Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.COC1C=CC(C[S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C@H:12]([C:28]([NH:30][C@@H:31]3[CH2:35][CH2:34][NH:33][CH2:32]3)=[O:29])[CH2:11]2)=CC=1.[N+:38]([C:41]1[CH:53]=[CH:52][C:44]([CH2:45][O:46][C:47]([NH:49][CH:50]=N)=[O:48])=[CH:43][CH:42]=1)([O-:40])=[O:39]>>[SH:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([C:28]([NH:30][C@@H:31]2[CH2:35][CH2:34][N:33]([CH:50]=[N:49][C:47]([O:46][CH2:45][C:44]3[CH:52]=[CH:53][C:41]([N+:38]([O-:40])=[O:39])=[CH:42][CH:43]=3)=[O:48])[CH2:32]2)=[O:29])[CH2:11]1
Reactant: N=CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@@H]3CCNC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Cl
Product: O=C(N=CN1CC[C@@H](NC(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Yield: 52.9 %

Procedure:
Following a procedure similar to that described in Preparations 23(iii) and 23(iv), but using 1.38 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-[(3R)-pyrrolidin-3-ylaminocarbonyl]pyrrolidine hydrochloride and 564 mg of N-(4-nitrobenzyloxycarbonyl)formamidine, 795 mg of the title compound were obtained as a powder.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:3]([OH:23])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(N2CCOCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 86.7 %

Procedure:
A solution of 3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionic acid methyl ester (210.8 mg, 0.66 mmol) in tetrahydrofuran (830 μL) was treated with a 0.8M aqueous lithium hydroxide solution (1.2 mL). The reaction mixture was stirred at 25° C. for 23 h and then concentrated in vacuo to remove tetrahydrofuran. The white residue was acidified to pH=2 with a 10% aqueous hydrochloric solution. The resulting aqueous phase was extracted with ethyl acetate (2×75 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Trituration from hexanes/diethyl ether afforded 3-cyclopentyl-2-(4-morpholin-4-yl-phenyl)-propionic acid (173.7 mg, 86%) as a white solid: mp 145-147° C.; EI-HRMS m/e calcd for C18H25NO3 (M+) 303.1834, found 303.1843.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH2:16][CH2:17][CH3:18])=[N:14][CH:13]=[N:12]2)=[CH:7][CH:6]=1)([O-])=O.[H][H]>[Pd].CO>[ClH:1].[ClH:1].[CH2:16]([C:15]1[N:11]([C:8]2[CH:7]=[CH:6][C:5]([NH2:2])=[CH:10][CH:9]=2)[N:12]=[CH:13][N:14]=1)[CH2:17][CH3:18]
Reactant: [H][H]
Reactant: CCCc1ncnn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCc1ncnn1-c1ccc(N)cc1
Yield: 91 %

Procedure:
A mixture of 38.3 parts of 1-(4-nitrophenyl)-5-propyl-1H-1,2,4-triazole monohydrochloride and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in water and neutralized with sodium hydrogen carbonate. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanol. The salt is filtered off and dried, yielding 35 parts (91%) of 4-(5-propyl-1H-1,2,4-triazol-1-yl)benzenamine dihydrochloride.
Reaction SMILES: [C:1]([O:18]CC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:21][OH:22].[Na].OC1C=CC2C(=CC=CC=2)N=1>C(O)C>[C:1]([NH:21][OH:22])(=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC
Reactant: NO
Agent: Oc1ccc2ccccc2n1
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCCCCCCC(=O)NO
Reaction time: 5 h
Yield: 85 %

