Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[BrH:13].OO.S([O-])([O-])=O.[Na+].[Na+]>>[Br:13][C:5]1[CH:6]=[C:7]([CH:8]([CH3:10])[CH3:9])[C:2]([F:1])=[CH:3][C:4]=1[O:11][CH3:12]
Reactant: Br
Reactant: COc1ccc(C(C)C)c(F)c1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: COc1cc(F)c(C(C)C)cc1Br
Temperature: 27.5 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
The crude 3-fluoro-4-isopropylanisole solution from the previous step (100 ml, 0.82 M, 82 mmol) was stirred at 20° C. in the dark. Aqueous 48 wt % HBr (16.6 g, 98.5 mmol) and aqueous 35 wt % hydrogen peroxide (14.0 g, 144 mmol) were added concomitantly over 40 min. The reaction mixture was maintained at 25-30° C. during the addition. The mixture was stirred at 30° C. for 3 h and then was cooled to 5° C. Sodium sulfite (4.2 g) was added in portions over 30 min while maintaining the quench temperature at <20° C. The aqueous layer was removed, and the organic layer was washed with 2 M KHCO3 (20 ml), concentrated, and flushed with heptane (50 ml) at 30-40° C. under reduced pressure to afford 2-bromo-4-isopropyl-5-fluoroanisole as a pale yellow liquid in 98% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[N:11]([CH2:27][CH3:28])[C:10]2=[O:29])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[S:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([OH:39])=[O:38])(=[O:33])=[O:32].CCN(C(C)C)C(C)C>C1COCC1>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([C@H:18]2[C@:12]3([N:11]([CH2:27][CH3:28])[C:10](=[O:29])[N:9]([C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]3=[O:14])[CH2:15][N:16]([S:31]([C:34]3[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=3)[C:37]([OH:39])=[O:38])(=[O:33])=[O:32])[CH2:17]2)=[CH:26][CH:25]=1)#[N:24]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CCN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(S(=O)(=O)c1cccc(C(=O)O)c1)C[C@H]2c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.6 %

Procedure:
To a mixture of Example 50 (100 mg, 0.23 mmol) and 3-(chlorosulfonyl)benzoic acid (57 mg, 0.26 mmol) in THF (5 ml) was added DIEA (45 μl, 0.26 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 hours then concentrated under vacuum. The residue was partitioned between EtOAc and water. The pH was adjusted to pH=2. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The obtained solid was chromatofraphed over silica gel using DCM/MeOH (80/20) to yield the above-titled compound (63 mg), mp=145° C. 1H NMR (CDCl3): 8.63 (1H, s), 8.41 (1H, d, J=7.5 Hz), 8.17 (1H, d, J=7.4 Hz), 7.77 (1 H, t, J=7.7 Hz), 7.62 (2H, d, J=7.7 Hz), 7.18-7.26 (3H, m), 6.60 (2H, s), 3.4-4.2 (7H, m), 1.45 (3H, t, J=6.8 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:8]=2[CH:21]=1)([OH:3])=O.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:9]1[C:8]2[CH:21]=[C:4]([C:1](=[O:3])[NH:34][S:31]([C:28]3[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:30][CH:29]=3)(=[O:33])=[O:32])[CH:5]=[CH:6][C:7]=2[N:11]=[C:10]1[CH3:12]
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccc([N+](=O)[O-])cc3)cc2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
N,N'-carbodiimidazole (0.432 g) was added at a time to a solution of 0.400 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole in 15 ml of N,N-dimethylformamide, and the solution was stirred at room temperature for 1 hour. Subsequently, a solution of 0.538 g of 4-nitrobenzenesulfonamide and 0.405 g of diazabicycloundecene in 5 ml of N,N-dimethylformamide, and the mixture was stirred at 100° C. for 84 hours. The reaction solution was cooled, and the solvent was distilled off under reduced pressure. Chloroform and hydrochloric acid were added to the residue, and the mixture was stirred to precipitate the crystals. The crystals precipitated were separated through filtration, and were dried to give 0.300 g of 1-(2-chlorobenzyl)-2-methyl-6-(4-nitrobenzenesulfonylcarbamoyl)benzimidazole (220).
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[C:12]([CH2:16]O)[NH:13]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([CH2:16][C:12]1[NH:13][C:14]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:19])[CH3:18])[CH:15]=2)=[N+:26]=[N-:27]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(CO)[nH]c2c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(CN=[N+]=[N-])[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
[6-(tert-Butyl-dimethyl-silanyloxy)-1H-indol-2-yl]-methanol (2.0 g, 7.21 mmol) is dissolved in DMF (950 ml), cooled to 0° C. TEA (2.01 ml, 14.42 mmol) and MsCl (0.83 g, 7.21 mmol) are added. The mixture is stirred at room temperature for 1 hour. NaN3 (2.34 g, 34 mmol) is added. The reaction is stirred at room temperature for 1 hour and then 80° C. overnight. The mixture is cooled to room temperature, concentrated. The residue is purified by column chromatography (10% ethyl acetate in hexanes) to give 2-Azidomethyl-6-(tert-butyl-dimethyl-silanyloxy)-1H-indole (1.40 g, 64%). 1H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 7.38 (d, 1H), 6.80 (s, 1H), 6.58 (m, 1H), 6.40 (s, 1H), 4.53 (d, 2H), 0.96 (s, 9H), 0.17 (s, 6H).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1[CH:17]=[CH:16][C:15]2[NH:14][CH:13]3[CH2:18][CH2:19][NH:20][CH2:21][CH:12]3[C:11]=2[CH:10]=1.C(Cl)C1C=CC=CC=1>C(N(CC)CC)C>[CH2:7]([N:20]1[CH2:19][CH2:18][CH:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:9]([CH3:8])=[CH:10][C:11]=3[CH:12]2[CH2:21]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: Cc1ccc2c(c1)C1CNCCC1N2
Solvent: CCN(CC)CC
Solvent: ClCc1ccccc1
Product: Cc1ccc2c(c1)C1CN(Cc3ccccc3)CCC1N2

