Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N1CCC(N(C2C=CC(OCC3C=CC=CC=3)=CC=2)[CH2:41][CH:42]=[C:43]([CH3:45])[CH3:44])CC1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:16]2[CH2:21][CH2:20][N:19]([CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCNCC1
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(CCC(C)C)CC1
Yield: 99 %

Procedure:
The preparation of (4-Benzyloxy-phenyl)-(3-methvl-but-2-enyl)-piperidin-4-yl-amine, (Ic): 4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (5.0 g, 11.1 mmol) was dissolved in CH2Cl2 (20 mL) and treated with TFA (20 mL). The reaction was stirred for ten minutes, then concentrated in vacuo. The residue was redissolved in EtOAc (400 mL), then washed with saturated bicarbonate solution (2×400 mL) and brine (1×400 mL), dried over Na2SO4, and concentrated in vacuo to give 3.9 g (99%) of the desired product as a pale oil.
Reaction SMILES: COC1C=CC(C[NH:8][CH2:9][C:10]2[C:11]([C:21]3[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=3[F:29])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])=CC=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>CC#N.O>[F:29][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=1[C:11]1[C:10]([CH2:9][NH2:8])=[CH:19][C:18]2[C:13](=[C:14]([CH3:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: COc1ccc(CNCc2cc3cccc(C)c3nc2-c2c(F)cccc2OC)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COc1cccc(F)c1-c1nc2c(C)cccc2cc1CN

Procedure:
Prepared according to Procedure G using N-(4-methoxybenzyl)(2-(2-fluoro-6-methoxyphenyl)-8-methylquinolin-3-yl)methanamine (1.1795 g, 2.8320 mmol, 1 eq) and ammonium cerium(iv) nitrate (5.434 g, 9.912 mmol, 3.5 eq) in CH3CN—H2O (2:1, 13 mL). After purification, (2-(2-fluoro-6-methoxyphenyl)-8-methylquinolin-3-yl)methanamine was obtained as yellow sticky solid. 1H NMR (DMSO-d6) δ ppm 8.41 (1 H, s), 7.82 (1 H, d, J=7.4 Hz), 7.55-7.60 (1 H, m), 7.45-7.54 (2 H, m), 7.03 (1 H, d, J=8.2 Hz), 6.92-7.00 (1 H, m), 3.71 (3 H, s), 3.59 (2 H, q, J=16.6 Hz), 2.64 (3 H, s), 1.88 (2 H, br. s.). Mass Spectrum (ESI) m/e=297.1 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]3[N:20]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:21](=[O:32])[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]#[N:31])[C:18]=3[C:17]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47](=[O:49])[NH2:48])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C1(C)C=CC=CC=1.[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60]>ClCCl>[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60].[CH2:33]([N:20]1[C:19]2[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=[C:17]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]([NH2:48])=[O:49])[C:18]=2[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[C:21]1=[O:32])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Oc3ccccc3C(N)=O)c3c2n(Cc2ccccc2)c(=O)n3Cc2ccccc2C#N)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1Cn1c(=O)n(Cc2ccccc2)c2c(N3CCNCC3)ncc(Oc3ccccc3C(N)=O)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[3-Benzyl-7-(2-carbamoylphenoxy)-1-(2-cyanobenzyl)-2-oxo-2,3-dihydro-1H-imidazo[4.5-c]pyridin-4-yl]-piperazine-1-carboxylic acid t-butyl ester (0.023 g) was dissolved in dichloromethane and trifluoroacetic acid (1 mL). After stirring this at room temperature for two hours, then toluene (5 mL) was added, and this was concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography to give the title compound (0.016 g).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH2:12][CH:13]([CH3:26])[C:14]2([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[OH:17])[CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:14]1([OH:17])[CH:13]([CH3:26])[CH2:12][CH2:11][CH:10]2[CH:15]1[CH2:16][NH:8][CH2:9]2
Reactant: COc1ccccc1C1(O)C(C)CCC2CN(Cc3ccccc3)CC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1C1(O)C(C)CCC2CNCC21
Temperature: 60 °C

