Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([OH:16])[C@@H:13]([CH2:17]O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br>ClCCl.CO.CN(C)C=O>[N:19]([CH2:17][C@@H:13]1[C@H:14]([OH:16])[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)N1C[C@H](CO)[C@H](O)C1
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 13 h
Yield: 85.1 %

Procedure:
(3R,4S)-[1-Benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol (2.33 g), sodium azide (1.81 g), triphenylphosphine (2.67 g) and N,N-dimethylformamide (46 mL) were mixed together. While the mixture was chilled in an ice water bath, carbon tetrabromide (3.38 g) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 13 hours and then at 60° C. for 3 hours. Subsequently, methanol (3 mL) was added and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (200 mL) and the solution was washed with saturated brine (2×50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate: hexane=2:1) to give (3R,4S)-3-azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine as a milky white syrup (2.18 g).
Reaction SMILES: O/[N:2]=[C:3](/[C:5]1[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=1)\[CH3:4].[ClH:14]>CO.[OH-].[OH-].[Pd+2]>[ClH:14].[NH2:2][CH:3]([C:5]1[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=1)[CH3:4]
Reactant: COC(=O)c1ccc(/C(C)=N/O)s1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(C(C)N)s1
Reaction time: 96 h
Yield: 93.1 %

Procedure:
To a degassed solution of methyl 5-[(1E)-N-hydroxyethanimidoyl]thiophene-2-carboxylate (3.43 mg, 17.2 mmol) and hydrochloric acid (12.0 M, 1.8 mL, 22.4 mmol) in methanol (100 mL) was added Pearlman's catalyst (84.6 mg, 0.2 mmol). The resulting reaction mixture was shaken under a 60 psi atmosphere of H2 for 4 days. The catalyst was removed by filtration through celite and the solvent was removed to afford a white solid (3.55 g, 93%). LC-MS: (FA) ES+ 186)
Reaction SMILES: [C:1]1([C:7]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([CH:17]=[CH2:18])=[CH:13][N:12]3[CH:19]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[CH2:17]([C:14]1[CH:15]=[CH:16][C:11]2[N:12]([CH:19]=[C:9]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[N:10]=2)[CH:13]=1)[CH3:18]
Reactant: [H][H]
Reactant: C=Cc1ccc2nc(C(=O)c3ccccc3)cn2c1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc2nc(C(=O)c3ccccc3)cn2c1
Yield: 18.6 %

Procedure:
A solution of 80 mg of phenyl(6-vinylimidazo[1,2-a]pyridin-2-yl)methanone in 20 mL of methanol is hydrogenated for 45 minutes at 45° C. under 1 bar of hydrogen in the presence of 34 mg of 10% palladium-on-charcoal. The product is chromatographed on silica, eluting with a gradient of cyclohexane and ethyl acetate, to give 15 mg of (6-ethylimidazo[1,2-a]pyridin-2-yl)(phenyl)methanone in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[NH:4][C:5]([C:22](F)([F:24])[F:23])=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]([CH:14]2[CH2:16][CH2:15]2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1CCN2C(=NCCC2)CC1>C1COCC1>[F:24][CH:22]([F:23])[C:5]1[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([CH:14]2[CH2:15][CH2:16]2)[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:3]([C:2]([F:27])([F:1])[F:26])[N:4]=1
Reactant: CCOC(=O)C1=C(C(F)(F)F)NC(C(F)(F)F)=C(C(=O)OCC)C1C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1C1CC1
Yield: 85 %

Procedure:
To a solution of 40 g (0.0916 mole) of diethyl 2,6-bis(trifluoromethyl)-2,6-dihydroxy-4-cyclopropyl-tetrahydropyran-3,5-dicarboxylate in 200 ml of THF is introduced 55.5 g (3.26 moles) of ammonia. The reaction mixture is concentrated to give 38.5 g (96.7%) of a solid. A portion (28 g) of this material is stirred with 27.08 g (0.129 mole) of trifluoroacetic anhydride for one day. The reaction mixture is concentrated and diluted with ether. The ether solution is washed with saturated sodium bicarbonate, dried (MgSO4), and concentrated to give 21 g (81.3%) of an oil, nD25 1.4460. This oil is identified as diethyl 2,6-bis(trifluoromethyl)-4-cyclopropyl-1,4-dihydro-pyridine-3,5-dicarboxylate. A portion (18 g) of this oil and 150 ml of THF is treated with 6.82 g (0.0449 mole) of DBU. The reaction mixture is held at reflux for 24 hours and concentrated. The residue is stirred with water and extracted with ether. The ether extract is washed with diluted HCl, dried (MgSO4), and concentrated. The residue is crystallized to give 13 g (76.0 %) of crude product. A portion (2.0 g) of this product is recrystallized from petroleum ether at low temperature to give 1.17 g (85%) of desired product, m.p. 30°-32° C.
Reaction SMILES: C1(C[O:8][C:9]2[C:14]([O:15]CC3C=CC=CC=3)=[CH:13][N:12]=[C:11]([CH:23]=[O:24])[CH:10]=2)C=CC=CC=1.[H][H]>CN(C)C=O.[Pd]>[OH:15][C:14]1[C:9](=[O:8])[CH:10]=[C:11]([CH:23]=[O:24])[NH:12][CH:13]=1
Reactant: [H][H]
Reactant: O=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=Cc1cc(=O)c(O)c[nH]1
Yield: 76.7 %

