Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:13])[C:4](=[O:14])[C:3]=1[C:15]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].[N+](=[CH2:29])=[N-].C(O)(=O)C.[CH3:34][OH:35]>>[CH3:34][O:35][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:13])[C:4](=[O:14])[C:3]=1[C:15]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([CH3:26])=[CH:20][C:16]=1[C:17]([O:19][CH3:29])=[O:18]
Reactant: CO
Reactant: COc1cc(C)cc(C(=O)O)c1C1=C(O)C(=O)c2c(O)cccc2C1=O
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)cc(OC)c1C1=C(OC)C(=O)c2c(O)cccc2C1=O

Procedure:
2-(3,5-Dihydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzoic acid (100 mg) was dissolved in methanol (20 ml) and treated with diazomethane at room temperature. After 2 hours of reaction, the excess diazomethane was decomposed with acetic acid, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, elution being carried out with chloroform. The above procedure gave methyl 2-(3-methoxy-5-hydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzoate (60 mg).
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4]O[C:2]=1[CH2:9][OH:10].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>Cl>[OH:8][C:5]1[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1
Reactant: O=c1cc(CO)occ1O
Reactant: Nc1ccccc1
Agent: Cl
Product: O=c1cc(CO)n(-c2ccccc2)cc1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a suspension of kojic acid (1.421 g, 10.00 mmol) in diluted hydrochloric acid (0.52 mL of concentrated hydrochloric acid diluted with 25 mL of water) was added aniline (1.40 mL, 15.4 mmol). The resulting mixture was heated under reflux for 20 h. The mixture, while warm (60° C.), was washed with dichloromethane two times and the organic phase was discarded. The aqueous phase was neutralized with solid sodium carbonate, upon which much off-white precipitate appeared. The mixture stood in a hood overnight. The crude product was isolated by filtration and purified by recrystallization with methanol to give a pale solid (1.064 g, 49%). Mp: 236-238° C. (lit.85 237-240° C.). 1H NMR (d6-DMSO): δ 4.20 (2H, s), 6.47 (1H, s), 7.35 (1H, s), 7.5-7.6 (5H, m). 13C NMR (d6-DMSO): δ 70.9, 102.5, 114.8, 118.2, 118.9, 130.5, 138.7, 146.7, 165.3, 179.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]CC)=[O:31])=[CH:25][C:24]=2[O:35][CH3:36])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:38])[N:17]2[CH3:37])(=[O:11])=[O:10].[OH-].[Li+].Cl>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=2[O:35][CH3:36])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:38])[N:17]2[CH3:37])(=[O:11])=[O:10]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc3c(cc(C)n3C)c2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CC(=O)O)ccc1Oc1ccc2c(cc(C)n2C)c1NS(=O)(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a room temperature solution of 3.4 (25 mg, 0.043 mmol) dissolved in a mixture of tetrahydrofuran (2 mL) and methanol (1 mL) was added a solution of lithium hydroxide (50 mg, 2.1 mmol) dissolved in water (1 mL). The reaction was stirred at room temperature for 1 h then poured into aqueous 1N hydrochloric acid solution. The aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were washed twice with water then brine, stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a colorless solid. LC-MS ESI (neg.) m/z: 547.0 (M−H). 1H NMR (400 MHz) (d6-DMSO) δ 12.30 (br s, 1H); 9.80 (br s, 1H); 7.63 (d, J=8.8 Hz, 1H); 7.53 (d, J=2.0 Hz, 1H); 7.31 (dd, J=2.4 & 8.8 Hz, 1H); 7.22 (d, J=8.8 Hz, 1H); 6.89 (d, J=1.6 Hz, 1H); 6.59 (d, J=1.6 Hz, 1H); 6.39 (d, J=8.8 Hz, 1H); 6.23 (dd, J=3.6 & 3.6 Hz, 1H); 3.70 (s, 3H); 3.63 (s, 3H); 3.52 (s, 2H): 2.41 (s, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:8]=[C:7]2[OH:20])([O-:3])=[O:2].[CH2:21]([N:23]([CH2:27][CH3:28])[C:24](Cl)=[O:25])[CH3:22].C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:21]([N:23]([CH2:27][CH3:28])[C:24](=[O:25])[O:20][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)[CH3:22]
Reactant: CCN(CC)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccccc3)cc(O)c2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Oc1cc(-c2ccccc2)nc2ccc([N+](=O)[O-])cc12
Yield: 77.7 %