Procedure:
To toluene (100 ml) are added 8-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (10 g), benzyl chloride (7.4 g) and triethylamine (8.1 g), and the mixture is refluxed for 15 hours. After cooling, the reaction mixture is washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The resulting residue is treated with ethanolic hydrogen chloride in the same manner as described in Example 1 (1) to give the dihydrochloride of the titled compound (11.0 g), m.p. 179° - 182°C (recrystallized from ethanol).
Reaction SMILES: C(OC(=O)C(C(O)=O)(CC)C(C[N+]([O-])=O)CC[C:9]1[CH:14]=[CH:13][C:12](CC(C)C)=[CH:11][C:10]=1[C:19]([OH:21])=[O:20])C>C(O)C.[Pt](=O)=O>[C:19]([O:21][CH2:9][CH:10]([CH3:19])[CH3:11])(=[O:20])[C:10]1[CH:9]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(CC)(C(=O)O)C(CCc1ccc(CC(C)C)cc1C(=O)O)C[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)COC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 10.32 grams of 2-ethylcarboxy-3-nitromethyl-5-(4-(2,2-dimethylethyl)carboxyphenyl)pentanoic acid ethyl ester and 1.5 grams of platinum(IV) oxide in 200 ml of ethanol was hydrogenated in a Parr apparatus at an initial pressure of 50 psig H2. Filtration of the catalyst and removal of the solvent in vacuo provided the crude product as an oil which crystallized upon dissolution in 50 ml ether and addition of about 200 ml hexane until just cloudy. After stirring overnight, the crystalline material was filtered, washed with hexane, dried; affording 3.54 grams (42%) of 4-(2-oxo-3-carboethoxypyrrolidin-4-yl)ethyl)benzoic acid, 2,2-dimethylethyl ester. Selected data: mp 98°-104° C., 1H NMR (CDCl3) δ7.89 (d, J=8.2 Hz, 2H), 7.18 (d, J=8.2 Hz, 2H), 6.75 (s, 1H), 4.23 (q, 2H), 3.54 (dd, J=9.0, 8.3 Hz, 1H), 3.12 (d, J=8.6 Hz, 1H), 3.00 (dd, J=9.4, 7.4 Hz, 1H), 2.87 (m, 1H), 2.66 (t, J=7.6 Hz, 2H), 1.86 (m, 2H), 1.57 (s, 9H), 1.28 (t, 3H); 13C NMR (CDCl3) δ173.2, 169.7, 165.6, 145.8, 130.1, 129.7, 128.0, 80.8, 62.6, 54.4, 46.5, 38.9, 35.1, 32.4, 28.1, 14.1; MS(FAB) m/z 362 (7, M+ +1), 306 (100), 288 (22), Anal. Calcd for C20H27NO5 : C, 66.46; H, 7.53; N, 3.87. Found: C, 66.44; H, 7.77; N, 3.86.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:31](=O)[CH3:32].C([BH3-])#N.[Na+]>CO>[CH2:31]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH3:32]
Reactant: NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Reactant: CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 159 from (Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride, acetaldehyde and sodium cyanoborohydride in methanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([I:34])C(=O)C1>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([C:18]2[C:23]([I:34])=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(-c2cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c2)nc(N)n1
Product: Cc1nc(N)nc(-c2cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c2)c1I