Procedure:
To a solution of I g of (3aRS,4RS,5RS,7aSR)-2-benzyl-4-(2-methoxyphenyl)-5-methyl-4-perhydroisoindolol in 15 cm3 of anhydrous ethanol are added 2 g of 20% palladium hydroxide on charcoal and the reaction mixture is then hydrogenated, with stirring, at a temperature of 60° C. and at atmospheric pressure. After reaction for 1 hour, the reaction mixture is filtered and then concentrated to dryness under reduced pressure (2.7 kPa). 0.74 g of (3aRS,4RS, 5RS, 7aSR)-4-(2-methoxyphenyl)-5-methyl-4-perhydroisoindolol is obtained in the form of a yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]([CH3:24])[C:8]([C@@:10]2([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:12][C@H:11]2[CH2:13][CH2:14]Cl)=[O:9])=[CH:4][CH:3]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl.[C:36]1([C:42]2([NH:48][C:49](=[O:51])[CH3:50])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(#N)C>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]([CH3:24])[C:8]([C@@:10]2([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:12][C@H:11]2[CH2:13][CH2:14][N:45]2[CH2:46][CH2:47][C:42]([NH:48][C:49](=[O:51])[CH3:50])([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:43][CH2:44]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)NC1(c2ccccc2)CCNCC1
Reactant: CN(Cc1ccc(F)cc1)C(=O)[C@@]1(c2ccc(Cl)c(Cl)c2)C[C@H]1CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CC(=O)NC1(c2ccccc2)CCN(CC[C@@H]2C[C@@]2(C(=O)N(C)Cc2ccc(F)cc2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
(1S,2S)-2-(2-Chloro-ethyl)-1-(3,4-dichloro-phenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide (91 mg, 0.22 mmol) is dissolved in acetonitrile (10 ml). Potassium iodide (73 mg, 0.44 mmol), potassium carbonate (91 mg, 0.66 mmol) and N-(4-Phenyl-piperidin-4-yl)-acetamide hydrochloride (67 mg, 0.26 mmol) are added. The reaction mixture is heated to reflux for 72 hours, then cooled to ambient temperature and concentrated in vacuo. The remanence is redissolved in ethyl acetate (15 ml), washed with water (10 ml), brine (10 ml), then dried over MgSO4, filtered and concentrated to an oil. The product is filtered through a plug of silica gel eluting with ethyl acetate:heptane:triethylamine (50:50:5) followed by ethyl acetate:ethanol:triethylamine (80:20:5) to furnish 70 mg (54%) of the title compound. LC/MS (m/z) 596.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[C:7]([CH3:13])=[N:8][N:9]([CH3:12])[C:10]=1[OH:11])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][N:28]([CH3:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(#N)C>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[C:7]([CH3:13])=[N:8][N:9]([CH3:12])[C:10]=1[O:11][CH2:26][CH2:27][N:28]([CH3:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:5]
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Reactant: CN(CCBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nn(C)c(OCCN(C)c2ccccc2)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 91.4 %

Procedure:
2.85 g of 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-5-hydroxypyrazole was dissolved in 50 ml of acetonitrile, and 1.38 g of potassium carbonate (anydrous) was added thereto. The resultant mixture was stirred at room temperature for 2 hours, 2.14 g of β-bromoethyl-N-methylaniline was added, and the mixture heated for 3 hours under reflux. After cooling, crystals were filtered off. The filtrate was distilled under reduced pressure and the residue was purified by silica gel chromatography (eluent, benzene:ethyl acetate at 8:1) to give 3.82 g of the desired product, Compound 2, having nD24 1.5975 (yield 91.4%).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1([CH3:18])[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:10]=2[O:9]1.[C:19](Cl)([Cl:21])=[O:20]>C1C=CC=CC=1>[Cl:21][C:19]([O:17][C:16]1[C:10]2[O:9][C:8]([CH3:18])([CH3:7])[CH2:12][C:11]=2[CH:13]=[CH:14][CH:15]=1)=[O:20]
Reactant: O=C(Cl)Cl
Reactant: CC1(C)Cc2cccc(O)c2O1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1(C)Cc2cccc(OC(=O)Cl)c2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 7.9 g. (0.1 mol) sample of pyridine was added dropwise to a solution of 16.4 g. (0.1 mol) 2,3-dihydro-2,2-dimethyl-7-benzofuranol and 9.9 g. (0.1 mol) phosgene in 100 ml. benzene at about 25° C. The reaction mixture was stirred at 25° C for 2 hours, filtered and evaporated under reduced pressure. The solid residue was washed with hexane and dried to give the product, m.p. 85°-87.5° C. Elemental analysis for C11H11O3Cl showed:
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)C2=CC=CC=C2C1=O.OO>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(#N)C>[C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: CC#N
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 18 %