Procedure:
The procedure is as in Example 70, starting with 6-nitro-2-phenyl-4-hydroxyquinoline (6 g) in tetrahydrofuran (60 cc), N,N-diethylcarbamoyl chloride (6.1 g), triethylamine (6.3 cc) and 4-dimethylaminopyridine (1.3 g). The residue is recrystallized twice in ethyl acetate. 6-Nitro-2-phenyl-4-quinolyl diethylcarbamate (6.4 g), m.p. 40° C., is thereby obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: COc1ccc([N+](=O)[O-])cc1N
Product: COc1ccc([N+](=O)[O-])cc1Nc1cc(C(F)(F)F)nc(-c2cnccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.153 mmol) and 2-methoxy-5-nitroaniline (39 mg, 0.230 mmol), similar to Example 180 and was isolated as a yellow solid (30 mg, 51%). 1H NMR (CDCl3): 9.760 (d, J=1.5 Hz, 1H), 8.86 (dd, J=1.8, 2.7 Hz, 1H), 8.74 (d, J=2.4 Hz, 1H), 8.10 (dd, J=2.7, 9.0 Hz, 1H), 7.34 (s, 1H), 7.07 (d, J=9.0 Hz, 1H), 4.08 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[C:4]([CH3:11])[CH:3]=1.Cl[CH:13]([CH:16]=O)[CH:14]=[O:15].C(=O)([O-])[O-].[Mg+2]>C(COC)OC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][C:13]([CH:14]=[O:15])=[CH:16][N:8]=2)=[C:4]([CH3:11])[CH:3]=1
Reactant: O=CC(Cl)C=O
Reactant: Cc1cc(Br)ccc1C(N)=S
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: COCCOC
Product: Cc1cc(Br)ccc1-c1ncc(C=O)s1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a suspension of 4-bromo-2-methyl-thiobenzamide (3.11 g, 13.5 mmol) and 2-chloromalonaldehyde (2.16 g, 20.3 mmol) in dimethoxyethane (20 ml) is added magnesium carbonate (567 mg, 6.75 mmol) and the resulting mixture stirred at 60° C. under N2 for 3 hours. The crude reaction is then filtered through a plug of silica, washed with EtOAc and the filtrate concentrated to give 2-(4-bromo-2-methyl-phenyl)-thiazole-5-carbaldehyde (3.8 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH:7]([OH:9])[CH2:6][CH2:5][CH:4]([C:10]2[N:11]([CH3:18])[N:12]=[CH:13][C:14]=2[N+:15]([O-])=O)[O:3]1.[NH2:19][C:20]1[S:24][C:23]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[N:22][C:21]=1[C:33](O)=[O:34].CCN(C(C)C)C(C)C.CCCP(=O)=O>CO.[OH-].[OH-].[Pd+2]>[NH2:19][C:20]1[S:24][C:23]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[N:22][C:21]=1[C:33]([NH:15][C:14]1[CH:13]=[N:12][N:11]([CH3:18])[C:10]=1[C@H:4]1[CH2:5][CH2:6][CH:7]([OH:9])[CH2:8][C@@H:2]([CH3:1])[O:3]1)=[O:34]
Reactant: CC1CC(O)CCC(c2c([N+](=O)[O-])cnn2C)O1
Reactant: Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: [Pd+2]
Agent: CCCP(=O)=O
Agent: [OH-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC(O)CC[C@H](c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnn2C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 2.9 %

