Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2.[CH:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:26]([CH:23]4[CH2:25][CH2:24]4)=[O:27])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2
Reactant: O=C(O)C1CC1
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Product: O=C(Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1)C1CC1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and cyclopropyl carboxylic acid; MS: m/e=362.2 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[C:44]([NH2:51])=[C:43]([Cl:52])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][C:24]([N:28]4[CH2:33][CH2:32][N:31]([CH2:34][C:35]([O:37]CC)=[O:36])[CH2:30][CH2:29]4)([CH3:27])[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:53]=[CH:54][CH:55]=[CH:56][C:4]=2[NH:3]1.[Li+].[OH-]>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:49])([F:48])[F:50])[C:44]([NH2:51])=[C:43]([Cl:52])[CH:42]=3)[C:19]([N:21]3[CH2:22][CH2:23][C:24]([N:28]4[CH2:33][CH2:32][N:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:30][CH2:29]4)([CH3:27])[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:53]=[CH:54][CH:55]=[CH:56][C:4]=2[NH:3]1
Reactant: CCOC(=O)CN1CCN(C2(C)CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Product: CC1(N2CCN(CC(=O)O)CC2)CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1

Procedure:
Prepared analogously to Example 19.1 from 100 mg (0.12 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-4-methyl-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 10.0 mg (0.42 mmol) LiOH.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH:2]=[CH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:14][C:15]1[CH:16]=[C:17](I)[CH:18]=[CH:19][CH:20]=1.C([O-])(=O)C.[Na+].O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:14][C:15]1[CH:20]=[C:19](/[C:3](/[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:2]/[C:1]([O:11][CH2:12][CH3:13])=[O:10])[CH:18]=[CH:17][CH:16]=1
Reactant: Clc1cccc(I)c1
Reactant: CCOC(=O)C=CCC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C(\CC(=O)OCC)c1cccc(Cl)c1
Temperature: 100 °C
Reaction time: 21 h
Yield: 20.1 %

Procedure:
A mixture of diethyl glutaconate (10.0 g. 53.7 mmol), 3-chloroiodobenzene (11.5 g, 48.2 mmol), sodium acetate (4.40 g, 53.7 mmol) and palladium acetate (1.1 g, 4.9 mmol) in DMF (30 mL) was heated to 100° C., stirred for 21 hours, cooled to room temperature, poured into water, filtered, and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel 8:1 hexanes/ethyl acetate to provide 2.88 g (20%) of the desired product. MS (DCI/NH3) m/z 297 (M+H)−; 1H NMR (CDCl3) δ 7.43 (m, 2H), 7.32 (m, 3H), 6.26 (s, 2H), 4. 19 (m, 4H), 1.21 (t, 3H), 1.31 (t, 3H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[CH:12][C:10]=3[N:11]=2)=[CH:5][CH:6]=1.[Na].C([Li])CCC.CN(C)[CH:26]=[O:27]>O1CCCC1.O>[CH:26]([C:2]1[S:3][C:4]([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[CH:12][C:10]=3[N:11]=2)=[CH:5][CH:6]=1)=[O:27]
Reactant: CN(C)C=O
Reactant: Clc1cc2nc(-c3ccc(Br)s3)[nH]c2cc1Cl
Agent: [Li]CCCC
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 42.2 %

Procedure:
To a solution of 2-(2-bromothiophen-5-yl)-5,6-dichlorobenzimidazole (100 mg, 0.287 mmol) in tetrahydrofuran (6 mL) was added sodium hydryde (60% oil dispersion; 14 mg, 0.35 mmol) at 0° C. under nitrogen atmosphere. After cooling to −78° C., n-butyllithium (1.6 mol/L in hexane; 0.36 mL, 0.57 mmol), dimethylformamide (0.085 mL, 1.1 mmol) were added, and the mixture was stirred for 10 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (19:1 to 9:1 chloroform/acetonitrle) to afford 2-(2-formylthiophen-5-yl)-5,6-dichlorobenzimidazole (36 mg, 42%).
Reaction SMILES: [CH3:1][C:2]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][NH:7]C(OC(C)(C)C)=O)=[O:5].FC(F)(F)C(O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(Cl)Cl.O>[CH3:1][C:2]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][NH2:7])=[O:5]
Reactant: Cc1cccc(C(=O)NNC(=O)OC(C)(C)C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cccc(C(=O)NN)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
N′-(2,3-Dimethyl-benzoyl)-hydrazinecarboxylic acid, tert-butyl ester (70.3 g, 266 moles) was placed in to a 500 mL round bottom flask. With gentle stirring, 200 mL of trifluoroacetic acid (290 g, 2.6 moles) was slowly added, resulting in a vigorous evolution of gas. The reaction mixture was then stirred at room temperature for 2 hours. Water (ca. 100 mL) was then added slowly to the mixture. The mixture was slowly added to 1 L of a cold 2 M K2CO3 solution, contained in a 2 L beaker, while stirring slowly (evolution of gas). About 200 mL of a 10% NaOH solution and 250 mL of CH2Cl2 were added. The reaction mixture was transferred to a large separatory funnel and gently shaken (gas evolution). The aqueous phase was extracted with CDCl3 and the extracts dried and evaporated to yield a white solid, which was dried in a 50° C. vacuum oven to yield 31.72 g (73% yield) of 2,3-dimethyl-benzoic acid hydrazide. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7-7.3 (m, 4H), 4.00 (br s, 2H), 2.271 (s, 6H).
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:23][N:24]=[N+]=[N-])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:50]([O:49][C:28]1[CH:27]=[C:22]([CH:21]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:23][NH2:24])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(CN=[N+]=[N-])cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(CN)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.5 %

