Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(Cl)Cl>[C:19]1([C:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:1]2[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a solution of 76.5 g of ethyl isonipecotate and 81.5 ml of triethylamine in 750 ml of methylene chloride, 149 g of triphenylmethyl chloride dividied in three portions was added portionwise at room temperature, and the mixture was stirred for 16 hours. The reaction mixture was added with water and extracted with methylene chloride. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated. The resulting brown liquid was added with diisopropyl ether, and the precipitated crystals were collected by filtration and washed with diisopropyl ether to give 184 g of pale yellow crystals. Recrystallization from ethanol gave colorless prisms having the melting point of from 147.5 to 148.5° C.
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:35])[C:13]2([CH2:15][CH2:14]2)[CH2:12][N:11]([C:16]2[C:17]([F:34])=[CH:18][C:19]3[C:29](=[O:30])[C:28]([C:31]([OH:33])=[O:32])=[CH:27][N:21]4[C@@H:22]([CH3:26])[CH2:23][O:24][C:25]=2[C:20]=34)[CH2:10]1)=O)(C)(C)C>Cl>[NH2:8][C:9]1([CH3:35])[C:13]2([CH2:15][CH2:14]2)[CH2:12][N:11]([C:16]2[C:17]([F:34])=[CH:18][C:19]3[C:29](=[O:30])[C:28]([C:31]([OH:33])=[O:32])=[CH:27][N:21]4[C@@H:22]([CH3:26])[CH2:23][O:24][C:25]=2[C:20]=34)[CH2:10]1
Reactant: C[C@H]1COc2c(N3CC4(CC4)C(C)(NC(=O)OC(C)(C)C)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Product: C[C@H]1COc2c(N3CC(C)(N)C4(CC4)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
(3S)-10-[7-(tert-butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptane-5-yl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (761 mg, 1.56 mmol) was dissolved in concentrated hydrochloric acid (6.5 mL) in an ice bath, and the mixture was stirred at room temperature for 120 minutes. The reaction mixture was washed with chloroform, and saturated aqueous solution of sodium hydroxide was added to the aqueous layer in an ice bath to a pH of 12.0. Hydrochloric acid was then added to adjust pH to 7.4, and the solution was extracted with lower layer of a mixed solution (chloroform:methanol:water, 7:3:1). After combining the organic layers, and drying with anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. Chloroform was added to the residue, and the insoluble content was removed by filtration. The filtrate distilled under reduced pressure. The residue was purified by crystallization from ethanol, and dried under reduced pressure to obtain 260 mg (0.68 mmol, 43%) of the title compound as a yellow powder.
Reaction SMILES: O[Li].O.CO[C:6](=[O:47])[CH2:7][C:8]1[CH:46]=[CH:45][CH:44]=[CH:43][C:9]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[C:25]([CH3:42])[CH:24]=2)[N:13]=1.C1C=CC2N(O)N=[N:54]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.O.CO>[NH2:54][C:6](=[O:47])[CH2:7][C:8]1[CH:46]=[CH:45][CH:44]=[CH:43][C:9]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]3)=[C:25]([CH3:42])[CH:24]=2)[N:13]=1
Reactant: On1nnc2ccccc21
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)ncc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
LiOH.H2O (41.0 mg, 0.960 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylphenyl)piperidine-1-carboxylate (A42) (0.196 g, 0.320 mmol) in THF (7 mL), water (1.5 mL) and MeOH (1 mL) and the resulting mixture stirred at room temperature for 19 hours. The volatiles were removed in vacuo, then the residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4 and the volatiles removed under reduced pressure. The residue was dissolved in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen then HOBt (0.056 g, 0.41 mmol), EDCl.HCl (0.079 g, 0.41 mmol) and DIPEA (0.28 mL, 1.3 mmol) were added. After 10 minutes ammonium carbonate (0.15 g, 1.6 mmol) was added in one portion and the resulting mixture stirred at room temperature for 19 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (65 