Procedure:
14.2 g. of ethyl palmitate and 2 g. of hydroxylamine are reacted at room temperature in 300 ml. of ethanol in the presence of 1.7 g. of the sodium salt of 2-hydroxyquinoline. The reaction is complete in 5 hours, and 11.7 g, of palmitohydroxamic acid are obtained (yield: 85%), m.p. 100° - 101° C. after recrystallization from ethanol-petroleum ether(1:1).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][C:5]=1[CH:14]1[CH2:18][CH2:17][O:16][CH2:15]1.C1([O:27][C:28](=O)[NH:29][C:30]2[CH:35]=[C:34]([O:36][CH:37]([CH3:39])[CH3:38])[C:33]([C:40]#[N:41])=[CH:32][N:31]=2)C=CC=CC=1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[C:40]([C:33]1[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[CH:35][C:30]([NH:29][C:28]([N:11]2[C:12]3[C:7](=[CH:6][C:5]([CH:14]4[CH2:18][CH2:17][O:16][CH2:15]4)=[C:4]([CH:3]([O:2][CH3:1])[O:19][CH3:20])[N:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:27])=[N:31][CH:32]=1)#[N:41]
Reactant: CC(C)Oc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Reactant: COC(OC)c1nc2c(cc1C1CCOC1)CCCN2
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)c1nc2c(cc1C1CCOC1)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of (racemic) 7-(dimethoxymethyl)-6-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine (Intermediate 337, 230 mg, 0.45 mmol), phenyl(5-cyano-4-isopropoxypyridin-2-yl)carbamate (Intermediate 96, 405 mg, 1.36 mmol) and DMAP (170 mg, 1.36 mmol) in DMF (2.7 ml) was stirred at 90° C. After 1 h, the reaction mixture was cooled to room temperature, diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine, dried over Na2SO4 and evaporated. The crude material was applied to a 12 g RediSep silica column and purified by normal phase chromatography, eluting with eluting with a gradient from 1% to 100% EtOAc/heptanes. Product-containing fractions were combined and evaporated. The resulting material was applied to a 12 g RediSep silica column and purified by normal phase chromatography, eluting with eluting with a gradient from 1% to 50% MeOH/DCM. Product-containing fractions were combined and evaporated to give the title compound as a white solid. (UPLC-MS 6) tR 1.28; ESI-MS 482.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].[I:26][C:27]1[CH:28]=[C:29]([CH2:33][NH2:34])[CH:30]=[CH:31][CH:32]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]=[CH:15][C:16]([C:19]([NH:34][CH2:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([I:26])[CH:28]=3)=[O:21])=[CH:17][N:18]=2)[CH2:8]1)[CH3:2]
Reactant: NCc1cccc(I)c1
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cccc(I)c3)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A mixture of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (2.00 g, 5.82 mmol), (3-iodophenyl)methanamine (1.00 mL, 7.20 mmol), N-methyl morpholine (2.00 mL, 18 mmol), EDCl (1.2 g, 5.9 mmol), and HOBT (455 mg, 2.91 mmol) in THF (30 mL) was stirred at room temperature overnight. The reaction was diluted with EtOAc (50 mL). The organic layer was washed with saturated aqueous solution of NH4Cl (50 mL), saturated aqueous solution of NaHCO3 (50 mL), and brine (50 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by flash column chromatography (0-50% EtOAc in Heptanes) to afford (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(3-iodobenzyl)pyrimidine-5-carboxamide (2.39 g, 74%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 2H), 7.69 (m, 1H), 7.64 (m, 1H), 7.32 (m, 1H), 7.10 (t, 1H), 6.98 (m, 2H), 6.88 (m, 2H), 6.13 (t, 1H), 4.58 (d, 2H), 4.48 (dd, 1H), 4.25 (m, 1H), 4.18 (m, 1H), 4.01 (m, 2H), 3.77 (dd, 1H), 3.64 (m, 1H), 2.13 (m, 1H), 1.97 (m, 2H), 1.59 (m, 1H), 1.39 (t, 3H). MS (ES+) 559.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].O1CCCC1.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Ni]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.75 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), tetrahydrofuran (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (25 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml tetrahydrofuran. The cis to trans ratio is 85 to 87/15 to 13. The amount of dehalogenated byproduct is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.75 to 0.78%].
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)C.[CH3:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[CH:11]1[O:13]C1>>[C:9]1([CH3:8])[C:10]([CH:11]=[O:13])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccccc1C1CO1
Agent: C[S+](C)C
Agent: [H-]
Agent: [I-]
Product: Cc1ccccc1C=O

Procedure:
Following the procedure of Example 16 and employing 57% sodium hydride (4.84 g., 0.115 mol), 23.5 g. (0.115 mol) of trimethylsulfonium iodide and 11.5 g. (0.0926 mol) of o-tolualdehyde there is obtained o-methylstyrene oxide.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([OH:35])=O)=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:36][C@@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:35])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:16]=23)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c8) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N:18](C)[C:19](=O)OC(C)(C)C)=[CH:14][CH:13]=2)[CH:3]=1.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[CH:14][CH:13]=2)[CH:3]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc(F)c3ccccc3n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(-c2cc(F)c3ccccc3n2)cc1
Yield: 54.9 %

