Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[CH3:2][N:3]([CH3:11])[C:4]([N:6]=[C:7](Cl)[S:8][CH3:9])=[O:5]>>[CH3:2][N:3]([CH3:11])[C:4](=[O:5])[NH:6][C:7](=[NH:1])[S:8][CH3:9]
Reactant: CSC(Cl)=NC(=O)N(C)C
Reactant: N
Product: CSC(=N)NC(=O)N(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 50 parts of conc. aqueous ammonia are added within 10 min. at 20°-25° C., 18.1 parts of N-dimethylcarbamoyl-1-methylthioformimidoyl chloride with agitation. When all has been added, the suspension of crystals which forms is stirred for 10 minutes to assure completion of the reaction. The reaction mass is then cooled to 0° C., the solids filtered and recrystallized from acetone to give 10.6 parts of methyl 4,4-dimethylthioallophanimidate (a compound of formula II), m.p. 136°-138° C.
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][C@H:20]1[CH2:29][O:30][CH2:31][C:32]([OH:34])=O)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([N:37](CC)CC)C.O.N>O1CCCC1>[CH2:9]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][C@H:20]1[CH2:29][O:30][CH2:31][C:32](=[O:34])[NH2:37])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(N)=O)N(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
A solution of isobutyl chloroformate (9 ml) in tetrahydrofuran (20 ml) was dropwise added to a solution of (2S,4R)-1-benzyloxycarbonyl-2-carboxymethyloxymethyl-4-methanesulfonyloxypyrrolidine (24.85 g) and triethylamine (10.75 ml) in tetrahydrofuran (120 ml) at -10°~-5° C. and the mixture was stirred at the same temperature for 30 minutes. The mixture was dropwise added to concentrated ammonia water (250 ml) at 0°-5° C. and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with water (200 ml×3), 1N hydrochloric acid (300 ml×2), saturated sodium hydrogen carbonate (300 ml) and brine in turn, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (250 g) and eluted with a mixture of methanol and chloroform (2:98 and then 4:96 V/V) to give (2S,4R)-1-benzyloxycarbonyl-2-carbamoylmethyloxymethyl-4-methanesulfonyloxypyrrolidine (15.52 g).
Reaction SMILES: [C:1]([NH:5][C@@H:6]1[C@H:10]([NH:11][C:12]2[N:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]4[C:27]([Cl:28])=[C:26]([O:29][CH3:30])[CH:25]=[C:24]([O:31][CH3:32])[C:23]=4[Cl:33])[CH:18]=3)[N:13]=2)[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)(=[O:4])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:28][C:27]1[C:26]([O:29][CH3:30])=[CH:25][C:24]([O:31][CH3:32])=[C:23]([Cl:33])[C:22]=1[C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([NH:11][C@@H:10]1[CH2:9][NH:8][CH2:7][C@@H:6]1[NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[N:21]=[CH:20]2
Reactant: C=CC(=O)N[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)N[C@H]1CNC[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1

Procedure:
A solution of tert-butyl (3S,4R)-3-acrylamido-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)pyrrolidine-1-carboxylate (1.26 g, 2.14 mmol) in DCM (8 mL) and TFA (3 mL, 39 mmol) was stirred 3 h at room temperature. The excess solvents were removed under reduced pressure. The yellow oil was dissolved into DCM (˜100 mL) and washed with aqueous saturated sodium bicarbonate solution (˜50 mL). The aqueous layer was then extracted with fresh DCM (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated down, and dried to yield N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)pyrrolidin-3-yl)acrylamide which was used without further purification in the next step.
Reaction SMILES: C(#N)C=C.C=CC1C=CC=CC=1.C(C1C=C[C:19]([OH:22])=[CH:18][CH:17]=1)(C)=C.C[CH:24]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:25]#N.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N>C(OCC)(=O)C>[C:28]([C:27]1[CH:24]=[CH:25][CH:17]=[CH:18][C:19]=1[OH:22])([CH3:29])=[CH2:30]
Reactant: C=C(C)c1ccc(O)cc1
Reactant: CC(C)CC(C)C#N
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: C=CC#N
Solvent: C=Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C(C)c1ccccc1O

