Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:5].C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.C(O)C>C(Cl)(Cl)Cl>[CH3:29][O:28][C:20]1[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)[C:38](=[O:40])[NH:1]2)=[CH:18][CH:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCCOc1c(OC)ccc(C(=O)NCCc2ccc([N+](=O)[O-])cc2)c1N
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCOc1c(OC)ccc2c(=O)n(CCc3ccc([N+](=O)[O-])cc3)c(=O)[nH]c12
Temperature: 50 °C
Reaction time: 11.5 h
Yield: 183.6 %

Procedure:
2-Amino-4-methoxy-N-[2-(4-nitrophenyl)ethyl]-3-pentyloxybenzamide (15.0 g, 37.4 mmol) obtained in Example 2-46, triethylamine (5.30 ml, 38.0 mmol) and chloroform (200 ml) were mixed, and a solution (10 ml) of triphosgene (4.75 g, 16.0 mmol) in chloroform was added dropwise to this solution. After stirring at 50° C. for 11.5 hours, ethanol (20 ml) was added to stop the reaction. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution (100 ml, 50 ml) and water (100 ml, 50 ml). This solution was dried over anhydrous magnesium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure. A hexane-chloroform solution (10:1, 110 ml) was added to the precipitated crystals, and the crystals were washed by stirring to give 7-methoxy-3-[2-(4-nitrophenyl)ethyl]-8-pentyloxy-1H-quinazoline-2,4-dione (12.56 g, 79%) as pale-yellow crystals.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2([OH:21])[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH2:14]2)=[C:7]([CH2:22][CH:23]=[CH2:24])[CH:6]=1)=O.Cl.[CH3:26][NH2:27]>C(O)C.[OH-].[Na+]>[CH3:26][NH:27][CH2:3][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2([OH:21])[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH2:14]2)=[C:7]([CH2:22][CH:23]=[CH2:24])[CH:6]=1
Reactant: C=CCc1cc(C=O)ccc1C#CC1(O)CN2CCC1CC2
Reactant: CN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C=CCc1cc(CNC)ccc1C#CC1(O)CN2CCC1CC2
Temperature: 5 °C
Reaction time: 12 h

Procedure:
Sodium borohydride (380 mg) was added to a solution of 3-[2-(4-formyl-2-allylphenyl)ethynyl]quinuclidine-3-ol (2.95 g) and methylamine hydrochloride (1.01 g) in ethanol (50 ml) whilst maintaining the temperature at 5° C. The resulting mixture was stirred at 25° C. for 12 hours, filtered and the filtrate evaporated to leave a residue which was suspended in 1M aqueous sodium hydroxide solution (30 ml) and extracted with ethyl acetate (3×50 ml). The ethyl acetate extracts were combined, washed with brine (50 ml), dried (Na2SO4) and evaporated. The residue was triturated with diethyl ether to give 3-[2-(4-methylaminomethyl-2-allylphenyl)ethynyl]quinuclidin-3-ol as a solid, m.p. 80° C.; microanalysis, found C, 75.1; H, 8.3; N, 8.6%; C20H26N2O.0.5H2O requires: C, 75.2; H, 8.5; N, 8.8%; NMR (CDCl3): 1.4 (-1H, m), 1.65 (1H, m), 2.1 (5H, m), 2.5 (3H, s), 2.8 (4H, t), 3.1 (1H, d), 3.3 (1H, dd), 3.5 (2H, d), 3.7 (2H, s), 5.1 (4H, m), 5.9 (1H, m), 7.1 (2H, m) and 7.4 (1H, d), m/z 311 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1[C:19]2[CH:18]([CH2:20][O:21][C:22](Cl)=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.[Cl:25][C@@H:26]1[CH2:30][NH:29][C@@H:28]2[C@@H:31]([OH:34])[CH2:32][O:33][C@H:27]12>O.O1CCOCC1>[Cl:25][C@@H:26]1[CH2:30][N:29]([C:22]([O:21][CH2:20][CH:18]2[C:19]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:16]3[C:17]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:23])[C@@H:28]2[C@@H:31]([OH:34])[CH2:32][O:33][C@H:27]12
Reactant: O[C@H]1CO[C@H]2[C@@H]1NC[C@H]2Cl
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1C[C@@H](Cl)[C@H]2OC[C@H](O)[C@H]21
Reaction time: 1.08 h
Yield: 76 %