Procedure:
tert-Butyl (4-(4-fluoroquinolin-2-yl)phenyl)(methyl)carbamate (4.5 mg, 0.013 mmol) was treated with TFA by using general procedure P. The crude product was purified by HPLC to afford T466 as an orange-colored solid (1.8 mg, 55%). 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J=8.4 Hz, 1H), 8.02-7.97 (m, 3H), 7.75 (t, J=7.6 Hz, 1H), 7.56 (d, J=10.0 Hz, 1H), 6.72 (d, J=8.4 Hz, 2H), 2.95 (s, 3H); MS (ESI): 253 (M+H+).
Reaction SMILES: [C:1]([O:10][CH2:11][CH:12]([OH:24])[CH2:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.Cl[C:32]([CH2:34][CH2:35][CH2:36][C:37]([O:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1[O:47][C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=1[Cl:55])=[O:38])=[O:33]>C(Cl)(Cl)Cl.CCOCC.O>[C:37]([O:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1[O:47][C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=1[Cl:55])(=[O:38])[CH2:36][CH2:35][CH2:34][C:32]([O:24][CH:12]([CH2:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][O:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:33]
Reactant: CCCCCCCC(=O)OCC(O)COC(=O)CCCCCCC
Reactant: O=C(Cl)CCCC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OC(=O)CCCC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-3-octanoyloxy-propyl octanoate (7.0 g.) and pyridine (1.5 g.) in chloroform (100 ml.) was treated dropwise at 0°-5° C. with a solution of 5-chloro-2-(2,4-dichlorophenoxy)phenyl 4-chloroformylbutyrate (A) (8.4 g.). The reaction mixture was then stirred at ambient temperature for 1 hour and diluted with ether (300 ml.) and water (200 ml). The organic phase was separated, washed successively with 2M hydrochloric acid (50 ml.), saturated sodium bicarbonate solution (3×50 ml.), and then dried (MgSO4) and evaporated. The residual oil was purified by chromatography on silica gel (50 g.) using a mixture of petrol 60-80 and ether (70:30 v/v) as eluant to give 5-chloro-2-(2,4-dichlorophenoxy)phenyl 2-octanoyloxy-1-(octanoyloxymethyl)ethyl glutarate as an oil.(9.1 g.); NMR (CDCl3): 0.9 (6H, t J=4.0 Hz, CH3), 1.1-7 (20H, complex m, CH2 ), 1.98 (2H,m, CH2), 2.2-2.7 (8H, complex, CO.CH2), 4.0-4.5 (4H,complex, CH2O), 5.25 (1H, br.t J=4.5 Hz, CH), 6.75-7.55 (6H,complex, aromatic H)ppm; mass spectrum (major diagnostic peaks): m/e 585 (16%) [M-0.CO(CH2)6CH3 ], 441. (21%), 385 (12%), 327 (100%), 288 (10%), 201 (10%), 127 (46%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]([O:14]CC)=[O:13])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[OH-].[Na+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CO.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=[O:13])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: CCOC(=O)Cn1cnc2c(-c3ccco3)nc(N)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1nc(-c2ccco2)c2ncn(CC(=O)O)c2n1
Yield: 72.1 %

Procedure:
A solution of ethyl 2-amino-6-(2-furyl)-9H-purine-9-acetate (200 mg, 0.69 mmol) in MeOH (3 mL) was treated with aq NaOH (2-M, 0.5 mL, 1 mmol), refluxed for 10 min, cooled, diluted with water, acidified with aq HCl (1-M) and the resulting solid filtered, washed with water and dried to give the title compound (129 mg, 72%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(CO)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3-Benzyloxy-4-nitrobenzaldehyde (10.3 g, 0.040 mol) is dissolved in methanol (120 mL) with heating and then cooled to 0° C. To this stirred solution, sodium borohydride (1.5 g, 0.40 mol) is added in portions over a period of 5 min. The mixture is allowed to warm to RT and stirred for 18 h. The solvent is removed under reduced pressure and EtOAc is added. The organic layer is washed with 1N HCl and brine, dried over sodium sulfate/magnesium sulfate, and concentrated to afford the title compound as a yellow-brown solid: (M+NH4)+=277.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[N:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>C(#N)C>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[N:4][CH:3]=1
Reactant: N#Cc1ncc(Br)c2ccccc12
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CC#N
Product: COc1ccc(CNc2cnc(C#N)c3ccccc23)c(OC)c1
Yield: 30.3 %

Procedure:
A mixture of compound 470B (699 mg, 3.00 mmol) and 2,4-dimethoxybenzylamine (4.8 mL, 30 mmol) in 15 mL of acetonitrile was refluxed for 16 h. After concentration in vacuo, the residue was purified on a 5×15 cm silica gel column, eluting with 3:2 hexane:ethyl acetate to afford 290 mg (30%) of 470C as a light yellow solid. HPLC: 1.76 min (retention time) (Phenomenex C-18, 5 micron column, 4.6×30 mm, eluting with 10-90% aqueous methanol over 2 min containing 0.1% TFA, 4 mL/min, monitoring at 254 nm).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:9])[CH:3]=1
Reactant: Nc1ccc(I)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(I)cc1N
Yield: 92 %

