Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[NH:11][C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=3[C:18]=2[N:19]=1)(=O)=O.[C:22]1([Sn](C)(C)C)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[Li+].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOCC>[C:22]1([C:7]2[CH:8]=[CH:9][C:10]3[NH:11][C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[C:18]=3[N:19]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[Sn](C)(C)c1ccccc1
Reactant: O=S(=O)(Oc1ccc2[nH]c3c(c2n1)CCCC3)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1ccc(-c2ccc3[nH]c4c(c3n2)CCCC4)cc1

Procedure:
A mixture of 2-trifluoromethanesulfonyloxy-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indole (99 mg, 0.31 mmol), phenyltrimethyltin (300 mg, 1.24 mmol), lithium chloride (40 mg, 0.93 mmol), tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.02 mol. eq.) and a crystal of 2,6-di-tert-butyl-4-methylphenol in 1,4-dioxane (2 mL) were refluxed for 10 hours under an atmosphere of nitrogen. The mixture was cooled and poured into ether and filtered through celite. The ether was extracted with 15% hydrochloric acid. The pH of the acidic, aqueous phase was raised to about pH 10 with 28% ammonium hydroxide, then was extracted with ether. The extract was washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by silica-gel chromatography (30% ethyl acetate in hexanes) gave 2-phenyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indole (Compound 4) as a white solid, m.p. 164°-165° C.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+:5].[S-]CC.[Na+].C[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[C:21]3[CH:36]=[CH:35][CH:34]=[CH:33][C:22]=3[S:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:19])=[CH:14][CH:13]=1.Cl>CN(C=O)C.O>[S-:3][CH2:1][CH3:2].[Na+:5].[OH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([C:20]2[C:21]3[CH:36]=[CH:35][CH:34]=[CH:33][C:22]=3[S:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:19])=[CH:16][CH:17]=1
Reactant: CCS
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3ccccc23)cc1
Agent: CC[S-]
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A ˜0.5 M solution of sodium thioethoxide was prepared by adding ethanethiol (1.60 mL, 21.4 mmol) to a suspension of 60% NaH dispersion in mineral oil (769 mg, 19.2 mmol) in 40 mL of anhydrous DMF at 0° C. The ice bath was removed and the solution was stirred at room temperature for 30 min. The 0.5 M solution of sodium thioethoxide was then added dropwise to the solution of 4.00 g (10.7 mmol) of 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 4-methoxyphenyl ketone in 10.0 mL of anhydrous DMF at room temperature. The reaction mixture was heated at 85° C. for 3 h, then allowed to cool to room temperature, and acidified with 20 mL of 1.0 N HCl. To this was added 200 mL of H2O and the mixture was extracted with EtOAc (3×400 mL). The combined organic layers were washed with 200 mL of brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by PrepLC (30% EtOAc in hexanes) to afford 3.017 g of the title compound (8.37 mmol, 78%) as a yellow foam.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[CH2:15]([OH:19])[CH2:16]CC.CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(O)CO>[Br:1][CH2:2][C:3]1([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)[O:19][CH2:15][CH2:16][O:4]1
Reactant: CCCCO
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: OCCO
Product: BrCC1(c2ccc3ccccc3c2)OCCO1
Reaction time: 8 h

Procedure:
