Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1)=[O:22].C([O-])([O-])=O.[Cs+].[Cs+].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>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:17][C:12]([F:18])([C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][N:3]=[C:2]2[NH:19][CH2:20][C:21]([NH:23][CH:24]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]2)=[O:22])=[CH:7][CH:8]=1)[C:13]([F:16])([F:15])[F:14]
Reactant: FC(F)(F)C(F)(F)c1ccc2ccnc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CN)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2nccc3ccc(C(F)(F)C(F)(F)F)cc23)C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Into a 8 mL sealed tube, was placed 1-chloro-7-(pentafluoroethyl)isoquinoline (as prepared in the previous step, 282 mg, 1.00 mmol, 1.00 equiv), tert-butyl 3-(2-aminoacetamido)azetidine-1-carboxylate (prepared as described in Example 1, Step E) (250 mg, 1.09 mmol, 1.09 equiv), Cs2CO3 (1.0 g, 3.07 mmol, 3.06 equiv), BINAP (24 mg, 0.04 mmol, 0.04 equiv), Pd(OAc)2 (10 mg, 0.04 mmol, 0.04 equiv) and tol (2 mL). The reaction mixture was stirred overnight at 120° C. The resulting mixture was concentrated under vacuum. The residue was purified by chromatography over a silica gel column with dichloromethane/methanol (10:1). This resulted in 0.12 g (25%) of tert-butyl 3-(2-[[7-(pentafluoroethyl)isoquinolin-1-yl]amino]acetamido)azetidine-1-carboxylate as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)c(Cl)c2)nc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Oc2ccc(Cl)c(Cl)c2)nc1

Procedure:
The 2-(3,4-dichlorophenoxy)-5-nitropyridine described above was divided into 4 portions of 23.7 g each, and each portion was then hydrogenated in absolute ethanol employing a palladium catalyst as well known in the art. After removal of the catalyst, the ethanol filtrates were combined and evaporated to dryness. The residue which remained was diluted with isopropyl alcohol and hexane and then chilled. The resulting solid was collected by filtration and vacuum dried to give 70.8 g of 2-(3,4-dichlorophenoxy)-5-pyridinamine as a rose colored powder, m.p. 78°-79.3° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][N:5]=1)[CH3:2].[O:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[O:12])[CH2:11][C:14]([OH:13])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CCNc1nccc(C(C)=O)n1
Product: CCNc1nccc(C(=O)CC(O)(C(=O)OCC)C(=O)OCC)n1
Temperature: 110 °C

Procedure:
A mixture consisting of 1.9 g of 1-(2-ethylaminopyrimidin-4-yl)ethanone and 1.86 ml of diethyl ketomalonate is heated at 110° C. for 18 hours. The mixture is purified by column chromatography (silica gel, mobile phase: methylene chloride:methanol=98:2).
Reaction SMILES: C[CH:2]([C@@H:6]1[CH2:11][CH2:10][N:9]([C@@H:12]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]=[CH2:26])=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:8]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH2:7]1)[C:3]([O-:5])=[O:4].[OH-].[Na+]>CO>[CH2:24]([C:21]1[CH:22]=[CH:23][C:18]([C@H:12]([N:9]2[CH2:10][CH2:11][C@@H:6]([CH2:2][C:3]([OH:5])=[O:4])[CH2:7][C@H:8]2[C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=2)[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:19][CH:20]=1)[CH:25]=[CH2:26]
Reactant: C=CCc1ccc([C@@H](CCC(C)C)N2CC[C@@H](C(C)C(=O)[O-])C[C@H]2c2ccc(C(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCc1ccc([C@@H](CCC(C)C)N2CC[C@@H](CC(=O)O)C[C@H]2c2ccc(C(F)(F)F)cc2)cc1
Temperature: 60 °C

