Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([Br:8])=[C:6]([Br:9])[C:5]([Br:10])=[C:4]([Cl:11])[C:3]=1[CH3:12].BrC1C(C)=C(Br)C(Br)=C(Br)C=1Br.C1C[NH2+]CC1.C1[O:34]C2OC1C2(C(I)I)CCC1(C(I)I)C2OC1CO2>>[Br:1][C:2]1[C:7]([Br:8])=[C:6]([Br:9])[C:5]([Br:10])=[C:4]([Cl:11])[C:3]=1[CH:12]=[O:34]
Reactant: IC(I)C1(CCC2(C(I)I)C3COC2O3)C2COC1O2
Reactant: Cc1c(Cl)c(Br)c(Br)c(Br)c1Br
Agent: C1CC[NH2+]C1
Agent: Cc1c(Br)c(Br)c(Br)c(Br)c1Br
Product: O=Cc1c(Cl)c(Br)c(Br)c(Br)c1Br

Procedure:
When 2,3,4,5-tetrabromo-6-chlorotoluene, mp 268°-269°, was substituted for pentabromotoluene in Example 7 and the resultant dioxonium compound was hydrolyzed according to the procedure of Example 35 an essentially quantitative yield of the title compound was obtained. The structure of the novel high melting compound was confirmed by infrared and nuclear magnetic resonance spectroscopy as well as by elemental analysis.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[C:15]2[C:23]([NH:25][CH3:26])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CNC(C1N(C)C2C(C=1)=CC=CC=2)=O>>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[C:15]2[CH2:23][NH:25][CH3:26])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)c1cc2ccccc2n1Cc1ccc(OCc2ccccc2)cc1
Agent: CNC(=O)c1cc2ccccc2n1C
Product: CNCc1cc2ccccc2n1Cc1ccc(OCc2ccccc2)cc1
Yield: 63.1 %

Procedure:
According to the procedure of Preparation 1 (b), except substituting 1-(4-benzyloxybenzyl)-N-methylindole-2-carboxamide (44.4 g, 120.1 mmole) for the N,1-dimethylindole-2-carboxamide, the title compound (27.0 g, 63%) was prepared as a white solid: MS (ES) m/e 358 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[CH3:48][N:49]([CH3:51])[NH2:50]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:48][N:49]([CH3:51])[NH:50][C:18](=[O:19])[C:15]1[CH:14]=[CH:13][C:12]([CH:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:17][CH:16]=1
Reactant: CN(C)N
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)NC(=O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 68.4 %

Procedure:
To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (80 mg, 0.19 mmol) obtained in Example 50 were added triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) and 1,1-dimethylhydrazine (21 μl, 0.23 mmol). The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the dichloromethane:methanol=50:1 eluate was concentrated under reduced pressure to give the title compound (60 mg, 0.13 mmol, 68%) as a colorless amorphous substance.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@H:9]([C:17](=[O:31])[NH:18][C@H:19]1[CH2:25][CH2:24][C@@H:23]([CH3:26])[N:22]([CH2:27][CH2:28][CH3:29])[CH2:21][C@@H:20]1[OH:30])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(C)(C)C>O1CCOCC1.CO>[NH2:8][C@@H:9]([CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[C:17]([NH:18][C@H:19]1[CH2:25][CH2:24][C@@H:23]([CH3:26])[N:22]([CH2:27][CH2:28][CH3:29])[CH2:21][C@@H:20]1[OH:30])=[O:31]
Reactant: CCCN1C[C@H](O)[C@@H](NC(=O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)CC[C@H]1C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCN1C[C@H](O)[C@@H](NC(=O)[C@@H](N)CC2CCCCC2)CC[C@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl in dioxane (4.0 M, 15 ml) was added to a stirred solution of [(S)-2-Cyclohexyl-1-((3S,4S,7R)-3-hydroxy-7-methyl-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (1.4 g, 3.0 mmol) in MeOH (5 ml). The reaction mixture was stirred for 2 h at RT, then was concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (1.4 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].Cl.Cl.[CH3:19][N:20]([CH3:28])[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].C(N(CC)CC)C.C>CCOC(C)=O>[CH3:19][N:20]([CH3:28])[C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:25]=[CH:26][CH:27]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Agent: C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)c1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1