Procedure:
A mixture of 5 mmol of benzhydrol, 0.5 mmol of N-hydroxyphthalimide, 0.0005 mmol of cobalt(II) acetate, and 5 ml of acetonitrile was stirred at 50° C. in an air atmosphere (1 atm) for 24 hours. An iodometric analysis of a reaction mixture revealed that hydrogen peroxide was formed in yield of 16% (selectivity: 89%). Separately, a gas chromatographic analysis of the reaction mixture revealed that the conversion rate from benzhydrol was 18%, and benzophenone was formed in yield of 18%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][CH:6]=1)(=[O:4])=[O:3].[Br:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]=[O:19]>C1C=CC=CC=1>[Br:13][CH2:14][CH2:15][N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][N:7]=1)=[O:12]
Reactant: O=CCNCCBr
Reactant: CS(=O)(=O)c1cnc(N=C=O)s1
Solvent: c1ccccc1
Product: CS(=O)(=O)c1cnc(NC(=O)N(CC=O)CCBr)s1
Reaction time: 1 h

Procedure:
5-Methylsulfonylthiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-β-bromoethylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about 1 hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-β-bromoethyl-3-(5-methylsulfonylthiazol-2-yl)ureido]acetaldehyde as the residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([N:18]1[CH2:22][CH:21]([NH:23][CH3:24])[C@H:20]([CH2:25][NH:26][C:27]([C:29]2[S:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[O:28])[CH2:19]1)=[O:17].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CC#N.C(N(CC)C(C)C)(C)C.CO>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([N:18]1[CH2:22][CH:21]([N:23]([S:36]([CH3:35])(=[O:38])=[O:37])[CH3:24])[C@H:20]([CH2:25][NH:26][C:27]([C:29]2[S:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[O:28])[CH2:19]1)=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CNC1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@H]1CNC(=O)c1ccc(Cl)s1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@H]1CNC(=O)c1ccc(Cl)s1)S(C)(=O)=O
Reaction time: 3 h

Procedure:
To a solution of (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-methylamino-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide (example 83; 26 mg) in 0.8 ml of CH3CN and 22 μl of N,N-diisopropylethylamine was added at 22° C. 6 μl of methanesulfonylchloride and stirring was continued for 3 h. The mixture was diluted with 0.5 ml of MeOH, evaporated and the residue was chromatographed on silica (AcOEt/MeOH, 15:1) to give (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-(methanesulfonyl-methyl-amino)-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Colorless solid. MS 582.0 ([M+H]+)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(OCC)(=O)C.O>[CH:15]1([NH:21][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[O:4])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1
Reactant: NC1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CNC1CCCCC1)Nc1ccc([N+](=O)[O-])cc1

Procedure:
2-Chloro-N-(4-nitrophenyl)-acetamide (11.5g) and cyclohexylamine (10.7g) were heated together 2 hours at 150° and then added to ethyl acetate/water. The product was extracted with ethyl acetate to yield 9.0g, m.p. 123°-125°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH2:11]1)[CH2:7][CH:8]=C)=[O:5])[CH3:2].I([O-])(=O)(=O)=[O:27].[Na+]>O1CCCC1.O.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Os](=O)(=O)(=O)=O>[CH2:1]([O:3][C:4]([CH:6]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:12][CH2:11]1)[CH2:7][CH:8]=[O:27])=[O:5])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC(C(=O)OCC)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 24 h
Yield: 58.3 %

