Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[Br:13]Br.O>C(O)(=O)C>[Br:13][C:8]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[CH:9]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Br)c(C=O)cc1OC
Reaction time: 8 h

Procedure:
3,4-Dimethoxybenzaldehyde (398.8 g) is dissolved in acetic acid (1.8 liter), and thereto is added dropwise bromine (136 ml) at room temperature over a period of four hours. The mixture is stirred overnight, and thereto is added dropwise slowly again bromine (60 ml), and the mixture is stirred overnight. The reaction solution is added to water (7 liters), and the precipitated crystals are collected by filtration, washed with water, and dissolved in chloroform (2 liters). The chloroform solution is washed, dried, concentrated, and the residue is crystallized from diisopropyl ether to give 6-bromo-3,4-dimethoxybenzaldehyde (470 g) as a colorless crystal.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[C:3]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].O.NN>[Ni].C(O)C>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:4]1[C:5]([CH3:7])=[CH:6][N:2]([CH3:1])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])c(C)cn1C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(Nc2ccccc2N)c(C)cn1C
Reaction time: 0.75 h
Yield: 80.5 %

Procedure:
A suspension of Raney nickel in ethanol is added to a warm solution (50° C.) of 80 g of ethyl 1,4-dimethyl-3-(2-nitrophenyl)amino-1H-pyrrole-2-carboxylate and 30 ml of hydrazine hydrate in 2 l of ethanol in such portions that a temperature of 70° C. is not exceeded. After 45 minutes nitrogen evolution is no longer observed when Raney nickel is added. The Raney nickel is filtered off hot and is washed with ethanol. After concentration of the filtrate, 58 g (82%) of the title compound of m.p. 90° C. (from isopropanol) are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([N+:13]([O-])=O)=[CH:6][C:5]=1[CH:16]([C:32]1[CH:37]=[C:36]([N+:38]([O-])=O)[CH:35]=[C:34]([CH:41]([CH3:43])[CH3:42])[C:33]=1[O:44][CH2:45][CH3:46])[C:17]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=1[O:29][CH2:30][CH3:31])[CH3:2]>CCO.C1COCC1.[Ni]>[CH:16]([C:17]1[C:18]([O:29][CH2:30][CH3:31])=[C:19]([CH:26]([CH3:28])[CH3:27])[CH:20]=[C:21]([CH:22]=1)[NH2:23])([C:32]1[C:33]([O:44][CH2:45][CH3:46])=[C:34]([CH:41]([CH3:43])[CH3:42])[CH:35]=[C:36]([CH:37]=1)[NH2:38])[C:5]1[C:4]([O:3][CH2:1][CH3:2])=[C:9]([CH:10]([CH3:11])[CH3:12])[CH:8]=[C:7]([CH:6]=1)[NH2:13]
Reactant: CCOc1c(C(C)C)cc([N+](=O)[O-])cc1C(c1cc([N+](=O)[O-])cc(C(C)C)c1OCC)c1cc([N+](=O)[O-])cc(C(C)C)c1OCC
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1c(C(C)C)cc(N)cc1C(c1cc(N)cc(C(C)C)c1OCC)c1cc(N)cc(C(C)C)c1OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a three-neck round-bottom flask, a sample of 4 (3.63 g, 5.69 mmol) was dissolved in a solution of EtOH/THF (25/180 mL). Rainey nickel (˜100 mg) was added to the mixture, which was then degassed by the freeze-pump-thaw method and the flask was backfilled with anhydrous H2 gas. The reaction was stirred at room temperature