To a stirred solution of 74.4 parts of 2-bromo-1-(2-naphthalenyl)-1-ethanone in 240 parts of butanol are added successively 3 parts of 4-methylbenzenesulfonic acid and 270 parts of benzene. Then there are added dropwise 28 parts of 1,2-ethanediol. Upon completion, stirring is continued overnight at reflux temperature. The reaction mixture is evaporated. The residue is dissolved in 2,2'-oxybispropane and the solution is stirred with a diluted sodium hydroxide solution. The layers are separated and the aqueous phase is extracted with 2,2'-oxybispropane. The extract is neutralized with water, dried, filtered and evaporated. The oily residue is crystallized from methanol. The product is filtered off and recrystallized from methanol, yielding 41 parts of 2-(bromomethyl)-2-(2-naphthalenyl)-1,3-dioxolane; mp. 64° C.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:6]=[C:7]([NH:19][C:20]2[C:25]3[C:26]4[CH2:34][CH2:33][C:32]5[N:31]([CH2:35][CH2:36]O)[N:30]=[CH:29][C:28]=5[C:27]=4[S:38][C:24]=3[N:23]=[CH:22][N:21]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.S(Br)([Br:41])=O>O>[Br:41][CH2:36][CH2:35][N:31]1[C:32]2[CH2:33][CH2:34][C:26]3[C:25]4[C:24](=[N:23][CH:22]=[N:21][C:20]=4[NH:19][C:7]4[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=5)=[C:5]([Cl:4])[CH:6]=4)[S:38][C:27]=3[C:28]=2[CH:29]=[N:30]1
Reactant: O=S(Br)Br
Reactant: OCCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Solvent: O
Solvent: ClCCl
Product: Clc1cc(Nc2ncnc3sc4c(c23)CCc2c-4cnn2CCBr)ccc1OCc1ccccn1
Temperature: 25 °C

Procedure:
To 30 mL dichloromethane cooled to 0° C. was added 2-(6-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl)ethanol (800 mg, 1.58 mmol), followed by thionyl bromide (1.15 g, 5.54 mmol). The contents were then stirred with warming to rt over a 24 h period, after which time water (5 mL) was added to quench the reaction mixture. The solvent was removed under reduced pressure. The crude residue was diluted with aq. 1M Na2CO3 and vigorously stirred for 1 h. The mixture was extracted with CH2Cl2, and the combined organic layers dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid was triturated with methanol (15 mL) to a light-brown solid (600 mg, 67%) containing 80% of the desired product, and 20% of the aromatized product. A sample of the crude product was purified via reverse phase HPLC to afford the desired product as a white solid. 1H-NMR (DMSO-d6) δ 8.58 (d, 1H), 8.38 (br s, 1H), 8.36 (s, 1H), 7.81 (dd, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.44-7.60 (m, 2H), 7.31 (td, 1H), 7.19 (d, 1H), 5.23 (s, 2H), 4.30 (t, 2H), 3.82 (t, 2H), 3.38 (t, 2H), 3.07 (t, 2H); LCMS RT=2.77 min; [M+H]+=567.0.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[C@H:3]([O:12][CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][NH:5][C@H:6]([C:8]([O:10]C)=O)[CH3:7].[NH2:22][CH:23]1[C:29](=[O:30])[N:28]([CH3:31])[C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=2[N:25]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:24]1=[O:42]>>[CH3:21][CH:2]([CH3:1])[C@H:3]([O:12][CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][NH:5][C@H:6]([C:8]([C:23]1([NH2:22])[C:29](=[O:30])[N:28]([CH3:31])[C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=2[N:25]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:24]1=[O:42])=[O:10])[CH3:7]
Reactant: COC(=O)[C@H](C)NC[C@@H](OCOCC[Si](C)(C)C)C(C)C
Reactant: CN1C(=O)C(N)C(=O)N(c2ccccc2)c2ccccc21
Product: CC(C)[C@@H](CN[C@@H](C)C(=O)C1(N)C(=O)N(C)c2ccccc2N(c2ccccc2)C1=O)OCOCC[Si](C)(C)C

Procedure:
Following General Procedure II-A, Method B and using N-(3-methyl-2-(S)-(2-trimethylsilylethyloxy)methyloxybutyl)-L-alanine, methyl ester (Intermediate A, Step C; 1 eq), the free acid was prepared. The residue was used, following General Procedure D, and using 3-amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No. 131604-75-6) to prepare the title intermediate.