Procedure:
To a solution of 4,5-bis(phenylmethoxy)-2-pyridinecarboxaldehyde (1.9 g, 6.0 mmol) in 25 ml of dry dimethylformamide was added 0.2 g of palladium on charcoal catalyst and hydrogen was bubbled through the mixture for three hours. The catalyst was removed by filtration, the solvent distilled off in vacuo and the residue triturated with ether to give 0.64 g of the title compound, melting point 174°-177° C., dec.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:15][CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1
Reactant: OCCOc1ccc(Br)cc1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
In DMF (150 ml) was dissolved 2-(4-bromophenoxy)-1-ethanol (15.7 g). To the mixture was added under ice-cooling 65% sodium hydride (4.3 g),and the mixture was stirred at room temperature for 2 hours. To the mixture was added dropwise iodobutane (17.3 g), and the mixture was stirred for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=4/1) to give 1-bromo-4-(2-butoxyethoxy)benzene (12.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9]COC)[CH:6]=[CH:5][C:4]=1[C:13]1[C:14]([CH2:26][NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([CH3:24])([CH3:23])[CH:17]=[C:16]2[CH3:25].Cl.O1CCOCC1>O1CCOCC1.C(OCC)(=O)C>[OH:9][C:7]1[CH:6]=[CH:5][C:4]([C:13]2[C:14]([CH2:26][NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([CH3:24])([CH3:23])[CH:17]=[C:16]3[CH3:25])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COCOc1ccc(-c2ccc3c(c2CNc2ccccc2OC)C(C)=CC(C)(C)N3)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccccc1NCc1c(-c2ccc(O)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61.6 %

Procedure:
6-(2-Methoxy-4-methoxymethoxyphenyl)-5-(2-methoxyphenylaminomethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 181 mg, 0.381 mmol) was dissolved in 1,4-dioxane (3 mL), 4N HCl/1,4-dioxane solution (1 mL) was added thereto, and then the mixture was stirred at room temperature for 2.5 hours. The mixture was diluted with ethyl acetate (30 mL), washed with saturated aqueous sodium hydrogen carbonate solution (30 mL), water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (101 mg) as a pale orange solid. (Yield 62%)
Reaction SMILES: C[O:2][CH:3]([O:8]C)[C:4](OC)=O.CO.[CH2:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH2:25])(=[O:24])=[O:23])[CH2:13][CH3:14].[OH-].[Na+]>O.O1CCOCC1>[CH2:12]([N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](=[O:24])(=[O:23])[NH:25][CH:4]1[C:3]([OH:8])=[O:2])[CH2:13][CH3:14]
Reactant: COC(=O)C(OC)OC
Reactant: CCCNc1ccccc1S(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CCCN1c2ccccc2S(=O)(=O)NC1C(=O)O
Reaction time: 1.5 h
Yield: 44 %