Procedure:
The ester from Step 1 (100 mg) was dissolved in methanol (1 mL) and sodium hydroxide (0.3 mL, 4N) was added. The mixture was heated at 60° C. overnight, cooled, evaporated and the residue dispersed between CH2Cl2 and HCl (0.1N). The organic extract was separated and washed with brine, dried (MgSO4) and evaporated. The residue was purified on silica using 10-95% ethyl acetate in iso-hexane as eluant.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:24][C:25]2[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([C@H:14]3[CH2:18][O:17][C:16]4([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[O:15]3)[N:10]=2)=[N:6][CH:7]=1.[SH:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].C(N(CC)C(C)C)(C)C>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]>[O:15]1[C:16]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[O:17][CH2:18][C@@H:14]1[C:11]1[N:10]=[C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2]([S:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:3][C:4]=2[O:24][C:25]2[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[S:13][N:12]=1
Reactant: Cc1ncccc1Oc1cc(Br)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
To a solution of (S)-N-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (3.1 g, 6.14 mmol) in dioxanes (30 mL) continuously purged with nitrogen was added Xanphos (0.177 g, 0.303 mmol), Pd2dba3 (0.14 g, 0.153 mmol), methyl 3-mercaptopropanoate (0.73 g, 6.14 mmol) and N,N-diisopropylethylamine (1.17 mL, 6.45 mmol) and the reaction was heated overnight at 80° C. The reaction was concentrated in vacuo and the residue purified over silica gel (5% MeOH/CH2Cl2) to afford (S)-methyl 3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate (2.3 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19]C)=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[S:7][C:6]=2[C:17]=1[Cl:18].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:19])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[S:7][C:6]=2[C:17]=1[Cl:18]
Reactant: COc1cc2cc(-c3ccccc3F)sc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1cc2cc(-c3ccccc3F)sc2c(Cl)c1Cl
Yield: 86.2 %

Procedure:
A mixture of 16.0 g of 6,7-dichloro-5-methoxy-2-(2'-fluorophenyl)benzo[b]thiophene and 150 g of pyridine hydrochloride is heated at 200°-250° for 1 hour with stirring under an atmosphere of nitrogen. The mixture is allowed to cool, diluted with water and the precipitate is collected. The precipitate is dissolved in dichloromethane and the solution is washed with water, dried and filtered. Evaporation of the solvent followed by treatment of the mixture with ether-hexane gives 13.2 g of 6,7-dichloro-2-(2'-fluorophenyl)-5-hydroxybenzo[b]thiophene as an amorphous solid.
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])[N:36]5[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:16][N:17]=4)=[O:23])[CH2:25][CH2:26]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: C1CCNCC1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CCCCC1

Procedure:
1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((2-methoxyphenyl)(piperidin-1-yl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and piperidine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[C:4]([Br:12])[C:3]=1[O:13][CH3:14].Cl.Cl[Sn]Cl.O>C(O)C>[Br:12][C:4]1[C:3]([O:13][CH3:14])=[C:2]([Br:1])[CH:7]=[C:6]([F:8])[C:5]=1[NH2:9]
Reactant: COc1c(Br)cc(F)c([N+](=O)[O-])c1Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1c(Br)cc(F)c(N)c1Br
Reaction time: 16 h
Yield: 90.8 %

Procedure:
To the solution of 8-4 (234.2 g, 0.784 mol) and concentrated HCl (720 mL) in ethanol (2.2 L) at room temperature, SnCl2.H2O (415 g, 2.0 mol) was added by portions. The mixture was stirred for 16 h. TLC showed the reaction was completed. The volatiles were removed in vacuo. The residue was quenched with cooled water (500 mL) and ethyl acetate (1.5 L). The aqueous layer was neutralized with KOH until PH=6˜7. The white precipitate was filtered off to get a clear solution, which was extracted with ethyl acetate (600 mL×3). The combined organic layers were washed with brine twice, dried over anhydrous sodium sulfate. After filtration and evaporation, 8-5 (212.7 g, 100%) was obtained as brownish white solid.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[F:14][C:15]1[C:20]([NH:21][CH:22]=[O:23])=[CH:19][CH:18]=[C:17]([F:24])[N:16]=1>CN(C)C=O.O.C(OCC)(=O)C>[F:14][C:15]1[C:20]([N:21]([CH2:2][C:3](=[O:5])[CH3:4])[CH:22]=[O:23])=[CH:19][CH:18]=[C:17]([F:24])[N:16]=1
Reactant: O=CNc1ccc(F)nc1F
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CN(C=O)c1ccc(F)nc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chloroacetone (1.83 ml), cesium carbonate (7.99 g) and potassium iodide (254 mg) were added to a solution of N-(2,6-difluoropyridin-3-yl)formamide (2.42 g) in N,N-dimethylformamide (50 ml), and the reaction solution was stirred at room temperature for two hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.52 g). The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)=[O:6])([CH3:4])[CH3:3].[CH3:19][Mg]Br>ClCCl>[CH3:4][C:2]([S:5]([NH:7][C@@H:8]([C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=1)[CH3:19])=[O:6])([CH3:1])[CH3:3]
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(C(F)(F)F)nc1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: C[C@@H](NS(=O)C(C)(C)C)c1ccc(C(F)(F)F)nc1
Temperature: -45 °C
Reaction time: 4 h