Reaction SMILES: CC(C)[O-].N#N.[CH3:7][NH:8][CH3:9].[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=O.[BH4-].[Na+].[BH4-].[OH-].[NH4+]>C(O)C>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:11]([N:8]([CH3:9])[CH3:7])[CH3:10])[CH:18]=[CH:17][CH:16]=1
Reactant: CNC
Reactant: COc1cccc(C(C)=O)c1
Agent: CC(C)[O-]
Agent: N#N
Agent: [BH4-]
Solvent: CCO
Product: COc1cccc(C(C)N(C)C)c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
0.5 l of titanic isopropoxide is slowly (5 minutes) added under inert conditions (N2, argon) to a solution of 75.5 g of dimethylamine in 1.5 l of ethanol cooled to 10° C. in a water-ice bath, which is placed in a 6-liter three-neck flask fitted with a KPG stirrer, inlet and outlet of the inert and a thermometer, and, finally, 148.4 g of 3-methoxyacetophenone (VI) are added (5 minutes). The addition of isopropoxide is slightly exothermic. The resulting temperature of the reaction mixture after addition reaches 35° C. The reaction mixture is then mixed at room temperature for 9 to 10 hours. During the reaction period, the mixture becomes slightly turbid. After said period, 56.6 g of sodium borohydride are slowly and carefully added to the reaction mixture. The duration of this addition is about 2 hours. The reaction mixture thickens into a slurry and foams and it needs to be mixed very intensively. The temperature is kept within the range from 25° C. to 30° C. by mild cooling with ice. If the reaction mixture is overcooled below 20° C. a dense, difficult-to-mix foam forms upon addition of the borohydride. After the borohydride is added, the resulting white slurry is mixed for 10 to 12 hours at room temperature. Then, the supply of the inert is stopped and 800 ml of an aqueous solution of ammonium hydroxide (2:1) are slowly (over 10 minutes) poured into the reaction mixture. The resulting mixture is mixed for 20 minutes. The fine white crystals of the inorganic material are sucked away and well washed with methanol (ca 1 l). The whole alcoholic fraction is evaporated from the filtrate in a rotary vacuum evaporator. The evaporation residue is diluted with 1,000 ml of water and extracted with 3×330 ml of ethylacetate. The combined ethylacetate extract are washed once with 100 ml of water and extracted with 3×200 ml of hydrochloric acid (5:2). The acidic aqueous extracts are combined and alkalized with 20% NaOH (ca 1 l) to pH 12 up to 14 and extracted with 3×300 ml of ethylacetate. The organic fraction is washed with 100 ml of water and 150 ml of brine. It is dried with anhydrous sodium sulfate. The desiccant is filtered off and the filtrate is evaporated to dryness in a rotary vacuum evaporator. The crude product is distilled and ca 60% of the desired product in the form of a colorless oil are obtained. b.p.=68° C. at 400 Pa, 108° C. at 800 Pa
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[C:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])=[O:26])=[CH:28][CH:29]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1sccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A flame dried flask was charged with methyl 3-amino-2-thiophenecarboxylate (5.0 g, 35.0 mmol), pyridine (2.82 mL, 35.0 mmol), and dry methylene chloride (160 mL). The solution was cooled to 0 ° C. and 4-tert-butylbenzoyl chloride (6.21 mL, 31.8 mmol) was added. After 1 h, the solvent was removed in vacuo and the remaining material was dissolved in ethyl acetate. The organic phase was washed four times with water and once with brine. The organic phase was then dried over magnesium sulfate, filtered, and the solvent removed in vacuo. The crude product was purified by column chromatography over silica gel using an eluent of 2% ethyl acetate in hexane and 5% ethyl acetate in hexane to afford the product (9.67g, 96% yield).
Reaction SMILES: C(=O)([O-])[O-].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:17]=2[C:23]2[O:27][CH:26]=[N:25][CH:24]=2)[N:8]=1.Cl[N:29]1[N:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[NH:30]1>CN(C=O)C>[CH3:14][O:13][C:11]1[CH:12]=[C:7]([O:6][CH3:5])[N:8]=[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][N:29]3[N:30]=[C:31]([O:37][CH3:38])[CH:32]=[C:33]([O:35][CH3:36])[NH:34]3)[C:17]=2[C:23]2[O:27][CH:26]=[N:25][CH:24]=2)[N:10]=1
Reactant: COC1=CC(OC)=NN(Cl)N1
Reactant: COc1cc(OC)nc(Oc2cccc(O)c2-c2cnco2)n1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC1=CC(OC)=NN(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2-c2cnco2)N1
Temperature: 25 °C

Procedure:
To DMF solution containing 0.14 g pottasium carbonate and 0.15 g 5-[2-(4, 6-dimethoxypyrimidine-2-yloxy)-6-hydroxyphenyl]oxazole, was added at once DMF solution containing 0.13 g 2-chloro-4,6-dimethoxytriazine. The solution reacted was stirred for a night at room temperature. After completing the reaction, the solution reacted was poured into ice water and then extracted with ethyl acetate. The organic layer obtained was washed with water and saturated saline solution in turn and was then dried by using anhydrous magnesium sulfate. The solvent used was removed by distillation under reduced pressure, affording the objective substance in an amount of 0.22 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30].CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[CH2:29]([N:31]([CH2:32][CH3:33])[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1)[CH3:30]
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Reactant: CCNCC
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 160 °C
Yield: 4.3 %

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (350 mg, 0.90 mmol, prepared as described in Example 18) in DMSO (14 ml). Diethylamine (0.027 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 160° C. for 2 h under microwave irradiation. Further diethylamine (0.027 ml, 0.26 mmol) was added and the mixture was heated at 160° C. for 2 h under microwave irradiation. Again, diethylamine (0.027 ml, 0.26 mmol) was added and the mixture was heated at 160° C. for 1 h under microwave irradiation. After this time, diethylamine (0.027 ml, 0.26 mmol) and DIPEA (0.113 ml) were both added to the mixture and it was heated at 160° C. for 2 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). Product-containing fractions were dried under a stream of nitrogen to afford the title compound (4.7 mg).
