Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:17]=[CH:16][C:15]2[C:11](=[CH:12][N:13]([CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:14]=2)[C:10]=1[CH3:25])=[O:8].C(N(CC)CC)C.[F:33][C:34]([S:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([F:36])[F:35]>C(Cl)Cl>[CH3:2][O:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:17]=[CH:16][C:15]2[C:11](=[CH:12][N:13]([CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:42](=[O:43])[C:41]4[CH:45]=[CH:46][C:38]([S:37][C:34]([F:36])([F:33])[F:35])=[CH:39][CH:40]=4)[CH2:23][CH2:24]3)[N:14]=2)[C:10]=1[CH3:25])=[O:8]
Reactant: O=C(Cl)c1ccc(SC(F)(F)F)cc1
Reactant: COCCNC(=O)c1ccc2nn(CC3CCNCC3)cc2c1C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNC(=O)c1ccc2nn(CC3CCN(C(=O)c4ccc(SC(F)(F)F)cc4)CC3)cc2c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
60 mg of the amine prepared in Example 1a were first dissolved in 2 ml DCM at 0° C. 0.034 ml of triethylamine and 43.2 mg of 4-[(trifluoromethyl)sulphanyl]benzoyl chloride were then added and the mixture stirred for 2 hrs at 0° C. The reaction mixture was then diluted with DCM and washed with 1-molar hydrochloric acid, saturated sodium hydrogen carbonate solution (pH 9) and saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated. The residue was purified chromatographically on the Biotage SP4. Gradient: DCM/Methanol 0-10%. The product fraction was taken up in ethyl acetate and extracted twice with saturated sodium hydrogen carbonate solution. The organic phase was concentrated and the residue again purified by HPLC. Yield: 26.5 mg of the title compound.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]([CH2:12][CH3:13])[C:9](O)=[O:10].S(Cl)([Cl:22])=O>>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]([CH2:12][CH3:13])[C:9]([Cl:22])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CCC(Cc1ccccc1-c1ccccc1)C(=O)O
Product: CCC(Cc1ccccc1-c1ccccc1)C(=O)Cl
Yield: 106.3 %

Procedure:
To a 300-ml three-necked round flask (equipped with a stirrer tip, a Zimroth condenser, a thermometer and a NaOH trap) were fed 39.9 g (157.2 mmol) of 3-(2-biphenylyl)-2-ethylpropionic acid and 77.7 ml (1,065 mmol) of thionyl chloride, and the contents in the flask were refluxed for 2.5 hours in a nitrogen atmosphere. After the reaction was completed, the unreacted thionyl chloride was distilled off under reduced pressure to obtain 45.6 g of a coarse product of an yellow-orange liquid. This acid chloride was used for the next reaction without any further purification.
Reaction SMILES: [N:1]1([C:7]2[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:15][C:16]1[C:24]2[N:23]=[C:22](Cl)[NH:21][C:20]=2[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1>>[Br:15][C:16]1[C:24]2[NH:23][C:22]([N:4]3[CH2:3][CH2:2][N:1]([C:7]4[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH2:6][CH2:5]3)=[N:21][C:20]=2[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Reactant: OCc1cccnc1N1CCNCC1
Product: OCc1cccnc1N1CCN(c2nc3cc(C(F)(F)F)cc(Br)c3[nH]2)CC1

Procedure:
(2-piperazin-1-ylpyridin-3-yl)methanol (0.48 g, 2.5 mmol, Example 46a) reacted with 4-bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.60 g, 2 mmol, Example 6b) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 456 (M+1).
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[C:12]([O:25][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:32][OH:33]>N1C=CC=CC=1>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[C:12]([O:25][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[CH:11]=2)[CH2:4][CH2:5][C:6](=[N:32][OH:33])[CH2:7][CH2:8]1)#[N:2]
Reactant: N#CC1(c2ccc(OCc3ccc(F)cc3)c(OC3CCCC3)c2)CCC(=O)CC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: N#CC1(c2ccc(OCc3ccc(F)cc3)c(OC3CCCC3)c2)CCC(=NO)CC1
Yield: 71.5 %

