. The solution was heated under reflux for 7 hours and concentrated. The residue was recrystallised from ether, the crystals suction filtered, washed with ether and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:13]1[O:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:13]([OH:15])[CH2:14][NH:27][CH2:23][CH2:24][CH2:25][CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Product: CCCCNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 81 %

Procedure:
From the reaction of (1.48 g, 5.0 mmol) of N-benzyloxycarbonyl 3(S)-amino-1,2-(S)-epoxy-4-phenylbutane and (7.314 g, 100.0 mmol) of n-butylamine, one obtains 1.50 g (80%) of N-[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]-N-butylamine, mp 125-128° C., FAB MS, Spectrum: MH+=371.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:10][C:9]=1[OH:18])(=[O:7])[CH3:6].[Br:19]Br.Cl>ClCCl>[C:5]([C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)=[C:10]([Br:19])[C:9]=1[OH:18])(=[O:7])[CH3:6]
Reactant: CC(=O)c1cc2c(cc1O)CCCC2
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc2c(c(Br)c1O)CCCC2
Temperature: 25 °C
Yield: 78.9 %

Procedure:
A mixture of aluminium chloride (8.15 g) and 7-acetyl-1,2,3,4-tetrahydro-6-hydroxynaphthalene (4.75 g) in dichloromethane (250 ml) was cooled to -10°. A solution of bromine (6.0 g) in dichloromethane (150 ml) was then added over 1 hour with constant stirring. The reaction mixture was allowed to warm to room temperature overnight, dilute HCl (400 ml) was added and the organic layer was separated, washed with water and dried (MgSO4). The solvent was filtered and the filtrate was evaporated to dryness leaving an oil which solidified on cooling to give 7-acetyl-5-bromo-1,2,3,4-tetrahydro-6-hydroxynaphthalene (5.3 g, 79%) mp 127°-130°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][CH2:16][S:17][C:18]4[S:22][C:21]([CH3:23])=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.BrBr.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][CH2:16][S:17][C:18]4[S:22][C:21]([CH3:23])=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc2c(s1)SCCC1CC(=O)N(c3ccc(Cl)cc3)N=C21
Agent: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Reaction time: 0.33 h
Yield: 61.5 %

Procedure:
To a solution of 3.6 g of 2-(4-chlorophenyl)-9-methyl-4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one in 50 ml of acetic acid is added dropwise a solution of 1.7 g of bromine in 15 ml of acetic acid stirring for 15 minutes at 40°-45° C. The mixture is stirred for 20 minutes at the same temperature and then poured into 200 ml of water. The precipitated crystals are collected by filtration and washed with water. The resulting crystals are subjected to column chromatography on silica gel and eluted with chloroform. The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 2.2 g of 2-(4-chlorophenyl)-9-methyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as pale brown crystals, melting at 150°-151° C.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:20]1[CH2:34][CH2:33][CH2:32][C@H:21]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([N:20]1[CH2:34][CH2:33][CH2:32][C@H:21]1[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 83 %

Procedure:
Diphenyl N-(Boc-D-Phe-Pro)amino(4-amidinophenyl)-methanephosphonate hydrochloride {Boc-D-Phe-L-Pro-(4-AmPhGly)P (OPh)2 }. Boc-D-Phe-OH (2.66 g, 10 mmole) and L-Pro-OBzl (2.42 g) were coupled using DCC, and Boc-D-Phe-Pro-OBzl was obtained in 83% yield; 1H NMR (CDCl3) δ 7.34 (s, 5H), 7.23 (m, 5H), 5.4 (d, 1H), 5.15 (q, 2H), 4.65 (m, 1H), 4.35 (m, 1H), 3.5 (m, 1H), 3.1-2.9 (m, 2H), 2.6 (m, 1H), 2.-1.7 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[F:24][C:25]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[CH:28]=[CH:27][C:26]=1[CH3:34]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:31]([C:29]3[CH:28]=[CH:27][C:26]([CH3:34])=[C:25]([F:24])[CH:30]=3)[C:32]2=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: Cc1ccc(N=C=O)cc1F
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc(C)c(F)c3)c(=O)n(C3CCCC3)c12
Yield: 66.8 %