Procedure:
A solution of 2-methyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-ol (79 mg, 0.30 mmol) in MeOH (20 mL) was passed through the H-Cube® (full H2, 70° C., flow rate: 1 mL/min, 30 mm 20% Pd(OH)2/C cartridge). The solvent was removed under reduced pressure and the crude residue was re-dissolved in MeOH (1 mL). 5-Amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (94 mg, 0.37 mmol) and DIPEA (0.24 mL, 1.40 mmol) were added. Propylphosphonic anhydride solution (0.19 mL, 50% wt in EtOAc, 0.39 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (10 mL). The organic layer was washed with 1 M aqueous NaOH (3×10 mL), 1 M aqueous HCl (2×10 mL) and brine (10 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel chromatography (0-5% 7 M NH3 in MeOH/DCM) gave 108 as a white solid (4 mg, 3% over two steps). 1H NMR (400 MHz, CDCl3) δ 9.69 (d, J=11.8 Hz, 1H), 8.16 (d, J=5.6 Hz, 1H), 7.37-7.30 (m, 1H), 7.04-6.97 (m, 2H), 6.15 (s, 2H), 5.00-4.93 (m, 1H), 4.17 (s, 1H), 4.03 (dd, J=8.0, 6.9 Hz, 1H), 3.77 (s, 3H), 2.11-1.74 (m, 5H), 1.28 (d, J=3.3 Hz, 1H), 1.21 (dd, J=9.2, 6.3 Hz, 3H). Alkyl OH not observed. LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH:10]=[CH:9][C:8]=3[CH:7]=[C:6](B(O)O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:22][C:23]1[CH:24]=[C:25](I)[CH:26]=[CH:27][CH:28]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(COC)OC>[Br:22][C:23]1[CH:24]=[C:25]([C:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]3[C:18]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[CH:6]=[CH:7][C:8]=3[CH:9]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: OB(O)c1cc2ccc3ccccc3c2c2ccccc12
Reactant: Brc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc(-c2cc3ccc4ccccc4c3c3ccccc23)c1
Yield: 63.5 %

Procedure:
In argon atmosphere, a mixture of 6.32 g (22.3 mmol) of 5-benzo[c]phenanthreneboronic acid, 5.07 g (18.6 mmol) of 3-bromoiodobenzene, 1.29 g (1.12 mmol) of tetrakis(triphenylphosphine)palladium (0), 80 ml of toluene, 80 ml of dimethoxyethane, and 33.8 g of a 2 M sodium carbonate aqueous solution was refluxed for 8 h under stirring. After the reaction, the reaction mixture was added with water and extracted with toluene. The organic phase was washed with water and dried over sodium sulfate, and then the toluene was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography to obtain 4.53 g (yield: 56.8%) of 5-(3-bromophenyl)benzo[c]phenanthrene.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O=P(Cl)(Cl)Cl.[CH2:15]([O:17]C(=O)C)C>CN(C=O)C.CCCCCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:15]=[O:17])=[CH:2]1
Reactant: CCOC(C)=O
Reactant: c1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: O=Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
1H-Indole (10 g, 85.360 mmol) in DMF (10 mL) was added dropwise to a stirred solution of POCl3 (8.67 mL, 93.896 mmol) in DMF over a period of 10 minutes at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (40% ethylacetate in hexane). The reaction mixture was quenched with chilled water, followed by the addition of aqueous NaOH solution and refluxed at 100° C. for 15 minutes. The reaction mixture was cooled to room temperature and maintained at 0° C. overnight. The precipitate formed was collected, washed with water and dried to afford 11.6 g of the product (94% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:24][CH2:25][OH:26].Cl[C:28]1[CH:37]=[N:36][C:35]2[C:30](=[CH:31][C:32]([O:38][CH3:39])=[CH:33][CH:34]=2)[N:29]=1>>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH2:10][CH2:9][N:8]([CH2:24][CH2:25][O:26][C:28]2[CH:37]=[N:36][C:35]3[C:30](=[CH:31][C:32]([O:38][CH3:39])=[CH:33][CH:34]=3)[N:29]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: OCCBr
Reactant: CCOC(=O)[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Reactant: COc1ccc2ncc(Cl)nc2c1
Product: CCOC(=O)[C@@H]1CN(CCOc2cnc3ccc(OC)cc3n2)CC[C@@H]1NC(=O)OCc1ccccc1

