Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][NH2:50])=[CH:45][CH:44]=1>O1CCCC1>[Br:1][C:2]1[S:3][C:4]([C:8]([NH:50][CH2:49][C:46]2[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(Br)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a mixture of 2-bromo-4-methylthiazole-5-carboxylic acid (2.00 g, 9.00 mmol) in anhydrous tetrahydrofuran (40 mL) was added N,N-diisopropylethylamine (4.67 mL, 27.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.41 g, 12.6 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes, followed by the addition of 1-hydroxybenzotriazole (1.70 g, 12.60 mmol) and (4-fluorophenyl)methanamine (2.50 g, 12.60 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was concentrated to half in vacuo. The residue was diluted with ethyl acetate (200 mL), washed sequentially with 10% aqueous hydrochloric acid (50 mL), saturated bicarbonate solution (50 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized in ethyl acetate and hexane to afford the title compound as a colorless solid (2.38 g, 81%): 1H NMR (300 MHz, CDCl3) δ 7.30-7.26 (m, 2H), 7.05-7.00 (m, 2H), 5.99-5.87 (m, 1H), 4.54 (d, J=5.7 Hz, 2H), 2.63 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([N+:22]([O-])=O)[C:12](=[O:21])[N:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:14]=1[CH3:15].Cl.[H][H]>CO.[Pt](=O)=O>[NH2:22][C@H:11]1[CH2:10][C@@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=2[F:1])[C@@H:14]([CH3:15])[N:13]([CH2:16][C:17]([F:19])([F:18])[F:20])[C:12]1=[O:21]
Reactant: Cc1cccc(-c2cc([N+](=O)[O-])c(=O)n(CC(F)(F)F)c2C)c1F
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: Cc1cccc([C@@H]2C[C@H](N)C(=O)N(CC(F)(F)F)[C@@H]2C)c1F

Procedure:
A mixture of 5-(2-fluoro-3-methylphenyl)-6-methyl-3-nitro-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one (1.95 g, 5.66 mmol), platinum(IV) oxide (0.643 g, 2.83 mmol), and concentrated aqueous hydrochloric acid solution (12 M, 4.72 mL, 56.6 mmol) in methanol (57 mL) was shaken under 50 psi of hydrogen at 23° C. for 5 h. The catalyst was removed by filtration through Celite® and washed thoroughly with methanol. The filtrate was concentrated, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane initially, grading to 5% MeOH (basified 0.1% concentrated aqueous ammonium hydroxide solution) in dichloromethane to give the title compound as a racemate. The enantiomers were separated by normal-phase HPLC using a ChiralCel® OD column, eluting with 40% hexane in ethanol (0.1% diethylamine used as a modifier) to afford the title compound as the second enantiomer to elute. MS: m/z=319.2 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[I-].[CH3:16][S+](C)(C)=O.CC(C)([O-])C.[Na+]>C1COCC1.COCCOC>[O:1]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[S+](C)(C)=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (0.50 g, 2.51 mmol) in THF/DME (2:1, 6 mL) at 60° C. was added trimethylsulfoxonium iodide (0.58 g, 2.63 mmol) and sodium t-butoxide (0.25 g, 2.63 mmol). The reaction mixture was stirred at 60° C. for 30 min, cooled to rt and concentrated. Water was added and the mixture was extract with EtOAc twice. The combined organics were dried over Na2SO4, filtered and concentrated. Purification on silica gel (3:1, hexanes:EtOAc) gave tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate as a clear oil that solidified upon standing.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:3]=1.[CH:23]([Mg]Br)=[CH2:24].O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:23]=[CH2:24])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:3]=1
Reactant: C=C[Mg]Br
Reactant: CS(=O)(=O)c1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reaction time: 0.5 h

Procedure:
A solution of (6-chloro-2-methanesulfonyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (821 mg, 2.16 mmol) in THF (15 mL) is cooled to 0° C. A 1 M solution of vinyl magnesium bromide in THF (5.4 mL, 5.4 mmol) is added and the mixture is stirred for 30 minutes before adding water (30 mL) and extracted thrice with EtOAc (50 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with 30% ethyl acetate:heptane to afford (6-chloro-2-vinyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (600 mg) as a solid.
Reaction SMILES: [C@@H:1]1([N:12]2[C:23]3[C:15](=[C:16]4[C:30](=[O:31])[NH:29][C:28](=[O:32])[C:17]4=[C:18]4[C:22]=3[NH:21][C:20]3[N:24]=[CH:25][CH:26]=[CH:27][C:19]4=3)[C:14]3[CH:33]=[CH:34][CH:35]=[N:36][C:13]2=3)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[K+].[K+].[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>O1CCCC1>[S:49]([O:3][C@@H:2]1[C@@H:4]([OH:5])[C@H:6]([OH:7])[C@@H:8]([CH2:10][OH:11])[O:9][C@H:1]1[N:12]1[C:23]2[C:15](=[C:16]3[C:30](=[O:31])[NH:29][C:28](=[O:32])[C:17]3=[C:18]3[C:22]=2[NH:21][C:20]2[N:24]=[CH:25][CH:26]=[CH:27][C:19]3=2)[C:14]2[CH:33]=[CH:34][CH:35]=[N:36][C:13]1=2)([C:46]1[CH:47]=[CH:48][C:43]([CH3:53])=[CH:44][CH:45]=1)(=[O:51])=[O:50]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1NC(=O)c2c1c1c3cccnc3[nH]c1c1c2c2cccnc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]2n2c3ncccc3c3c4c(c5c6cccnc6[nH]c5c32)C(=O)NC4=O)cc1

