Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:12]([SiH:15](Cl)Cl)[CH:13]=[CH2:14].[Na+].[Cl-]>C(OCC)C>[CH2:12]([SiH:15]([CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:13]=[CH2:14]
Reactant: BrCCCc1ccccc1
Reactant: C=CC[SiH](Cl)Cl
Agent: [Cl-]
Agent: [Mg]
Agent: [Na+]
Solvent: CCOCC
Product: C=CC[SiH](CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 86 %

Procedure:
To a 500 mL Schlenk flask containing magnesium turnings (2.71 g, 111.5 mmol) in diethyl ether (250 mL) was added dropwise a solution of 1-bromo-3-phenylpropane (20.0 g, 100.5 mmol) over 4 hours. The resulting pale yellow solution was stirred for 10 hours at room temperature then cooled to 0° C. and treated with allyldichlorosilane (7.085 g, 50 mmol) via syringe. The resulting white slurry was stirred for 4 hours at room temperature then heated to reflux for 20 minutes. After filtration and aqueous work-up, the solvent was removed in vacuo to give a colorless liquid. Yield: 86%. FTIR (NaCl, cm−1): 3083, 3066, 3021, 2927, 2842, 2069, 1598, 1569, 1488, 1456, 1142, 1067, 1025, 987, 920, 891, 834, 745, 701. 1H NMR (CDCl3): 7.28, 7.17, 5.74, 4.89, 4.54, 3.74, 2.62, 1.67, 0.64.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:31])[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[Cl:30])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[Cl:30][C:21]1[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:20]=1[O:19][CH2:18][C:17]([NH:16][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:3]=1)=[O:31]
Reactant: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 100 mg (0.217 mmol) N-[3-amino-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Example 160) in 5 mL pyridine was added at 0° C. to 18 μL (0.239 mmol) of methanesulphonylchloride, the mixture was slowly heated to RT and stirred for 3 h at RT. The reaction mixture was poured onto ice water and the aqueous phase was exhaustively extracted with EtOAc. The combined org. phases were dried over sodium sulphate and evaporated down i. vac. The residue was lyophilised.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH2:18](I)[CH3:19]>>[CH2:18]([C:8]1[CH:9]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:11]=[C:3]([C:2]([F:16])([F:17])[F:1])[C:4]=1[C:5]([OH:7])=[O:6])[CH3:19]
Reactant: CCI
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Product: CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O

Procedure:
In analogy to the procedure described for the synthesis of example B.1, the title compound was prepared from 2,4-bis-trifluoromethyl-benzoic acid (commercial) and ethyliodide.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]([C:19](=[O:40])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]2[C:36]([C:37]#[N:38])=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][C:33]=3[F:39])[N:28]=2)[CH:21]=1)[CH3:18])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([N:17]([CH3:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7][C:6]([OH:41])=[O:5])=[O:40])=[CH:21][C:22]=1[C:27]1[C:36]([C:37]#[N:38])=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[F:39])[N:28]=1
Reactant: CN(C(=O)c1ccc(Cl)c(-c2nc3cccc(F)c3cc2C#N)c1)c1ccccc1OCCCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)c1ccc(Cl)c(-c2nc3cccc(F)c3cc2C#N)c1)c1ccccc1OCCCC(=O)O
Yield: 31.6 %

Procedure:
4-(2-{[4-Chloro-3-(3-cyano-5-fluoro-quinolin-2-yl)-benzoyl]-methyl-amino}-phenoxy)-butyric acid tert-butyl ester (80.2 mg) was stirred in 50% trifluoroacetic acid in dichloromethane (2 mL) for 2 hrs and purified via reverse phase preparative LCMS to afford 4-(2-{[4-chloro-3-(3-cyano-5-fluoro-quinolin-2-yl)-benzoyl]-methyl-amino}-phenoxy)-butyric acid 33-1 (22.9 mg). MS [M+H]+: 518.4; tR=3.47 min. (method 3)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1onc(-c2ccc(Cl)cc2)c1-c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)cc1
Yield: 76 %