Procedure:
This compound was prepared according to the method of Close et. al., J. Org. Chem., 1961, 26, 3423-3433, incorporated by reference herein in its entirety. Thus, a solution of methyl dimethoxyacetate (3.6 g, 27.3 mmol) in water (50 l) was refluxed for 2.5 hours. A stillhead was attached and the methanol so generated was allowed to distill off (a total of 10 ml of liquid was collected, of which 5 ml was replenished with water). To the hot solution was added 2-(propylamino)benzenesulfonamide (4.5 g, 21.0 mmol) (prepared according to the procedure of Biressi et. al., Farmeco. Ed. Sci. (It.), 1969, 24, 199-220, incorporated by reference herein in its entirety) and 1,4-dioxane (5 ml, to give a homogeneous solution) and reflux was continued for 1.5 hours. The mixture was adjusted to pH 3 (2N NaOH), extracted with ethyl acetate and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 4.8 g crude product which was recrystallized (ethyl acetate/hexanes) to give 2.5 g (44%) of the title compound as a white solid; NMR (DMSO-d6) δ 0.85 (t, J=7 Hz, 3H), 1.47-1.57 (m, 2H), 2.94-3.04 (m, 1H), 3.38 (br, 1H), 3.40-3.46 (m, 1H), 5.27 (d, J=6 Hz, 1H), 6.70 (t, J=7 Hz, 1H), 6.84 (d, J=7 Hz, 1H), 7.36 (t, J=7 Hz), 7.43 (d, J=7 Hz, 1H), 8.44 (d, J=7 Hz, 1H), 13.04 (br, 1H); MS: 269 m/z (M-H)- ; Anal. Calc'd for C11H14N2O4S: C, 48.88; H, 5.23; N, 10.37; S, 11.84; Found: C, 49.17; H, 5.21; N, 10.27; S, 11.54.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[O:13]=[C:14]1[NH:18][C:17](=[O:19])[C:16]2([CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)[NH:15]1.[CH:32]1(O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>>[CH:32]1([N:18]2[C:17](=[O:19])[C:16]3([CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]3)[NH:15][C:14]2=[O:13])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)NC(=O)NC2=O
Reactant: OC1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC2(C1)NC(=O)N(C1CCCCC1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl azodicarboxylate (0.315 mL, 0.00200 mol) was added to a mixture of tert-butyl 2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate (269.3 mg, 0.001000 mol), cyclohexanol (0.156 mL, 0.00150 mol), and triphenylphosphine (524 mg, 0.00200 mol) in tetrahydrofuran (6 mL, 0.08 mol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by Combiflash with ethyl acetate/hexane. LC-MS: 296.2 (M−Bu+2H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23]>C(Cl)Cl.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 27.4 %

Procedure:
To a mixture of crude methyl 3-cyano-4-hydroxybenzoate (2.50 g) from above and Et3N (1.31 g, 13.0 mmol) in anhydrous DCM (20 mL) was added Tf2O (1.82 g, 6.50 mmol) dropwise and then the reaction mixture was stirred at 30° C. for 2 hours. The resulting mixture was suspended in water (50 mL) and extracted with DCM (50 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/EtOAc=10/1) to give Intermediate 1 (550 mg, 2-step yield: 28%) as a colorless oil. 1H NMR (CDCl3 300 MHz): δ 8.43 (d, J=2.1 Hz, 1H), 8.37 (dd, J=8.7, 2.1 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 3.98 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:13][C:14]1[C:15]([N:22]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[CH2:23][CH:24]2[CH2:26][CH2:25]2)=[N:16][C:17]([CH3:21])=[C:18]([CH3:20])[CH:19]=1)[C:8]1[N:9]=[N:10][NH:11][N:12]=1.[OH-].[Na+].[CH2:42](Cl)Cl.S(OC)(OC)(=O)=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:39][C:2]([F:38])([F:1])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:13][C:14]1[C:15]([N:22]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[CH2:27][CH:28]2[CH2:30][CH2:29]2)=[N:16][C:17]([CH3:21])=[C:18]([CH3:20])[CH:19]=1)[C:8]1[N:9]=[N:10][N:11]([CH3:42])[N:12]=1
Reactant: ClCCl
Reactant: Cc1cc(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c(N(CC2CC2)CC2CC2)nc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: Cc1cc(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c(N(CC2CC2)CC2CC2)nc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.6 %