Procedure:
Under an argon atmosphere, 3,4,5-tris(octadecyloxy)benzyl azide (3.00 g, 3.21 mmol) was dissolved in dehydrating tetrahydrofuran (35 mL) and, under ice-cooling, lithium aluminum hydride (162 mg, 4.30 mmol) was added. The reaction mixture was stirred at room temperature for 2 hr. After completion of the reaction, purified water (2 mL) and 4.0 mol/L aqueous sodium hydroxide solution (2 mL) were added dropwise to the reaction mixture to decompose unreacted lithium aluminum hydride, and the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure, acetonitrile was added, and the precipitated solid was collected by filtration and dried under reduced pressure to quantitatively give the title compound (3.09 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][C:10]([F:13])([F:12])[F:11].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[O:9][C:10]([F:12])([F:11])[F:13]
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc(Br)c(OC(F)(F)F)c1
Solvent: ClCCl
Product: FC(F)(F)Oc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Bromo-3-(trifluoromethoxy)phenol (1.0 g, 0.0039 mol), phenylboronic acid (1900 mg, 0.016 mol), TEA (3.2 mL, 0.023 mol), cupric acetate (1.3 g, 0.0070 mol) and DCM (40 mL) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=6.82 (dd, J 8.97, 2.65 Hz, 1H), 7.00 (dd, J=2.78, 1.26 Hz, 1H), 7.02-7.10 (m, 2H), 7.16-7.24 (m, 1H), 7.36-7.45 (m, 2H), 7.55 (d, J=8.84 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH:33]([CH3:35])[CH3:34])=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]([CH:33]([CH3:34])[CH3:35])[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C1CCCC1NC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCC1N(C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1)C(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1665 g, 0.5 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). 2-Isopropylamino-cyclopentanecarboxylic acid ethyl ester (0.0996 g, 0.5 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1003 g, 0.525 mmol). Then N-methylmorpholine (115 μL, 1.05 mmol) was added. The mixture was stirred at 25° C. for 5 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, 2-{isopropyl-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester, as a yellow oil. LC-MS (ESI) calcd for C21H30N4O7S2 514.16, found 515.3 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][C@H:7]([C:10](O)=[O:11])[CH2:6]1)=[O:4].CSC.B>C1COCC1>[OH:11][CH2:10][C@H:7]1[CH2:8][CH2:9][C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1
Reactant: COC(=O)[C@@H]1CC[C@H](C(=O)O)C1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)[C@@H]1CC[C@H](CO)C1
Temperature: -78 °C
Yield: 89 %

Procedure:
(1S,3R)-3-(methoxycarbonyl)cyclopentanecarboxylic acid (15.9 gm, 92.3 mmol, 1 equi.) was dissolved in anhydrous THF (250 mL) and cooled down to −78° C. under nitrogen atmosphere. To this was added borane dimethyl sulfide complex (2M solution in THF, 1.66 equi., 147.7 mmol, 74 mL) and stirring was maintained for one hour allowing the temperature to raise to 0° C. temperature and stirred at room temperature for another three hours. The mixture was cooled down to −20° C. and quenched with a slow addition of 1M KH2PO4. Reaction was warmed up to room temperature and stirred for further 20 min and extracted with ether. Organic layer was washed with brine and dried over MgSO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography with (10% to 80% EtOAc in hexanes) to provide 13 g of (1R,3S)-methyl 3-(hydroxymethyl)cyclopentanecarboxylate 99.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:30]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:31])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added cyclohexanecarbonyl chloride (126 mg, 0.86 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization from ethyl acetate-hexane gave the title compound (166 mg, 69%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])[CH3:3].[CH2:11]([O:13][C:14]([C:16]#[C:17][C:18](OCC)=[O:19])=[O:15])[CH3:12]>>[CH3:1][CH:2]([C:4]1[CH:10]=[CH:9][CH:8]=[C:6]2[C:5]=1[C:18](=[O:19])[CH:17]=[C:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[NH:7]2)[CH3:3]
Reactant: CC(C)c1cccc(N)c1
Reactant: CCOC(=O)C#CC(=O)OCC
Product: CCOC(=O)c1cc(=O)c2c(C(C)C)cccc2[nH]1