Procedure:
Acrylonitrile (270 g), styrene (630 g), p-isopropenylphenol (100 g), ethyl acetate (250 g) and 2,2'-azobis(2,4-dimethylvaleronitrile (5 g) were fed and polymerized at 60° C. for 4 hours, followed by further adding ethyl acetate (250 g) and 2,2'-azobis(2,4-dimethylvaleronitrile) (5 g) and further polymerization at 60° C. for 4 hours. Solvent was then removed under reduced pressure to obtain a copolymer of isopropenylphenol (hereinafter abbreviated to phenolic polymer B). The viscosity of 5% solution of phenolic polymer B in ethyl acetate, at 25° C., was 1.75 cps.
Reaction SMILES: [CH2:1]([OH:10])[CH:2]([OH:9])[CH:3]([OH:8])[CH:4]([OH:7])[CH:5]=[O:6].O=C[C@@H]([C@H]([C@@H](CO)O)O)O.[O:21]=[C:22]([OH:31])[C@@H:23]([C@H:25]([C@@H:27]([CH2:29][OH:30])[OH:28])[OH:26])[OH:24].O=C[C@@H]([C@H]([C@H](CO)O)O)O>>[CH2:1]([OH:10])[C@@H:2]1[O:9][C:5](=[O:6])[C@H:4]([OH:7])[C@H:3]1[OH:8].[O:21]=[C:22]([OH:31])[C@@H:23]([C@H:25]([C@H:27]([CH2:29][OH:30])[OH:28])[OH:26])[OH:24]
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: O=CC(O)C(O)C(O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Product: O=C(O)[C@H](O)[C@@H](O)[C@@H](O)CO
Product: O=C1O[C@@H](CO)[C@H](O)[C@H]1O

Procedure:
Microbial synthesis begins with pentose oxidation using fermentor-controlled cultures (e.g., 1 L scale) of Pseudomonas fragi ATCC4973. (Buchert, J.; Viikari, L.; Linko, M.; Markkanen, P. Biotechnol. Lett. 1986, 8, 541. and Weimberg, R. J. Bio. Chem. 1961, 236, 629). D-xylose (100 g/L) is oxidized at 30° C. to D-xylonic acid and produces a 70% yield (77 g/L). L-arabinose is similarly oxidized and produces a 54% overall yield to a mixture of L-arabino-1,4-lactone (40 g/L) and L-arabinonic acid (15 g/L). The lactone is subsequently hydrolyzed to L-arabinonic acid. Escherichia coli constructs are then employed for the conversion of D-xylonic acid and L-arabinonic acid into the respective enantiomers of 1,2,4-butanetriol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:14][C@H:15]([C:17]([OH:19])=O)[CH3:16])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:5])[CH3:2].Cl.[C:21]([O:25][C:26](=[O:39])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32](=[O:38])[C@@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:39])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32](=[O:38])[C@@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:17](=[O:19])[C@H:15]([CH3:16])[NH:14][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCCCCSC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1
Agent: Cl
Product: CCCCCSC[C@H](N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)OCC

Procedure:
Following the general procedure of Example 27, the title compound was prepared as a colorless oil from 700 mg of the β-isomer of N-[(R)-1-ethoxycarbonyl-2-pentylthioethyl]-alanine prepared in Reference Example 30 and 730 mg of the hydrochloride of (S)-prolyl-(S)-proline t-butyl ester prepared in Reference Example 28. Yield 930 mg.
Reaction SMILES: C(OC(=O)[N:7]([CH2:15][CH2:16]O)[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH3:14])[CH2:10][CH2:9]1)(C)(C)C.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:50]1([SH:56])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C1COCC1>[CH3:14][CH:11]1[CH2:10][CH2:9][CH:8]([NH:7][CH2:15][CH2:16][S:56][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:13][CH2:12]1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)OC(=O)N(CCO)[C@H]1CC[C@H](C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1CCC(NCCSc2ccccc2)CC1
Reaction time: 18 h