Procedure:
A solution of 4-cyano-4-[3-cyclopentyloxy-4-(4-fluorobenzyloxy)phenyl)cyclohexan-1-one (0.525 g, 1.49 mmol) and hydroxylamine hydrochloride (0.114 g, 1.63 mmol) in pyridine (5 mL) was stirred at room temperature under an argon atmosphere for 18 h. The mixture was partitioned between 1 N hydrochloric acid and methylene chloride, the organic extract was dried (magnesium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 35% ethylacetate/hexanes, provided a white solid (0.45 g, 82%): m.p. 55°-57° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26]CC)=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([O:43][C@H:44]([CH2:46][CH:47]=[CH2:48])[CH3:45])[C:37]=1[CH2:49][OH:50].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:50][CH2:49][C:37]4[C:38]([O:43][C@H:44]([CH2:46][CH:47]=[CH2:48])[CH3:45])=[CH:39][C:40]([F:42])=[CH:41][C:36]=4[F:35])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([OH:26])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CC[C@H](C)Oc1cc(F)cc(F)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(COCc4c(F)cc(F)cc4O[C@@H](C)CC=C)nn23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.5 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.2 g, 0.342 mmol) and (S)-(2,4-difluoro-6-(pent-4-en-2-yloxy)phenyl)methanol (0.094 g, 0.411 mmol) in DMF (1 mL) was added sodium hydride (0.021 g, 0.513 mmol) and the mixture was stirred at rt. After 4 h, the mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried (Na2SO4), filtered and concentrated and purified by Prep HPLC: to afford (S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2,4-difluoro-6-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (0.030 g, 0.046 mmol, 13.35% yield) as a colorless oil. LCMS (M+H) calcd for C35H47F2N4O6: 657.34. found: 657.5.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[O:5])=[N-]>O1CCOCC1.[Cu]>[CH3:10][C:9]1([CH3:11])[CH:3]2[CH:8]1[CH2:7][O:6][C:4]2=[O:5]
Reactant: CC(C)=CCOC(=O)C=[N+]=[N-]
Agent: [Cu]
Solvent: C1COCCO1
Product: CC1(C)C2COC(=O)C21
Reaction time: 5.5 h

Procedure:
A solution of 3-methyl-2-butenyl diazoacetate (980 mg, 6.4 mmoles) in dioxane (15 ml) was added dropwise to a solution of bis[2-butoxy-α-[2-butoxy-5-(1,1-dimethylethyl)phenyl]-5-(1,1-dimethylethyl)-α-[(S)-1-[[2-hydroxyphenyl)methylene]amino]ethyl]benzenemethanolate (2-)]copper (83 mg, 0.064 mmole) in dioxane (55 ml) at 110°. When the evolution of nitrogen started, the temperature was slowly lowered to 52°-3°. The addition took 5.5 hours, and the evolution of almost theoretical amounts of nitrogen was observed. After the addition was completed, the reaction mixture was stirred at 52°-3° for 2 hours, evaporated to dryness, and distilled under vacuum to afford 6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane enriched with the (1R,5S) isomer (500 mg). The optical rotation of the product was [α]D29 =-53.5° (CHCl3).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][CH:9]=1.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[CH3:19][C:20]([S@:23]([NH:25][CH:14]([C:11]1[CH:12]=[N:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:18])([F:17])[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCCOCC(F)(F)F)nc1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCCOCC(F)(F)F)nc1
Yield: 24 %