Procedure:
As described for Example 44, 3-(4-chloro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (100 mg, 0.32 mmol), using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone, was converted to the title compound (105 mg, 76%) which was obtained as a yellow solid. MS: m/e=492.9 [M+OAc]+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:29]=1[C:30]([O:32][CH3:33])=[O:31]>>[Br:8][CH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:29]=1[C:30]([O:32][CH3:33])=[O:31]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: COC(=O)c1c(C)cccc1CBr
Yield: 32 %

Procedure:
NBS (40.85 mmol, 1 equiv.) and benzoyl peroxide (10.21 mmol, 0.25 equiv.) were added to a solution of methyl 2,6-dimethylbenzoate (40 mmol, 1 equiv.) in CCL4 (75 ml), and the mixture was heated for 20 min at boiling temperature. The reaction mixture was filtered out over celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (1.5% ethyl acetate/hexane). Yield: 32%
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH2:17][OH:18])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>CC#N.O=[Mn]=O>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH:17]=[O:18])[CH:11]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1ccc(Cl)c(CO)c1)C(=O)OC(C)(C)C
Agent: O=[Mn]=O
Solvent: CC#N
Product: CN(Cc1ccc(Cl)c(C=O)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 87 %

Procedure:
MnO2 (372 mg, 3.85 mmol) was added to a sol. of (4-chloro-3-hydroxymethyl-benzyl)-methyl-carbamic acid tert-butyl ester (110 mg, 0.385 mmol) in CH3CN (7.70 mL). The mixture was stirred at rt for 4.5 h, and MnO2 (186 mg, 1.93 mmol) was added again. The mixture was stirred for 1 h, and the mixture was filtered over Celite. The precipitate was washed with CH3CN and CH2Cl2. The filtrate was evaporated under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (95 mg, 87%) that was used further without purification. LC-MS: tR=0.99 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].I[CH2:9][CH2:10][CH3:11].[H-].[Na+]>CN(C=O)C>[CH2:9]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH2:10][CH3:11]
Reactant: CCCI
Reactant: O=Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1ccnc1C=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
In DMF 15 ml, 2-imidazole carboxaldehyde (500 mg) was dissolved. Then, the solution was added with 1-iodopropane (1.52 ml) and sodium hydride (208 mg), followed by stirring at room temperature for 5 days. After completion of the reaction, the solvent was distilled off and the residue was then added with chloroform, followed by washing with water and saturated saline solution. The resultant was dried with anhydrous sodium sulfate, and the solvent was distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (600 mg) as a yellow oily substance.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]([CH3:9])([OH:8])[CH3:7])[CH2:3][OH:4].[N:10]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(N(CC)CC)C>ClCCl>[OH:4][CH2:3][C@@H:2]([NH:1][C:16]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:17])[CH2:5][C:6]([OH:8])([CH3:9])[CH3:7]
Reactant: CC(C)(O)C[C@H](N)CO
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O)C[C@@H](CO)NC(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(S)-2-amino-4-methylpentane-1,4-diol (0.6 g, 4.5 mmol) was dissolved in anhydrous dichloromethane (10 mL) and the solution was cooled to 0° C. Next, 4-morpholinecarbonyl chloride (0.78 mL, 6.75 mmol) was added, followed by triethylamine (0.75 mL, 5.4 mmol). The reaction was stirred for 3 hrs at 0-5° C. The solvent was evaporated and the residue was purified using silica gel chromatography (10% methanol-dichloromethane) to afford Cmpd 66. Yield: 0.675 g (61%). MS (m/z): (M+H)=247.
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])[C:2](C)=[CH2:3].[O:14]=[O+][O-].CSC>ClCCl.CO>[C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])[C:2]([CH3:3])=[O:14]
Reactant: C=C(C)C(=O)OCc1ccccc1
Reactant: O=[O+][O-]
Solvent: CO
Solvent: CSC
Solvent: ClCCl
Product: CC(=O)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A stirred solution of 25 mL (147.5 mmole) of benzyl methacrylate in 500 mL of dichloromethane and 125 mL of methanol was cooled to −78° C. and ozonized until the solution was pale blue, indicating excess ozone. The solution was purged with nitrogen until the blue color of ozone had dissipated, and then 14.1 mL (192 mmole, 1.3 equivalents) of dimethyl sulfide was added rapidly dropwise under nitrogen. After stirring for one hour more at −78° C. the solution was removed from the cold bath and allowed to stir at room temperature for 3 hours. The solution may be stored overnight in the freezer at this point. Volatiles were removed on the rotary evaporator at 40° C. and the residue was taken up in 100 mL of dichloromethane and washed with 100 mL of water to remove dimethyl sulfoxide. The water layer was back extracted with a small volume of dichloromethane. The combined organics were washed with water in this fashion twice more. The final organic layer was filtered through cotton, concentrated on the rotary evaporator, and high-vacuum dried leaving an essentially quantitative yield of benzyl pyruvate as a colorless liquid. A small amount of formaldehyde methyl hemiacetal and/or the methyl hemiacetal of benzyl pyruvate may be present but do not interfere in the next step.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](OCC)=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[Cl-].[NH4+]>O1CCCC1>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH:7]([CH2:19][O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CCCCCOC(COCc1ccc(OC)cc1)Cn1ccnc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(COCC(Cn2ccnc2)OCCCCCCO)cc1