Procedure:
To a solution of (2-Hydroxy-ethyl)-(trans-4-methyl-cyclohexyl)-carbamic acid tert-butyl ester (0.50 g, 1.94 mmol) in THF (20 mL) was added DEAD (372 mg, 2.14 mmol) and resin bound triphenyl phosphine (polystyrene 2% cross linking, loading=3 mmol/g, 0.97 g). The mixture was stirred for 15 m before thiophenol (0.21 g, 1.94 mmol) was added. The mixture was stirred for 18 h before another portion of resin bound triphenyl phosphine (0.97 g) and DEAD (372 mg, 2.14 mmol) was added. The mixture was stirred for 1 h before a new portion of thiophenol (0.21 g, 1.94 mmol) was added. The mixture was stirred for 18 h before it was filtered. The resin was washed with THF (2×20 mL) and the combined filtrates were concentrated in vacuo. The residue was divided between DCM (100 mL) and H2O (100 mL). The aqueous layer was extracted once more with DCM (100 mL). The organic fractions were combined, dried (MgSO4), filtered and concentrated in vacuo to give the crude intermediate (4-methyl-cyclohexyl)-(2-phenylsulfanyl-ethyl)-amine.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](CCNCCCCCCC)[CH:8]=1.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[N:35]=[C:36]=[O:37].C([N:41]([CH2:45][CH3:46])[CH:42]([CH3:44])C)(C)C.Cl>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:46][CH2:45][N:41]([CH2:42][CH2:44][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:36]([NH:35][C:29]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=2[F:27])=[O:37])=[CH:9][CH:8]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCNCCc1cccc(CC(OCC)C(=O)OC)c1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)OC)cc1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 164.5 %

Procedure:
To a solution of 2-ethoxy-3-[3-(2-heptylamino-ethyl)-phenyl]-propionic acid methyl ester HCl salt (41 mg, 0.106 mmol), and 2,4-difluorophenylisocyanate (0.17 mmol, 0.0138 mL) in toluene (4.5 mL) was added N,N-diisopropylethylamine (0.32 mmol, 0.055 mL). The mixture was allowed to stir at room temperature for 18 hours, then was poured over 1M HCl (5 mL). The aqueous layer was isolated and extracted with diethyl ether (2×). The organic layers were combined, washed with 2M HCl (2×), brine (2×), dried over anhydrous sodium sulfate, and concentrated to give a clear oil. The crude solid was chromatographed on silica gel (Merck silica gel 60, art#9385-3) eluting with 20% ethyl acetate/hexanes to give 3-(4-{2-[3-(2,4-difluoro-phenyl)-1-heptyl-ureido]-ethyl}-phenyl)-2-ethoxy-propionic acid methyl ester as a clear oil (44 mg, 82%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:5][CH:6]=1.[C:15]1(=[O:25])[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[OH2:26]>>[CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:3][CH:2]=1.[C:15]([O-:20])(=[O:25])[C:16]1[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:18]([O-:26])=[O:19]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: O
Agent: Nc1nc(N)nc(-c2ccccc2)n1
Product: O=C([O-])c1ccccc1C(=O)[O-]

Procedure:
187 g of benzoguanamine, 148 g of phthalic anhydride and 5 L of water were placed into the a flask provided with a stirrer and a reflux tube, and were continuously refluxed for 5 hours to form a crystal, which was then filtered out and dried to obtain benzoguanamine phthalate.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:5]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:4]=2[N:3]=1.Cl[CH2:22][C:23]([CH2:25]Cl)=O.C(=O)([O-])[O-:28].[K+].[K+]>O1CCOCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:4]2[N:3]3[CH:25]=[C:23]([CH2:22][OH:28])[N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[C:5]=2[CH:16]=1
Reactant: O=C(CCl)CCl
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: OCc1cn2c(n1)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Temperature: 98 °C
Reaction time: 22 h
Yield: 35.5 %

Procedure:
A solution of 9.1 g of 2-amino-7-chloro-5-(2-chlorophenyl)-3H-1,4-benzodiazepine (K. Meguro, H. Tawada & Y. Kuwada, Yakugaku Zasshi, 1973, 93, 1253-1262) and 11.4 g of 1,3-dichloroacetone in 195 ml of dioxan was treated with 24.9 g of anhydrous potassium carbonate and stirred at 98° C. for 22 h. After cooling the inorganic salts were filtered off, the filtrate was treated with 0.75 g of p-toluenesulphonic acid and stirred at 98° C. for 2.5 h. 60 ml of 1N aqueous sodium hydroxide solution and 2.0 g of active charcoal were added to this solution and the mixture was stirred at 80° C. for 2.5 h. After cooling the mixture was filtered and the filtrate was concentrated in a vacuum. The residue was taken up in 300 ml of dichloromethane and the solution was shaken with 200 ml of 6N aqueous hydrochloric acid. The crystals which thereby separated were filtered off (4.2 g) and the filtrate was extracted a further three times with 200 ml of 6N aqueous hydrochloric acid each time The combined aqueous extracts were made weakly basic (pH 8 to 9) with aqueous sodium hydroxide solution and the precipitate was filtered off. The filter cake together with the crystals (4.2 g) filtered off earlier were taken up in chloroform and in 2N aqueous sodium hydroxide solution, the mixture was filtered clear and the aqueous phase is extracted a further twice with chloroform. The chloroform extracts were dried over sodium sulphate, concentrated in a vacuum to 100 ml and chromatographed over 210 g of silica gel. A small amount of byproduct was eluted with chloroform. The desired product was eluted with chloroform containing 1 to 4% ethanol and was crystallized from ethyl acetate. There were obtained 3.8 g of 8-chloro-6-(2-chlorophenyl)-4H-imidazo-[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 174-175° C., which was converted into the hydrochloride, m.p. 257-259° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][C:6]([NH2:8])=[O:7].[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.O>C1(C)C=CC=CC=1>[N:9]1([CH2:2][CH2:3][O:4][CH2:5][C:6]([NH2:8])=[O:7])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: C1CNCCN1
Reactant: NC(=O)COCCCl
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)COCCN1CCNCC1
Yield: 39.5 %