Procedure:
To a solution of the compound of Example 12 (0.17 mmol) in 10 ml of tetrahydrofuran there are added 23.5 mg of potassium carbonate and 1.7 mmol of para-toluenesulphonic acid chloride. The mixture is heated at reflux for 48 hours. After evaporating off the solvent, the residue is taken up in a water/ethyl acetate mixture and is then filtered over a frit. The crystals are successively washed with ethyl acetate and then with methanol, allowing the expected product to be isolated.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:13]=1)[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8].[C:14](=[NH:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:14](=[N:27][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:13]=2)[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CON(C)C(=O)c1cncc(Br)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Product: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1

Procedure:
Prepared according to the method described for Preparation 51 using 5-bromo-N-methoxy-N-methylnicotinamide and benzophenone imine.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:14])=[O:13])[CH:6]=1)([CH3:4])[CH3:3].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:32](O)=[O:33]>>[CH:32]([C:9]1[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=[C:7]([S:12]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:13])=[O:14])[C:8]=1[OH:11])=[O:33]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C)C=NS(=O)(=O)c1cc(C(C)(C)C)ccc1O
Agent: C1N2CN3CN1CN(C2)C3
Product: CN(C)C=NS(=O)(=O)c1cc(C(C)(C)C)cc(C=O)c1O

Procedure:
2.84 g (0.01 mol) of 4-(1,1-dimethylethyl)-2-dimethylaminomethyleneaminosulfonylphenol are boiled under reflux with 1.4 g of urotropine in 10 ml of trifluoroacetic acid for 6 h. The mixture is poured onto ice-water, and the rubber-like mass which has separated out is taken up in ether, the solution is washed to neutrality and the solvent is removed in vacuo. The residue is chromatographed on silica gel using ethyl acetate/toluene 4:1 as the eluting agent. 2-formyl-4-(1,1-dimethylethyl)-6-dimethylaminomethyleneaminosulfonylphenol of melting point 182°-183° C. is obtained, and this is immediately dissolved in 2N sodium hydroxide solution. The solution is left on a steam bath for 30 minutes, and then the solution is acidified to pH 2-3 with 2N hydrochloric acid, and filtered with suction.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:37])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=2[CH3:36])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:37][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=2[CH3:36])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)c(C)c1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)c(C)c1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-(2,4-dimethyl-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 479.11 [M+H]+; tR=3.24 min (System 3).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:27]1[N:28]=[C:29]([NH:32]C(=O)C(F)(F)F)[S:30][CH:31]=1)[C:5]([NH:7][CH:8]1[C:25](=[O:26])[N:10]2[C:11]([C:22]([OH:24])=[O:23])=[C:12]([CH2:15][S:16][C:17]3[S:18][CH:19]=[N:20][N:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6].O.O.O.C([O-])(=O)C.[Na+].Cl>O>[CH3:1][O:2][N:3]=[C:4]([C:27]1[N:28]=[C:29]([NH2:32])[S:30][CH:31]=1)[C:5]([NH:7][CH:8]1[C:25](=[O:26])[N:10]2[C:11]([C:22]([OH:24])=[O:23])=[C:12]([CH2:15][S:16][C:17]3[S:18][CH:19]=[N:20][N:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.2 %

Procedure:
7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(23 g) was suspended in a solution of sodium acetate trihydrate (74.8 g) in water (230 ml) and the suspension was stirred for 15 hours at ambient temperature. The reaction mixture was adjusted to pH 5.0 with conc. hydrochloric acid and insoluble material was filtered off. The filtrate was adjusted to pH 2.5 and precipitating crystals were collected by filtration and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (14 g), mp 172° to 175° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[C:13](NC1C=CC(C(O)=O)=CC=1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:13]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Product: COc1cc(C(=O)O)ccc1NC(=O)OC(C)(C)C