under a constant H2 stream for two days and then filtered to remove the Rainey nickel The solvent was removed under reduced pressure. The residue was dissolved in diethyl ether and extracted with a 10% HCl solution (3×, 50 mL). The aqueous phase was washed with hexanes (3×50 mL) followed by addition of 2 M NaOH to a final pH of 10. The precipitated solid was extracted into dichloromethane (3×50 mL). The combined organics were dried with sodium sulfate and the volatiles removed under reduced pressure. The residue was then recrystallized from methanol yielding 2.53 g (81%) of 5 as a colorless crystalline solid. 1H NMR (CDCl3-d) δ ppm 1.14 (18 H, d, J=6.9 Hz), 1.19 (9 H, t, J=7.0 Hz), 3.09 (6 H, br. s.), 3.21 (3 H, spt, J=6.9 Hz), 3.38 (6 H, q, J=6.9 Hz), 6.26 (3 H, d, J=2.9 Hz), 6.37 (3 H, d, J=2.7 Hz), 6.51 (1 H, s). 13C-{1H} NMR, δ 15.5, 24.0, 26.3, 38.4, 69.4, 111.1, 115.2, 138.9, 141.6, 142.9, 147.3. Anal. calcd. for C34H49N3O3: C, 74.55; H, 9.02; N, 7.67. Found: C, 74.26; H, 9.24; N, 7.59.
Reaction SMILES: [C:1](#[N:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:7][OH:8].[ClH:9]>COC(C)(C)C>[ClH:9].[C:1](=[NH:6])([O:8][CH3:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC#N
Reactant: CO
Agent: Cl
Solvent: COC(C)(C)C
Product: CCCCC(=N)OC
Temperature: 5 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A 10 gallon, glass-lined fixed reactor was charged with 7.0 kg (84.6 mol) of valeronitrile and 2.96 kg (92.2 mol, 1.1 eq) of methanol. The solution was stirred with cooling to about 5° C. under an atmosphere of nitrogen. A flow of hydrogen chloride gas from a gas cylinder was bubbled into the solution below the surface of the mixture at a rate such that the reaction temperature did not exceed 15° C. After about one hour, 3.67 kg (101 tool, 1.19 eq) of hydrogen chloride had been disbursed from the gas cylinder and addition was stopped. Stirring was continued for an additional 18 h at 0° C. Tert-butyl methyl ether (9.7 kg) was added to the suspension and stirring was continued for 3 h at 0° C. The slurry was then centrifuged under an atmosphere of nitrogen. After drying overnight under nitrogen and for several hours under reduced pressure at ambient temperature the product weighed 9.66 kg (76% yield uncorrected for purity) and had amp of 91°-92° C. The crude product was hygroscopic and was stored in sealed bottles under nitrogen at -5° C.
Reaction SMILES: C([C@@:8]1([C:33]([O-:35])=[O:34])[N:12]([C:13]([O:15][CH2:16][CH:17]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[C@H:11]2[CH2:30][CH2:31][CH2:32][C@H:10]2[CH2:9]1)C1C=CC=CC=1.C1CCCCC=1>CCO.[Pd]>[CH:28]1[C:29]2[CH:17]([CH2:16][O:15][C:13]([N:12]3[C@H:8]([C:33]([OH:35])=[O:34])[CH2:9][C@@H:10]4[CH2:32][CH2:31][CH2:30][C@H:11]34)=[O:14])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]=2[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1[C@H]2CCC[C@H]2C[C@]1(Cc1ccccc1)C(=O)[O-]
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: O=C(O)[C@@H]1C[C@@H]2CCC[C@@H]2N1C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 36.8 %