Procedure:
The title compound is prepared in 24% yield (0.33 g, yellow oil) from 1-(6-(2-(2,2,2-trifluoroethoxy)ethoxy)pyridin-3-yl)ethanone (1.0 g, 3.80 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:6]=2[CH:5]=[C:4]([O:24]C)[CH:3]=1.Br>C(O)(=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:6]=2[CH:5]=[C:4]([OH:24])[CH:3]=1
Reactant: COc1cc(Br)c2nc(-c3ccccc3)n(-c3ccc(C)cc3)c2c1
Agent: Br
Solvent: CC(=O)O
Product: Cc1ccc(-n2c(-c3ccccc3)nc3c(Br)cc(O)cc32)cc1

Procedure:
1.2 g of 4-bromo-6-methoxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazole, 6 ml of acetic acid and 6 ml of aqueous hydrobromic acid (62%) are boiled for 5.5 hours. Then, it is precipitated with water, and the precipitate is suctioned off. The latter was then dispersed between ethyl acetate and 2N sodium hydroxide solution. After the organic phase was washed with water, it was concentrated by evaporation.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]1[OH:9].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:9][CH:3]2[CH:4]([CH3:8])[CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])=[O:19])=[CH:13][CH:12]=1
Reactant: CC1CCCC(C)C1O
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1CCCC(C)C1OC(=O)Cc1ccc(O)cc1
Yield: 51 %

Procedure:
A mixture of 2,6-dimethylcyclohexyl alcohol (11.4 g), 4-hydroxyphenylacetic acid (9.12 g), p-toluenesulfonic acid (1 g) and benzene (300 mL) was refluxed with continuous water separation for 20 hours. The mixture was filtered and the filtrate was washed with a 10% Na2CO3 solution, then with water. Drying over MgSO4 and evaporation in vacuo afforded 8.02 g of 2,6-dimethylcyclohexyl 4-hydroxyphenylacetate. That product has the structural formula: ##STR25##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]([CH3:23])[CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH:10]([CH3:23])[CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCC(C)CNc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(CNc1ccc(Cl)cc1)COc1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 80.5 %

Procedure:
Methyl 4-[3 [N-[4-chlorophenyl)amino]-2-methylpropoxy]benzoate (2.80 g) was dissolved in methanol (30 ml) and thereto was added a solution of sodium hydroxide (1.00 g) in water (8 ml), and the mixture was heated with stirring at 60° C. for 15 hours. The reaction mixture was cooled and thereto was added conc. hydrochloric acid (2.20 ml), and the mixture was concentrated under reduced pressure. To the residue was added water and it was crushed, and was collected by filtration. The resultant was dissolved in methanol, and filtered. Water (about half volume of the filtrate) was added to the filtrate gradually, and the resulting crystal was collected by filtration to give the desired product (2.16 g). mp. 148°-150° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:24]([CH2:27][CH3:28])([O-:26])=[O:25]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[C:27](/[N+:24]([O-:26])=[O:25])\[CH3:28])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc(/C=C(\C)[N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Yield: 63 %

