Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a stirred mixture of 6-nitro-7-chloro-1,4-dihydro-2,3-quinoxalinedione (35 mg, 0.145 mMol) in ethanol (2 mL) was added SnCl2.2H2O (163 mg, 0.724 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring for 0.5 h to form a clear solution and continually refluxed for another 0.5 h. It was then cooled to room temperature and the yellow precipitate was collected by filtration, followed by washing with cold ethanol (1×1 mL) to give 25 mg (82%) of crude title compound (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 14 mg of pure title compound as bright yellow needles, mp: >350° C. (dec. from 335° C.). IR (KBr, cm-1): 3406, 3356, 3212, 1668, 1637, 1518, 1437. NMR (1H, DMSO-d6): d 5.306 (s, 2H); 6.551 (s, 1H); 6.940 (s, 1H); 11.606 (s, 1H); 11.788 (s, 1H). HRMS: calcd for C8H6N3O2Cl (M+) m/z: 211.0147; found 211.0159. Potency relative to DCK: 28.0%.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[CH:5][S:4][CH:3]=1.[C:8](OC)(OC)(OC)[CH2:9][CH2:10][CH2:11][CH3:12].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[CH2:9]([C:8]1[NH:1][C:2]2=[CH:3][S:4][CH:5]=[C:6]2[N:7]=1)[CH2:10][CH2:11][CH3:12]
Reactant: Nc1cscc1N
Reactant: CCCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCCCc1nc2cscc2[nH]1

Procedure:
To a solution of 3,4-diaminothiophene (156 mg) in ethanol (10 ml) was added trimethyl orthovalerate (0.29 ml) and pyridinium p-toluenesulfonate (4 mg). The mixture was refluxed for one hour and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel developed by ethyl acetate to give 2-butyl-1H-thieno[3,4-d]imidazole (155 mg) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH2:21][CH3:22])[CH2:15][C@H:14]1[C@@H:13]([CH3:23])[S:12][C:11]([NH:24]C(=O)C1C=CC=CC=1)=[N:10]2.FC1C=C(F)C=CC=1[C@]12CO[C@@H](COC)C[C@H]1[C@@H](C)SC(NC(=O)C1C=CC=CC=1)=N2.FC1C=C(F)C=CC=1[C@]12CO[C@@H](COC)C[C@H]1[C@@H](C)SC(N)=N2>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH2:21][CH3:22])[CH2:15][C@H:14]1[C@@H:13]([CH3:23])[S:12][C:11]([NH2:24])=[N:10]2
Reactant: CCOC[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: COC[C@H]1C[C@H]2[C@@H](C)SC(N)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: COC[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Product: CCOC[C@H]1C[C@H]2[C@@H](C)SC(N)=N[C@@]2(c2ccc(F)cc2F)CO1

Procedure:
N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(ethoxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C25) was deprotected using the method described for conversion of N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(methoxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C20) to (4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(methoxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine (2) in Example 2. The product was obtained as a white solid. Yield: 15.0 mg, 42.1 μmol, 79%. LCMS m/z 357.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.32 (ddd, J=9, 9, 7 Hz, 1H), 6.92-7.01 (m, 2H), 4.11 (dd, J=11.1, 2.0 Hz, 1H), 3.74-3.82 (m, 1H), 3.73 (d, J=11.1 Hz, 1H), 3.48-3.60 (m, 3H), 3.45 (dd, half of ABX pattern, J=10.4, 4.0 Hz, 1H), 3.06-3.14 (m, 1H), 2.75 (ddd, J=12.1, 3.9, 3.7 Hz, 1H), 1.57-1.64 (m, 1H), 1.36-1.47 (m, 1H), 1.15-1.22 (m, 6H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:13][C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])[CH2:15][CH3:16]>C1COCC1>[CH3:17][C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:8]3[CH:9]=[CH:10][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7]3)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:13])[CH2:15][CH3:16]
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: CCNC(=O)c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)c1ccn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)CC)n3CC2CCOCC2)c1
Yield: 40.1 %