Procedure:
4-Amino-3-methoxybenzoic acid (1 g, 5.98 mmol) was reacted according to the same procedure as that used in the process for preparing N-BOC-4-aminobenzoic acid. The resulting solid was recrystallized from ethyl acetate and hexanes to provide the desired product (1.5 g) as tan crystals: m.p. 176-178° C.; 1H NMR (CD3OD) d 1.52 (9H, s), 3.92 (3H, s), 7.56 (1H, s), 7.62 (1H, d, J=8.4 Hz), 7.96 (1H, s), 8.03 (1H, d, J=8.4 Hz); 13C NMR (CD3OD) d 28.53, 56.35, 81.78, 112.01, 118.58, 124.20, 125.76, 133.84, 149.04, 154.20, 169.60; HRMS Calc. for C13H17NO5, 267.1107; Found, 267.1103.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][C:12]=2[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=1.[CH3:31][NH2:32]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH:32][CH3:31])[CH2:13][C:12]=2[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=1
Reactant: CN
Reactant: COc1cc2c(c(-c3ccccc3F)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(OC)cc(-c3ccccc3F)c2O1

Procedure:
The title compound was prepared (0.039 g, 51%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-fluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.102 g, 0.24 mmol) and methylamine (0.074 g, 2.4 mmol). mp 110-112° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8](O)=[O:9].[N:25]1([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][OH:40])=[CH:33][CH:32]=2)[CH:29]=[N:28][N:27]=[N:26]1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:24][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:40][CH2:39]/[CH:38]=[CH:37]/[C:34]2[CH:35]=[CH:36][C:31]([CH2:30][N:25]3[CH:29]=[N:28][N:27]=[N:26]3)=[CH:32][CH:33]=2)=[O:9])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: OC/C=C/c1ccc(Cn2cnnn2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(Cn3cnnn3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 217 mg (1 mM) of (E)-3-{4-(1,2,3,4-tetrazol-1-ylmethyl)phenyl}-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 442 mg (83.4%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH:45]6[CH2:47][CH2:46]6)[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH:45]6[CH2:46][CH2:47]6)[CH:42]=[CH:43][N:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4C4CC4)cc2)CCN3CC(C)C)cc1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4C4CC4)cc2)CCN3CC(C)C)cc1
Yield: 73.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-cyclopropylimidazol-2-yl]methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (700 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (389 mg) in dichloromethane (15 ml) at −78° C. The reaction vessel was removed from a dry ice-acetone bath, and an aqueous solution of sodium thiosulfate was added to the reaction vessel with strongly stirring. The mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate), and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-cyclopropylimidazol-2-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (526 mg) (Compound 367) as yellow crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:12][C:13]1[N:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][CH:14]=1>>[Br:12][C:13]1[N:18]=[C:17]([CH2:19][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CCOC(=O)C1CCCCN1
Product: CCOC(=O)C1CCCCN1Cc1cccc(Br)n1

Procedure:
13] Ethyl (2-piperidyl)carboxylate (0.92 mL, 5.92 mmol) was added to a solution of 6-bromo-2-pyridinecarboxaldehyde (1.0 g, 5.38 mmol) to give ethyl 1-[(6-bromopyridin-2-yl)methyl]-piperidine-2-carboxylate as a colorless oil). MS m/z: 327.1 (M+H). Calc'd for C14H1gBrN2O2—327.22.
Reaction SMILES: [CH2:1]([C:8]1([N:34]([CH3:36])[CH3:35])[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]=2[Si](CC)(CC)CC)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([CH2:17][CH2:16][CH2:15][C:11]2([OH:14])[CH2:12][CH2:13][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([N:34]([CH3:36])[CH3:35])[CH2:9][CH2:10]2)=[CH:19]1
Reactant: CC[Si](CC)(CC)c1[nH]c2ccccc2c1CCCC1(O)CCC(Cc2ccccc2)(N(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C1(Cc2ccccc2)CCC(O)(CCCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-benzyl-4-dimethylamino-1-[3-(2-(triethylsilyl)-1H-indol-3-yl)propyl]cyclohexanol (2.50 g, 4.95 mmol) in anhydrous tetrahydrofuran (25 mL) was mixed with tetra-n-butyl ammonium fluoride trihydrate (6.25 g, 19.8 mmol), boiled with reflux for 7 h and then stirred overnight at room temperature. Since the conversion was not yet complete, the reaction mixture was boiled with reflux for a further 7 h and then stirred over the weekend at room temperature. The reaction mixture was concentrated to low volume in a vacuum and the residue purified by means of flash chromatography (400 g, 20×7.5 cm) with dichloromethane/methanol (95:5+1% conc. aqueous ammonia).
Reaction SMILES: [OH:1][B:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:24][N+:25]([O-:27])=[O:26])[O:3]1.C1C(=O)N([Cl:35])C(=O)C1>CN(C=O)C>[C:19]([O:18][C:17](=[O:23])[NH:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:7]1[C:6]2[B:2]([OH:1])[O:3][CH:4]([CH2:24][N+:25]([O-:27])=[O:26])[C:5]=2[C:10]([Cl:35])=[CH:9][CH:8]=1)([CH3:21])([CH3:22])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCOc1ccc(Cl)c2c1B(O)OC2C[N+](=O)[O-]
Temperature: 80 °C
Yield: 39.7 %

