Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:15])[CH:8]=1)([CH3:3])[CH3:2].[NH3:25]>C(O)C>[ClH:23].[CH:1]([NH:4][C:5](=[NH:25])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:15])[CH:8]=1)([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)NC(=S)Nc1cccc(NC(=O)Nc2ccc(Cl)cc2)c1
Solvent: CCO
Product: CC(C)NC(=N)Nc1cccc(NC(=O)Nc2ccc(Cl)cc2)c1
Product: Cl
Reaction time: 0.5 h

Procedure:
1-(3-Isopropylthioureido)-3-(3-p-chlorophenylureido)-benzene (1.5 crystallized g.) is dissolved in ethanol (100 ml.) saturated with ammonia gas, and the solution stirred for 24 hours at room temperature with yellow mercuric oxide (1.02 g.). The mixture is boiled for 1/2 hour to coagulate the fine precipitate, and is filtered hot. The solid is washed thoroughly with 3 × 50 ml. portions of boiling ethanol, and the filtrate and washings are combined and evaporated to dryness. The remaining gum is dissolved in methanol (10 ml.) and saturated ethereal hydrogen chloride (3 ml.) is added followed by dry ether (150 ml.). The precipitated oil rapidly solidifies, is filtered off and crystallised from ethanol to give 1-(3-isopropylguanidino)-3-(3-p-chlorophenylureido)benzene hydrochloride, m.p. 224°-225° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][N:5]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=1.[Cl-].[CH2:23]([O:25][C:26](=[O:38])[CH:27]([OH:37])[CH:28]([NH3+:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:24]>>[F:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][N:5]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH:36][CH:28]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]([OH:37])[C:26]([O:25][CH2:23][CH3:24])=[O:38])=[O:11])[CH:6]=1
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Reactant: O=C(O)c1cccnc1-n1cc(F)c(-c2ccccc2)n1
Agent: [Cl-]
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc(F)c(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.1 by reacting 2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinic acid and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride. ESI-MS [M+H]+: 489.2
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CN(C)C=O.[N+:14]([C:17]1[O:21][C:20]([CH:22]=[CH:23][C:24]2[N:33]=[C:32](Cl)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]>O>[N+:14]([C:17]1[O:21][C:20]([CH:22]=[CH:23][C:24]2[N:33]=[C:32]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[OH:8])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(C=Cc2nc(Cl)c3ccccc3n2)o1
Reactant: Nc1ccccc1O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(C=Cc2nc(Nc3ccccc3O)c3ccccc3n2)o1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
An Erlenmeyer flash equipped with magnetic stirrer and oil bath for heating was charged with 5.0 g (0.046 mole) of o-aminophenol and 100 ml of dimethylformamide. The charge was stirred to dissolve o-aminophenol and 6.0 g (0.02 mole) of 2-[2-(5-nitro-2-furyl)vinyl]-4-chloroquinazoline (IV) added. The reaction mixture was reacted at 80° to 90°C for 2 hours to form an organic precipitate; 100 ml of water was added to the warm mixture which was then allowed to cool and placed overnight in a refrigerator to crystallize. The solids were collected, washed with methanol and dried to obtain 7.5 g of brown-tan solid which melted 224°-6°C with decomposition. A solution of the product in 100 ml of dimethylformamide was treated with activated carbon and filtered. A first portion of 75 ml of methanol was added to the warm filtrate then an additional 25 ml portion. Cooling and scratching gave 5.5 g of orange crystals of the purified product which melted at 230°-1°C with decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[C:14]([O:16][CH3:17])=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]([NH:22][C:23](=[O:25])[CH3:24])[C:6]=2[CH:26]=1.[N:27]1([CH2:33][CH2:34][C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:27]1([CH2:33][CH2:34][C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[C:14]([O:16][CH3:17])=[CH:15][C:10]=4[CH2:9][CH2:8][C@H:7]([NH:22][C:23](=[O:25])[CH3:24])[C:6]=3[CH:26]=2)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(O)CCN1CCCCC1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(N)cc1[C@@H](NC(C)=O)CC2
Product: COc1cc2c(c(OC)c1OC)-c1ccc(NC(=O)CCN3CCCCC3)cc1[C@@H](NC(C)=O)CC2
Yield: 61 %

Procedure:
Using an analogous procedure to that described for Example 21, N-[(5S)-3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide was reacted with 1-piperidinepropionic acid to give N-[(5S)-3-(3-piperidinopropanoylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)([N:11]=[C:12]([NH:17]C(=O)C4C=CC=CC=4)[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.N1C=CC=CC=1.Cl.CON>C(O)C>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:4][CH:3]=1
Reactant: O=C(NC1=N[C@@]2(c3cccs3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Agent: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NC1=N[C@@]2(c3cccs3)CN(c3ncc(F)cn3)C[C@H]2CS1
Temperature: 50 °C
Yield: 76.7 %