Procedure:
Following the same procedure in Example 29, using N-ethyl-1H-pyrrole-3-carboxamide (166 mg, 1.2 mmol) (see the step B in example 31 for preparation), sodium hydride (240 mg, 60%, 6.0 mmol) and 2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (385 mg, 1.0 mmol) in THF (20 mL). The crude product was purified by MPLC using EtOAc on silica gel to give 195 mg (40%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.78 (t, J=7.42 Hz, 3 H), 1.13 (t, J=7.23 Hz, 3 H), 1.41-1.56 (m, 4 H), 1.59 (s, 6 H), 1.95 (q, J=7.49 Hz, 2 H), 2.21-2.35 (m, 1 H), 3.24-3.34 (m, 4 H), 3.85-3.94 (m, 2 H), 4.42 (d, J=7.62 Hz, 2 H), 6.65 (dd, J=3.32, 1.76 Hz, 1 H), 7.29 (dd, J=3.32, 2.34 Hz, 1 H), 7.78-7.82 (m, 1 H), 7.92 (d, J=8.8 Hz, 1 H), 7.96 (dd, J=8.8, 1.8 Hz, 1 H), 8.27 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=487.0; Anal. Calcd for C25H34N4O4S+110 TFA+0.1H2O (602.46): C, 53.83; H, 5.89; N, 9.30. Found: C, 53.79; H, 6.00; N, 9.19.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([C:20]1[N:21]([CH3:26])[N:22]=[C:23](O)[CH:24]=1)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:16][O:17][C:18]([C:20]1[N:21]([CH3:26])[N:22]=[C:23]([O:14][CH2:13][C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[N:10][C:11]=2[CH3:15])[CH:24]=1)=[O:19]
Reactant: Cc1nnn(-c2ccc(F)cc2)c1CO
Reactant: COC(=O)c1cc(O)nn1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(C)nnn2-c2ccc(F)cc2)nn1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.2 %

Procedure:
To a solution of [3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-methanol (500 mg, 2 mmol) in THF (30 mL) was added 5-hydroxy-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (377 mg, 2 mmol) and triphenylphosphine (823 mg, 3 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 1.44 mL, 3 mmol) was added and the reaction mixture was stirred for 24 h at room temperature. Concentration and purification by chromatography (silica, 20 to 50% ethyl acetate in heptane and then 2% methanol in dichloromethane) afforded the title compound (671 mg, 81%) as a white solid. MS: m/e=346.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18](Cl)[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[C:6]1=[O:17].C(O)C.COCCN(S(F)(F)[F:38])CCOC>ClCCl>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13]([F:38])=[CH:12][CH2:11]2)[C:6]1=[O:17]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COc1cc(Cl)c(CC2CCN(C3CCC(=O)CC3)C2=O)c(Cl)c1
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(CC2CCN(C3CC=C(F)CC3)C2=O)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
Dissolve 3-(2,6-Dichloro-4-methoxybenzyl)-1-(4-oxocyclohexyl)-pyrrolidin-2-one (Preparation 17) (2.09 g, 5.4 mmol) in dichloromethane (50 mL) and ethanol (0.06 mL, 1.08 mmol) and cool to 0° C. Add deoxo-fluor (1.69 mL, 9.18 mmol) over several minutes. Stir overnight at room temperature. Add saturated sodium bicarbonate and extract aqueous layer with dichloromethane. Wash the organic layer with brine and dry with Na2SO4, filter and concentrate to dryness. Purify the crude mixture over silica gel (4/1 hexane in ethyl acetate) to give 650 mg (32%) of the title compound: mass spectrum (m/e): 374 (M+1).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]1([Si:25]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:26]2[CH:27]=[CH:28][C:29]3[N:30]([Si](C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:31]4[C:36]([C:37]=3[CH:38]=2)=[CH:35][C:34]([Si:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:33][CH:32]=4)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:52]1([Si:39]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:34]2[CH:33]=[CH:32][C:31]3[NH:30][C:29]4[C:37]([C:36]=3[CH:35]=2)=[CH:38][C:26]([Si:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)=[CH:27][CH:28]=4)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: c1ccc([Si](c2ccccc2)(c2ccccc2)c2ccc3c(c2)c2cc([Si](c4ccccc4)(c4ccccc4)c4ccccc4)ccc2n3[Si](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: c1ccc([Si](c2ccccc2)(c2ccccc2)c2ccc3[nH]c4ccc([Si](c5ccccc5)(c5ccccc5)c5ccccc5)cc4c3c2)cc1
Reaction time: 1 h
Yield: 120.8 %