Procedure:
A mixture of tert-butyl 4-(1-hydroxy-3-(nitromethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-7-yloxy)-butylcarbamate (640 mg, 1.7 mmol) in DMF (20 mL) was added NCS (226 mg, 1.7 mmol) in DMF (5 mL). The mixture was heated to 80° C. for 2 h. After the reaction was quenched with an aqueous LiCl solution (100 mL), the resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC to give the product (280 mg, yield 67.5%). 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 7.47-7.49 (d, 1H), 6.96-6.98 (d, 1H), 6.80 (s, 1H), 5.74-5.77 (m, 1H), 5.31-5.35 (m, 1H), 4.67-4.72 (m, 1H), 4.02-4.05 (m, 2H), 2.94-2.99 (m, 2H), 1.68-1.72 (m, 2H), 1.50-1.56 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]#[C:12][CH2:13][OH:14])[CH:4]=[CH:3][N:2]=1>C(O)C.CO.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][CH2:13][OH:14])[CH:4]=[CH:3][N:2]=1
Reactant: OCC#Cc1cccc2ccncc12
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: OCCCc1cccc2ccncc12
Reaction time: 20 h
Yield: 33.3 %

Procedure:
A solution of 0.4 g of 3-(8-isoquinolinyl)-2-propyn-1-ol in a mixture of 10 mL of ethanol and 5 mL of methanol was hydrogenated over 0.06 g 10% Pd/C at room temperature and atmospheric pressure for 22 hours andthen at 50 psi for 20 hours. After the catalyst was removed by filtration and the filtrate was concentrated, the residual oil was purified by HPLC (methanol-chloroform; 1:19) and crystallized from ethyl acetate-hexane to yield 0.136 g of 8-isoquinolinepropanol, mp 66°-69° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][CH2:15][C:16]2=[O:19])=[CH:12][CH:11]=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH:14]1[C:13]2[C:17](=[CH:18][C:10]([F:9])=[CH:11][CH:12]=2)[C:16](=[O:19])[CH2:15]1
Reactant: O=C1CCc2ccc(F)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CC(Br)c2ccc(F)cc21
Temperature: 25 °C
Yield: 65.8 %

Procedure:
A mixture of N-bromosuccinimide (2.76 g, 15.51 mmoles, Aldrich), benzoyl peroxide (0.01 g, 0.04 mmoles, Aldrich) and 6-fluoro-1-indanone (2.29 g, 15.25 mmoles) in carbon tetrachloride (20 mL) was refluxed under nitrogen for two hours. The mixture was cooled to ambient temperature, filtered, and the solids were washed with dichloromethane. The washings and filtrate were combined, washed successively with 1.0 N sodium hydroxide (2×30 mL), water (2×30 mL) and brine (30 mL), and evaporated in vacuo. The residue was chromatographed on silica gel eluting first with hexane, gradually increasing the polarity to hexane:ethyl acetate (95:5). The fractions containing the major spot were combined and evaporated in vacuo to give a 2.30 g (66%) of 3-bromo-6-fluoro-1-indanone as a yellow oil which was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N:7]1[C:14]([Cl:15])=[N:13][C:11](Cl)=[N:10][C:8]=1[Cl:9].[CH2:16]([NH:19][CH2:20][CH:21]=[CH2:22])[CH:17]=[CH2:18].[OH-].[Na+]>O1CCOCC1>[Cl:15][C:14]1[N:7]=[C:8]([Cl:9])[N:10]=[C:11]([N:19]([CH2:20][CH:21]=[CH2:22])[CH2:16][CH:17]=[CH2:18])[N:13]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C=CCNCC=C
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CCN(CC=C)c1nc(Cl)nc(Cl)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
After 10.6 g (0.10 mol) of sodium carbonate and 20.0 g (0.10 mol) of cyanuric chloride were added and dissolved into 140 g of 1,4-dioxane, 9.9 g (0.10 mol) of diallylamine was gradually added thereinto and further, 4.2 g (0.10 mol) of caustic soda was added thereinto. By generating the heat of reaction, the temperature of reaction solution was raised to about 60° C. and the reaction was continued at the temperature for 3 hours. Thereafter, the reaction mixture was cooled and filtered to remove the sodium chloride generated as the byproduct. The obtained filtrate was distilled under reduced pressure to recover the solvent. Therefore, 18.3 g (0.05 mol) of 4,6-dichloro-2-diallylamino-1,3,5-triazine was obtained.