Procedure:
1-Cyclopentyl-3-(3-fluoro-4-methyl-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (28 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-fluoro-5-isocyanato-2-methyl-benzene (0.5 mmol) following general procedure C. LCMS: m/z 420 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[Cl:11])=[N:4][CH:3]=1.O[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: Clc1nc[nH]c2ncc(Br)c1-2
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c3c(Cl)ncnc32)CC1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
To a solution of 5-bromo-4-chloro-1H-pyrrolo[2,3-d]pyrimidine (214 mg, 0.921 mmol), 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (556 mg, 2.76 mmol) and triphenylphosphine (483 mg, 1.841 mmol) in Tetrahydrofuran (THF) (10 mL) was added by drop wise DEAD (0.291 mL, 1.841 mmol). The solution was let stir at room temp. After 2 hr the reaction was concentrated and purified by silica gel chromatography to afford 1,1-dimethylethyl 4-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (330 mg, 86% yield) as a white solid
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8][CH:7]=1)=[O:4].[C:18]([OH:21])(=[O:20])C>[Pt]=O>[F:17][C:2]([F:1])([F:16])[C:3]([NH:5][CH:6]1[CH:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:9][N:8]([C:18]([O:21][C:10]([CH3:15])([CH3:11])[CH3:9])=[O:20])[CH2:7]1)=[O:4]
Reactant: CC(=O)O
Reactant: O=C(Nc1cncc2ccccc12)C(F)(F)F
Agent: O=[Pt]
Product: CC(C)(C)OC(=O)N1CC2CCCCC2C(NC(=O)C(F)(F)F)C1
Temperature: 2.5 °C
Reaction time: 15 h

Procedure:
A solution of 2,2,2-trifluoro-N-isoquinolin-4-ylacetamide (1.57 g) and platinum oxide (150 mg) in acetic acid (25 ml) was subjected to hydrogenation (5 atm) at 60° C. for 8 hr. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate, and evaporated under reduced pressure. The residue was extracted with THF (30 ml×2), and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. THF (25 ml) and diisopropylethylamine (1 g) were added to the residue, and the mixture was cooled to 0 to 5° C. Di-tert-butyl dicarbonate (1.42 g) was added and the mixture was stirred at room temperature for 15 hr. The solvent was evaporated under reduced pressure, and ethyl acetate (50 ml) was added to the residue. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with hexane-ethyl acetate (9:1-7:3) was concentrated under reduced pressure to give the object compound (1.8 g) as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:16])[CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[OH:8].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[CH3:16][N:4]([CH3:3])[CH2:5][CH2:6][CH:7]([O:8][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1
Reactant: CN(C)CCC(O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCC(Oc1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1
Reaction time: 0.75 h
Yield: 116.1 %

Procedure:
2.85 g of sodium hydride in a 50% oil suspension were added at 20° C. to a solution of 6.32 g of α-[2-dimethylamino-ethyl]-4-chlorobenzene methanol in 60 ml of dimethylformamide and 5.1 g of p-chloronitrobenzene were added thereto under nitrogen. The mixture was stirred for 45 minutes and 100 ml of water were added thereto at 25° C. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness to obtain 11.5 g of N,N-dimethyl-γ-(4-nitrophenoxy)-4-chlorobenzene-propanamine in the form of an orange oil.
Reaction SMILES: C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2(O)[CH2:34][CH2:33][CH:32]([CH:35]3[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][CH3:42])[CH2:36]3)[CH2:31][CH2:30]2)=[C:25]([F:44])[C:24]=1[F:45])[CH3:21]>O>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:34][CH2:33][CH:32]([CH:35]3[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][CH3:42])[CH2:36]3)[CH2:31][CH:30]=2)=[C:25]([F:44])[C:24]=1[F:45])[CH3:21]
Reactant: CCCC1CCC(C2CCC(O)(c3ccc(OCC)c(F)c3F)CC2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CCC(C2CC=C(c3ccc(OCC)c(F)c3F)CC2)C1
Temperature: 25 °C
Yield: 82 %