Procedure:
To a solution of (2S,3aS,6aS)-1-(9H-fluoren-9-yl)methyl 2-benzylhexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate (1.68 g, 3.6 mmol) in EtOH 95% (15 ml) was added Palladium on carbon 10% (0.2 g, 0.18 mmol) and cyclohexene (3.5 ml, 36 mmol). The resulting mixture was refluxed for 7 h. The solvent was evaporated and the crude was diluted with CH2Cl2 (20 ml). The suspension was filtered on celite the organic phase was evaporated under vacuum. The residue was purified by flash chromatography (CH2Cl2/CH3CN 50:50) to give the title compound as a white foam (0.5 g, 37%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][CH2:25][CH2:26]O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][CH2:25][CH2:26][N:30]3[C:31](=[O:33])[CH2:32][S:28][C:29]3=[O:34])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: O=C1CSC(=O)N1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2CCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2CCCN1C(=O)CSC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propan-1-ol (0.5 g, 1.4 mmol, 1 eq.), thiazolidine-2,4-dione (0.20 g, 1.7 mmol, 1.2 eq.), triphenylphosphine (1.1 g, 4.2 mmol, 3.0 eq.) in THF (25 mL) in ice/water bath was added DIAD (0.85 mmol, 4.2 mmol, 3.0 eq.) dropwise. The resulting solution was stirred at this temperature for 0.5 h and then stirred at room temperature for another 2 h. The volatile phase was removed off under reduced pressure. The residue was applied on silica gel and eluted to give 3-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl)thiazolidine-2,4-dione (0.4 g, 62%) as an off-white solid.
Reaction SMILES: [O-]I(=O)(=O)=O.[Na+].C[OH:8].O.[Cl:10][C:11]1[CH:12]=[C:13]([C:19]2([C:40]([F:43])([F:42])[F:41])[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4([F:39])[CH2:33][N:32]([C:34](=[O:38])[CH2:35][S:36][CH3:37])[CH2:31]4)=[CH:26][CH:25]=3)[CH2:20]2)[CH:14]=[C:15]([Cl:18])[C:16]=1[F:17]>CO>[Cl:10][C:11]1[CH:12]=[C:13]([C:19]2([C:40]([F:41])([F:42])[F:43])[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]4([F:39])[CH2:33][N:32]([C:34](=[O:38])[CH2:35][S:36]([CH3:37])=[O:8])[CH2:31]4)=[CH:28][CH:29]=3)[CH2:20]2)[CH:14]=[C:15]([Cl:18])[C:16]=1[F:17]
Reactant: CO
Reactant: CSCC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CS(=O)CC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 0 °C

Procedure:
A solution of sodium (meta)periodate (49 mg, 0.23 mmol) in 1:1 methanol/water (6 mL) was cooled with a ice bath and a solution of 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidin-1-yl)-2-(methylthio)ethanone (102 mg, 0.19 mmol) in methanol (˜2 mL) was added drop wise via pipette. A precipitate forms and the reaction was allowed to stir with the ice bath in place slowly warming to ambient overnight. When complete, the reaction was partitioned between water (5 mL) and CH2Cl2 (5 mL). Aqueous extracted with additional CH2Cl2 (2×5 mL). Organic phase collected and condensed. The crude material was adsorbed on silica and chromatographed on a 12 g silica column, eluting with a gradient of 0% to 100% ethyl acetate in heptane. Fractions containing the desired material were combined and concentrated. CH2Cl2 (˜100 μL) was added to the resulting film. Placing the flask on high vacuum overnight resulted in formation of a white foam. Yield 90 mg (86%). LC/MS retention time=3.317 minutes, MS calculated for (C22H17Cl2F5N2O3S), 554.03; found 555.0 M+H+.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([C:23]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]3)=[O:24])[CH:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[CH2:33]([O:35][NH2:36])[CH3:34].C([O-])(=O)C.[Na+].O>O.CCO>[C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([CH:16]3[CH2:17][CH2:18][C:19](=[N:36][O:35][CH2:33][CH3:34])[CH2:20][CH2:21]3)[C:23]([C@H:25]3[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]3)=[O:24])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)C2CCC(=O)CC2)CC1
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCON=C1CCC(N(c2cc(C3=CCCCC3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-Cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid (0.055 g, 0.12 mmol) in 1 ml of H2O/EtOH (2:1) was added ethoxyamine hydrochloride (0.024 g, 0.24 mmol) and sodium acetate (0.032 g, 0.24 mmol). The reaction mixture was stirred at room temperature for 24 h and treated with water. The aqueous layer was extracted with CH2Cl2 (3×) and the organic layer was dried with sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by HPLC to obtain 5-cyclohex-1-enyl-3-[(4-ethyoxyimino-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (0.015 g, 26%).
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][CH2:17][C:18](Br)=[O:19]>>[CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH:10][C:18](=[O:19])[CH2:17][Br:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Cc2ccccc2)c1N
Reactant: O=C(Br)CBr
Product: Cc1cccc(Cc2ccccc2)c1NC(=O)CBr