Procedure:
A solution of sodium carbonate (155 mg, 1.46 mmol) in water (2.5 mL) then a solution of 9-fluorenylmethoxycarbonyl chloride (189 mg, 0.73 mmol) in 1,4-dioxane (1.5 mL) was added whilst stirring to a solution of aminoalcohol (77) in 1,4-dioxane (1 mL). The mixture was stirred for 65 minutes then water (20 mL) was added and the product extracted into dichloromethane (3×10 mL), then dried (Na2SO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 10:90 to 50:50 gave alcohol (78) (194 mg, 76%) as a white solid. TLC (Rf=0.45, EtOAc:heptane 1:1), analytical HPLC single main peak, Rt=15.51 min., HPLC-MS 386.1/388.1 [M+H]+, 408.1/410.1 [M+Na]+; [α]D23.0−7.46° (c=2.01, CHCl3); δH (500 MHz, CDCl3) mixture of rotamers 1:1; 1.15 (0.5H, s, OH), 3.05 (0.5H, t, J=9.58 Hz, FmocNCH2), 3.09 (0.5H, s, OH), 3.23 (0.5H, t, J=10.38 Hz, FmocNCH2), 3.43 (0.5H, d, J=4.37 Hz, FmocNCH), 3.53 (0.5H, brs, OCH2CHOH), 3.62 (0.5H, dd, J=10.20 and 1.92 Hz, OCH2CHOH), 3.75 (0.5H, dd, J=10.21 and 4.53 Hz, OCH2CHOH), 3.84-3.97 (2H, m, 1×FmocNCH2, 0.5×OCH2CHOH and 0.5×CHCl), 4.02 (0.5H, dd, J=9.96 and 4.65 Hz, OCH2CHOH), 4.06-4.12 (0.5H, m, CHCl), 4.15-4.26 (1.5H, m, Fmoc CH and 0.5×FmocNCH), 4.39-4.46 (1.5H, m, 0.5×OCH2CHOH, 0.5×Fmoc CH2 and 0.5×CHCHCl), 4.50 (0.5H, dd, J=10.64 and 6.70 Hz, Fmoc CH2), 4.67 (0.5H, t, J=4.29 Hz, CHCHCl), 4.75 (0.5H, dd, J=10.86 and 3.69 Hz, Fmoc CH2), 4.82 (0.5H, dd, J=10.82 and 3.97 Hz, Fmoc CH2), 7.30-7.81 (8H, aromatic CH); δC (125 MHz, CDCl3) 47.22/47.41 (Fmoc CH), 50.55/50.93 (FmocNCH2), 54.60/55.28 (CHCl), 65.94/67.60 (Fmoc CH2), 69.08/69.56 (FmocNCH), 75.00/75.35 (OCH2CHOH), 76.23/76.86 (OCH2CHOH), 81.27/81.84 (CHCHCl), 119.87/119.92/120.09/124.42/124.46/124.82/124.88/127.10/127.50/127.51/127.89/127.96/127.98/128.53 and 128.65 (aromatic CH), 141.24/141.36/141.44/143.44/143.57/143.83 and 143.84 (aromatic quaternary), 153.41/154.42 (Fmoc C═O).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)=[O:4].Cl>O1CCOCC1>[CH3:33][C:25]1[CH:24]=[C:23]([CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([S:12]([NH:11][C@@H:10]3[CH2:9][CH2:8][NH:7][CH2:6][C@@H:5]3[C:3]([OH:4])=[O:2])(=[O:13])=[O:14])=[CH:16][CH:17]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@@H]3C(=O)O)cc2)c2ccccc2n1
Temperature: 60 °C