Procedure:
3-Benzyloxy-4-methoxybenzaldehyde (8.0 g, 33.05 mmol), ammonium acetate (2.55 g, 33.05 mmol) and nitroethane (120 ml) were stirred under reflux for 22 h. The reaction mixture was cooled to rt and nitroethane was removed in vacuo. The solid residue was dissolved in ethyl acetate (200 ml), washed with water (40 ml) and brine (2×40 ml), dried (MgSO4) and concentrated in vacuo. Recrystallisation from ethanol afforded the title compound (6.19 g, 63%) as yellow crystals. mp=102-104° C. 1H NMR (270 MHz; CDCl3) 2.27 (3H, s, CH3), 3.94 (3H, s, OCH3), 5.19 (2H, s, CH2Ph), 6.91 (1H, d, J=2.0 Hz, CH), 6.94 (1H, d, J=8.4 Hz, CH), 7.05 (1H, dd, J=8.4, 2.0 Hz, CH), 7.30-7.43 (4H, m, 4×CH), 7.97 (1H, s, CH). 13C NMR (67.5 MHz; CDCl3) 14.03 (CH3), 56.15 (OCH3), 71.25 (CH2Ph), 111.69 (CH), 115.77 (CH), 124.93 (C), 124.94 (CH), 127.16 (CH), 128.19 (CH), 128.83 (CH), 133.84 (CH), 136.65 (C), 145.92 (C), 148.00 (C), 151.51 (C). LC/MS (APCI−) tr=1.07 min, m/z 297.93 (M−H)−.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][N:31]2[CH2:35][CH:34]([CH3:36])[NH:33][C:32]2=[O:37])=[CH:28][CH:27]=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:33]4[CH:34]([CH3:36])[CH2:35][N:31]([CH2:30][C:29]5[CH:38]=[CH:39][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)[C:32]4=[O:37])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: COc1ccc(CN2CC(C)NC2=O)cc1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cn3)C2=O)cc1
Yield: 64.2 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (106 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 1, 3-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (132 mg) was obtained. The obtained 3-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (132 mg) was dissolved in trifluoroacetic acid (2 mL), trifluoromethanesulfonic acid (0.11 mL) was added, and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution, and the solvent was evaporated, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol) to give the title compound (83 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22].C(Cl)[Cl:30].Cl>C(OCC)(=O)C.CCOCC>[ClH:30].[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1C
Reactant: ClCCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1C
Yield: 85 %

Procedure:
[4-Nitro-2-(2-methylphenyl)benzoyl]methionine methyl ester was reduced to a corresponding amine by stannous chloride in ethyl acetate at 78° C. The free amine was treated with methylene chloride and 3 N HCl in ether to give [4-amino-2-(2-methylphenyl)benzoyl]methionine methyl ester hydrochloride (85% yield); [α]25D=−28.3 (c=1.0, methanol); 1H NMR (CD3OD) δ 7.74 (d, J=8.2 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.23-7.30 (m, 5H), 4.47 (m, 1H), 3.69 (s, 3H), 2.06-2.18 (m, 4H), 1.99 (s, 3H), 1.97 (m, 2H), 1.74 (m, 1H); 13C NMR (CD3OD) δ 173.3, 170.8, 143.3, 139.7, 138.1, 137.2, 133.5, 131.49 130.8, 130.6, 129.6, 128.8, 126.2, 123.1, 66.9, 52.9, 31.5, 30.8, 20.4, 15.1.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([OH:11])=O)=[CH:7][N:8]=1)[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]#[CH:31]>O1CCCC1>[CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]#[CH:31])=[O:11])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCSc1ncc(C(=O)O)s1
Reactant: C#CCCCCN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCCCCNC(=O)c1cnc(SCC)s1
Temperature: -30 °C