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 550 mg (1.5 mmol) [3-(2-amino-6-methyl-pyrimidin-4-yl)-5-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (GP40) and 336 mg (1.5 mmol) NIS. Yield: 733 mg (99%).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18](O)=[O:19])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:18](=[O:19])[CH2:17][S:16][C:13]2[S:12][C:11]([NH:10][C:8](=[O:9])[C@@H:7]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=3)[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[N:15][CH:14]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CSc2cnc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)s2)CC1

Procedure:
(R)-4-(2-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-5-ylsulfanyl}-acetyl)-piperazine-1-carboxylic acid tert-butyl ester was prepared from (R)-{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-5-ylsulfanyl}-acetic acid and tert-butyl-1-piperazinecarboxylate as described in Example 12. 1H-NMR (CDCl3): δ 7.87 (d, 2H), 7.54 (d, 2H), 7.44 (s, 1H), 3.87 (t, 1H), 3.66 (s, 2H), 3.61-3.46 (m, 8H), 3.05 (s, 3H), 2.24 (m, 1H), 1.89 (m, 1H), 1.79-1.54 (m, 5H), 1.48 (m, 11H), 1.14 (m, 2H); HPLC-MS: m/z: 637 (M+1), 582 (M+1-C(CH3)3)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38].[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:25])([F:24])[F:26])(=[O:12])=[O:13])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH2:35][N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Reactant: C1COCCN1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCN4CCOCC4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 500 mg of the compound obtained in Example 219 and morpholine (0.13 ml) as starting material, 300 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 220.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[N:17][CH:16]=[CH:15]2)=[O:10])(C)(C)C.[ClH:29]>C(Cl)Cl>[ClH:29].[ClH:29].[NH2:7][C@H:8]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[N:17][CH:16]=[CH:15]2)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1ccc2cnccc2c1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: N[C@@H](C(=O)Nc1ccc2cnccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-tert-butyl-2-(isoquinolin-6-ylamino)-2-oxo-1 phenyl-ethylcarbamate (E1) in CH2Cl2 was added HCl (4M in dioxane) and the solution was stirred overnight at room temperature. The reaction was concentrated to give (R)-2-amino-N-(isoquinolin-6-yl)-2-phenylacetamide dihydrochloride (E2).
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH:18](=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1.C(OCC)(=O)C>C1COCC1.O>[OH:27][CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]1=[O:9]
Reactant: COc1cccc(C=O)c1
Reactant: O=C1CCCCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(C(O)C2CCCCCCC2=O)c1
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a solution of cyclooctanone (4.0 g) in THF (40 ml) was added LDA (23 ml, 1.5M solution in cyclohexane) at -78° C. under N2, and then after 30 minutes, a solution of m-anisaldehyde (4.1 g) in THF (10 ml) was added in the solution. After being stirred for 2 hours at the same temperature, the solution was poured into the mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 2-{hydroxy-(3-methoxyphenyl)methyl}cyclooctanone (6.9 g). MS (m/z): 245 (M+ -17) IR (Neat): 3400, 1690 cm-1NMR (CDCl3, δ): 1.0-2.3 (10H, m), 2.8-3.2 (2H, m), 3.3-3.6 (1H, m), 3.79 (3H, s), 4.8-5.0 (1H, m), 6.7-7.0 (3H, m), 7.1-7.3 (1H, m)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CN2CCCC2)CC1
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of the product of Example 2 (2.0 g) in DCM (40 mL) was added pyrrolidine (1.0 g) followed by sodium triacetoxyborohydride (2.8 g). The resulting mixture was stirred overnight, and treated with 10% NaOH (20 mL). The resulting mixture was extracted with DCM (300 mL). The combined extracts were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated under reduced pressure to give the title compound as a light pink-brown oil (2.4 g).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH:21]2[CH2:26][CH:25]([CH2:27][OH:28])[CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O.O>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH:21]2[CH2:26][CH:25]([CH:27]=[O:28])[CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)C1CC(CO)CN(C(=O)OC(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)C1CC(C=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 91.3 %

Procedure:
To a solution of tert-butyl 3-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-(hydroxymethyl)piperidine-1-carboxylate (420 mg) and triethylamine (0.87 ml) in DMSO (6 ml) was added dropwise a solution of sulfur trioxide pyridine complex (500 mg) in DMSO (5 ml) at room temperature, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (5:95-70:30) was concentrated under reduced pressure to give the object compound (382 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1.[CH2:22]([NH:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)CO>O>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:5][C:6]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:29]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:30]=1
Reactant: NNCc1ccccc1
Reactant: N#Cc1c(-c2ccccc2)cc(N2CCOCC2)nc1Cl
Solvent: OCCO
Solvent: O
Product: Nc1nn(Cc2ccccc2)c2nc(N3CCOCC3)cc(-c3ccccc3)c12
Temperature: 130 °C