Procedure:
To a suspension of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-5,6-dimethyl-pyridin-2-yl)-bis-cyclopropylmethyl-amine (0.3 g, 0.54 mmol), obtained in step (viii), in water (4 mL) was added sodium hydroxide (0.04 g, 1.0 mmol), and this mixture was stirred for 15 min at RT, followed by the addition of DCM (4 mL). Dimethyl sulfate (0.13 g, 1.03 mmol) was then added to this mixture, followed by the addition of tetrabutylammonium bromide (0.008 g, 0.024 mmol). The mixture was then stirred for 0.5 h, after which the organic layer was separated from the aqueous layer which was extracted with DCM (3×10 mL). The combined organic layer was washed with brine, dried over sodium sulfate, and then concentrated under vacuum to afford the title compound as light yellow oil (0.200 g, yield: 66.6%).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[NH:8][CH:9]=[CH:10][CH:11]=1)=O.[N+]([O-])(O)=O.[F:17][C:18]([F:33])([O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH2:32])=[NH:31])[CH:26]=[CH:27][CH:28]=1)[CH:19]([F:21])[F:20].[OH-].[Na+]>C(O)C(C)C>[F:17][C:18]([F:33])([O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[N:32]=[C:5]([C:7]3[NH:8][CH:9]=[CH:10][CH:11]=3)[CH:4]=[CH:3][N:31]=2)[CH:26]=[CH:27][CH:28]=1)[CH:19]([F:20])[F:21]
Reactant: CN(C)C=CC(=O)c1ccc[nH]1
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)CO
Solvent: O=[N+]([O-])O
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3ccc[nH]3)n2)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a solution of 100 mg (0.61 mmol) of 3-dimethylamino-(1H-pyrrol-2-yl)2-propen-1-one [described in EP-A-0 233 461]in 4 ml of isobutanol are added 185 mg (0.60 mmol) of 3-(1,1,2,2-tetrafluoroethoxy)phenylguanidine nitrate. Following the addition of 32.5 mg (0.81 mmol) of sodium hydroxide, the reaction mixture is stirred for 3 hours at 110° C. The suspension is concentrated under reduced pressure, the residue is dissolved in 4 ml of methylene chloride/tetrahydrofuran (1:1 ), and the solution is extracted with 2.4 ml of water. The organic phase is dried over sodium sulfate and concentrated on a rotovap. Recrystallisation from diethyl ether/tetrahydrofuran gives N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-(1H-pyrrol-2-yl)-2-pyrimidine-amine; FAB-MS:353 (M+ +1 ), m.p. 142-143, Rf =0.83 (methylene chloride:methanol=9:1).
Reaction SMILES: [NH:1]([C:5]1[CH:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][C:6]=1[CH2:7][N:8]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:9])C(C)=O.C(O)C.Cl.N>O>[NH2:1][C:5]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][C:6]=1[CH2:7][N:8]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[CH3:9]
Reactant: CCOC(=O)c1ccc(NC(C)=O)c(CN(C)C2CCCCC2)c1
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: CN(Cc1cc(C(=O)O)ccc1N)C1CCCCC1

Procedure:
A mixture of 21 gm of 2-acetamino-5-carbethoxy-N-cyclohexyl-N-methyl-benzylamine, 100 ml of ethanol, 90 ml of water and 60 ml of concentrated hydrochloric acid was refluxed for 1 hour. Thereafter, the reaction solution was cooled, poured over ice, made alkaline with ammonia and extracted three times with chloroform. The aqueous alkaline phase was evaporated to dryness in vacuo, the residue was thoroughly stirred with ethanol, and the mixture was filtered. The filtrate was evaporated to dryness in vacuo, and the residue was recrystallized from ethanol, yielding 2-amino-5-carboxy-N-cyclohexyl-N-methyl-benzylamine, m.p. 200°-205°C.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Si:12]([O:19][CH2:20][CH:21]=O)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(O)(C(F)(F)F)=O.[BH3-]C#N.[Na+]>CO>[C:15]([Si:12]([CH3:14])([CH3:13])[O:19][CH2:20][CH2:21][NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[I:1])([CH3:18])([CH3:17])[CH3:16]
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OCCNc1ccc([N+](=O)[O-])cc1I
Reaction time: 2 h
Yield: 24.9 %