Procedure:
A TBAF solution (1M in THF, 4.6 ml, 4.6 mmol) is added to a solution of 3,6,9-tris-(triphenylsilyl)carbazole (8.7 g, 9.2 mmol) in CH2Cl2 (150 ml). After stirring for one hour, thin layer chromatography shows complete deprotection. The solvent is removed under reduced pressure, and the residue is heated under reflux in cyclohexane (150 ml). After cooling, the suspension is filtered. The residue is filtered through SiO2 (10:1 cyclohexane:EtOAc) to obtain the desired product (7.6 g, 97%). 1H NMR (CDCl3, 400 MHz): δ=7.4 (m, 20H), 7.6 (m, 14H), 8.18 (s, 2H), 8.20 (s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([N:21]1[CH2:25][CH:24]([OH:26])[C@:23]([CH3:34])([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.O>[CH2:11]([O:18][C:19]([N:21]1[CH2:25][C:24](=[O:26])[C@:23]([CH3:34])([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)[C@]1(C)CN(C(=O)OCc2ccccc2)CC1O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)[C@]1(C)CN(C(=O)OCc2ccccc2)CC1=O
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
To a solution of oxalyl chloride (1.01 mL, 11.7 mmol) in dichloromethane (40 mL), a solution of dimethyl sulfoxide (1.11 mL, 15.6 mmol) in dichloromethane (5 mL) was added at −78° C., and the mixture was stirred for 10 minutes. After adding a solution of tert-butyl (R)-1-benzyloxycarbonyl-4-hydroxy-3-methylpyrrolidine-3-carboxylate (1.97 g, 5.87 mmol) in dichloromethane (15 mL) and stirring the mixture for 1 hour, triethylamine (5.98 mL, 42.9 mmol) was added, and the mixture was stirred −78° C. for 30 minutes and in an ice bath for 30 minutes. To the reaction mixture were added saturated aqueous solution of ammonium chloride (50 mL) and water (100 mL), and the mixture was extracted with ethyl acetate (200 mL×2). The organic layer was washed with water (100 mL) and saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate=10:1→3:2) to obtain 1.68 g (85.8%) of the title compound as a colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CS(C)=O>[CH2:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C=CCOc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
The reaction mixture of 4-hydroxybenzoic acid, methyl ester (20.0 g, 131.0 mmol), allyl bromide (17.0 g, 138.0 mmol) and potassium carbonate (45.0 g, 329.0 mmol) in DMSO (30.0 mL) was stirred at room temperature for 8 hours. EtOAc (150 mL) was added, and the organic phase was washed with water (30×3 mL). The organic layer was dried over MgSO4. The solvent was removed. The product thus obtained was of sufficient quality for use in the next step without further purification, (25.0 g, yield 99%). 1H NMR (400 MHz, CDCl3) δ ppm 7.91 (2H, m), 6.86 (2H, m), 5.98 (1H, dt, J=17.2, 5.3 Hz), 5.35 (1H, dd, J=17.2, 1.6 Hz), 5.24 (1H, dd, J=10.6, 1.6 Hz), 4.52 (2H, d, J=5.5 Hz), 3.81 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O[CH2:16][CH2:17][O:18][C:19](=[O:31])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH2:16][CH2:17][O:18][C:19](=[O:31])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:11])=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)OCCO
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(COc1ccc([N+](=O)[O-])cc1)OCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a mixture of (4-nitrophenoxy)acetic acid 22 (80 g, 406 mmol) and (4-nitrophenoxy)-acetic acid-2-hydroxyethyl ester 23 (80 g, 332 mmol) in anhydrous dichloro-methane (2 L) under nitrogen atmosphere was added a solution of 1,3-di-cyclohexyl carbodiimide (128 g, 620 mmol) in anhydrous dichloromethane (750 ml) drop wise. The reaction mixture was stirred at room temperature for 8 hours. The solids were filtered off and dichloromethane distilled off to get crude 24. The crude 24 was purified by column chromatography on silica gel using hexane:ethyl acetate (95:5) to get pure 24 (75 grams, 54%) as a white powder with an m.p. between 138-139° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:10]([O:17][C:18]([NH:20][CH:21]([CH2:25][CH2:26][S:27][CH3:28])[C:22](O)=[O:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(Cl)CCl>C(#N)C.O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:22](=[O:23])[CH:21]([NH:20][C:18](=[O:19])[O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:25][CH2:26][S:27][CH3:28])[CH:6]=[CH:7][CH:8]=1
Reactant: CSCCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1c(N)cccc1Br
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CSCCC(NC(=O)OCc1ccccc1)C(=O)Nc1cccc(Br)c1C
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 54.9 %