Procedure:
A solution of ethyl 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanoate (Example 4; 10 g, 0.025 mol) in anhydrous tetrahydrofuran (50 ml) was added dropwise to a stirred slurry of lithium aluminium hydride (1.8 g, 0.047 mol) in anhydrous tetrahydrofuran (20 ml) under a nitrogen atmosphere. When the addition was complete the suspension was heated under reflux for 1 hour. Aqueous sodium hydroxide (2M, 2 ml) was added and the mixture was poured into an aqueous saturated solution of ammonium chloride (1000 ml) and extracted with dichloromethane. The combined extracts were dried (Na2SO4) and the solvent was evaporated off under reduced pressure to give the crude product which was purified by column chromatography (silica gel, ethyl acetate to 10% ethanol in ethyl acetate) to give 1-[2-[(6-hydroxyhexyl)oxy]-3-[(4-methoxyphenyl)methoxy]-propyl]-1H-imidazole as a pale yellow oil.
Reaction SMILES: [C:1](#[N:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+]>O>[CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCN
Reaction time: 0.25 h
Yield: 94 %

Procedure:
300 g of oleonitrile were fed into a 1 liter autoclave and 2 g of Catalyst A, 6 g of water and 0.5 g of 48% sodium hydroxide were put thereinto. After purging with nitrogen gas, the reaction was carried out under the hydrogen pressure of 1.0 MpaG at the reaction temperature of 130° C. The reaction-finishing point was determined at the point where the hydrogen gas was no longer absorbed. The reaction system was aged further for 15 minutes. Absorption of hydrogen gas proceeded smoothly and the absorption was completed in 1.3 hour. After finish of the reaction and aging, the reaction product was taken out from the reactor and the catalyst was removed off. Then, the reaction product was distilled and purified under 0.27 kPa at 220° C. Oleylamine was obtained with yield of 94%.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25][CH2:24]2>CN(C)C=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1)[CH2:25][CH2:24]2
Reactant: COc1ccc2c(c1)CCNC2
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(Cc1cnc(C)nc1N)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
A suspension of 0.80 g (0.00412 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 17 ml of dimethylformamide was treated with 1.7 ml (0.0124 mol) of triethylamine and 0.87 g (0.0053 mol) of 6-methoxy-1,2,3,4-tetrahydro-isoquinoline and the mixture was stirred at room temperature under argon for 3 hours. The mixture was completely freed from the solvents and the residue was triturated in 20 ml of water. The resulting crystals were filtered off under suction, chromatographed over silica gel with dichloromethane/methanol 9:1 as the eluent and recrystallized from ethyl acetate/n-hexane. 0.26 g (22%) of 5-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-2-methyl-pyrimidin-4-ylamine was obtained as white crystals; m.p. 142°-143°.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-:16].[Na+].[Na+].[Cl-].[C:22]1([S+:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClCCl>O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:35]1([S+:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)([O-])c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4-trifluoromethylbenzenesulfonyl chloride (20.53 g, 83.9 mmol) in water (150 ml) containing sodium carbonate (9.43 g, 88.10 mmol) was heated at reflux for 22 hours. After cooling to room temperature, triphenylsulfonium chloride (50% aqueous solution, 50.00 g) was added over 15 minutes. After stirring the biphasic mixture for 30 minutes, dichloromethane (300 ml) was added and the mixture stirred at room temperature for 20 hours. The layers were separated and the organic layer washed with water (7×150 ml) until the washings were neutral (pH 7 ). After drying (MgSO4 ), removal of the solvent in vacuo gave a pale yellow foam which was further dried by heating at 80°-100° C. for 108 hours under vacuum. In this way, triphenylsulfonium 4 -trifluoromethylbenzenesulfonate was isolated as a pale yellow glass (36.77 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:13]=1.[BrH:14]>>[BrH:14].[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:13]=1
Reactant: COc1ccc2c(c1)CNCCC2
Agent: Br
Product: Oc1ccc2c(c1)CNCCC2