Procedure:
To a solution of 2-iodo-4-nitroaniline (2.0 g, 7.6 mmol) and 2-(tert-butyldimethylsilyloxy)-acetaldehyde (3.5 g, 75% purity, 15 mmol) in methanol (30 mL) was added TFA (1.5 mL) at 0° C. The reaction mixture was stirred at this temperature for 30 min before NaCNBH3 (900 mg, 15 mmol) was added in portions. The mixture was stirred for 2 h and was then quenched with water. The resulting mixture was extracted with EtOAc (30 mL×3), the combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum, and the residue was purified by chromatography on silica gel (5% ethyl acetate/petroleum) to afford [2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-(2-iodo-4-nitro-phenyl)-amine (800 mg, 25%). 1H NMR (300 MHz, CDCl3) δ 8.57 (d, J=2.7 Hz, 1 H), 8.12 (dd, J=2.4, 9.0 Hz, 1 H), 6.49 (d, J=9.3 Hz, 1 H), 5.46 (br s, 1 H), 3.89 (t, J=5.4 Hz, 2 H), 3.35 (q, J=5.4 Hz, 2 H), 0.93 (s, 9 H), 0.10 (s, 6 H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].N1C=CC=CC=1.Cl[C:16]([O:18][CH:19]=[CH2:20])=[O:17]>O1CCCC1>[CH:19]([O:18][C:16]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:17])=[CH2:20]
Reactant: C=COC(=O)Cl
Reactant: O=C1CCC(=O)N1O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=COC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
To a 500 mL 3-neck round bottom flask fitted with a mechanical stirrer, condenser, nitrogen blanket, dropping funnel, ice-saltwater bath, and thermometer were added 10.0 (87.0 mmol) of N-hydroxy succinimide, 6.9 g (87.0 mmol) of pyridine, and 100 mL tetrahydrofuran was added. To the reaction mixture 9.25 g (87.0 mmol) of vinyl chloroformate was added so that the temperature remained below 10° C. After stirring at room temperature for 18 hours the reaction mixture was washed with 100 mL 2N HCl, and 100 mL 2N NaOH. The organic phase was dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting liquid chromatographed (silica gel, chloroform) to yield 10.0 g (54.0 mmol, 62.1% yield) of an oil. FTIR (neat, capillary) 3516.50, 3132.04, 3099.40, 3003.94, 2960.21, 1830.80, 1823.25, 1792.36, 1734.05, 1671.98, 1653.62, 1646.30, 1429.97, 1380.77, 1368.60, 1306.35, 1260.89, 1241.83, 1201.12, 1162.09, 1154.49, 1134.29, 1087.59, 1049.93, 1005.21, 990.18, 948.77, 941.86, 908.06, 897.29, 892.42, 812.37, 769.04, 756.85, 724.90, 707 81. NMR (CDCl3) 6.73-7.09 (1H,q), 4.61-5.24 (2H,m), 2.78 (4H,S). ##STR16##
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][O:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:38][C:35]3[CH:34]=[CH:33][C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[CH:37][CH:36]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN(c1ccccc1COc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(OCc5ccccc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-(2-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yloxymethyl}-phenyl)-methanesulfonamide was prepared from N-[2-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yloxymethyl)-phenyl]-N-methyl-methanesulfonamide (102.0 mg, 0.2781 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (60.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.016 g, 11%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.07 (d, J=6.7 Hz, 1H), 7.74-7.69 (m, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.43-7.38 (m, 2H), 7.34-7.30 (m, 1H), 6.96 (d, J=8.1 Hz, 2H), 6.90 (d, J=7.8 Hz, 1H), 6.73 (t, J=7.3 Hz, 1H), 6.62 (s, 1H), 5.49 (br s, 2H), 3.32 (s, 3H), 3.18-3.13 (m, 4H), 2.99 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=522 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21].[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25]>CO>[CH3:28][O:27][C:23](=[O:26])[CH2:24][CH2:25][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: Cc1c(CC(N)=O)c2cc(N)ccc2n1Cc1ccccc1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCNc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1
Yield: 55 %

Procedure:
A solution of 147 mg (0.5 mmol) of 5-amino-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide (Example 18) and 2 mL of methyl acrylate in 5 mL of MeOH was stirred for 65 hours, then concentrated at reduced pressure. The residue was chromatographed on silica and eluted with a gradient (EtOAc→5% MeOH/EtOAC) to give a major product and a minor product in the later fractions. The major product was 105 mg (55% yield) of 3-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]amino]propanoic acid methyl ester.
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=2)([OH:15])[CH3:14])[N:10]=[N:9]1)C>CO.O>[Br:22][C:18]1[N:17]=[C:16]([C:13]([C:11]2[N:10]=[N:9][N:8]([CH2:7][CH2:6][OH:5])[CH:12]=2)([OH:15])[CH3:14])[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)Cn1cc(C(C)(O)c2cccc(Br)n2)nn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)(c1cn(CCO)nn1)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of NaBH4 (92 mg, 2.42 mmol) in MeOH (3.0 mL) at room temperature was added ethyl{4-[1-(6-bromopyridin-2-yl)-1-hydroxyethyl]-1H-1,2,3-triazol-1-yl}acetate (430 mg, 1.21 mmol) in MeOH (7.0 mL). The reaction was stirred at room temperature for 2 h. It was then diluted with water and extracted with EtOAc (2×) and 5:1 CH2Cl2:MeOH (5×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (0-5% MeOH/EtOAc) afforded the title compound as a colorless solid.