Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[N:30]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=4)[CH2:29][C@@H:28]3[CH3:42])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.O>C1COCC1.CO>[F:41][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=1)[CH2:34][N:30]1[C@H:31]([CH3:33])[CH2:32][N:27]([C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:43])[C@@H:28]([CH3:42])[CH2:29]1
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4cccc(F)c4)C[C@@H]3C)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CN([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCC(C(=O)O)CC3)c2)[C@@H](C)CN1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To a solution of 1-{3-[(R)-[(2S,5R)-4-(3-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester (463 mg, Example 124) in THF (4 mL) was added 1N NaOH solution (3 mL). The reaction was stirred at room temperature overnight. The reaction solution was neutralized by the addition of 1 N HCl solution (3 mL). The resulting solution was concentrated under vacuum to give crude product, which was subjected to reverse phase C-18 column chromatography conducted on CombiFlash™ Sq 16×(gradient: 100% H2O to 100% MeOH) to give 1-{3-[(R)-[(2S,5R)-4-(3-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-(3-hydroxyphenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid (183 mg; 41%). 1H NMR (300 MHz, CD3OD) δ 7.48 (m, 2H), 7.37 (m, 2H), 7.27 (m, 1H), 7.16 (m, 3H), 7.04 (m, 1H), 6.71 (m, 3H), 5.21 (s, 1H), 4.47 (m, 1H), 4.13 (d, J=13.5 Hz, 1H), 3.66 (m, 1H), 3.51 (d, J=13.5 Hz, 1H), 3.09 (m, 2H), 2.81 (m, 3H), 2.68 (m, 1H), 2.55 (m, 1H), 2.30 (m, 1H), 2.06 (m, 2H), 1.83 (m, 1H), 1.65 (m, 2H), 1.21 (d, J=6.0 Hz, 3H), 1.15 (d, J=6.5 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.[Pd]>[N:16]1([CH:13]2[CH2:14][CH2:15][N:10]([C:6]3[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=3)[CH2:11][CH2:12]2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1cccc(N2CCC(N3CCOCC3)CC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(N2CCC(N3CCOCC3)CC2)c1
Yield: 42.9 %

Procedure:
4-[1-(3-Nitro-phenyl)-piperidin-4-yl]-morpholine (1.60 g, 0.00549 mol) was dissolved in Methanol (45 mL) and the solution was carefully added to Palladium on Carbon 10% (90.10, carbon black. Palladium, 0.750 g) in a Parr vessel under nitrogen. The mixture was then placed on a Parr hydrogenator and was allowed to shake until uptake of hydrogen had ceased (˜3 hours). The catalyst was then removed via filtration and the filtrate was reduced to afford 615 mg of 3-(4-Morpholin-4-yl-piperidin-1-yl)-phenylamine without further purification. 1H NMR (400 MHz, DMSO, d6) δ 6.81 (t, 1H, J=7.88 Hz), 6.14 (m, 1H), 6.11 (m, 1H), 6.00 (m, 1H), 4.80 (s, 2H), 3.57 (m, 6H), 2.46 (m, 5H), 1.82 (m, 2H), 1.43 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[N:9]=[CH:8][CH:7]=[C:6]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[O:31])=[C:25]([F:40])[CH:24]=1)#[N:2].O>CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[N:9]=[CH:8][CH:7]=[C:6]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[O:31])=[C:25]([F:40])[CH:24]=1)#[N:2]
Reactant: CCOC(=O)CCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)c2cc1C#N
Solvent: CO
Solvent: O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCCCC(=O)O
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 30.3 %

Procedure:
N-(4-(6-Cyano-7-(3-(ethoxycarbonyl)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea (800 mg) was dissolved in methanol (45 ml), 2N Noah water (15 ml) was added, and the mixture was heated and stirred for 40 minutes at 80° C. After completion of the reaction, the reaction solution was poured into ice water and neutralized with 1N Hal, and the precipitated solid was filtered out. The obtained solid was washed with water and dried to obtain 230 mg of the title compound.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:19][CH3:20]>B(Br)(Br)Br.C(Cl)Cl>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:19][CH3:20]
Reactant: CCc1cc2c(OC)cccc2n1Cc1ccccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 69.3 %