Procedure:
8-Methoxy-2,3,4,5-tetrahydro-1H-benz[c]azepine (3.65 g) was dissolved in 48% aqueous hydrogen bromide solution (36 ml) and the mixture was refluxed for 2 hours. The solvent was evaporated and ethanol and diethyl ether were added to the obtained residue. The mixture was filtrated and dried under reduced pressure to give the title compound (4.56 g).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[C:3](=[N:4]O[N+:6]=2[O-])[CH:2]=1.[N:11]#[C:12][NH2:13].[Na].[Na]>CO.O>[NH2:13][C:12]1[N:11]=[N:6][C:7]2[CH:8]=[CH:9][CH:1]=[CH:2][C:3]=2[N:4]=1
Reactant: N#CN
Reactant: [O-][n+]1onc2ccccc21
Agent: [Na]
Solvent: O
Solvent: CO
Product: Nc1nnc2ccccc2n1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 21.9 %

Procedure:
To a suspension of 13.6 g (0.1 mol) of benzofuroxan in a mixture of 40 ml of methanol and 40 ml of water at 20° C. are added in portions 17.2 g (0.2 mol) of disodium cyanamide. In the course of addition, the temperature rises to 50° C.-60° C. and the solution assumes a blue-violet color. It is stirred for a further 40 minutes at about 60° C. and the precipitate which separates out is then removed by filtration from the mother liquor, which is retained and processed further. The precipitate is dissolved in water, the solution is filtered and the filtrate is acidified with acetic acid, whereupon 12.5 g of 3-amino-1,2,4-benzotriazine-1,4,-di-N-oxide (71% of theory) separates out in the form of reddish-golden crystals which melt, with decomposition, at 220° C. On acidifying the mother liquor with acetic acid, a further 3.2 g (18% of theory) of 3-amino-1,2,4-benzotriazine is obtained and after re-crystallization from dimethylformamide, this material melts, with decomposition, at 220° C. Total yield reported is: 89% of theory.
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([OH:28])=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:32]([O:37]C)(=[O:36])[C@H:33]([CH3:35])O>>[Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[C:22]([O:28][C@H:33]([CH3:35])[C:32]([OH:37])=[O:36])=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: COC(=O)[C@H](C)O
Reactant: CC(C)c1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(C(C)C)c1O
Product: CC(C)c1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(C(C)C)c1O[C@H](C)C(=O)O