Procedure:
To a solution of 0.3 g (0.525 mmol) of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (Example 28, Step 6) in 1,4-dioxane (4 mL) was added concentrated HCl (4 mL). The reaction was heated to 60° C. for 19 h. The solvent was then removed in vacuo to give (3S,4R)-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid as the hydrochloride salt (0.210 g, 72.4%). MS: 457 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](=[O:9])[CH:7]=[CH:6][NH:5][C:4]=1[CH3:10].[CH2:11](I)[CH2:12][CH3:13]>CN(C)C=O.C(Cl)(Cl)Cl.[Ag]=O>[CH3:1][O:2][C:3]1[C:4]([CH3:10])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:11][CH2:12][CH3:13]
Reactant: COc1c(C)[nH]ccc1=O
Reactant: CCCI
Agent: O=[Ag]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCOc1ccnc(C)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Methoxy-2-methyl-4(1H)-pyridone(1.39 g) and propyl iodide (2.0 ml) were dissolved in dimethylformamide (20 ml), to which silver oxide (2.31 g) was added in small portions and stirred vigorously at room temperature for 5 hours. The reaction mixture was diluted with chloroform (100 ml), washed with water, dried and evaporated. The residue was purified by flash chromatography (chloroform) on silica gel, to give 3-methoxy-2-methyl-4-propoxypyridine (1.7 g) as a light brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:18]1([C:32](C)=[CH2:33])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:6].[OH-].[Na+].OO.C1C[O:46][CH2:45]C1>>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:18]1([CH2:32][CH2:33][CH2:45][OH:46])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]1=[O:31])[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[O:6]
Reactant: C=C(C)C1(C(CCNC(=O)c2ccc(F)c(F)c2)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reactant: C1CCOC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)C(CCNC(=O)c1ccc(F)c(F)c1)C1(CCCO)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A cold (0° C.) solution of tert-butyl α-[2-[(3,4-difluorobenzoyl)amino]ethyl]-2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetate (1.62 g, 3.07 mmol) in dry THF (10 mL) is treated with monochloroborane methylsulfide complex (640 μL, 6.14 mmol). The ice bath is removed, and after 4.5 h, 3N NaOH (7.4 mL, 22.1 mmol) is added dropwise, followed by 30% H2O2 (2.5 mL). The solution is stirred for 1 hour at room temperature and then for 1 hour at 50° C. After cooling to room temperature and dilution with saturated NH4Cl (5 mL) and H2O (15 mL), the product is extracted into EtOAc (3×50 mL). The extracts are combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 1.6 g of a yellow gel. The material is purified by silica gel chromatography (75 g SG; 75% EtOAc/hexane) to provide 713 mg (43%) of the title compound as a white, amorphous solid:
Reaction SMILES: [C:1]([CH2:4][O:5][C:6](=[O:20])[C@:7]([NH:18][NH2:19])([CH3:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)(O)=O.Cl[CH2:22][C:23]1[CH:24]=[C:25]([CH:40]=CC=1)[C:26]([O:28]CC1C=CC(OC)=CC=1OC)=[O:27]>>[OH:16][C:11]1[CH:10]=[C:9]([CH2:8][C@@:7]([NH:18][NH2:19])([CH3:17])[C:6]([O:5][CH2:4][C:1]2[CH:40]=[C:25]([CH:24]=[CH:23][CH:22]=2)[C:26]([OH:28])=[O:27])=[O:20])[CH:14]=[CH:13][C:12]=1[OH:15]
Reactant: COc1ccc(COC(=O)c2cccc(CCl)c2)c(OC)c1
Reactant: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)OCC(=O)O
Product: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)OCc1cccc(C(=O)O)c1
Yield: 26 %

Procedure:
Following the procedure described for preparation of compound 229, and substituting tert-butyl bromomethyl acetate with 2,4-dimethoxybenzyl m-chloromethyl-benzoate, provided the title compound (26% over 2 steps) as a white solid. 1H NMR (400 MHz, CD3OD): δ1.42 (3H, s), 2.79 (1H, d), 2.90 (1H, d), 5.2 (2H, m), 6.35 (1H, dd), 6.56 (1H, d); 6.60 (1H, d), 7.45 (2H, m), 7.97 (2H, m). MS (ESI) m/z 361.15 (M+H+) and 359.17 (M−H−).
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][OH:19])[CH2:8][O:7][CH:6]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[O:5][CH2:4]1)[CH3:2].CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.Cl>[CH3:27][S:28]([O:19][CH2:18][C:3]1([CH2:1][CH3:2])[CH2:4][O:5][CH:6]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[O:7][CH2:8]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1(CO)COC(c2c([N+](=O)[O-])cnn2C)OC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(COS(C)(=O)=O)COC(c2c([N+](=O)[O-])cnn2C)OC1
Temperature: 25 °C