Procedure:
The title compound is prepared as a yellow oil following Scheme 1 and in analogy to Example 1 using (3R,4S)-4-benzyloxycarbonylamino-piperidine-3-carboxylic acid ethyl ester (prepared according to procedures described in WO2005/066176), 2-bromo-ethanol and 2-chloro-7-methoxy-quinoxaline as starting materials.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(#N)C.CN(C)C=O.[I:20]N1C(=O)CCC1=O>>[OH:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][C:5]([I:20])=[CH:4][N:3]=1
Reactant: Oc1ncccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CC#N
Product: Oc1ncc(I)cc1C(F)(F)F
Temperature: 80 °C
Yield: 80 %

Procedure:
A solution of 2-hydroxy-3-(trifluoromethyl)pyridine C in a mixture of N-iodosuccinimide (NIS), acetonitrile, and dimethylformamide (DMF) is heated at 80° C. for 2 hours to produce 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I (greater than 80% yield). The 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I is then mixed with POCl3 in DMF and heated to 130° C. in a microwave for 20 minutes to produce 2-chloro-3-trifluoromethyl-5-(iodo)pyridine J (yield of 50 to 55%). The 2-chloro-3-trifluoromethyl-5-(iodo)pyridine K is reacted in a solution of pMBnNH2, palladium(II) acetate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), triethylamine, and cesium carbonate in toluene to produce 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K (yield of 40%). The 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K is reacted in a solution of zinc cyanide, tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and 1,1′-bis (diphenylphosphino)ferrocene (dppf) in DMF to provide 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K (yield of 92%). The 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K is reacted in a solution of dichloromethane and trifluoroacetic acid to provide 2-cyano-3-trifluoromethyl-5-(amino)pyridine H (yield greater than 95%). The 2-cyano-3-trifluoromethyl-5-(amino)pyridine H is reacted with thiophosgene in water at 25° C. for 2 hours to provide 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile A (yield of 74% to 95%).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([CH3:26])[CH:12]=[CH:11][C:10]([S:13]([O:16][CH2:17][C@H:18]([OH:25])[CH2:19][CH2:20][C@@H:21]([CH3:24])[CH2:22][CH3:23])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>[C:7]1([CH3:26])[CH:8]=[CH:9][C:10]([S:13]([O:16][CH2:17][C@H:18]([O:25][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[CH2:19][CH2:20][C@@H:21]([CH3:24])[CH2:22][CH3:23])(=[O:14])=[O:15])=[CH:11][CH:12]=1
Reactant: C1=COCCC1
Reactant: CC[C@H](C)CC[C@@H](O)COS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC[C@H](C)CC[C@H](COS(=O)(=O)c1ccc(C)cc1)OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.6 %

Procedure:
In a 50 ml egg-plant type flask were charged 1.7 g of 3,4-dihydro-2H-pyran, 30 ml of diethyl ether, 5.0 g of (2R, 5S)-2-hydroxy-5-methylheptyl p-toluenesulfonate, and 50 mg of p-toluenesulfonic acid, and the mixture was stirred at room temperature overnight. The resulting reaction mixture was neutralized with a saturated sodium hydrogencarbonate aqueous solution, and diethyl ether was distilled off under reduced pressure to obtain 6.5 g of a crude product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[C:58]([C:63]([F:66])([F:65])[F:64])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[C:58]([C:63]([F:65])([F:66])[F:64])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(C(F)(F)F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 106 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:9) to give 113 mg light yellow viscous oil (72%). MS (ISP) 497.4 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.Cl[CH2:17][C:18]([CH3:30])([CH3:29])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].ClCC(C)(C)C(Cl)=O.C(O)C1C=CC=CC=1.C(N(C(C)C)C(C)C)C.[I-].[Na+]>CN(C)C=O>[CH2:22]([O:21][C:19]([C:18]([CH3:30])([CH3:29])[CH2:17][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3][CH2:2]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: CC(C)(CCl)C(=O)OCc1ccccc1
Agent: CC(C)(CCl)C(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1CCN(CC(C)(C)C(=O)OCc2ccccc2)CC1
Temperature: 120 °C
Reaction time: 14 h
Yield: 1.3 %