Procedure:
Benzyl 4-[1-(ethoxycarbonyl)but-3-en-1-yl]piperidine-1-carboxylate (4.08 g, 11.8 mmol) was dissolved in tetrahydrofuran (45 mL), and osmium tetroxide (0.45 mL, 2.5% solution in t-butanol) was added followed by a solution of sodium periodate (7.57 g, 35.4 mmol) in water (37 mL). After 24 h, the reaction was diluted with saturated aqueous sodium sulfite and saturated aqueous sodium bicarbonate and extracted with ethyl acetate (4×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (50% hexanes/ethyl acetate→100% ethyl acetate) to give the title compound (2.39 g). MS 348.1 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:32]=[CH:33][C:34]5[NH:38][C:37]([C@@H:39]6[CH2:43][C@H:42]([CH3:44])[CH2:41][N:40]6C(OC(C)(C)C)=O)=[N:36][C:35]=5[CH:52]=4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:18]=1)=O)(C)(C)C.Cl>C(Cl)Cl>[CH3:44][C@@H:42]1[CH2:41][NH:40][C@H:39]([C:37]2[NH:38][C:34]3[CH:33]=[CH:32][C:31]([C:28]4[CH:27]=[CH:26][C:25]([C:22]5[CH:21]=[CH:20][C:19]([C:17]6[N:18]=[C:14]([C@@H:9]7[CH2:10][C@H:11]([CH3:13])[CH2:12][NH:8]7)[NH:15][CH:16]=6)=[CH:24][CH:23]=5)=[CH:30][CH:29]=4)=[CH:52][C:35]=3[N:36]=2)[CH2:43]1
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(-c4ccc(-c5ccc6[nH]c([C@@H]7C[C@H](C)CN7C(=O)OC(C)(C)C)nc6c5)cc4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CN[C@H](c2nc(-c3ccc(-c4ccc(-c5ccc6[nH]c([C@@H]7C[C@H](C)CN7)nc6c5)cc4)cc3)c[nH]2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL flask, (2S,4S)-tert-butyl 2-(6-(4′-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)-[1,1′-biphenyl]-4-yl)-3H-benzo[d]imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (2.55 g, 3.628 mmol) is dissolved in CH2Cl2 (10 mL). The solution is cooled to 0° C. and HCl (18.14 mL of 2.0 M, 36.28 mmol) is added. The reaction mixture is then stirred vigorously for 30 min at rt. The solution is concentrated and then dried under high vacuum. The yellow salt (2.353 g) is used in the next reaction without further purification.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:40]([O:42]C(C)(C)C)=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:25][CH:24]=[N:23][C:22]=4[C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])=[CH:18][C:17]4[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCCl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:40]([OH:42])=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:25][CH:24]=[N:23][C:22]=4[C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])=[CH:18][C:17]4[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(c1)C=C(c1ocnc1C(=O)N1CCOCC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1ccc2c(c1)C=C(c1ocnc1C(=O)N1CCOCC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Yield: 97 %

Procedure:
Dissolve tert-Butyl 13-cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (203 mg, 0.325 mmol) in 1,2-dichloroethane (3 ml) add TFA (3 ml, 38.9 mmol), The reaction was capped under a nitrogen atmosphere at 25° C. for 2 hrs. Reaction volatiles were removed in vacuuo and the residue dissolved in 80 mL of ethyl acetate with heating. The solution was washed with 1N aqueous hydrochloric acid (2×40 mL), brine and dried over magnesium sulfate. The product solution was filtered, volatiles removed and the sample dried in vacuuo at room temperature overnight to give 179 mg (97%) of a yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.74-1.03 (m, 4 H) 1.06-1.31 (m, 6H) 1.32-1.50 (m, 3H) 1.56 (d, J=9.16 Hz, 2H) 1.77 (d, J=8.85 Hz, 2H) 1.86-2.18 (m, 5H) 2.83-2.91 (m, 1H) 3.60 (s, 3H) 3.64-3.89 (m, 4H) 3.88-3.93 (m, 4H) 3.95-4.08 (m, 1H) 4.43 (d, J=15.56 Hz, 1H) 5.64 (d, J=14.95 Hz, 1H) 6.99 (d, J=2.75 Hz, 1H) 7.07 (dd, J=8.70, 2.59 Hz, 1H) 7.48-7.56 (m, 2 H) 7.85-7.94 (m, 2H) 8.15 (s, 1H). LC-MS retention time 1.65 min; 568 m/z (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]([C:9]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:10]=1[O:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:28]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([C:9]1[CH:26]=[C:25]([CH2:27][Br:28])[CH:24]=[CH:23][C:10]=1[O:11][CH:12]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Oc1ccc(C)cc1C(=O)c1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1ccc(CBr)cc1C(=O)c1ccccc1)c1ccccc1
Yield: 35.6 %