Procedure:
Prepared from 5.00 g of 4-chloro-6-nitroquinoline-3-carbonitrile, 5.38 g of 3-dimethylaminoaniline dihydrochloride and 5.17 g of triethylamine in the same manner as Example 377. The crude product was taken up in EtOAc, treated with Darco, filtered through Celite, evaporated and dried in vacuo (50° C.). The yield of 4-(3-dimethylaminophenylamino)-6-nitroquinoline-3-carbonitrile was 5.62 g as brick red crystals: mass spectrum (electrospray, m/e): M+H 334.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:10]Br)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].CCCC[N+](CCCC)(CCCC)CCCC.[F-:29]>>[Br:1][C:2]1[C:3]([CH2:10][F:29])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8]
Reactant: [F-]
Reactant: Cc1cc(C)c(Br)c(CBr)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: Cc1cc(C)c(Br)c(CF)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-2-(bromomethyl)-4,6-dimethylpyridine (1.00 g) and TBAF (17.9 mL, 1 M solution in THF) was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 30%) to give the title compound (651 mg).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+].[CH3:24][CH:25](Cl)[O:26][C:27]([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:28].C(OCC)(=O)C>CN(C=O)C.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[C:8]2[C:12]([O:14][CH:25]([O:26][C:27]([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:28])[CH3:24])=[O:13])[CH3:3]
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: COc1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(C(=O)OC(C)OC(=O)OC3CCCCC3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Temperature: 50 °C
Yield: 19.2 %

Procedure:
Sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.43 g) was dissolved in dry DMF (4.3 ml) and thereto was added triethylbenzylammonium chloride (0.25 g). Thereto was dropped 1-chloroethylcyclohexylcarbonate (0.62 g) and the mixture was stirred under heating to 50° C. One hour later, the mixture was cooled to room temperature and thereto was added ethyl acetate. The mixture was washed with bicarbonate solution, water and brine, successively. The organic layer was dried over sodium sulfate, concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2→1:3→ethyl acetate only) to give 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.12 g, yield 20%).
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:5]([OH:18])[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[CH:10]=1.[O:26]=[C:27]1[N:38]([C@@H:39]([CH3:43])[C:40](O)=[O:41])[CH2:37][CH2:36][C@@:28]21[N:32]([CH2:33][CH2:34][CH3:35])[CH2:31][CH2:30][CH2:29]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>C(Cl)Cl>[CH2:19]([C@H:4]([NH:3][C:40](=[O:41])[C@@H:39]([N:38]1[CH2:37][CH2:36][C@:28]2([N:32]([CH2:33][CH2:34][CH3:35])[CH2:31][CH2:30][CH2:29]2)[C:27]1=[O:26])[CH3:43])[C@H:5]([OH:18])[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:16])[CH3:17])[CH:10]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)c1cccc(CNC[C@@H](O)[C@@H](N)Cc2ccccc2)c1
Reactant: CCCN1CCC[C@@]12CCN([C@@H](C)C(=O)O)C2=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCN1CCC[C@@]12CCN([C@@H](C)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cccc(C(C)C)c1)C2=O
Yield: 37.2 %

Procedure:
A solution of 100 mg (2R,3S)-3-amino-1-(3-isopropyl-benzylamino)-4-phenyl-butan-2-ol dihydrochloride, 79 mg (S)-2-((S)-6-oxo-1-propyl-1,7-diaza-spiro[4.4]non-7-yl)-propionic acid, 102 mg TBTU and 0.171 mL N-methyl morpholine in 5 mL CH2Cl2 is stirred for 5 h at ambient temperature. The solution is diluted with DCM and subsequently washed with bicarbonate, brine, 0.1N HCl and bicarbonate. After drying with MgSO4 all volatiles are evaporated in vacuo and the product is purified by column chromatography (silica gel, DCM/MeOH 95:5) to give 53 mg (37%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:14]1([C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](C(=O)N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
trans-4-(Methoxycarbonyl)cyclohexanecarboxylic acid (20.0 g) obtained in Reference Example 1(2) is dissolved in chloroform (200 ml), and thereto are added pyrrolidine (9.2 g), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (24.7 g) and triethylamine (13.6 g) under ice-cooling. The mixture is then stirred at room temperature for 17 hours. Ice-water is poured to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed successively with 10% hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform, then chloroform/methanol=20/1) to give methyl trans-4-(pyrrolidin-1-ylcarbonyl)cyclohexanecarboxylate (11.8 g).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]([O:7][CH2:8][C:9]#[N:10])=[O:6].C(N(CC)CC)C.[C:18](Cl)(=[O:23])[CH2:19][CH2:20][CH:21]=[CH2:22]>ClCCl>[CH3:2][N:3]([CH2:4][C:5]([O:7][CH2:8][C:9]#[N:10])=[O:6])[C:18](=[O:23])[CH2:19][CH2:20][CH:21]=[CH2:22]
Reactant: C=CCCC(=O)Cl
Reactant: CNCC(=O)OCC#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCC(=O)N(C)CC(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
Cyanomethyl 2-(methylamino)acetate hydrochloride (Compound SP703) (3.00 g, 18.3 mmol) and triethylamine (6.34 ml, 45.5 mmol) were dissolved in dichloromethane (30 ml) under a nitrogen atmosphere, and pent-4-enoyl chloride (2.60 g, 22.0 mmol) was added dropwise at 0° C. The reaction solution was stirred at room temperature for 2 hours and 30 minutes and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, and the solid was removed by filtration. The solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether=1:10→2:7) to afford cyanomethyl 2-(N-methylpent-4-enamido)acetate (Compound SP704) (3.40 g, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH3:26])=[CH:20][CH:19]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]([CH3:26])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:33][CH:34]=2)[N:5]=1)[CH3:2]
Reactant: CN(CCOc1ccc(CCl)cc1)c1ccccn1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCCN(C)c3ccccn3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl]propionate (415 mg), 2-[N-[2-(4-chloromethylphenoxy) ethyl]-N-methylamino]pyridine (554 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 80.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-1H-pyrazol-4-yl]propionate (771 mg, yield: 85%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3].[H][H]>[Ni].CN(C)C=O>[NH:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1C
Reactant: [H][H]
Agent: [Ni]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(N)cc1C