Procedure:
Treatment of 3-(1-methylethyl)aniline (6.0 g) with diethylacetylenedicarboxylate (7.1 ml), as described in Example 1b, gave ethyl 5-(1-methylethyl)-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.23 g), mp 176°-178° C., δ (360 MHz, DMSO-d6) 1.19 (6H, d (CH3)2), 1.36 (3H, t, CO2CH2CH3), 4.41 (2H, q, CO2CH2), 4.84 (1H, m, CH(CH3)2), 6.56 (1H, S, 3-H). 7.28 (1H, d, 6-H), 7.58 (1H, t, 7-H), 7.79 (1H, d, 8-H) and 11.80 (1H, bs, NH), and ethyl 7-(1-methylethyl)-4-oxo-1,4-dihydroquinoline-2-carboxylate (1.17 g) mp 186°-188° C., (360 MHz, DMSO-d6) 1.25 (6H, d, (CH3)2),1.35 (3H, t, CH2CH3), 3.00 (1H, m, CH(CH3)2), 4.42 (2H, q, CH2), 6.63 (1H, S, 3-H), 7.29 (1H, d, 6-H), 7.80 (1H, s, 8-H), 8.00 (1H, d, 5-H) and 11.86 (1H, bs, NH).
Reaction SMILES: [O:1]1[C:6]2[CH2:5][O:4][CH2:3][C:2]1=2.[C:7]1([C@H:13]([NH2:15])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Al](C)C>>[C:7]1([CH:13]([NH:15][CH:6]2[CH2:5][O:4][CH2:3][CH:2]2[OH:1])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: C1OCC2=C1O2
Agent: C[Al](C)C
Product: CC(NC1COCC1O)c1ccccc1

Procedure:
According to the procedure of Overman, et al. (J. Org. Chem. 1985, 50, 4154), 3,4-epoxy-2,5-dihydrofuran was treated with (R)-1-phenylethylamine and trimethylaluminum to give a 1:1 mixture of diastereomers. The mixture was purified by silica gel chromatography to provide the desired compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][C:9](=[O:32])[C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2].[Br:33]Br.Br.O>C(O)(=O)C>[C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH:8]([Br:33])[C:9](=[O:32])[C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C(Br)[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A solution of methyl 3α-acetoxy-7-keto-5β-cholanoate. (5.6 g, 12.54 mmoles) in acetic acid (100 ml) was added with a bromine solution (2.8g) in acetic acid (10 ml) and immediately after with 48% hydrobromic acid (0.74 ml). The resulting reaction mixture was left to react overnight under strong magnetic stirring, then it was poured into water (300 ml) and filtered under vacuum to obtain a solid (8,03 g) which was subjected to flash chromatography on silica, eluting with methylene chloride/methanol 99.5:0.5, to yield 6.0 g of a pure product (91%).
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[N:5]1.[H][H]>[Pd].C(O)C>[NH2:9][C:6]1[CH:7]=[CH:8][N:4]([CH2:3][C:2]([CH3:12])([OH:13])[CH3:1])[N:5]=1
Reactant: CC(C)(O)Cn1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(O)Cn1ccc(N)n1
Yield: 93.1 %

Procedure:
In a Parr shaker bottle was placed 2-methyl-1-(3-nitro-pyrazol-1-yl)-propan-2-ol (prepared in example 74, 100 mg, 0.54 mmol), 10% palladium on activated carbon (10 mg) and ethanol (5 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 1 h. The reaction was then filtered through a pad of celite and washed with ethanol and concentration in vacuo afforded l-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (78 mg, 94%) and taken on to the next step without characterization.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:10]=2)[C:6]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[Cl:29].[C:30]([O:34][C:35]([N:37]([CH2:41][CH:42]([OH:57])[CH2:43][O:44][C:45]1[CH:53]=[CH:52][CH:51]=[C:50]2[C:46]=1[CH:47]=[C:48]([C:54](O)=[O:55])[NH:49]2)[CH:38]([CH3:40])[CH3:39])=[O:36])([CH3:33])([CH3:32])[CH3:31].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:30]([O:34][C:35]([N:37]([CH2:41][CH:42]([OH:57])[CH2:43][O:44][C:45]1[CH:53]=[CH:52][CH:51]=[C:50]2[C:46]=1[CH:47]=[C:48]([C:54]([NH:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:21]([O:23][CH3:24])=[O:22])=[CH:13][CH:14]=3)[C:6]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[Cl:29])=[O:55])[NH:49]2)[CH:38]([CH3:39])[CH3:40])=[O:36])([CH3:32])([CH3:33])[CH3:31]
Reactant: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: CC(C)N(CC(O)COc1cccc2[nH]c(C(=O)O)cc12)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(CNC(=O)c2cc3c(OCC(O)CN(C(=O)OC(C)(C)C)C(C)C)cccc3[nH]2)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reaction time: 96 h