Procedure:
Step 1 A solution of 3-bromo-2-methylaniline (0.662 mL, 5.37 mmol) and racemic 2-(benzyloxycarbonylamino)-4-(methylthio)butanoic acid (1.523 g, 5.37 mmol) in acetonitrile (25 mL) was treated with 1-hydroxy-7-azabenzotriazole (0.878 g, 6.45 mmol), diisopropylethylamine (1.877 mL, 10.75 mmol) and EDC (1.236 g, 6.45 mmol) and stirred at rt. After 20.5 h, the mixture was diluted with water and ethyl acetate. The organic phase was separated, washed with 1 M aqueous HCl and NaHCO3 (aq) and filtered to remove a flocculent white solid. The filtrate was dried and concentrated, and the residue was recrystallized from ethanol to give racemic benzyl 1-(3-bromo-2-methylphenylamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate as a tan solid (1.33 g, 69%). 1H NMR (400 MHz, chloroform-d) δ 8.08 (1H, br. s.), 7.68 (1H, d, J=7.9 Hz), 7.39 (1H, d, J=7.9 Hz), 7.34 (5H, s), 7.04 (1H, t, J=8.0 Hz), 5.58 (1H, d, J=7.9 Hz), 5.14 (2H, s), 4.53 (1H, q, J=7.0 Hz), 2.55-2.72 (2H, m), 2.28 (3H, br. s.), 2.17-2.27 (1H, m), 2.12 (3H, s), 2.01-2.10 (1H, m). Mass spectrum m/z 451, 453 (M+H)+.
Reaction SMILES: C([O:3][CH:4]1[CH:8]([NH:9][C:10]([CH:12]2[N:16]3[C:17](=[O:36])[CH:18]([NH:23][C:24]([C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][N:27]=4)=[O:25])[CH2:19][CH:20]=[CH:21][CH2:22][CH:15]3[CH2:14][CH2:13]2)=[O:11])[CH2:7][C:6](=[O:37])[O:5]1)C.FC(F)(F)C(O)=O>O>[OH:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:16]3[C:17](=[O:36])[C@@H:18]([NH:23][C:24]([C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][N:27]=4)=[O:25])[CH2:19][CH:20]=[CH:21][CH2:22][C@@H:15]3[CH2:14][CH2:13]2)=[O:11])[CH2:7][C:6](=[O:37])[O:5]1
Reactant: CCOC1OC(=O)CC1NC(=O)C1CCC2CC=CCC(NC(=O)c3nccc4ccccc34)C(=O)N21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(NC(=O)[C@@H]2CC[C@H]3CC=CC[C@H](NC(=O)c4nccc5ccccc45)C(=O)N32)C(O)O1
Yield: 78 %

Procedure:
6-[(Isoquinoline-1-carbonyl)-amino]-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid (2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide, 15, (1.42 g, 2.80 mmol) is stirred in a solution of trifluroacetic acid 5 mL acetonitrile 5 mL, and water 2.5 mL for 2 hours. Solvents are removed in vacuo and the resulting residue dissolved in ethyl acetate and re-concentrated to remove any excess TFA. The crude product is purified over silica (ethyl acetate:0.1% acetic acid,) to afford 1.18 g (78% yield) of the desired product as a yellow foam. 1H NMR (CDCl3): δ 9.30 (m, 1H), 8.85 (d, 7.6 Hz, 1H), 8.48 (d, J=5.4 Hz, 1H), 7.87–7.34 (m, 6H), 5.92–5.71 (m, 3H), 5.54 (m, 1H), 4.71–4.35 (m, 3H), 3.03 (m, 4H), 2.43 (m, 3H), 2.19 (m, 2H), 1.98 (m, 1H). 13C NMR (CDCl3): δ 173.9, 172.5, 171.4, 165.9, 147.9, 140.7, 137.6, 131.4, 130.8, 128.9, 127.5, 127.2, 125.6, 124.9, 61.7, 59.1, 50.4, 34.2, 33.4, 32.3, 27.0. ESI MS 479.11 (M+H). HRMS calc. 479.1931, found 479.1941.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[I:7][C:8]1[CH:9]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH:11]=[CH:12][CH:13]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[I:7][C:8]1[CH:9]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCCCCl)c1cccc(I)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(I)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(3-iodophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 533.0 (M+H)+.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.C(CCCCCCCCCCCCCCCC(O)=S)(=O)C.[CH:47]1([N:53]=[C:54]=[N:55][CH:56]2[CH2:61][CH2:60][CH2:59]CC2)CCCCC1>O1CCCC1>[CH3:1][N:53]([C:54]1[CH:59]=[CH:60][CH:61]=[CH:56][N:55]=1)[CH3:47]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(=O)CCCCCCCCCCCCCCCC(O)=S
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 120 mg of radicicol, 206 mg of 16-acetylthiohexadecanoic acid, 5 ml of dry tetrahydrofuran, 330 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 235 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][C:26](Cl)=[O:27])[CH3:22].CC[O-].[Na+]>C1C=CC=CC=1.O>[CH2:21]([O:23][C:24]([C:25]1[C:26](=[O:27])[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:5]2[C:6]([C:8]=1[CH3:9])=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:29])[CH3:22]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COc1ccc(CNc2ccc(Cl)cc2C(C)=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1c(C)c2cc(Cl)ccc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 80 °C
Yield: 83.5 %