Procedure:
A mixture of 13.15 g of (2-chloroethoxy)acetamide (0.1 mol) and 43 g of anhydrous piperazine (0.5 mol) in 250 ml of toluene is introduced into a round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. The mixture is heated at the reflux temperature for 4 hours. The precipitate formed is filtered off while hot and the solvent of the filtrate is evaporated off under reduced pressure to dryness. The evaporation residue is purified by chromatography on silica gel (eluent: 14/5/1 (v/v/v) of dichloromethane/methanol/28% aqueous ammonia solution). 7.4 g of 2-[2-(1-piperazinyl)ethoxy]acetamide are obtained in the form of a yellow oil
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1.[OH-].[Na+]>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:2][C:3](=[O:5])[CH3:4])=[CH:9][CH:8]=1
Reactant: CC(=O)CCl
Reactant: Sc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99084.2 %

Procedure:
Chloroacetone (32.3 g, 0.347 mol) was added to a mixture of 4-chlorothiophenol (50 g, 0.347 mmol) and sodium hydroxide (14 g, 0.347 mol) in water (400 ml) and the mixture was stirred at 25° C. for 1 hour. The mixture was extracted with ethyl ether and the organic phase was washed with water, dried with magnesium sulfate and concentrated to give 69 g (99%) of 1-[(4-chlorophenyl)thio]-2-propanone.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc(Br)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-bromobenzoyl chloride, there is obtained ethyl N-(p-bromobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 116°-117° C.;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH:24]([O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([C:37]([F:40])([F:39])[F:38])[CH:29]=1)([CH3:26])[CH3:25]>>[CH:24]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)=[C:30]([C:37]([F:38])([F:39])[F:40])[CH:29]=1)([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: CC(C)Oc1ccc(B(O)O)c(C(F)(F)F)c1
Product: CC(C)Oc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and 4-isopropoxy-2-(trifluoromethyl)phenylboronic acid (248 mg, 1.0 mmol) to afford after chromatographic purification the title compound (186 mg, 74%). 1H NMR (CDCl3, 300 MHz) δ7.11-7.18 (m,2H), 6.90-6.94 (m, 1H), 6.78 (s, 1H), 6.74 (s, 1H), 4.50-4.54 (m, 1H), 3.75-3.85 (m, 1H), 3.59-3.70 (m, 1H), 2.79-3.40 (m, 8H), 1.74-1.84 (m, 2H), 1.40 (m, 9H) 1.21 (d, 6H, J=5.9 Hz) ppm. MS-ApCI: 503 [M+H+].
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([N:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]=1[O:36][CH3:37])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.CC(O)=O.CS(C)=O>CC(O)=O>[CH3:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[C:17]2[C:18]3[S:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:12][C:13]=3[C:14]([O:36][CH3:37])=[CH:15][CH:16]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc1NC(=S)NC(=O)c1ccccc1
Agent: Br
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)c2sc(NC(=O)c3ccccc3)nc12

Procedure:
From 1-benzoyl-3-{5-[bis-(4-methyl-benzyl)-amino]-2-methoxy-phenyl}-thiourea with HBr—AcOH (2 equiv.) and DMSO (1.1 equiv.) in AcOH. ES-MS m/e (%): 508 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][C:8](O)=[CH:7][CH:6]=1)[CH3:4].Br[CH2:13][CH2:14][CH:15]([CH3:23])[CH2:16][CH2:17][CH:18]1[O:22][C:19]1([CH3:21])[CH3:20].[OH2:24]>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[O:22]1[C:19]([CH3:21])([CH3:20])[CH:18]1[CH2:17][CH2:16][CH:15]([CH3:23])[CH2:14][CH2:13][O:24][C:5]1([CH2:3][CH3:4])[CH:10]=[CH:9][CH:8]=[CH:7][CH2:6]1
Reactant: CC(CCBr)CCC1OC1(C)C
Reactant: O
Reactant: CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCC1(OCCC(C)CCC2OC2(C)C)C=CC=CC1