Procedure:
Prepared from of 4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-2,6-diisopropyl-phenol (Example 40) and commercially available (S)-lactic acid, methyl ester. White solid: mp: 214-215° C.; NMR (CDCl3); δ8.37 (ddd, J=8, 1, 1, 1H), 7.80 (d, J=8 Hz, 1 H), 7.70 (ddd, J=8, 1, 1 Hz, 1 H), 7.66 (ddd, J=8, 8, 1, 1 H), 7.48 (ddd, J=8, 8, 1 Hz, 1 H), 7.37 (ddd, J=8, 8, 1 Hz, 1 H), 7.18 (s, 2 H), 7.01 (ddd, J=8, 8, 1 Hz, 1 H), 6.53 (d, J=8 Hz, 1 H), 4.75 (q, J=7 Hz, 1 H), 3.47 (septuplet, J=7 Hz, 1 H), 3.41 (septuplet, J=7 Hz, 1 H), 1.71 (d, J=7 Hz, 3 H), 1.25 (d, J=7 Hz, 6 H), 1.20 (d, J =7 Hz, 3 H), 1.19 (d, J=7 Hz, 3 H); MS (EI): 560 (90%), 562 (100); Anal. Calc. for C31H29BrO3S: C, 66.31, H, 5.21, N, 0.00. Found: C, 65.90, H, 5.18, N, 0.02.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10](=[S:15])([NH2:14])[CH2:11][CH2:12][CH3:13]>C(O)C>[CH2:11]([C:10]1[S:15][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:14]=1)[CH2:12][CH3:13]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCCC(N)=S
Solvent: CCO
Product: CCCc1nc(C(=O)OCC)cs1

Procedure:
Ethyl 3-bromo-2-oxopropanoate (6.32 mL) was added to a solution of butanethioamide (example 87, step a) (5.2 g) in ethanol (100 mL) and the resulting mixture heated at reflux overnight. The solvent was evaporated and the residue partitioned between ethyl acetate (100 mL) and saturated sodium hydrogen carbonate solution (100 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2×100 mL). The combined organic solutions were washed with brine (100 mL) dried over sodium sulphate, filtered and evaporated. Purification was by silica gel chromatography eluting with 10:1 isohexane:ethyl acetate. The fractions containing product were combined and evaporated to give the subtitled compound as a yellow oil. Yield 5.24 g.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[N:22]=[C:21]([CH2:32][CH2:33][CH:34]([OH:36])[CH3:35])[CH:20]=2)=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[N:22]=[C:21]([CH2:32][CH2:33][C:34](=[O:36])[CH3:35])[CH:20]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(-n2nc(CCC(C)O)cc2-c2ccc(Cl)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(-n2nc(CCC(C)=O)cc2-c2ccc(Cl)cc2)cc1
Reaction time: 4 h
Yield: 69.6 %

Procedure:
To a suspension of pyridinium chlorochromate (3.65 g, 16.93 mM) in CH2Cl2 (20 ml) was added the alcohol 20, (3.02 g, 8.46 mM) in CH2Cl2 (15 ml). After stirring for 4 hours, the reaction solution was decanted from the chromium precipitates that were washed with EtOAc (2×150 ml). The reaction solution and the washes were combined, filtered through florosil, and concentrated in vacuo. Chromatography (120 g, Baker 40 gm silica gel) with Et2O:hexane (1:1 to 100% Et2O) as eluent, followed by crystallization from Et2O:hexane afforded 23, (2.09 g, 70%) as a white crystalline solid, mp=85°-86° C.
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.[OH-].[NH4+].Cl[CH2:14][C:15]([NH:17][C:18]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)=[O:16]>C(O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:18]2[NH:17][C:15](=[O:16])[CH2:14][N:2]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]=2[CH:28]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Yield: 326.5 %

Procedure:
A mixture of ethanol (1100 mls), hexamethylenetetramine (35 g., 0.25 mol), 26% ammonium hydroxide (58 ml), and 2-chloroacetamido-5-chlorobenzophenone (308.2 g., 1.0 mol) were permitted to react as described in Example 11 except that the reflux period was increased from 5 to 7 hours. The reaction product, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (221 g.) isolated in a manner identical with Example 11, was obtained in 81.6% yield, melting point 208.5° to 209° C.