Procedure:
In a glass pressure vessel, a solution of N-[(4aR,7aR)-6-(5-fluoropyrimidin-2-yl)-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (6 g, 13.6 mmol) in ethanol (240 mL) is treated with pyridine (11 mL). O-methylhydroxylamine hydrochloride (11.4 g, 136.5 mmol) is added and the mixture is heated at 50° C. for 4 hours. The solution is concentrated and diluted with 1 M hydrochloric acid and ethyl acetate. The aqueous layer is separated and neutralized with 50% w/w aqueous solution of sodium hydroxide to adjust the pH to 9. The white precipitate is filtered and dried under vacuum. The crude product is crystallized in hot methyl-t-butyl ether until a complete solution is formed then the solution is cooled to room temperature. The solid precipitate is filtered and dried under vacuum to give the title compound (3.5 g, 76%). ES/MS (m/e): 336 (M+H).
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[C:16](=O)[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]3=[O:20])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[NH2:21][C:22]1C=C(OC)C=C[C:23]=1C(O)=O.[C:33](O)(=[O:41])C1C(=CC=CC=1)N>>[CH3:33][O:41][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]4[C:12](=[O:20])[CH2:13][C:14]([CH3:18])([CH3:19])[CH2:15][C:16]=4[N:21]=[C:22]([CH3:23])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: COc1ccc(C(=O)O)c(N)c1
Reactant: Nc1ccccc1C(=O)O
Reactant: CC1(C)CC(=O)C(c2c[nH]c3cc(F)ccc23)C(=O)C1
Product: COc1ccc2c(c1)[nH]c1c(C)nc3c(c12)C(=O)CC(C)(C)C3

Procedure:
Utilizing the procedures described in Example 3 a-c except substituting 2-(6-methoxy-1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione for 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione in step 3a, and 2-amino-4-methoxybenzoic acid for anthranilic acid in step 1a of Example 1, the title compound was prepared and crystallized from toluene; m.p. 250-252° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C@H:9]3[C@@H:11]([OH:35])[C@H:12]([OH:34])[C@@H:13]([CH2:15][O:16][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[O:14][C@H:8]3[N:7]([CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[C:6]=2[CH:43]=1.[O:44]1[CH2:48]CC[CH2:45]1.CN(C)C=O.[H-].[Na+].Cl[CH2:57][O:58][CH3:59]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C@H:9]3[C@@H:11]([O:35][CH2:57][O:58][CH3:59])[C@H:12]([O:34][CH2:45][O:44][CH3:48])[C@@H:13]([CH2:15][OH:16])[O:14][C@H:8]3[N:7]([CH2:36][CH2:37][N:38]([CH2:39][CH3:40])[CH2:41][CH3:42])[C:6]=2[CH:43]=1
Reactant: COCCl
Reactant: C1CCOC1
Reactant: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@H]21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](OCOC)[C@H](OCOC)[C@@H](CO)O[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of 3.00 g of the compound (24) obtained in Example 23 in 50 ml of a mixed solution of tetrahydrofuran-dimethylformamide (4:1), 600 mg of 60% oily sodium hydride and 1.17 ml of chloromethylmethyl ether were added, and the mixture was stirred for two hours at room temperature. The reacted solution was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and saturated aqueous sodium chloride successively, and was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the solution of the resulting crude material in 75 ml of tetrahydrofuran, 9 ml of a 1M tetrabutylammoniumfluoride-tetrahydrofuran was added, and the solution was stirred overnight at room temperature. The reaction solution was concentrated, the residue was dissolved in ethyl acetate, and the solution was washed with water, and saturated chloride successively. The organic layer aqueous sodium was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain the title compound.
Reaction SMILES: C(O)=O.[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH2:17][CH3:18].Br[CH2:20][C:21](=[O:37])[CH2:22][C@H:23]1[C@H:28]([O:29][CH3:30])[CH2:27][CH2:26][CH2:25][N:24]1[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32]>>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[N:10]([CH2:20][C:21](=[O:37])[CH2:22][C@H:23]3[C@H:28]([O:29][CH3:30])[CH2:27][CH2:26][CH2:25][N:24]3[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH2:17][CH3:18]
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: CCSc1cc2c(=O)[nH]cnc2cc1Br
Solvent: O=CO
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(Br)c(SCC)cc2c1=O