mL) and saturated NaHCO3 (65 mL). The aqueous layer was extracted with EtOAc (2×50 mL) then the combined organic layers were washed with brine (50 mL) and dried over MgSO4. The solvent was removed in vacuo and the residue purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-80% EtOAc in petroleum benzine 40-60° C.) to give the title compound A43 as a white solid (0.16 g, 84%); 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.20 (s, 1H), 7.46 (dd, J=8.4, 2.0 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.28-7.18 (m, obscured by solvent), 7.13 (d, J=8.4 Hz, 1H), 6.33 (s, 1H), 5.68 (s, 1H), 4.40-4.16 (m, 2H), 3.68 (s, 2H), 3.17-2.95 (m, 4H), 2.91-2.68 (m, 3H), 2.34 (s, 3H), 1.73 (d, J=12.3 Hz, 2H), 1.68-1.53 (m, 2H), 1.50 (s, 9H). LCMS-A: rt 6.670 min; m/z 598.1 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:54])/[C:16](/[N:20]2[CH:23]([S:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:22]([NH:35][C:36](=[O:52])[CH:37]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:21]2=[O:53])=[C:17](\[OH:19])/[CH3:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:57])=[N-]>C(Cl)Cl.CO.CCOCC>[C:1]1([CH:7]([O:14][C:15](=[O:54])/[C:16](/[N:20]2[CH:23]([S:24][S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)(=[O:27])=[O:26])[CH:22]([NH:35][C:36](=[O:52])[CH:37]([NH:44][C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:21]2=[O:53])=[C:17](\[O:19][CH3:57])/[CH3:18])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: CO/C(C)=C(\C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of 0.54 g (0.7 mmol) of 2-[4-(p-toluenesulphonylthio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester in 20 ml of methylene chloride/methanol, 1:1, is stirred for 15 minutes with an excess of a solution of diazomethane in ether at 0° C. and is then concentrated by evaporation in vacuo. Preparative layer chromatography of the residue on silica gel, using toluene/ethyl acetate, 1:1, as the running agent, and elution of the zone which is visible in UV light gives 2-[4-(p-toluenesulphonylthio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-methoxy-crotonic acid diphenylmethyl ester, which is recrystallised from methylene chloride/diethyl ether/hexane.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:28][C@@H:27]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:26][C@@H:25]1[NH:34]C(=O)OC(C)(C)C)[N:17]=[CH:16]2.Cl>C(Cl)Cl.O1CCOCC1>[NH2:34][C@@H:25]1[C@H:24]([NH:23][C:18]2[N:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])[CH:14]=3)[N:19]=2)[CH2:28][C@@H:27]([C:29]([N:30]([CH3:32])[CH3:31])=[O:33])[CH2:26]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4C[C@@H](C(=O)N(C)C)C[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4C[C@@H](C(=O)N(C)C)C[C@@H]4N)ncc3c2)c1Cl
Reaction time: 3 h

Procedure:
Tert-butyl ((1S,2R,4R)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-4-(dimethylcarbamoyl)cyclopentyl)carbamate (0.086 g, 0.142 mmol) was taken up in DCM (2 ml) and treated with 4M HCl in dioxane (3 ml) and stirred for 3 hours. The solvent was removed to give crude (1S,3S,4R)-3-amino-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N,N-dimethylcyclopentane-1-carboxamide, quantative yield. MS (ES+) C24H27Cl2N5O3 requires: 504, found: 505 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][C:5]#[C:6][CH:7]([OH:9])[CH3:8])[CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(Cl)Cl>CCOCC>[CH:1]1([CH2:4][C:5]#[C:6][C:7](=[O:9])[CH3:8])[CH2:3][CH2:2]1