Procedure:
19.4g (0.1 mole) of 4-acetamino-3-methyl-nitrobenzene, 30g of dimethylformamide and 1g of fresh-developed Raney nickel were fed in an autoclave, 50kg/cm2 of hydrogen was then fed thereto, and, after the reaction was carried out at 60° to 120° C while stirring, the reaction mixture was removed immediately, the Raney nickel was removed while hot, and thereafter the product was poured into 100ml of methanol to separate the 4-acetamino-3-methylaniline produced.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:14]1(=[O:40])[N:18]([C:19]2[N:24]=[C:23]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[NH2:33])[CH:22]=[CH:21][CH:20]=2)[C:17](=[O:35])[C:16]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:15]12>>[C:17]1(=[O:35])[N:18]([C:19]2[N:24]=[C:23]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[NH:33][C:9](=[O:10])[C:8]3[CH:12]=[CH:13][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[CH:22]=[CH:21][CH:20]=2)[C:14](=[O:40])[C:15]2=[CH:39][CH:38]=[CH:37][CH:36]=[C:16]12
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1C(=O)Nc1cccc(N2C(=O)c3ccccc3C2=O)n1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2cccc(N3C(=O)c4ccccc4C3=O)n2)cc1
Yield: 123.1 %

Procedure:
Using the procedure described in Example 93, Part A, 4-tert-butylbenzoyl chloride (0.47 mmol) and N-(6-phthalimidopyridin-2-yl)-2-aminobenzamide (0.47 mmol) yielded 300 mg (100%) of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH:18]=[CH2:19])=[CH:12][CH:11]=2)[CH:3]=1.[Zn](CC)[CH2:21]C.ICI>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH:18]3[CH2:21][CH2:19]3)=[CH:12][CH:11]=2)[CH:3]=1
Reactant: CC[Zn]CC
Reactant: C=COCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Solvent: CCOCC
Solvent: ICI
Product: Clc1ccc(Br)cc1Cc1ccc(COC2CC2)cc1
Reaction time: 8 h

Procedure:
To a stirred mixture of 4-bromo-1-chloro-2-(4-(vinyloxymethyl)benzyl)benzene (0.7 g, 2.07 mmol) and Et2Zn (5.18 mL, 5.18 mmol, 1.0 M in hexane) in dry ethyl ether (10 mL) was added diiodomethane (0.42 mL, 5.18 mmol) dropwise during 20 min at room temperature under argon. After stirring overnight, the reaction mixture was poured slowly into ice cold dilute hydrochloride solution with stirring. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (20 mL) and then with brine (20 mL), and then dried over sodium sulfate. The residue was concentrated and purified by column chromatography (eluent EA:PE=1:200) to obtain intermediate CV (0.6 g) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 7.33˜7.24 (m, 5H), 7.18 (d, 2H), 4.55 (s, 2H), 4.07 (s, 2H), 3.40˜3.37 (m, 1H), 0.69˜0.49 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:4]([C:3]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=1[CH3:1])=[O:6])[CH2:47][CH2:48][CH3:49]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: Cc1ccc(C)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2,5-dimethylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.84-0.94 (m, 3 H) 1.27-1.33 (m, 2 H) 1.68-1.77 (m, 2 H) 2.30 (s, 6 H) 2.48 (s, 3 H) 4.12 (t, 2 H) 6.20 (1, 1 H) 7.10 (s, 2 H) 7.28 (s, 1 H); MS (ESI) m/z 303 (M+H)+.
Reaction SMILES: [CH:1]1([CH:7]([NH:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)[C:8]2[CH:12]=[C:11]([C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[S:10][C:9]=2[CH2:21][CH3:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[C:8]2[CH:12]=[C:11]([C:13]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:14])[S:10][C:9]=2[CH2:21][CH3:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1sc(C(=O)C2CCCCC2)cc1C(Nc1ccc(C(=O)OC)cc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1sc(C(=O)C2CCCCC2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Yield: 87.9 %