Procedure:
A solution of 2 (0.20 g, 1.18 mmol) in 3 mL of anhydrous benzene was treated with ethyl-3-chloro-3-oxopropionate (165 μL, 0.20 g, 1.30 mmol). The reaction mixture was heated to 80° C. for 1 h. The reaction was allowed to cool to room temperature and was concentrated in vacuo. The resulting oil was dissolved in 3 mL of ethanol, treated with NaOEt (40.0 mg, 0.59 mmol). The suspension was heated to 80° C. for 10 min, allowed to cool to room temperature, and diluted with H2O. The resulting white precipitate was filtered to give 3 (0.38 g, 80%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.69 (d, J=2.3 Hz, 1H), 7.39 (dd, J=2.3, 9 Hz, 1H), 7.26 (d, J=9 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 6.81 (d, j=8.6 Hz, 2H), 5.47 (br S, 2H), 4.46 (q, J=7.2 Hz, 2H), 3.75 (s, 3H), 2.46 (s, 3H), 1.43 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([NH:21][CH2:18][CH2:19][CH3:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCNC1CCC(Cc2ccccc2)(N(C)C)CC1

Procedure:
6.00 g 4-benzyl-4-dimethylamino-cyclohexanone (see example 3) were dissolved in 90 ml analytical grade tetrahydrofuran, and 1.53 g n-propylamine followed by 3.36 ml glacial acetic acid were added, while stirring in an ice-bath. 7.68 g sodium triacetoxyborohydride were then added in portions in the course of 15 minutes and the mixture was subsequently stirred for approx. 65 hours. For working up, 45 ml two molar sodium hydroxide solution were added dropwise (pH>10) and the mixture was extracted three times with 50 ml diethyl ether each time. The combined organic phases were washed twice with 50 ml water each time, dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained (6.43 g) was chromatographed over silica gel with diethyl ether with the addition of five percent by volume of aqueous ammonia solution (25 wt. %). 707 mg of the nonpolar diastereoisomer of 1-benzyl-N,N-dimethyl-N′-propyl-cyclohexane-1,4-diamine were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:16]1[N:25]=[C:24]2[C:19]([C:20](=[O:38])[C:21]([C:33]([O:35]CC)=[O:34])=[CH:22][N:23]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:18][C:17]=1[F:39]>C(O)C>[F:39][C:17]1[CH:18]=[C:19]2[C:24](=[N:25][C:16]=1[N:12]1[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]1)[N:23]([C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[CH:22]=[C:21]([C:33]([OH:35])=[O:34])[C:20]2=[O:38]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2nc(Cl)c(F)cc2c1=O
Solvent: CCO
Product: COc1ccccc1N1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)CC1
Yield: 63.1 %

Procedure:
In 40 ml of ethanol was dissolved 0.81 g (0.0042 mole) of 1-(2-methoxyphenyl)piperazine, and to the solution was added gradually 1.02 g (0.0028 mole) of ethyl 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3carboxylate at 30° C. while stirring. After completion of the addition, the mixture was reacted at the same temperature for 4 hours. After the reaction mixture was cooled, crystals precipitated were collected by filtration and washed with ethanol. To the crystals were added 12 ml of a 6N hydrochloric acid aqueous solution, and the mixture was refluxed by heating for 6 hours. After cooling, the reaction mixture was adjusted to pH 8.5 with a 1N sodium hydroxide aqueous solution, and crystals precipitated were collected by filtration and applied to silica gel column chromatography (the eluent used was a mixture of chloroform:methanol=9.5:0.5) to obtain 0.87 g of the title compound as slightly yellow powder.