Reactant: CC(O)C#CCC1CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)C#CCC1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-tetrahydropyranyl-but-3-yne (1.14 parts) in 15 parts by volume of tetrahydrofuran are cooled to -20° C. and 4.63 parts by volume of 1.6N n-butyl lithium are added. The reaction mixture is allowed to warm to 0° C. and again cooled to -20° C. and then 1 part of bromomethylcyclopropane in 3 parts by volume of tetrahydrofuran are added. The reaction mixture is allowed to warm to room temperature and 15 parts by volume of hexamethylphosphoric triamide is added and the reaction is stirred over three hours. The reaction mixture is poured into ether/water and extracted several times with ethyl acetate. The extracts are washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed by evaporation at reduced pressure and the residual oil is chromotographed with 10% ethyl acetate/hexane to provide 5-cyclopropyl-2-tetrahydropyranyl-pent-3-yne. This material is dissolved in a solution of 25 parts by volume of tetrahydrofuran, 25 parts by volume methanol, and 25 parts by volume of 1N HCl and stirred at room temperature for 1 hour. The reaction mixture is poured into a mixture of ether and water. The aqueous layer is extracted with ethyl acetate and the extracts are combined and washed with water and saturated sodium chloride. The organic layer is dried over anhydrous sodium sulfate and chromatographed with 15% ethyl acetate/hexane to provide 5-cyclopropyl-pent-3-yne-2-ol. 1.5 parts of this alcohol is reacted with 3.25 parts of pyridinium chlorochromate in 35 parts by volume of methylene chloride. The reaction mixture is stirred for three hours at room temperature, 100 parts by volume of ether is added and the mixture is stirred for 1 hour then filtered through Florisil. The solvent is removed by evaporation at reduced pressure. The residue is dissolved in hexane and again filtered. The solvent is evaporated under reduced pressure to provide 5-cyclopropyl pent-3-yne-2-one.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([O:18]C)=[C:13]([CH3:20])[CH:12]=3)[O:8][C:6]=2[N:7]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[C:13]([CH3:20])[C:14]([OH:18])=[C:15]([CH3:17])[CH:16]=3)[O:8][C:6]=2[N:7]=1
Reactant: COc1c(C)cc(-c2nc3cnc(Cl)nc3o2)cc1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-c2nc3cnc(Cl)nc3o2)cc(C)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A solution of 1.2 g of 5-chloro-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[5,4-d]pyrimidine in 42 ml of dichloromethane was cooled to 0° C., and 10 ml of a 1 M solution of boron tribromide in dichloromethane were added over a period of 10 min. The mixture was stirred at 0° C. for 1 h, and a further 3 ml of a 1 M solution of boron tribromide in dichloromethane were then added. After another hour of stirring, 20 ml of saturated aqueous sodium bicarbonate solution were added slowly. The precipitate was filtered off and washed with water, which gave 1 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:5]=1[NH2:6].[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1>>[CH3:14][N:15]1[CH:19]=[C:18]([C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:3][C:2]([F:13])([F:12])[F:1])[CH:10]=2)[CH:17]=[N:16]1
Reactant: Nc1ccc(Br)cc1OC(F)(F)F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(-c2ccc(N)c(OC(F)(F)F)c2)cn1

Procedure:
The title compound was prepared according to the method described for Preparation 98 using 2-trifluoromethoxy-4-bromoaniline and 1-methylpyrazole-4-boronic acid pinacol ester.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]=1[N+:16]([O-:18])=[O:17])[O:8][CH2:9][C:10](Cl)=[O:11])([O:3][CH3:4])=[O:2].[CH2:23]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]=1[N+:16]([O-:18])=[O:17])[O:8][CH2:9][C:10]([N:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:11])([O:3][CH3:4])=[O:2]
Reactant: CCCCCCNCCCCCC
Reactant: COC(=O)c1cc(OCC(=O)Cl)cc(C(=O)OC)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCN(CCCCCC)C(=O)COc1cc(C(=O)OC)c([N+](=O)[O-])c(C(=O)OC)c1

Procedure:
A stirred solution of (3,5-dicarbomethoxy-4-nitrophenoxy)acetyl chloride in tetrahydrofuran, cooled in an ice bath, is treated dropwise with a tetrahydrofuran solution containing 1 equivalent each of dihexylamine and triethylamine. After the addition, the precipitated amino hydrochloride is removed by filtration and the tetrahydrofuran filtrate is concentrated under reduced pressure to an oil which is used directly in the next step.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[C:10]([OH:13])(=[O:12])C>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>[C:5]([CH:4]1[CH2:8][CH2:9][N:1]([C:10]([O:13][C:4]([CH3:8])([CH3:5])[CH3:3])=[O:12])[CH2:2][CH2:3]1)(=[O:6])[NH2:7]
Reactant: NC(=O)C1CCNCC1
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.4 %

Procedure:
To a solution of isonipecotamide (500 mg, 3.90 mmol) in a mixture of 5% aqueous sodium carbonate (7 ml) and 1,4-dioxane (3 ml) was added Boc-anhydride (1.30 ml, 5.85 mmol) and stirred for 5 h at room temperature. The pH was adjusted to 5-6 with acetic acid and volatiles were evaporated under vacuo. The residue was triturated with n-pentane and diethyl ether to yield 740 mg (82.4%) of tert-butyl 4-carbamoylpiperidine-1-carboxylate as a white solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[N:24]1C(=O)C(=CC2C=CC=CC=2)S[C:25]1=[S:37])(=O)C.[CH2:38]([NH2:41])[CH:39]=[CH2:40]>CO>[C@@H:6]1([NH:24][C:25]([NH:41][CH2:38][CH:39]=[CH2:40])=[S:37])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](N2C(=O)C(=Cc3ccccc3)SC2=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C=CCN
Solvent: CO
Product: C=CCNC(=S)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-5-benzylidenerhodanine(2.204 g., 0.004 mole) was added to a solution of allylamine(2.74 g., 0.048 mole) in 50 ml. of methanol in a pressure bottle. The reaction mixture was stirred at room temperature for 24 hours in the pressure bottle with the stopper well closed. The reaction mixture was filtered and the filtrate was evaporated to a syrupy material. The residual syrup was dissolved in the minimum amount of acetone, and anhydrous ether was added to the solution to give a sticky solid. The supernatant was decanted and the residue was dissolved in the minimum amount of acetone. Benzene was added to the solution to give a precipitate. The white precipitate was filtered, partially dissolved in ethyl acetate, and then chromatographed on a column of silica gel(1×20 cm) using ethyl acetate as the first solvent(60 ml.), acetone-ethyl acetate(3:7) as the second solvent(50 ml.), and acetone as the third solvent(80 ml.). The third acetone effluent was reduced to ca.25 ml. and was set aside at 5° overnight. No precipitate was formed. The solution was evaporated to dryness below 30° in vacuo. The formed solid was recrystallized from acetone to give a white precipitate. The precipitate was filtered, washed with acetone, and dried at room temperature in vacuo, yielding 0.591 g. (43.9%); m.p. 95°-97°(dec.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][CH:31]=3)[CH:19]=[CH:20][C:21]=2OS(C(F)(F)F)(=O)=O)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[CH2:43]([Sn](CCCC)(CCCC)CCCC)[CH:44]=C.O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][CH:31]=3)[CH:19]=[CH:20][C:21]=2[CH:43]=[CH2:44])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc(N(CC)CC)c(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 103.2 %

Procedure:
g of ethyl 3″-tert-butyl-4″-diethylamino-4′-trifluoromethanesulfonyloxy[1,1′;3′,1″]terphenyl-4-carboxylate (2 mmol) are dissolved at room temperature in 23 mL of dimethylformamide, and 250 mg of LiCl (6 mmol) and 0.74 mL of allyltributyltin (2.4 mmol) are then added. The reaction medium is heated and, at 40° C., 70 mg of dichlorobis(triphenylphosphine)palladium (0.1 mmol) are added and the reaction medium brought to 120° C. and stirred for 20 minutes. The reaction is stopped by adding 30 mL of water and then extracted with 30 mL of ethyl acetate. The organic phases are washed with 80 mL of water and then dried over magnesium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on silica gel (eluent: heptane). 940 mg of ethyl 3″-tert-butyl-4″-diethylamino-4′-vinyl[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=100%).