Procedure:
Commercial 4-iodo-2-nitroaniline was reduced with 5 eq tin dichloride dihydrate in ethanol solution (75° C., 2 h) to give 92% 4-iodo-1,2-phenylenediamine as light red solid.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][O:30][CH2:31][C@H]1CC[C@H](N)CC1.C(=O)CC(C)C.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:29][O:30][CH2:31][C@H:4]1[CH2:5][CH2:6][C@H:1]([N:7]([CH2:21][CH2:22][CH:23]([CH3:28])[CH3:24])[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:2][CH2:3]1
Reactant: COC[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: CC(C)CC=O
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COC[C@H]1CC[C@H](N(CCC(C)C)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
{2-[3-(trans-4-Methoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid was prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethylureido)-thiazol-5-ylsulfanyl]-acetic acid using, trans-4-methoxymethyl-cyclohexylamine, isovaleraldehyde and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:35]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)#[N:36]>CN(C1C=CN=CC=1)C>[C:35]([C:37]1[CH:38]=[CH:39][C:40]([S:43]([N:23]2[CH2:24][CH2:25][CH:20]([C:11]3[C:10]4[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:9]=4)[NH:13][N:12]=3)[CH2:21][CH2:22]2)(=[O:45])=[O:44])=[CH:41][CH:42]=1)#[N:36]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)cc1
Yield: 41.2 %

Procedure:
Following the general procedure of Example 11, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) (50 mg, 0.14 mmol), diisopropylethylamine (100 uL, 0.56 mmol), DMAP (25 mg, 0.014 mmol) and 4-cyanobenzenesulfonyl chloride (34 mg, 0.168 mmol) were reacted to give the title compound (28 mg, 41%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:13]SC)=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1Cl.C(O)C>[OH-].[K+].[Ni]>[NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CSCc1c(C(F)(F)F)ccc(Cl)c1N
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(N)cccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Dissolve 2 g. of 3-amino-4-chloro-2-methylthiomethylbenzotrifluoride in 50 ml. of 90% ethanol which is 1 N in potassium hydroxide. Add 2 teaspoonfuls of Raney nickel (W-2). Stir at 70° C. for 3 hours, cool and filter. Add 50 ml. of water and extract three times with hexane. Dry and evaporate the combined organic extracts to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C([Li])(C)(C)C.CCCCC.[CH2:21]([C:28]1([N:35]([CH3:37])[CH3:36])[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([C:28]1([N:35]([CH3:36])[CH3:37])[CH2:33][CH2:32][C:31]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)([OH:34])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cn1ccc2ccccc21
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CN(C)C1(Cc2ccccc2)CCC(O)(c2cc3ccccc3n2C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
A solution of N-methylindole (1.50 mg, 3.81 mmol) in dry THF (20 ml) was cooled to −5° C. under a stream of argon. Thereafter, tert-butyllithium (4.19 mmol, 2.47 ml of a 1.7 molar pentane solution) was added dropwise such that a reaction temperature of 0° C. was not exceeded during the addition. When the addition had ended the reaction mixture was stirred for a further two hours at 0° C. A solution of 4-benzyl-4-dimethylaminocyclohexanone (3.88 mg, 3.81 mmol) in dry THF (7 ml) was then added dropwise at 0° C. The mixture was stirred for 15 minutes at 0° C. and then for four hours at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution (20 ml), the organic phase was separated and the aqueous phase was extracted four times with methylene chloride (20 ml). The combined organic phases were dried over sodium sulfate and filtered and the solvent was removed in vacuo. Purification was carried out by means of flash chromatography over silica gel with cyclohexane/ethyl acetate (v/v=4:1). 456 mg 4-benzyl-4-dimethylamino-1-(1-methyl-1H-indol-2-yl) cyclohexanol with a melting point of 105-107° C. were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][C:15]([OH:17])=[O:16])[CH2:9]1)=O)(C)(C)C.[CH2:18](O)[CH3:19]>>[NH:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CC(=O)O)C1
Product: CCOC(=O)C[C@H]1CCCNC1
Reaction time: 1 h

Procedure:
To a mixture of (R)-2-(1-(tert-butoxycarbonyl)piperidin-3-yl)acetic acid (6 g, 24.66 mmol) in ethanol (20 mL) was bubbled HCl (g) for 10 minutes. The reaction mixture was stirred for 1 hr and then HCl was bubbled through the mixture for 5 minutes. After 1 hour, solvents were removed from the mixture in vacuo. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3. The aqueous layer was backextracted 2 times with 10% IPA/chloroform. The organic layers were combined, dried, and concentrated in vacuo to yield 4.05 g of (R)-ethyl 2-(piperidin-3-yl)acetate. MS (M+1)=172. HPLC Peak RT=0.96 minutes.