Procedure:
In a 1.0 liter four-necked flask fitted with a reflux condenser a mechanical stirrer, dropping funnel and a gas inlet tube is placed 50 ml of dry tetrahydrofurane and 1.5 g NaH (prepared from 50% suspension through washing with tetrahydrofuran). 7.5g of p-ethylphenol in 50 ml of tetrahydrofuran is then added dropwise with stirring while a nitrogen atmosphere is maintained in the flask. The mixture is stirred until solution of NaH is complet, and 13.0 g. 1-bromo-6,7-epoxy-3,7-dimethyloctane in 20 ml hexamethylphosphoric triamide is added dropwise and with stirring. The resulting mixture is boiled under reflux, with stirring for 3 hours. After the addition of 1.0 liter of water the mixture is extracted with 0.5 liters of hexane and hexane extract is dried over sodium sulfate, filtered and concentrated in vacuo with water aspirator. The product was chromatographed on silica gel, fractions eluted with a mixture hexane-ethyl-acetate (9:1 parts by volume) afforded 6,7-Epoxy-1-(1-ethylphenoxy)-3,7-dimethyl-octane nD24 - 1,4973.
Reaction SMILES: [H-].[Na+].[C:3]([PH:7](=[O:15])[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])([CH3:6])([CH3:5])[CH3:4].[CH2:16](Br)[CH:17]([CH3:19])[CH3:18]>O1CCCC1>[C:3]([P:7](=[O:15])([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])([CH3:5])([CH3:4])[CH3:6]
Reactant: CC(C)CBr
Reactant: CCOC(OCC)[PH](=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(OCC)P(=O)(CC(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dry sodium hydride (0.42 g) is suspended in 50 ml of dry tetrahydrofuran under an argon atmosphere. To this stirred suspension is added 3.6 g (0.017 mol) of tertiary-butyl(diethoxymethyl)-phosphine oxide dissolved in 25 ml of dry tetrahydrofuran, at room temperature. Stirring is continued for 10 minutes at room temperature, during which time the solid dissolves and a gas is evolved. To the clear solution obtained is added a solution of 2.4 g (0.017 mol) of iso-butyl bromide in 25 ml of dry tetrahydrofuran. After the addition is complete, the reaction mixture is heated under reflux for 15 hours, then allowed to cool at room temperature and washed with 20 ml of water. The organic extracts are dried and evaporated under reduced pressure. The crude product is purified by chromatography on silica using ethyl acetate as eluent to give tertiary-butyl-(iso-butyl)(diethoxymethyl)phosphine oxide as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12]Br>C(O)C>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc(C)cc1
Solvent: CCO
Product: COC(=O)c1ccc(CBr)cc1
Reaction time: 8 h

Procedure:
A methyl 4-methylbenzoate (MMB) solution (110 g, 0.73 mol) in CB (150 g) in a 250 mL round bottomed flask was heated by a heating mantle connected to a temperature controller to temperatures between 136 to 140° C. Liquid bromine (84.4 g, 0.53 mol or ~72 mol %), (Aldrich, 99.5+%, A.C.S. reagent) was fed via Viton tubings using Cole-Parmer computerized Drive with Easy-Load pump head. The bromine feed rate was adjusted to 0.50 mL/minute throughout the 52 minutes of addition time. Heating and stirring were continued for a few minutes after all bromine had been added, and then the reaction mixture was allowed to cool down. The "smoking" orange mixture was transferred to a separatory funnel and was washed with water (250 mL) to produce a colorless organic phase. The bottom layer (organic) was separated and concentrated under reduced pressure (rotary evaporator) to remove most of the chlorobenzene. The residual oily mixture was allowed to stand overnight. An impure crystalline solid was obtained. The crude solid was dissolved in 20% aqueous ethanol solution (450 mL) and allowed to cool in a refrigerator for 2 hours. The resulting white crystals were washed with 50% aqueous ethanol (200 mL) to produce 50.5 g (42% based on added bromine) of highly pure (~99%) material. No attempt was made to optimize the recovered yield.