Procedure:
To a mixture of methyl 4-({cyclohexyl[5-(cyclohexylcarbonyl)-2-ethylthiophen-3-yl]methyl}amino)benzoate (347 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred with heating under reflux overnight, and concentrated under reduced pressure. The residue was dissolved in water (30 mL), and 1N hydrochloric acid (5 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (296 mg, 88%) as a white solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([CH2:31][CH:32]=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([BH3-])#N.[Na+]>CO.CC(O)=O>[C:25]1([CH2:31][CH2:32][N:16]2[CH2:17][CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:14]([CH2:13][N:10]3[CH2:9][CH2:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:12][CH2:11]3)[CH2:15]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(C2CCN(CC3CNCC3c3ccccc3)CC2)cc1
Reactant: O=CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CCN2CC(CN3CCC(c4ccccc4)CC3)C(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.1 %

Procedure:
A mixture of 50 mg (0.16 mmol) 3-(SR)-((4-phenyl)piperidin-1-yl)methyl-4-(SR)-phenylpyrrolidine (from Example 30, Step A) and 37 mg (0.31 mmol) of phenylacetaldehyde and 100 mg 4 A powdered molecular sieves in 3 mL of MeOH was treated with 18 mg (0.28 mmol) of sodium cyanoborohydride and 2 drops of HOAc and stirred at rt for 18 h. The mixture was filtered onto a pad of Celite; the pad and flask were rinsed well with MeOH (25 mL). The filtrate was concentrated in vacuo and the residue was partitioned between 25 mL of EtOAc and 15 mL of sat'd NaHCO3 and the layers were separated. The organic layer was dried over MgSO4 and concentrated in vacuo. Flash chromatography on 15 g of silica gel using 2:1 v/v hexanes/EtOAc afforded 32 mg (48%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ1.66-2.04 (6H), 2.42-3.13 (15H), 7.20-7.37 (15H). Mass Spectrum (NH3 -CI): 427 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13]([C:15]3([OH:21])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:12][CH:11]=2)=[N:8][CH:9]=1)([O-])=O.CO>[Zn].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13]([C:15]3([OH:21])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[N:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2cnc(C3(O)CCOCC3)s2)nc1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(-c2cnc(C3(O)CCOCC3)s2)nc1
Temperature: 50 °C

Procedure:
To a solution of Example 7A (0.106 g, 0.344 mmol) in a solvent mixture of methanol (2 mL) and acetic acid (2 mL) was added Zn powder (0.067 g, 1.03 mmol). The reaction was heated to 50° C. for 5 h, and was then cooled to room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO3 (5 mL) and ethyl acetate (5 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×5 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound which was used without further purification. MS (ESI) m/z 278 [M+H]+.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:11](=[CH:12][CH:13]=[C:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH2:20][CH2:21][CH2:22][C:23]([CH3:25])=[CH2:24])[C:10]1([CH3:37])[CH3:36])(C(C)(C)C)(C)C.C1C=CC=CC=1.[ClH:44]>C(O)C>[Cl:44][C:23]([CH2:22][CH2:21][CH2:20][C@H:19]([C@@H:18]1[C@:27]2([CH3:35])[C:15]([C:14]3[CH2:13][CH2:12][C@@H:11]4[C@:31]([C:30]=3[CH2:29][CH2:28]2)([CH3:34])[CH2:32][CH2:33][C@H:9]([OH:8])[C:10]4([CH3:37])[CH3:36])=[CH:16][CH2:17]1)[CH3:26])([CH3:25])[CH3:24]
Reactant: C=C(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: Cl
Solvent: CCO
Solvent: c1ccccc1
Product: C[C@H](CCCC(C)(C)Cl)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
A mixture of 3β-(tert-butyldimethylsilyloxy)-4,4-dimethylcholesta-5,7,25-triene (50 mg), benzene (5 mL), ethanol (5 mL) and concentrated HCl (2 mL) was heated under reflux for 4 hours. The reaction was concentrated to half volume under reduced pressure and water (5 mL) was added. Extraction of the aqueous phase with dichloromethane and concentration under reduced pressure gave a residue, which was purified by flash chromatography. Recrystallisation from ethyl acetate:hexane gave the title compound as a white solid (35 mg).