Procedure:
To a solution of (5-ethyl-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methanol (trans isomer) (610 mg, 2.25 mmol, intermediate 66) in dry DCM (15 mL) at 0° C. was added Et3N (0.45 mL, 3.38 mmol) followed by methanesulfonyl chloride (0.21 mL, 2.70 mmol). The reaction mixture was slowly warmed to room temperature over 1.5 hr. The mixture was re-cooled to 0° C. and diluted with aqueous 1 M HCl (10 mL) and DCM (20 mL). The organic layer was washed with aqueous saturated NaHCO3 (15 mL) and water (15 mL), separated, dried over Na2SO4 and concentrated under reduced pressure to give (5-ethyl-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methyl methanesulfonate as a white solid (816 mg, quantitative). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 6.38 (s, 1H), 4.14 (s, 3H), 4.05-3.88 (m, 6H), 3.22-2.92 (m, 3H), 1.96 (q, J=7.6 Hz, 2H), 1.03 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:15]=[CH:16][S:17][CH:18]=3)=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[CH:4][CH:3]=[C:2]3[Cl:1])([C:14]2[N:15]=[CH:16][S:17][CH:18]=2)[OH:13])=[CH:22][CH:21]=1
Reactant: O=C(c1ccc2nccc(Cl)c2c1)c1cscn1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)(c1ccc2nccc(Cl)c2c1)c1cscn1
Reaction time: 2 h

Procedure:
To a solution of (4-chloroquinolin-6-yl)(thiazol-4-yl)methanone (52 mg, 0.189 mmol) in THF (2 mL) was slowly added (4-chlorophenyl)magnesium bromide (0.246 mL, 0.246 mmol, 1M in THF) and the resulting solution was kept at 0° C. for 2 hr. The reaction was quenched with saturated NH4Cl at 0° C. and the aqueous mixture was extracted with EtOAc twice. The combined organics were concentrated and purified by silica column (40% EtOAc/hexanes) chromatography to yield (4-chlorophenyl)(4-chloroquinolin-6-yl)(thiazol-4-yl)methanol. (ES, m/z) [M+H]+ 387, 389.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:3]1.[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[C:21]([OH:27])=[O:22].[CH3:1][C@@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([OH:16])=[O:15])[CH2:3]1
Reactant: C[C@H]1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN[C@H](C(=O)O)C1
Reaction time: 2 h

Procedure:
To di(tert-butyl) (2S,4S)-4-methylpyrrolidine-1,2-dicarboxylate (Ref: J. Amer. Chem. Soc., 1996, 118, 36, 8700–8706, 2.4 g, 8.42 mmol) in CH2Cl2 (15 mL) was added TFA (15 mL) and the reaction was stirred for 2 hours. The reaction was concentrated in vacuo and re-dissolved in CH2Cl2 (15 mL), TFA (15 mL) was added and the reaction was stirred for 1 hour. The reaction was concentrated in vacuo to afford (4S)-4-methyl-L-proline trifluoroacetate and used directly in the next step.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:24]=[C:25]=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:18]([NH:24][C:25](=[O:26])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCN=C=O
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: CCCCCCNC(=O)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (35.0 mg, 0.155 mmol) using the same procedure employed for Example 2 (2), but with n-hexylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (16.7 mg, 30%) having the following characteristics.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][CH2:10][NH2:11])[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[Na+].[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19]>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH:11][CH2:10][CH2:9][CH2:8][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:19]
Reactant: NCCCn1ccnc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCn1ccnc1)c1cccc(Cl)c1
Reaction time: 18 h

Procedure:
A mixture of 6.0 g. of 1H-imidazole-1-propanamine dihydrochloride, 45 ml. of 2N sodium hydroxide and 150 ml. of methylene chloride was stirred at room temperature and 3.9 ml. of 3-chlorobenzoyl chloride was added. The reaction mixture was stirred for 18 hours, then methylene chloride and 15 ml. of 1N sodium hydroxide were added and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to remove the solvent. The residue was triturated with diethyl ether and the crystalline product recovered by filtration and recrystallized from ethanol, giving the desired product, m.p. 125°-127° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5]NC(=N)N.[NH2:13][C@H:14](C(O)=O)CC1N=CNC=1>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][CH2:14][NH2:13]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
Arginine; and Histidine (at pH 6.0)
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[C:10]([F:20])[C:8]=2[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=[C:10]([F:20])[C:8]=2[NH:9][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1c(F)cc(-c2ccccc2)cc1-c1ccccc1
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: Fc1cc(-c2ccccc2)cc(-c2ccccc2)c1Nc1ccccc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 73.7 %