Procedure:
2-benzyl-6-methylaniline [A. W. H. Wardrop et al.: J. Chem. Soc., Perkin Trans. 1, 12, 1279 (1976)] and bromoacetyl bromide were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [CH2:1]([O:3][CH:4]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:9]1)[C:5]([OH:7])=O)[CH3:2].Cl.Cl.[CH2:21]([O:28][C:29](=[O:41])[NH:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1)=[NH:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29](=[O:41])[N:30]=[C:31]([NH2:32])[C:33]1[CH:34]=[CH:35][C:36]([CH2:39][NH:40][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:9]2)=[CH:37][CH:38]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Reactant: CCOC(C(=O)O)n1ccc(-c2ccncc2)n1
Agent: Cl
Product: CCOC(C(=O)NCc1ccc(C(N)=NC(=O)OCc2ccccc2)cc1)n1ccc(-c2ccncc2)n1

Procedure:
According to general method C, ethoxy-(3-pyridin-4-yl-pyrazol-1-yl)-acetic acid was reacted with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester dihydrochloride (CAS 172348-75-3) to give (RS)-[amino-(4-{[2-ethoxy-2-(3-pyridin-4-yl-pyrazol-1-yl)-acetylamino]-methyl}-phenyl)-methylene]-carbamic acid benzyl ester. White powder. MS 513.3 ([M+H]+)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][O:5][C@@H:4]([CH2:7][OH:8])[CH2:3]1.[NH2:9][C:10]1[C:11]([Cl:17])=[N:12][CH:13]=[N:14][C:15]=1Cl.C(N(CC)CC)C>C(O)(C)(C)C>[NH2:9][C:10]1[C:15]([NH:1][C@H:2]2[CH2:6][O:5][C@@H:4]([CH2:7][OH:8])[CH2:3]2)=[N:14][CH:13]=[N:12][C:11]=1[Cl:17]
Reactant: N[C@H]1CO[C@@H](CO)C1
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: Nc1c(Cl)ncnc1N[C@H]1CO[C@@H](CO)C1
Yield: 58 %

Procedure:
To a 50 mL round bottom flask fitted with a reflux condenser was added (2R-cis)-4-aminotetrahydro-2-furanmethanol, Compound IV(f), (184 mg, 1.57 mmole), 5-amino-4,6-dichloro-pyrimidine (770 mg, 4.70 mmole), triethylamine (0.44 mL, 3.16 mmole) and t-butyl alcohol (16 mL). The reaction mixture was heated to reflux temperature under an atmosphere of argon for 72 hours, at which time the volatile materials were removed by rotary evaporation. The residue was dissolved in 100 mL EtOAc, washed with saturated NaHCO3 solution (50 mL) and saturated NaCL solution (50 mL), then dried over MgSO4. After filtration and evaporation, the product was purified by flash column chromatography (50% EtOAc/50% Hexane) to yield 220 mg (58%) of Compound IX.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]Br)=[CH:6][C:5]=1[OH:14].[C:16]([C:20]1[CH:28]=[CH:27][C:23]([CH:24]=[N:25][OH:26])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:28]=[CH:27][C:23]([CH:24]=[N:25][O:26][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:15])=[C:5]([OH:14])[CH:6]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1ccc(OCCBr)cc1O
Reactant: CC(C)(C)c1ccc(C=NO)cc1
Product: CC(C)(C)c1ccc(C=NOCCOc2ccc(C(=O)O)c(O)c2)cc1