Procedure:
To a stirred solution of tert-butyl (piperidin-4-ylmethyl)carbamate (38.8 g, 181 mmol) in N,N-dimethylformamide (100 mL) was added benzyl 3-chloropivalate {14.2 g, 124 mmol, prepared from 3-chloropivaloyl chloride (25.6 g, 165 mmol) and benzyl alcohol (19.6 g, 181 mmol), ethyldiisopropylamine (64.0 g, 495 mmol) and sodium iodide (27.1 g, 181 mmol) at ambient temperature. The resulting mixture was stirred at 120° C. for 14 h. The volatile components were removed by evaporation and the resulting residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (1:1) to give 640 mg (1%) of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:21]=[C:22]([CH2:26][OH:27])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(=O)C1C=CC=CC=1.C[N+]1([O-])CCOCC1>ClCCl.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([C:20]2[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=2)[CH:26]=[O:27])(=[O:18])=[O:19])=[CH:15][CH:16]=1
Reactant: O=S(=O)(c1ccc(CCc2ccc(F)cc2F)cc1)c1cccc(CO)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: O=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1cccc(S(=O)(=O)c2ccc(CCc3ccc(F)cc3F)cc2)c1
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a solution of [3-({4-[2-(2,4-difluorophenyl)ethyl]phenyl}sulfonyl)phenyl]methanol (prepared from 3-({4-[E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)benzaldehyde (Example 50 Step 1) according to the method of Example 117) in dichloromethane (4 mL) was added 4 Å molecular sieves (0.1 g) and the mixture stirred for 10 minutes. 4-Methylmorpholine N-oxide (68 mg, 0.58 mmol) was added in one portion and the reaction stirred for 10 minutes, then tetrapropylammonium perruthenate (6.9 mg, 0.02 mmol) added. The reaction was stirred for 30 minutes then diluted with ethyl acetate, filtered through a pad of silica and washed with further ethyl acetate. The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 25% ethyl acetate/isohexane, to yield 3-({4-[2-(2,4-difluorophenyl)ethyl]phenyl}sulfonyl)benzaldehyde (103 mg, 68%). δH (400 MHz, CDCl3): 10.06 (1H, s), 8.40 (1H, s), 8.18 (1H, d, J=7.8 Hz), 8.07 (1H, d, J=7.6 Hz), 7.87 (2H, d, J=8.3 Hz), 7.69 (1H, t, J=7.7 Hz), 7.30 (2H, d, J=8.2 Hz), 6.99 (1H, q, J=7.9 Hz), 6.79–6.73 (2H, m), 2.95–2.87 (4H, m). m/z ES+) 387 [MH+].
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[F:30][C:31]1[CH:32]=[C:33]([C:37](=[N:39]O)[NH2:38])[CH:34]=[CH:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([C:37]2[N:39]=[C:27]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]4)=[O:10])[CH2:12]3)[O:29][N:38]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: NC(=NO)c1cccc(F)c1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3cccc(C(F)(F)F)c3)C2)CC1
Product: N#CC1CCN(C(=O)N2CC(c3cccc(C(F)(F)F)c3)CC(c3nc(-c4cccc(F)c4)no3)C2)CC1

Procedure:
100 mg (0.24 mmol) of the compound from Example 152A and 56 mg (0.37 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 87 mg (68% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30]>>[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccco1
Product: O=C(Nc1ccc2[nH]cc(C3CCNCC3)c2n1)c1ccco1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.062 mMol) 2-furoyl chloride, the title compound was prepared.