Procedure:
In the manner of Example 4, 0.743 g (0.00224 mol) of 7-bromo-6-ethylthioquinazolin-4(3H)-one formic acid salt and 0.750 g (0.00224 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate were converted into the title compound. After flash chromatography on silica gel (eluant 3% methanol in chloroform) there was obtained the pure product: yield 0.61 g (51%); mass spectrum m/e 537 (molecular ion with expected isotope pattern), 41 (parent peak, CH2 =CH--CH2 +) among others. 1H-NMR(CDCl3) 1.4 ppm (triplet, 3H, SCH2CH3), 1.4-2.1 (multiplet, 4H, OCHCH2CH2CH2N), 2.8-3.4 (multiplet, 6H, NCH2, SCH2CH3, COCH2CH), 3.4 (singlet, 3H, OCH3), 4.0 (broad singlet, 1H, CHNCO), 4.6 (doublet, 2H, CH2CH=CH2), 5.0 (singlet, 2H, NCH2CO), 5.0-5.5 (multiplet, 2H, CH=CH2), 5.6-6.1 (octet, 1H, CH2 =CH), 7.3 (singlet, 1H, aromatic H), 7.9 (singlet, 2H, aromatic H, N=CH--N).
Reaction SMILES: [N:1]1([C:65](OC(C)(C)C)=O)[CH2:64][CH2:63][CH2:62][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([N:19]([CH3:61])[C@H:20]([C:28]([NH:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][S:56][CH3:57])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>CSC.C(S)(S)C>[NH:1]1[CH2:65][CH2:64][CH2:63][CH2:62][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([N:19]([CH3:61])[C@H:20]([C:28]([NH:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][S:56][CH3:57])=[O:51])[CH2:46][CH:47]([CH3:48])[CH3:49])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Agent: CC(S)S
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-DTrp-MePheOH (0.800 g.) and HDTrp-Leu-MetNH2 acetate salt (part B of Example 17, 0.721 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocPro-DTrp-MePhe-DTrp-Leu-MetNH2 in 31% yield. De-t-butoxycarbonylation of BocPro-DTrp-MePhe-DTrp-Leu-MetNH2 (0.400 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-MePhe-DTrp-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:2) salt dihydrate in 23% yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([OH:16])[C:10]3[N:11]([N:13]=[CH:14][CH:15]=3)[CH:12]=2)[CH:4]=[N:3]1.[Br:17]N1C(=O)CCC1=O>C(#N)C.ClCCl>[Br:17][C:15]1[CH:14]=[N:13][N:11]2[CH:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=[C:9]([OH:16])[C:10]=12
Reactant: Cn1cc(-c2cc(O)c3ccnn3c2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC#N
Product: Cn1cc(-c2cc(O)c3c(Br)cnn3c2)cn1
Reaction time: 0.5 h

Procedure:
6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (75.0 mg, 0.350 mmol) was suspended in acetonitrile (4 ml). N-bromosuccinimide (68.5 mg, 0.385 mmol) was added and the mixture was allowed to stir. After 30 minutes, additional N-bromosuccinimide (6.9 mg, 0.039 mmol) was added and the mixture was allowed to stir for 1 h. The reaction mixture was diluted in dichloromethane, washed with water and 1 N aqueous sodium hydroxide. The pH of the combined aqueous layers was adjusted to pH 7 with 6 N HCl, then the aqueous layers were extracted with ethyl acetate (2×) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane gradient) to afford 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol.
Reaction SMILES: [Br:1]Br.[Cl:3][CH:4]([CH:13]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:1][C:4]([Cl:3])([CH:13]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: BrBr
Reactant: O=C(c1ccccc1)C(Cl)C(COCc1ccccc1)OCc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)C(Cl)(Br)C(COCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of bromine (16.0 g., 0.1 m.) in 100 ml. of chloroform is added dropwise to a stirred solution of 39.5 g. (0.1 m.) of 2-chloro-3,4-dibenzyloxybutyrophenone and 0.2 g. of dibenzoyl peroxide in 650 ml. of chloroform. After stirring for 30 minutes at 25°C., the reaction mixture is washed with water, aqueous saturated sodium bicarbonate and again with water. The chloroform solution is dried and concentrated in vacuo to leave a residue of α-bromo-2-chloro-3,4-dibenzyloxybutyrophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:13]([F:15])[F:14])[CH:11]=1)S[CH2:7][CH2:6][C@@:5]2([C:17]([OH:19])=[O:18])[OH:16].O.O[O:22][S:23]([O-:25])=O.[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:13]([F:14])[F:15])[CH:11]=1)[S:23](=[O:25])(=[O:22])[CH2:7][CH2:6][C@@:5]2([C:17]([OH:19])=[O:18])[OH:16]
Reactant: O=C(O)[C@@]1(O)CCSc2c(OC(F)F)cc(Cl)cc21
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)[C@@]1(O)CCS(=O)(=O)c2c(OC(F)F)cc(Cl)cc21
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of (R)-6-chloro-8-difluoromethoxy-4-hydroxythiochromane-4-yl-carboxylic acid (0.50 g, 1.6 mmol; from step (vi) above), wet alumina (prepared by adding H2O (1 mL) to alumina (5.0 g) and shaking until a free flowing powder was obtained, ca. 0.82 g, 8.0 mmol), and Oxone® (4.9 g, 8.0 mmol) in CHCl3 (19 mL) was heated to 40-45° C. for 20 h. The reaction was cooled to room temperature, filtered through a Buichner funnel with EtOAc (50 mL), and concentrated in vacuo to afford 0.54 g (98%) of the sub-title compound as a brown foam which was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:40][C:37]2[C:38]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=2
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3I)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccccc3I)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 620.2 (M+H)+.
Reaction SMILES: ClC1C=CC(C([N:8]([C:10](=[O:27])[C@H:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=2[CH3:26])[C:12]([OH:15])([CH3:14])[CH3:13])[NH2:9])=O)=CC=1.CCN(P1(N(C)CCCN1C)=N[C:37]([CH3:40])([CH3:39])[CH3:38])CC>C1COCC1>[Cl:25][C:19]1[C:18]([CH3:26])=[C:17]([NH:16][C@@H:11]([C:10]2[O:27][C:40]([C:37]3[CH:38]=[CH:20][C:19]([Cl:25])=[CH:18][CH:39]=3)=[N:9][N:8]=2)[C:12]([OH:15])([CH3:13])[CH3:14])[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: Cc1c(N[C@@H](C(=O)N(N)C(=O)c2ccc(Cl)cc2)C(C)(C)O)ccc(C#N)c1Cl
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(Cl)cc3)o2)C(C)(C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 669.2 %