Procedure:
The title compound was prepared as a white solid (3.056 g, 76%) from 4-(2-bromo-ethoxy)-2-hydroxy-benzoic acid methyl ester and 4-tert-butyl-benzaldehyde oxime using a procedure similar to that of step 1 of example 6. mp=161.4-162.7° C.; mass spectrum (+APCI, M+H) m/z 358. 1H NMR (400 MHz, DMSO-d6); δ 13.60 (bs, 1H), 11.50 (bs, 1H), 8.24 (s, 1H), 7.68 (d, 1H), 7.54 (d, 2H), 7.42 (d, 2H), 6.52 (m, 2H), 4.40 (t, 2H), 4.29 (t, 2H), 1.38 (s, 9H). Elemental analysis: Calcd. for C20H23NO5: C, 67.21; H, 6.49; N, 3.92, Found: C, 66.86; H, 6.42; N, 3.88.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH:18]([CH3:20])[CH3:19])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[CH:18]([CH3:20])[CH3:19])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N(Cc1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)N(Cc1ccccc1N)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of isopropyl-(2-nitro-benzyl)-carbamic acid tert-butyl ester (730 mg, 2.48 mmol) in ethyl acetate (10 ml) was added acetic acid (0.156 ml, 2.73 mmol) and catalytic amount of palladium 10 wt. % on activated carbon. The mixture was stirred overnight under hydrogen atmosphere. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (15% ethyl acetate-hexane) to afford (2-amino-benzyl)-isopropyl-carbamic acid tert-butyl ester (f) (568 mg, 2.15 mmol, 87%) as reddish oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[H][H]>O.N.[Ru]>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(O)C=Cc1ccncc1
Reactant: [H][H]
Agent: [Ru]
Agent: N
Solvent: O
Product: O=C(O)CCC1CCNCC1
Yield: 97.7 %

Procedure:
A solution of 3-pyridin4-yl-acrylic acid (4.20 g, 28.0 mmol) in water (50 mL) and ammonia (aq, 25%, 4 mL) was hydrogenated at 60 bar in a high pressure steel autoclave in presence of ruthenium (5% on alumina, 439 mg). When hydrogen pressure remained constant (3 days) the catalyst was removed from the reaction mixture by filtration. The catalyst was washed with ethanol and water, and the ethanol was removed from the solution on a rotavapor and the aqueous solution was freeze dried to give 3-piperidin4-yl-propionic acid (4.30 g, 100%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH2:16][CH2:15]1.[OH2:30]>>[F:27][C:26]([F:29])([F:28])[C:22]1[CH:21]=[C:20]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][N:6]3[CH:5]=[N:4][C:3]4[C:2](=[O:30])[NH:10][CH:9]=[N:8][C:7]3=4)[CH2:15][CH2:16]2)[CH:25]=[CH:24][CH:23]=1
Reactant: O
Reactant: FC(F)(F)c1cccc(N2CCN(CCCn3cnc4c(Cl)ncnc43)CC2)c1
Product: O=c1[nH]cnc2c1ncn2CCCN1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
6-Chloro-9-{3-[4-(3-trifluoromethylphenyl)piperazin-1-yl]propyl}-9H-purine (200 mg) was dissolved in 3 mL of trifluoroacetic acid(TFA) and 1 mL of water and stirred for 16 hours at 25 C. The TFA was evaporated and 10 mL of 2N NaOH was added. The solution was extracted twice with 20 mL of dichloromethane. The organic layer was separated, dried with sodium sulfate and concentrated to give the title compound as an oil. The oil was dissolved in 5 mL of 50% dichloromethane in hexanes. A solution of 4N HCl in dioxane (200 uL) was added and the mixture stirred for 30 minutes followed by vacuum filtration of the suspension. A white powder of the product HCl salt was recovered.
Reaction SMILES: N.[C:2]([O:6][C:7](=[O:30])[N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=1[CH2:28][OH:29])[CH:9]1[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:12][CH2:11][CH2:10]1)([CH3:5])([CH3:4])[CH3:3].[H][H]>CO.[Ni]>[C:2]([O:6][C:7](=[O:30])[N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=1[CH2:28][OH:29])[CH:9]1[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:12][CH2:11][CH2:10]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C#N)cc1CO)C1CCCc2cccnc21
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(CN)cc1CO)C1CCCc2cccnc21
Yield: 54.6 %