Procedure:
In this preparation 0.1 mole of 2-ethylthio-5-carboxythiazole is dissolved in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, and 0.1 moles of triethylamine is added and the resulting mixture cooled to -30° C. 0.1 Mole of ethylchloroformate is then added dropwise with stirring and the resulting mixture allowed to warm to 0° C. The mixture is then stirred for ten minutes, then cooled to -30° C and 0.11 mole of 1-aminohex-5-yne in 50 ml. of tetrahydrofuran added dropwise. The mixture is allowed to warm to room temperature (about 20° C), poured into 500 ml. of ethyl acetate, washed with water, then washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The mixture is then filtered and the solvent from the resulting filtrate is evaporated under vacuum yielding 2-ethylthio-5-(hex-5-ynylaminocarbonyl)thiazole as a solid, which is then further purified by recrystallization from ethyl acetate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH:18]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:18]1([NH:25][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH2:12][CH2:13]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCCCCC1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1cc2[nH]ncc2cc1NC1CCC(NC2CCCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and cycloheptylamine (57 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (20 mg) and a syn-form compound (31 mg).
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[CH:4][C:5]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)=O.N[C:14]1[C:18](C)=[CH:17][NH:16][N:15]=1>C(O)(=O)C>[CH3:17][C:18]1[CH:14]=[N:15][N:16]2[C:5]([C:7]3[CH:11]=[CH:10][S:9][CH:8]=3)=[CH:4][CH:3]=[N:2][C:12]=12
Reactant: CN(C)C=CC(=O)c1ccsc1
Reactant: Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: Cc1cnn2c(-c3ccsc3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(3-thienyl)-2-propen-1-one and 0.01 mole of 3-amino-4-methylpyrazole in glacial acetic acid is heated at reflux temperature for 8 hours. The solvent is removed in vacuo to give the product of the example.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][C:16](N2CCOCC2)=[CH:15][CH:14]=1)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Br:25]CC(C1C=CC(Br)=CC=1)=O>>[Br:25][C:16]1[CH:17]=[CH:18][C:13]([CH:2]([OH:1])[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:14][CH:15]=1
Reactant: CN(CC(O)c1ccc(N2CCOCC2)cc1)C(=O)OC(C)(C)C
Reactant: O=C(CBr)c1ccc(Br)cc1
Product: CN(CC(O)c1ccc(Br)cc1)C(=O)OC(C)(C)C

Procedure:
As described for the preparation of tert-Butyl 2-hydroxy-2-(4-morpholin-4-ylphenyl)ethyl(methyl)carbamate (Preparations 87-88), 2,4′-dibromoacetophenone was converted to the title compound, isolated as a pale yellow solid.
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:8]=[C:9]([CH:42]=[CH:43][C:44]=1[N+:45]([O-])=O)[O:10][C:11]1[C:12]([CH:34]2[CH2:38][CH2:37][CH2:36][N:35]2[C:39](=[O:41])[CH3:40])=[CH:13][C:14]2[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[N:16][C:15]=2[CH:33]=1)([O-])=O>[Ni].C(O)C>[NH2:4][C:7]1[CH:8]=[C:9]([CH:42]=[CH:43][C:44]=1[NH2:45])[O:10][C:11]1[C:12]([CH:34]2[CH2:38][CH2:37][CH2:36][N:35]2[C:39](=[O:41])[CH3:40])=[CH:13][C:14]2[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[N:16][C:15]=2[CH:33]=1
Reactant: CC(=O)N1CCCC1c1cc2c(cc1Oc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCCC1c1cc2c(cc1Oc1ccc(N)c(N)c1)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.030 ml of hydrazine monohydrate and 20 mg of developed Raney nickel catalyst were added to an ethanol (1 ml) solution of 72 mg of 1-(2-(6-(3,4-dinitro-phenoxy)-2-pyridin-2-yl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone, and the reaction liquid was stirred at room temperature for 2 hours. The catalyst was removed through filtration through Celite, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=9/1) to obtain the entitled compound as a brown oily substance.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[O:9]([CH:17]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=2)[CH2:22][CH2:21]1)[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[O:9]([CH:17]([CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([N:26]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=2)[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:22][CH2:21]1)[Si:10]([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:11])[CH3:12]
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccc(NC2CCN(CCC(O[Si](C)(C)C(C)(C)C)C3CCCCC3)CC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC(O[Si](C)(C)C(C)(C)C)C3CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
After adding 2-furoyl chloride (0.14 mL, 1.4 mmol) dropwise to a solution of 1-(3-tert-butyldimethylsiloxy-3-cyclohexylpropyl)-4-(5-methylpyridin-2-yl)aminopiperidine (423 mg, 0.95 mmol) and triethylamine (0.264 mL) in methylene chloride (4 mL) while cooling on ice, the mixture was stirred at room temperature for 18 hours. NH silica Chromatorex DM1020 was added to the reaction mixture, which was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60 g NH silica Chromatorex DM2035, hexane:ethyl acetate=4:1) to obtain the title compound as an oil (458 mg) (89.4% yield).