Reaction SMILES: [OH-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([Br:26])[CH:24]=4)[N:19]([CH3:27])[CH:18]=3)[C:13]([O:15]C)=[O:14])=[CH:11][C:6]=2[O:5][CH2:4]1.CO>O1CCOCC1>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([Br:26])[CH:24]=4)[N:19]([CH3:27])[CH:18]=3)[C:13]([OH:15])=[O:14])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: COC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(Br)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cn1cc(C(C(=O)O)c2ccc3c(c2)OCO3)c2cc(Br)ccc21

Procedure:
Aqueous sodium hydroxide (14.7 ml of 1M) was added to a solution of methyl 2-(1,3-benzodioxol-5-yl)-2-(5-bromo-1-methyl-1H-3-indolyl)acetate from (b) (1.97 g, 4.9 mmol) in a 3:1 mixture of methanol and 1,4-dioxane at ambient temperature. The mixture was heated to reflux for 1 hour before recooling and removing the organic solvents in vacuo. The residue was redissolved in water and acidified with drops of concentrated hydrochloric acid. The resultant precipitate was extracted with diethylether, dried (magnesium sulphate) and the solvent removed in vacuo. The residue was crystallised from diisopropylether to give the subtitle compound (1.59 g).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([S:16](=[O:32])(=[O:31])[NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)=[CH:8][CH:7]=1)=[O:5].[CH3:34][Mg]Br>C1COCC1>[CH2:24]([N:21]1[CH2:20][CH2:19][CH:18]([NH:17][S:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]([C:4](=[O:5])[CH3:34])=[CH:7][CH:8]=2)(=[O:32])=[O:31])[CH2:23][CH2:22]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CON(C)C(=O)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a 0° C. solution of 4-(1-benzyl-piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid methoxy-methyl-amide 35 (200 mg, 0.43 mmol) in THF (5 mL) was slowly added methylmagnesium bromide (5.71 mL, 17.1 mmol, 1M THF solution). After stirring at 25° C. for 4 h, the resultant mixture was quenched with saturated ammonium chloride solution. The aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. The crude material was purified by Flash column chromatography (hexane/EtOAc) to provide 118 mg of 4-acetyl-naphthalene-1-sulfonic acid (1-benzyl-piperidin-4-yl)-amide 36 in 56% overall yield (for two steps).LCMS showed m/z: 423 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15](=[O:17])[CH3:16])[CH:12]=[C:11]([Cl:18])[N:10]=2)[CH2:5][CH2:4]1.[Br:19][C:20]1[CH:21]=[C:22]([C:26](O)=[O:27])[NH:23][C:24]=1[CH3:25]>>[C:15]([C:13]1[CH:12]=[C:11]([Cl:18])[N:10]=[C:9]([N:6]2[CH2:7][CH2:8][CH:3]([NH:2][C:26]([C:22]3[NH:23][C:24]([CH3:25])=[C:20]([Br:19])[CH:21]=3)=[O:27])[CH2:4][CH2:5]2)[CH:14]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Reactant: Cc1[nH]c(C(=O)O)cc1Br
Agent: Cl
Product: CC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)c1

Procedure:
The title compound was synthesized by an analogous method to Example 42 starting from 1-1-[2-(4-aminopiperidin-1-yl)-6-chloropyridin-4-yl]ethanone hydrochloride salt (Intermediate 197) and 4-Bromo-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 18).