Procedure:
The crude material of (R)-4-chloro-N-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)benzohydrazide (intermediate 15a) (230 mg, 0.53 mmol) was added to THF (50 mL) stirred at room temperature. PS-BEMP (721 mg, 1.59 mmol base) was added to the solution followed by slow addition of p-TSCl (111 mg, 0.58 mmol). The reaction mixture was stirred for 1 h and the progress of the reaction was monitored by TLC. After the completion of the reaction the BEMP reagent was filtered off and the solution concentrated to get the crude material. The crude material was chromatographed with hexanes:EtOAc (6:4) to provide the product (740 mg): 1H NMR (500 MHz, CDCl3, δ in ppm) 7.95 (d, J=9 Hz, 2H), 7.50 (d, J=9 Hz, 2H), 7.39 (d, J=9 Hz, 1H), 6.63 (d, J=9 Hz, 1H), 5.37 (d, J=9 Hz, 1H), 4.74 (d, J=9 Hz, 1H), 2.36 (s, 3H), 1.52 (s, 3H), 1.36 (s, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([NH:12][C@H:13]1[C@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O.C(OCC)(=O)C>[Cl-].C[N+](C)(C)C.CN1CCCC1=O>[N:1]([C@H:18]1[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][C@H:13]1[NH:12][C:10]([O:9][C:5]([CH3:6])([CH3:8])[CH3:7])=[O:11])=[N+:2]=[N-:3]
Reactant: CCOC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: [N-]=[N+]=[N-]
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 74 h

Procedure:
Sodium azide (357.6 mg) and tetramethylammonium chloride (91.0 mg) were added at room temperature to a solution (2 mL) of ethyl (1S,3R,4R)-3-[(t-butoxycarbonyl)amino]-4-methanesulfonyloxycyclohexanecarboxylate (1.01 g) in N-methyl-2-pyrrolidone, followed by stirred at 60° C. for 74 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with aqueous saturated sodium bicarbonate solution and water, followed by drying over magnesium sulfate anhydrate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 648.3 mg of the title compound. Spectral data of this compound were found to be identical with those of the compound of Example 5.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:35]=4[N:34]=3)[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:35]=4[N:34]=3)[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(-c3nc4cc(F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(C)cc(-c3nc4cc(F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
A solution of 1.4 g (2.4 mMol) of tert.butyl 4'-[(2-ethyl-4-methyl -6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and 15 ml of trifluoroacetic acid in 30 ml of methylene chloride is stirred for 14 hours at ambient temperature, then concentrated by evaporation, the residue is mixed with about 30 ml of water and made alkaline with 2N sodium hydroxide solution. After extracting twice with 30 ml of diethyl ether, the aqueous phase is acidified with 20% citric acid. The crude product precipitated is suction filtered and purified by column chromatography (100 g silica gel; eluant: methylene chloride/ethanol=96:4).