Reaction SMILES: C(N(CC)CC)C.[Cl-].[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([OH:21])=[C:15]([NH3+:20])[CH:16]=[N:17]2)=[CH:12][CH:11]=1.[C:22]([O:25][CH2:26][C:27](Cl)=[O:28])(=[O:24])[CH3:23]>ClCCl>[C:22]([O:25][CH2:26][C:27]([NH:20][C:15]1[CH:16]=[N:17][C:18]2[C:13]([C:14]=1[OH:21])=[CH:12][CH:11]=[C:10]([Br:9])[CH:19]=2)=[O:28])(=[O:24])[CH3:23]
Reactant: CC(=O)OCC(=O)Cl
Reactant: [NH3+]c1cnc2cc(Br)ccc2c1O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1cnc2cc(Br)ccc2c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
Triethylamine (161 g, 1.59 mol) was added to a suspension of 7-bromo-4-hydroxyquinolin-3-aminium chloride (224 g, 0.815 mol) in dichloromethane (2.25 L), and the mixture was cooled to approximately 0° C. Acetoxyacetyl chloride (112 g, 0.820 mol) was added over a period of one hour. The reaction was stirred at room temperature for one hour and then allowed to stand for three days. A solid was present and was isolated by filtration and pressed dry. The solid was stirred in deionized water (2 L) for two hours, isolated by filtration, dried overnight on the filter funnel, and further dried in a vacuum oven at 60 to 70° C. to provide 223 g of 2-[(7-bromo-4-hydroxyquinolin-3-yl)amino]-2-oxoethyl acetate as a reddish brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[C:36](=[O:42])[CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][NH2:32].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:32][CH2:31][C:30]1[CH:33]=[CH:34][C:35]([C:36](=[O:42])[CH2:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[C:28]([Cl:27])[CH:29]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)(C)CC(=O)c1ccc(CN)cc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1Cl
Yield: 65.9 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (90 mg, 0.212 mmol) with 3-chloro-4-(3,3-dimethyl-butyryl)-benzylamine (102 mg, 0.43 mmol) by using tris(dibenzylideneacetone)dipalladium(0) (39 mg, 0.0424 mmol), BINAP (53 mg, 0.0848 mmol) and cesium carbonate (97 mg, 0.297 mmol) in anhydrous toluene (10 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 7-chloro-6-[3-chloro-4-(3,3-dimethyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (72 mg, 49%). MS (ES+) m/z: 516 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@:9]2(O)[CH2:17][C@H:16]3[C@@:12]([CH3:23])([C@@H:13]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][CH2:15]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH-].[K+].C(Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:17][C@H:16]3[C@@:12]([CH3:23])([C@@H:13]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][CH2:15]3)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCc1ccccc1
Reactant: COc1ccc([C@@]2(O)CC[C@@]3(C)[C@@H](CC[C@@H]3OC(C)(C)C)C2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: CC(C)(C)O[C@H]1CC[C@H]2CC(c3ccc(OCc4ccccc4)cc3)=CC[C@@]21C

Procedure:
8.0 g (26.6 mmol) of compound A that is presented according to Example 1c is mixed with 80 ml of a 50% potassium hydroxide solution, 32 ml of benzyl chloride and 1 g of tetrabutyl-ammonium hydrogen sulfate. It is allowed to react for about 4 hours at 50° C. while being stirred vigorously, and the crude mixture, which contains the title compound, is further reacted without purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.N1CCC[CH2:14]1.CI.O>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8]([CH:5]1[CH2:6][CH2:7][C:2](=[O:1])[CH:3]([CH3:14])[CH2:4]1)=[O:9])[CH3:12]
Reactant: C1CCNC1
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CI