Procedure:
A mixture consisting of 3.0 gm (0.01 mol) of 2-chloro-6-morpholino-4-phenyl-3-cyano-pyridine, 3.7 gm (0.03 mol) of benzyl-hydrazine and 30 ml of ethylene glycol was refluxed for 5 hours at about 130° C. The resulting solution was taken up in 100 ml of water, whereupon the reaction product separated out as a pasty precipitate which was collected and immediately recrystallized from methanol. 2.2 gm (57% of theory) of the compound named in the heading were obtained; after recrystallization from ethyl acetate it had a melting point of 147°-150° C.
Reaction SMILES: [OH-].[K+].[C:3]([CH2:6][C:7]1[CH:8]=[C:9]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:10]=[CH:11][C:12]=1I)([OH:5])=[O:4].[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>[Cu].CCCCCC.C(OCC)(=O)C.C(O)(=O)C>[C:3]([CH2:6][C:7]1[CH:8]=[C:9]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:10]=[CH:11][C:12]=1[S:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:5])=[O:4]
Reactant: CC(C(=O)O)c1ccc(I)c(CC(=O)O)c1
Reactant: Sc1ccccc1
Agent: [Cu]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C(=O)O)c1ccc(Sc2ccccc2)c(CC(=O)O)c1
Temperature: 100 °C
Yield: 69 %

Procedure:
0.3 M Aqueous potassium hydroxide solution (10 mL, oxygen was removed by addition of 20 mg of sodium hydrosulfite in advance) was mixed with 2-(3-carboxymethyl-4-iodophenyl)propionic acid (prepared in the manner as described in Example 12, 203 mg, 0.607 mmol.) and thiophenol (95 wt. %, 94 mg, 0.81 mmol.). The resulting mixture was heated for 19 hours under reflux (temperature: approx. 100° C.) after addition of 20 mg of powdery copper. The reaction mixture was cooled, made acidic by addition of hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was extracted with an aqueous saturated sodium hydrogen carbonate solution. The aqueous portion was washed with ethyl acetate, made acidic by addition of hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated to leave a residue. The residue was subjected to silica gel column chromatography (Wako Gel C-200, Wako Jyunyaku Industry Co., Ltd., hexane/ethyl acetate/acetic acid=7/3/1, v/v/v) to obtain 133 mg (0.420 mmol., yield: 69%) of the desired compound.
Reaction SMILES: C([NH:8]C1C=C(C=C(S(Cl)(=O)=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.[CH2:28]([S:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([S:48](Cl)(=[O:50])=[O:49])[C:41]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([S:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([S:48](=[O:50])(=[O:49])[NH2:8])[C:41]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCSc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1-c1ccccc1
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Product: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
By replacing in Example 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid with 3-n-butylthio-5-chlorosulfonyl-4-phenylbenzoic acid, and following the procedure described, 3-n-butylthio-4-phenyl-5-sulfamylbenzoic acid is obtained as a hydrate with a melting point of 75°-77° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([CH:13]=[CH:14][C:15]#[N:16])=[C:11]([N+:19]([O-])=O)[CH:10]=2)[CH:4]=1.O.O.[Sn](Cl)[Cl:25].[ClH:27].C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C.O1CCOCC1>[ClH:25].[ClH:27].[NH2:16][C:15]1[CH:14]=[CH:13][C:12]2[C:11](=[CH:10][C:9]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=3)=[CH:18][CH:17]=2)[N:19]=1
Reactant: COc1ccnc(-c2ccc(C=CC#N)c([N+](=O)[O-])c2)c1
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccnc(-c2ccc3ccc(N)nc3c2)c1

Procedure:
To a suspension of 4-(4-methoxypyridin-2-yl)-2-nitrocinnamonitrile (308 mg) in ethanol (30 ml) was added tin (II) chloride dihydrate (1.41 g), and the mixture was refluxed for 30 minutes. Then to the solution was added hydrochloric acid (12N, 5 ml), and the mixture was refluxed for 6 hours. After cooling, the reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 150 g, 10% methanol in dichloromethane). The compound obtained was dissolved in ethyl acetate, and a solution of hydrogen chloride in 1,4-dioxane (4N, 1 ml) was added. The precipitate was collected by filtration and dried to give 2-amino-7-(4-methoxypyridin-2-yl)-quinoline dihydrochloride (77 mg).