Procedure:
By the method used in Example 1, Part D, 911 mg (2.6 mmol) of 1-([1,1'-biphenyl]-2-ylmethyl)-2-ethyl-4-methoxy-1H-indole was O-demethylated by treating it with 10 mL of 1M BBr3 /CH2Cl2. The crude produce was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 590 mg (69% yield) of 1-([1,1'-biphenyl]-2-ylmethyl)-2-ethyl-4-hydroxy-1H-indole as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2([CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])O)#N.[CH:24]([OH:26])=[O:25].[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29]>C(O)C>[CH:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[CH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[O:25].[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[CH:24]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[CH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[O:26]
Reactant: O=CO
Reactant: CN(C)CCCC1(O)c2ccccc2CCn2cc(C#N)cc21
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CN(C)CCC=C1c2ccccc2CCn2cc(C=O)cc21

Procedure:
2-Cyano-11-(3-dimethylaminopropyl)-11-hydroxy-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine (.62 g.) and 6.2 g. Ni-Al 1:1 alloy powder (BDH Chemicals Ltd., Pool England) in 50 ml. 75% formic acid is refluxed for 1 hr. The dark red suspension is cooled, filtered to remove the insolubles, washed with formic acid and evaporated to dryness. The yield of this red oil is 3.4 g. (57%) and it slowly crystallizes on cooling. The oxalate salt of 2-formyl-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]-benzazepine is prepared by dissolving the above product in the minimum volume of ethanol and adding dropwise a saturated ethanolic solution of oxalic acid. The resulting crystals are collected by filtration and dried to give 2-formyl-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine oxalate, m.p. 181° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][S:13]([O-:15])=[O:14].[Na+].O>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CS(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
8 g of 3,4-difluoronitrobenzene and 1.01 eq of sodium methanesulfinate (95%) was dissolved in 10 ml of DMSO. The solution was stirred at 60° C. for 3 hours. When the reaction was completed, the solution was added to 100 ml of water to form pale yellow solid, followed by filtration and washing with 50 ml of cool water and 30 ml of n-hexane separately to give 8.8 g of the title compound as a pale yellow solid (yield 79%).
Reaction SMILES: [CH2:1]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]3[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][CH:41]=3)=[CH:34][CH:33]=2)=[O:30])[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].ClC1C=CC=C(C(OO)=[O:56])C=1.CSC.O>ClCCl>[CH2:1]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:21]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]3[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][CH:41]=3)=[O:56])=[CH:34][CH:33]=2)=[O:30])[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCC)cc2)CCN3CC(C)C)cc1
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a solution of 1-isobutyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (600 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (272 mg) in dichloromethane (15 ml) at −78° C. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate), to give 1-isobutyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (433 mg) (Compound 390) as yellow amorphous.
Reaction SMILES: [OH2:1].[OH-].[Li+].C1[CH2:8][O:7]CC1.O.OO.C([C@@H]1COC(=O)N1C(=O)[C@H:26]([C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)C1C=CC=CC=1>C1COCC1>[C:42]([O:41][C:39]([N:35]1[CH2:36][CH2:37][CH2:38][C@H:34]1[C@H:26]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:8]([OH:7])=[O:1])=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)cc1
Reactant: O
Reactant: C1CCOC1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 72 %