Product: CCOC(=O)C1CCC(=O)C(C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 4-oxocyclohexane carboxylate (10.0 g, 58.8 mmol) and pyrrolidine (5.87 g, 82.7 mmol) in toluene (100 mL) and molecular sieves (40 g of 4 Å sieves) are heated to reflux overnight using Dean Stark apparatus. The mixture is filtered and the excess pyrrolidine is removed in vacuo. The resulting mixture is diluted with toluene (50 mL) and treated with methyl iodide (8.96 g, 63.1 mmol). After heating at reflux for 15 hours, the mixture is allowed to cool to RT and silica (3 g) and water (30 mL) are added. The mixture is stirred at RT for 3 hours and partitioned between water and diethyl ether. The organic portion is separated and washed with water, brine, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with iso-hexane:EtOAc (19:1 increasing to 9:1) affords the title compound. 1H NMR (400 MHz, DMSO-d6) δ 4.15 (2H, q), 2.89 (1H, m), 2.51 (1H, m), 2.38 (1H, m), 2.21 (3H, m), 1.89 (1H, m), 1.62 (1H, m), 1.22 (3H, t), 0.95 (3H, d).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:17])=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[C:6]([CH3:17])=[C:7]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1c(-c2ccccc2)[nH]c2cc(Br)ccc12
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cc(Br)ccc12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 6-bromo-3-methyl-2-phenyl-1H-indole (1.284 g, 4.489 mmol) was reacted with k-t-butoxide (0.529 g, 4.711 mmol) and benzyl bromide (0.809 g, 4.711 mmol) in DMF (10 ml) to give the product (1.440 g, 3.827 mmol, 85%) as a white solid, mp 97-101° C. 1H NMR (DMSO-d6)δ 2.20 (s, 3H), 5.32 (s, 2H), 6.79-6.80 (m, 2H), 7.14-7.21 (m, 4H), 7.36-7.39 (m, 2H), 7.43 (t, J=7.2 Hz, 1H), 7.48 (t, J=6.9 Hz, 2H), 7.53 (d, J=8.4 Hz, 1H), 7.60 (d, J=1.7 Hz, 1H); [ESI(+)], m/z 376/378 (M+H)+.
Reaction SMILES: C1(S([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=O)(=O)=O)C=CC=CC=1.C(C1CCCCCCCCCCC1=O)C=C.C1(S)C=CC=CC=1.C(Cl)C(Cl)Cl.C(OO)(=O)C.OS([O-])=O.[Na+].[OH-].[Na+]>O>[C:13]12[CH2:12][CH2:11][CH:10]=[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=2
Reactant: O=C1CCCCCCCCCCC1CCCS(=O)(=O)c1ccccc1
Agent: C=CCC1CCCCCCCCCCC1=O
Agent: CC(=O)OO
Agent: O=S([O-])O
Solvent: ClCC(Cl)Cl
Solvent: O
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 91 %

Procedure:
2-(3-Phenylsulfonyl-prop-1-yl)-cyclododecanone used hereinabove (Examples 1 and 2) as starting material was prepared as follows: 222 g (1 mole) of 2-allyl-cyclododecanone--Helv. 54, 2889 (1971)--in admixture with 132 g (1.2 mole) of thiophenol and 3.0 g of α,α'-azoisobutyronitrile were heated at 100° for 10 hours, an additional amount of 6.0 g of α,α'-azoisobutyronitrile being added over this period, portionwise, to the reaction mixture. After dilution with an excess amount of trichloroethane and cooling in an ice-bath, 376 ml (2.6 mole) of 40% peracetic acid were progressively added to the reaction mixture, under good stirring (reaction temperature: 25°-30°). After treatment with an excess amount of an aqueous solution of NaHSO3 (elimination of peroxides), a 10% solution of NaOH in water was added thereto until pH 8-9 (temperature ca. 10°). After extraction with methylene chloride (2×300 ml), successive washings and water and brine, drying over Na2SO4, evaporation and crystallization of the crude residue in a CH2Cl2 /diethyl ether/petrol ether mixture, there were finally isolated 332 g (91% yield) of the desired compound, m.p. 97°-102°.