Procedure:
To a solution of 0.314 g (0.87 mmol) of the product of Step A dissolved in 10 mL of CCl4 was added 0.155 g (0.87 mmol) of N-bromosuccinimide and 15 mg (catalytic amount) of AIBN. The mixture was stirred at reflux for 7 hours, then cooled filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 15% ethyl acetate/hexane to afford 0.136 g (36%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)=[C:10]([CH3:26])[CH:9]=1)=[O:6].[OH-].[K+]>CO.O>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:11]2[C:10]([CH3:26])=[CH:9][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([OH:27])=[O:2])=[CH:13][C:12]=2[CH3:14])=[CH:17][C:18]=1[CH:23]([CH3:25])[CH3:24]
Reactant: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(C(C)C)c2)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(NC(=O)CC(=O)O)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-[4-(4-hydroxy-3-isopropyl-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid methyl ester (29 mg, 0.08 mmol) in a mixture of MeOH (1 mL) and H2O (1 mL) was added 3 N KOH (0.9 mmol, 0.3 mL). After stirring at RT for 4 h, H2O (10 mL) was added. The solution was washed with EtOAc (2×10 mL) and acidified with 1 N HCl. The aqueous solution was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine, dried and concentrated to give the title compound of Step E and Example 1 (20 mg) as a white solid. MS (APCl−) Calc.: 357.1, Found: 356.1 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][CH:19]([CH3:21])[CH3:20])[C@H:10]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=[O+][O-].C1(P(=C[C:45]([O:47][CH3:48])=[O:46])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][CH:19]([CH3:21])[CH3:20])[C@H:10]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])/[CH:11]=[CH:12]/[C:45]([O:47][CH3:48])=[O:46])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@@H](OS(C)(=O)=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[O+][O-]
Solvent: ClCCl
Product: COC(=O)/C=C/[C@@H](OS(C)(=O)=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.6 %

Procedure:
A solution of 0.22 g (0.69 mmol) of the resultant compound of Example 32 in 15 ml of dichloromethane was cooled to -78° C. and treated with a stream of O3 in air until the blue color persisted. The solution was subsequently purged with air until the blue color was discharged, treated with 0.5 ml of dimethylsulfide, allowed to warm to ambient temperature over 40 min, and treated with 0.29 g (0.87 mmol) of methyl (triphenylphosphoranylidene)acetate. The resulting solution was stirred at ambient temperature for 4 h, concentrated in vacuo, partitioned between dichloromethane and water, dried over MgSO4, and concentrated. Silica gel chromatography using 30% ethyl acetate in hexane provided 0.08 g (31%) of the desired compound (Rf 0.17, 30% ethyl acetate in hexane). 1H NMR (CDCl3) δ 0.89 (d, J=7 Hz, 3 H), 0.93 (d, J=7 Hz, 3 H), 1.22 (m, 2 H), 1.44 (s, 9 H), 1.69 (m, 1 H), 3.06 (s, 3 H), 3.78 (s, 3 H), 3.92 (m, 1 H), 4.58 (br d, 1 H), 5.40 (m, 1 H), 6.16 (dd, J=15, 2 Hz, 1 H), 6.87 (dd, J=15, 6 Hz, 1 H). Mass spectrum: (M+H)+ =380.