Procedure:
Lithium hydroxide hydrate (0.0471 g, 1.12 mmol) was added to a solution of THF/water (3:1, 19 mL) and stirred until dissolved. The mixture was cooled to 0° C. and treated with 30% hydrogen peroxide (0.231 mL, 2.24 mmol) and stirred for 10 minutes. A solution of (S)-tert-butyl 2-((S)-2-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2-oxoethyl)pyrrolidine-1-carboxylate (0.280 g, 0.561 mmol) in THF (2 mL) was added. The reaction was stirred for 30 minutes at 0° C. TLC did not show much progress, therefore the reaction was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched by addition of 1.5 M Na2SO3 (1 mL) and stirred for 15 minutes. The reaction mixture was diluted with Et2O and separated. The aqueous portion was washed (2×) with Et2O then adjusted to a pH of 1 with 3N HCl. The aqueous portion was extracted (3×) with ethyl acetate. The combined organic layers were washed with water (2×), saturated NaCl, dried over Na2SO4 and concentrated in vacuo to a thick oil which slowly solidified to give (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid as a foam (0.55 g, 72%). 1H NMR (CDCl3, 400 MHz) δ 7.30 (d, 2H), 7.21 (d, 2H), 4.53-4.40 (m, 1H), 4.37-4.27 (m, 1H), 3.34-3.22 (m, 1H), 2.98-2.90 (m, 1H), 2.02-1.90 (m, 1H), 1.83-1.74 (m, 1H), 1.64-1.53 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: C([N:8]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[C:24](=[O:25])[N:23]([CH3:26])[N:22]=[N:21]3)[CH:18]=2)[NH:13][C:12]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>[OH-].[OH-].[Pd+2].O>[CH3:34][C:29]1[CH:28]=[C:27]([C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH2:10][CH2:9][NH:8][CH2:35][CH2:36][CH2:37][CH2:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[CH:18][C:17]([N:20]2[C:24](=[O:25])[N:23]([CH3:26])[N:22]=[N:21]2)=[CH:16][CH:15]=3)[CH:32]=[C:31]([CH3:33])[CH:30]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(-n4nnn(C)c4=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)cc(-c2[nH]c3ccc(-n4nnn(C)c4=O)cc3c2CCNCCCCc2cccnc2)c1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
To a stirred solution of 1-[3-{2-[benzyl-(4-pyridin-3-yl-butyl)amino]ethyl }-2-(3,5-dimethylphenyl)-1H-indol-5-yl] -4-methyl-1,4-dihydrotetrazol-5-one (20 mg in 4 mL methanol) was added 15 mg of 10% palladium hydroxide on carbon catalyst followed by acetic acid (0.020 mL of a 30% solution in water). The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 30 minutes the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (methylene chloride:methanol:ammonium hydroxide, 90:6.5:1) gave the title compound (16 mg). m/e=496 (M+H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19][C:20](=[O:28])[CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([OH:18])[CH2:13]1)[CH:6]=[CH:5]2.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[Cl:1][C:2]1[C:3]([NH:19][C:20](=[O:28])[CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([O:18][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCC[C@@H](O)C3)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CCCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Reaction time: 24 h