Procedure:
2,4-diphenyl-6-fluoroaniline (12 mmol), bromobenzene (10 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.15 mmol), (±)-2,2′-bis(diphenylphosphine)-1,1′-binaphthalene (0.3 mmol) and sodium tert-butoxie (14 mmol) are put in a two-neck round-bottom flask and dissolved in toluene (30 mL). Subsequently, the resulting solution is stirred in a bath under a temperature of about 100° C. for 24 hours. After completion of the reaction, toluene is removed. The reaction mixture is extracted with dichloromethane and water, and then being distilled under reduced pressure. The resulting residence is filtered by silica gel column and distilled under reduced pressure again. Next, by re-crystallizing and filtering with dichloromethane and petroleum ether, 2,4-diphenyl-6-fluoro-N-phenylbenzenamine (2.5 g) is yielded.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>C1COCC1>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(OCc2ccccc2)c1
Yield: 90.9 %

Procedure:
A mixture of 2-(3-hydroxyphenyl)acetic acid (0.6 g, 3.95 mmol), benzyl bromide (0.710 g, 4.14 mmol), potassium hydroxide (0.550 g, 9.87 mmol), KI (13 mg, 0.079 mmol) in THF (20 mL) was refluxed for 18 h. The solvent was removed and the residue was dissolved in 50 mL of water and extracted with ether. The aqueous layer was acidified with aqueous 1N HCl and the white precipitate that formed was filtered off to afford 2-(3-(benzyloxy)phenyl)acetic acid as a gray solid (0.87 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[C:21]3[CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:20]=3[NH:19][N:18]=2)=[O:16])[CH2:11][CH2:10]1.Cl>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([C:17]2[C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[NH:19][N:18]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cc(F)ccc4Cl)CC3)c2C1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2cc(F)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 188.6 %

Procedure:
To a solution of tert-butyl 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (49, 78 mg, 0.17 mmol) in CH2Cl2 (2 mL) was added HCl (2N in Et2O, 2 mL). The mixture stirred for 18 h at ambient temperature. The reaction mixture was concentrated under reduced pressure to yield (4-(2-chloro-5-fluorophenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone hydrochloride (50) as a white solid (64 mg, 94%): 1H NMR (300 MHz, DMSO-d6) δ 9.19 (br s, 2H), 7.49 (dd, J=8.7, 5.4 Hz, 1H), 7.27 (dd, J=10.2, 3.0 Hz, 1H), 7.17-7.07 (m, 1H), 5.34-5.05 (m, 1H), 4.79-4.56 (m, 1H), 4.38-4.19 (m, 2H), 3.44-3.07 (m, 4H, overlaps with H2O), 3.01-2.76 (m, 3H), 1.92-1.73 (m, 2H), 1.71-1.50 (m, 2H), missing N—H pyrazole; ESI MS m/z 363 [M+H]+.
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[C:7]([C:9]1[CH:14]=[CH:13][N:12]([CH3:15])[CH2:11][CH:10]=1)=[O:8]>CO.[Pt]=O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[OH:8])[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(C(=O)C2=CCN(C)C=C2)c1
Agent: O=[Pt]
Agent: [I-]
Solvent: CO
Product: COc1cccc(C(O)C2CCN(C)CC2)c1
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A mixture of 4-[3-methoxybenzoyl]-1-methylpyridine iodide (730 mg, 2.1 mmol) and platinum oxide (100 mg, 0.44 mmol) in methanol was stirred under a hydrogen atmosphere for 2 h. The catalyst was filtered and washed with methanol then water. The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in methylene chloride, washed with 1N sodium hydroxide, dried over sodium sulfate and concentrated in vacuo to give 490 mg of a clear colorless oil. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 425 mg (87%) of a white solid. Mp 102-104° C. MS(m/e): 235(M+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24](OS(C)(=O)=O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([O:1][C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=Cc1cc(C(F)(F)F)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2C=O)CC1
Temperature: 100 °C
Yield: 53.4 %

Procedure:
A mixture of 2-hydroxy-5-trifluoromethyl-benzaldehyde (1.36 g, 7.17 mmol), 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.2 g, 7.88 mmol) and K2CO3 (2.96 g, 21.5 mmol) in anhydrous N,N-dimethylformamide (15 mL) was heated at 100° C. for 1 h. After cooled to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM (50 mL). The solution was washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by chromatography to give the title compound (1.43 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH3:25])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22]([N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)=[O:24])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CSCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CCCC(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2cccc(CCCC(=O)N3CCSCC3)c2)=C(C)C1=O
Yield: 29.5 %

Procedure:
4-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]-n-butyric acid (73 mg, 0.20 mmol) obtained in Example 62 and thiomorpholine (0.030 ml, 0.30 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (26 mg, 0.059 mmol, yield 29%).