Procedure:
5-Aminomethyl-2-n-butyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloroimidazole (prepared by the procedure of Example 148, Part C, in EP No. 0253310) (0.71 g, 1.7 mmol), 1 eq), 4-[3-(N-t-butoxycarbonyl-N-isopropylamino)-2-hydroxypropoxy]indole-2-carboxylic acid (prepared by the procedure of Example 1, Part g, in EPO No. 174162) (0.84 g, 1.7 mmol, 1 eq), 1-hydroxybenzotriazole (0.24 g, 1.8 mmol, 1.05 eq), dicyclohexylcarbodiimide (0.37 g, 1.8 mmol, 1.05 eg) and DMF (25 mL) were mixed at 0° C. and left in the refrigerator for 4 days at that temperature. The dicyclohexylurea was filtered off and the mixture concentrated and chromatographed in 1:1 hexane/ethyl acetate yielding 970 mg of a white solid; mp 157.5°-160° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].C(N(CC)CC)C.[C:19](=S)=[S:20]>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:19]([SH:20])=[N:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NNC(=O)c1cccc(N)c1
Reactant: S=C=S
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1cccc(-c2nnc(S)o2)c1

Procedure:
3-Aminobenzhydrazide (5.76 g) was dissolved in ethanol (40 mL), and triethylamine (4.8 mL) and carbon disulfide (2.1 mL) were added to the solution. The mixture was heated under reflux for 4 hrs. The solvent was evaporated, and water was added. The precipitated solids were collected by filtration to give the title compound (5.06 g) as a pale-yellow powder.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O-:17].[Na+]>CO>[CH2:1]([C:8]1[N:9]=[C:10]([C:14](=[NH:15])[O:17][CH3:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(Cc2ccccc2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cccc(Cc2ccccc2)n1
Temperature: 20 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
2-Benzyl-6-cyanopyridine (0.84 g, 0.0043 moles) was added to a solution of sodium methoxide in methanol [prepared by dissolving sodium metal (0.11 g, 0.0047 gram atoms) in methanol (10 ml)] and the mixture stirred at 20° C. for 5 hours. The methanol was evaporated, the residue taken up in chloroform and the precipitate filtered off through a silica bed. Removal of the solvent from the filtrate gave methyl 6-benzyl-2-picoline imidate (0.81 g, 84%) which was used in the next stage without further purification.
Reaction SMILES: C1(C[O:8][NH:9][C:10](=[O:38])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:21]=3[CH:37]=2)C=CC=CC=1>C(O)C.[Pd]>[OH:8][NH:9][C:10](=[O:38])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[N:24]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:21]=2[CH:37]=1
Reactant: O=C(CCCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1)NOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(CCCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1)NO
Reaction time: 3 h

Procedure:
23 mg of N-(phenylmethoxy)-6-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanamide was dissolved in 4 ml of ethanol, mixed with 15 mg of palladium on carbon (10%) and stirred under a hydrogen atmosphere for 3 hours. After catalyst was separated out, it was concentrated by evaporation in a vacuum, and the residue was crystallized from diethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C@@H:11]1[CH2:16][NH:15][CH2:14][C@H:13]([CH3:17])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:16][C@H:11]([CH3:10])[N:12]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[C@H:13]([CH3:17])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CNC[C@H](C)N1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@@H]1CN(Cc2ccc(Br)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.8 %

Procedure:
A mixture of 4-bromobenzaldehyde (1.85 g, 10 mmol), 1,1-dimethylethyl (2R,6S)-2,6-dimethyl-1-piperazinecarboxylate (2.15 g, 10 mmol) and sodium triacetoxyborohydride (3.18 g) in 1,2-DCE (35 ml) was stirred at room temperature for 3 days. Saturated aq. NaHCO3 solution was added and the mixture stirred for 30 mins. The product was extracted into EtOAc and the extracts dried (Na2SO4) and concentrated. The residue was dissolved in DCM and treated with PS-hydrazine resin with stirring for 2 h. The resin was removed by filtration and the solvent removed in vacuo. Chromatography (0-40% EtOAc/hexane) gave the title compound (3.52 g). MS (ES): MH+ 383/385.