Procedure:
To a stirred solution of N-[6-chloro-2-[(3R)-3-hydroxy-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 37) (0.715 g) in dichloromethane (10 mL) was added triethylamine (0.99 mL) followed by methanesulfonyl chloride (0.275 mL). The reaction was stirred under nitrogen for 24 hours followed by the removal of volatiles under vacuum. The resulting mixture was taken up in methanol (20 mL) and placed down a Varian® SCX cartridge, washed with methanol (50 mL) and eluted with ammonia in methanol (0.7M, 50 mL). The solvent was removed to afford the sub-titled compound (0.64 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@@H:5]([NH:7][C:8](=[O:18])[C@@H:9]([NH2:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6])[CH3:2].FC(F)(F)C([O-])=O.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[C@@H:5]([NH:7][C:8](=[O:18])[C@@H:9]([NH:17][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)[C@H](C)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of (S)-2-((S)-2-Amino-3-phenyl-propionylamino)-propionic acid ethyl ester.trifluoroacetate salt (10 g, 37.9 mmol) and DIPEA (19.5 mL, 113.6 mmol) in DCM (100 mL) was added benzoyl chloride (4.0 mL, 34.1 mmol) at −20° C. and stirred at −20° C. for 1 h. The reaction mixture was filtered to remove salts and the filtrate was washed with 10% citric acid solution (2×50 mL), 5% NaHCO3 solution (2×50 mL) and brine solution (50 mL) respectively, dried over Na2SO4, filtered and concentrated in vacuo to give a residue that was dissolved in CHCl3 (20 mL) and triturated with n-pentane. The precipitated solid was filtered and washed with a mixture of Et2O and n-pentane (50 mL, 1:1), then dried to obtain (S)-2-((S)-2-Benzoylamino-3-phenyl-propionylamino)-propionic acid ethyl ester (6.5 g, 47%) as a white solid. Rf: 0.8 (10% MeOH/CHCl3); 1H NMR (400 MHz, DMSO-d6): δ 8.60-8.55 (1H, m), 7.76 (2H, d, J=6.8 Hz), 7.52-7.35 (5H, m), 7.27 (2H, t, J=7.6 Hz), 7.18 (1H, t, J=7.6 Hz), 4.80-4.70 (1H, m), 4.30-4.22 (1H, m), 4.07 (2H, q), 3.11 (1H, dd, J=4, 14 Hz), 3.01-2.98 (1H, m), 1.34 (3H, d, J=7.2 Hz), 1.18 (3H, t, J=6.8 Hz); m/z 369 (MH)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:30]([NH:39][CH3:40])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@H:30]([N:39]([CH3:40])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:18])[CH3:17])[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in WO2002079134) (0.88 g, 2.76 mmol) in CH2Cl2 (2 ml) was added drop wise to a stirred solution of rac-((3S,4R)-1-benzyl-4-phenyl-pyrrolidin-3-yl)-methyl-amine (0.72 g, 2.70 mmol) and ethyl-diisopropyl-amine (0.64 ml, 3.76 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 1 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:4) yielded 1.05 g (74%) of the title product as colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH:23]=[C:22]([C@:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][CH3:26])[N:21]=[N:20]4)=[CH:15][CH:16]=3)[N:11]=[C:10]([C:32](=O)[CH3:33])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:36][OH:37]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH:23]=[C:22]([C@:24]([OH:31])([C:27]([F:28])([F:30])[F:29])[CH2:25][CH3:26])[N:21]=[N:20]4)=[CH:15][CH:16]=3)[N:11]=[C:10](/[C:32](=[N:36]\[OH:37])/[CH3:33])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C(C)=O)nc3c2)nn1)C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(/C(C)=N\O)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of (S)-1-[4-(4-fluorophenyl)-7-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)quinolin-2-yl]ethanone (50 mg, 0.11 mmol) and hydroxylamine hydrochloride (11 mg, 0.16 mmol) in pyridine (1 mL) was stirred at rt overnight. The solution was concentrated and purification on silica gel (eluting with acetone/dichloromethane, 2:8) gave the title compound. MS (+ESI): 488 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1([CH2:11][OH:12])[CH2:10][CH2:9]1.Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]([N:22]([O:24][CH3:25])[CH3:23])=[O:21])=[CH:16][CH:15]=1>O1CCCC1>[CH3:25][O:24][N:22]([CH3:23])[C:20]([C:17]1[CH:18]=[N:19][C:14]([O:12][CH2:11][C:8]2([CH3:7])[CH2:10][CH2:9]2)=[CH:15][CH:16]=1)=[O:21]
Reactant: CC1(CO)CC1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(OCC2(C)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
To a solution of potassium tert-butoxide (1.68 g) in tetrahydrofuran (30 mL), a solution of 1-methylcyclopropanemethanol (1.29 g) in tetrahydrofuran (5 mL) was added and the mixture was stirred at room temperature for 10 minutes. After the reaction mixture was cooled to 0° C., a solution in tetrahydrofuran (5 mL) of the compound (3.00 g) obtained in step (1) above was added and after being brought to room temperature, the reaction mixture was stirred for an hour. The reaction mixture was then concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-50:50) to give N-methoxy-N-methyl-6-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxamide as a colorless oil (2.02 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCCc1ccccc1
Temperature: 120 °C
Reaction time: 40 h

Procedure:
To a suspension of 10 g (46.66 mmol.) of cis-1-tert-butoxycarbonyl-3,5-dimethyl piperazine and 12.90 g (93.3 mmol.) of potassium carbonate in N,N-dimethylformamide (50 ml) was added, at room temperature, 11.15 g (56 mmol.) of 1-bromo-3-phenylpropane. The mixture was stirred for 40 hours at 120° C., which was then cooled to room temperature. To the reaction system was added water, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography (ethyl acetate/hexane 20-30%) to give the object compound as a yellow oily product. The yield was 12.21 g (79%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12](Cl)(=[O:14])=[O:13].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][S:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:14])=[O:13])[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: O=S(=O)(Cl)CCCCCCCCCCBr
Product: O=S(=O)(CCCCCCCCCCBr)NC1CC1
Yield: 97.3 %

Procedure:
The reaction was carried out in the same manner as in Preparation Example 3 except for using 10-bromodecanesulfonyl chloride (450 mg, 1.41 mmol) in place of 6-bromohexanesulfonyl chloride, and cyclopropylamine (177 mg, 3.10 mmol), to give N-cyclopropyl-10-bromodecanesulfonamide (467 mg) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[N:10]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3ccncc23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccncc23)CC1

Procedure:
from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-azaindole (20 mg, 0.094 mmol), benzenesulfonyl chloride (24 μL, 0.188 mmol) and 1M NaN(TMS)2 (250 μL, 0.25 mmol) in THF (1 mL) at RT.