Procedure:
Ammonia gas was bubbled through a solution of (4-cyano-2-hydroxymethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-carbamic acid tert-butyl ester (1.39 g, 3.55 mmol) in MeOH (40 mL) for 18 minutes. A prewashed mixture of Raney Nickel (˜1 gram) was added to the nitrile and the mixture was shaken for 16 hours under 30 psi hydrogen. The mixture was filtered through a celite plug and the filtrate was concentrated under reduced pressure. Purification via column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 94:5:1, v/v/v) afforded (4-aminomethyl-2-hydroxymethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-carbamic acid tert-butyl ester as an off-white solid (0.77 g, 55%). 1H NMR (CDCl3) δ 1.05 (s, 9H), 1.76 (m, 2H), 2.25 (m, 2H), 2.67 (m, 2H), 3.85 (s, 2H), 3.92 (d, 1H, J=15.0 Hz), 4.27 (m, 1H), 4.37 (d, 1H, J=9.0 Hz), 5.02 (d, 1H, J=12.0 Hz), 5.43 (d, 1H, J=15.0 Hz), 7.00 (m, 1H), 7.19 (m, 2H), 7.22 (m, 1H), 7.45 (m, 1H), 8.14 (d, 1H, J=3.0 Hz).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:40])[CH2:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:30][CH:29]=3)=[O:27])=[CH:19][C:18]=2[Cl:41])[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:40])[CH2:25][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:32][CH:33]=3)=[O:27])=[CH:19][C:18]=2[Cl:41])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCc2ccc(NC(=O)CC(=O)c3ccc(-c4ccccc4)cc3)cc2Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CCc2ccc(NC(=O)CC(=O)c3ccc(-c4ccccc4)cc3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.19 g (0.33 mmol) of N-{4-[2-(4-tert-butoxycarbonylaminopiperidin-1-yl)ethyl]-3-chlorophenyl}-3-biphenyl-4-yl-3-oxopropionamide (compound 1.41) is dissolved in 7 mL of methylene chloride, 500 mL of trifluoroacetic acid is added, and the mixture is stirred for 12 hours at ambient temperature. After this time, saturated sodium hydrogen carbonate solution is added and the precipitate formed is suction filtered. The residue is dried in vacuo over sodium hydroxide. Yield: 160 mg (100% of theory); Rf value: 0.10 (silica gel, methylene chloride/methanol=9:1); m.p. above 144° C. (decomposition); C28H30ClN3O2; EII mass spectrum: m/z=476/478 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:11][C:10]([CH3:13])([OH:12])[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:57]1[C:58](=[O:65])[N:59]([CH3:64])[CH:60]=[C:61]([Br:63])[CH:62]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:63][C:61]1[CH:62]=[C:57]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:11][C:10]([OH:12])([CH3:13])[CH2:9]3)=[CH:6][N:7]=2)[C:58](=[O:65])[N:59]([CH3:64])[CH:60]=1
Reactant: CC1(O)CN(c2ccc(N)nc2)C1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(N3CC(C)(O)C3)cn2)c1=O
Yield: 56.1 %

Procedure:
A mixture of 207b (1.84 g, 10.3 mmol), XantPhos (714 mg, 1.24 mmol), Pd2 dba3 (755 mg, 0.82 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (3.27 g, 12.3 mmol) and Cs2CO3 (10 g. 30.9 mmol) in 1,4-dioxane (50 mL) was heated at reflux for 2 h. After the completion of the reaction, the mixture was filtered off, and washed with MeOH (100 mL). The filtrate was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to give 207c (2.11 g, 54%). MS: [M+H]+ 365.