Procedure:
Toluene (50 ml) and p-toluenesulfonic acid monohydrate (0.15 g) were added to 1-(4-ethoxy-2,3-difluorophenyl)-4-(3-propylcyclopentyl)cyclohexanol (5.0 g) obtained in the first step, in a reaction vessel equipped with a Dean-Stark apparatus under an atmosphere of nitrogen. The mixture was refluxed for 1.5 hour, while forming water was removed with a Dean-Stark apparatus. After the mixture had been cooled to room temperature, the reaction solution was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane=1/10 by volume) to give 1-ethoxy-2,3-difluoro-4-(4-(3-propylcyclopentyl)cyclohex-1-enyl)benzene (3.9 g).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3C=C[S:42]C=3CCC2C)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[CH:18]=[CH:17][S:42][C:14]=3[CH2:15][CH2:16][CH:12]2[CH3:13])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2c3ccsc3CCC2C)n1
Product: CCc1nc(NC2c3ccsc3CCC2C)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.08, 6.87, 6.80, 5.55, 5.08, 4.45, 4.40, 2.91-2.78, 2.58, 2.22, 2.05-1.98, 1.79, 1.28, 1.10, 1.00.
Reaction SMILES: [C:1](=[O:27])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3](C(OC(C)(C)C)=O)[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[C:37]1([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[C:37]1([N:43]2[CH2:48][CH2:47][N:46]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]3)=[O:27])[CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)C(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(OCC1CCNCC1)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
(1-(tert-Butoxycarbonyl)piperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 2; 5.0 g, 13.1 mmol) was dissolved in DMF (30 mL). DIPEA (4.58 mL, 26.3 mmol) and 1-phenylpiperazine (2.01 mL, 13.1 mmol) were added. The reaction mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and then washed sequentially with sat aq NaHCO3 solution (6×200 mL), 10% citric acid solution (50 mL) and brine (50 mL). The solution was dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (20 mL) and TFA (10 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was dissolved in water (20 mL), sat aq NaHCO3 solution (100 mL) was added and the aqueous layer was extracted with DCM (3×200 mL). The combined organic layers were then washed with brine (50 mL), dried (MgSO4) and the solution was concentrated in vacuo to give (piperidin-4-yl)methyl 4-phenylpiperazine-1-carboxylate (3.825 g, 95.9% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][C:11]([F:26])([F:25])[C:12]1[CH:13]=[C:14]([NH:19][CH2:20][CH:21](O)[CH2:22][CH3:23])[CH:15]=[CH:16][C:17]=1[F:18]>CS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[N:19]([C:14]3[CH:15]=[CH:16][C:17]([F:18])=[C:12]([C:11]([F:26])([F:10])[F:25])[CH:13]=3)[CH2:20][CH:21]([CH2:22][CH3:23])[O:6]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCC(O)CNc1ccc(F)c(C(F)(F)F)c1
Reactant: O=Cc1cccc(Cl)c1
Agent: CS(=O)(=O)O
Product: CCC1CN(c2ccc(F)c(C(F)(F)F)c2)C(c2cccc(Cl)c2)O1

Procedure:
Meta-chlorobenzaldehyde (2.3 g, 0.016 mole) was combined with 5 g of 1-(3-trifluoromethyl-4-fluorophenylamino)-2-butanol and 3 drops of methane sulfonic acid was added. The mixture was heated on the steam bath for about one hour and stripped on the rotary evaporator. The product, a sticky, thick liquid, was characterized by IR and NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[S:16](=[O:18])(=[O:17])[CH2:15][CH2:14][CH2:13][S:12]2(=[O:20])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH2:23]([CH:25]1[O:27][CH2:26]1)Cl.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:23][CH:25]3[O:27][CH2:26]3)[S:12](=[O:19])(=[O:20])[CH2:13][CH2:14][CH2:15][S:16]2(=[O:17])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: ClCC1CO1
Reactant: COc1ccc(C2S(=O)(=O)CCCS2(=O)=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2(CC3CO3)S(=O)(=O)CCCS2(=O)=O)cc1OC
Temperature: 100 °C

Procedure:
9.6 of 2-(3,4-dimethoxyphenyl)-m-dithiane-1,1,3,3-tetraoxide (prepared as described in Example 2) are dissolved in 35 ml of dimethylformamide and, with stirring under argon, treated with 1.2 g of sodium hydride at room temperature. The suspension is stirred at 40° C for a further 0.5 hour, then cooled and treated with 2.8 g of epichlorohydrin. The mixture is then heated at 100° C for 16 hours. After cooling to room temperature, the suspension is poured on to water and the oily material extracted with chloroform. After evaporation of the solvent, the residue is chromatographed on silica gel with chloroform/ethanol (98:2). The 2-(3,4-dimethoxyphenyl)-2-(2,3-epoxypropyl)-m-dithiane-1,1,3,3-tetraoxide obtained is recrystallized from methylene chloride/ethanol and has a melting point of 175°-176° C.