Procedure:
To a solution of 2-methyl-N-{(1E)-[6-(trifluoromethyl)-3-pyridinyl]methylene}-2-propanesulfinamide (76.8 g, 276 mmol) in dichloromethane (920 mL) at −45° C. was added methylmagnesium bromide (3.0 M in THF; 184 mL, 552 mmol). The mixture was stirred at −45° C. for 4 h. The reaction mixture was warmed to −20° C. Additional methylmagnesium bromide (3.0 M in THF; 276 mL, 828 mmol) was added at −20° C. The reaction mixture was warmed to 0° C. and was quenched with saturated aqueous ammonium chloride (300 mL). The mixture was allowed to warm to ambient temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The concentrate was recrystallized using ethyl alcohol (500 mL). Then white solid was filtered and dried under reduced pressure (41.6 g). MS 295.0 (M+1).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH:8]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:21](=O)([O-])[O-].[K+].[K+].ClC(OCC)=O.[H-].COCCO[Al+]OCCOC.[Na+].[H-].[OH-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:21][NH:13][C:10]1[CH:11]=[N:12][C:7]([N:1]2[CH2:6][CH2:5][S:4][CH2:3][CH2:2]2)=[CH:8][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: Cc1ccccc1-c1cc(N2CCSCC2)ncc1N
Reactant: O=C([O-])[O-]
Agent: CCOC(=O)Cl
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CNc1cnc(N2CCSCC2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 2.46 g (8.6 mmol) 6-thiomorpholin-4-yl-4-o-tolyl-pyridin-3-ylamine in 38 ml tetrahydrofuran were added 2.38 g (17 mmol) potassium carbonate (dissolved in 25 ml water) and 1.03 g (9.5 mmol) ethyl cloroformate. The reaction mixture was stirred for 1 h at room temperature and evaporated to remove tetrahydrofuran. The aqueous layer was extracted twice with 50-ml portions of dichloromethane and the organic layer was dried (sodium sulfate) and evaporated in vacuo. The residual oil was dissolved in 30 ml tetrahydrofuran and 7.4 ml (2.6 mmol) 3.5 M sodium bis(2-methoxyethoxy)aluminum hydride solution in toluene were added within 30 min. The reaction mixture was stirred at 50° C. overnight. After cooling to 0° C., 7.5 ml 1 N sodium hydroxide solution were added dropwise. Tetrahydrofuran was removed in vacuo and 10 ml of water were added. The aqueous layer was extracted twice with 20-ml portions of dichloromethane and the combined organic layers were dried (sodium sulfate), evaporated and purified by flash chromatography to give 2.37 g (92%) of the title compound as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26][NH2:27].CN1CCOCC1>CS(C)=O.C(OCC)(=O)C>[N+:18]([C:3]1[CH:4]=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:27][CH2:26][C:25]1[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:23]([C:22]([F:21])([F:35])[F:36])[CH:24]=1)([O-:20])=[O:19]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1cc(NS(=O)(=O)c2ccccc2)ccc1F
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(NS(=O)(=O)c2ccccc2)ccc1NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
N-{4-fluoro-3-nitro-phenyl}-benzenesulphonamide (3.0 g, 10 mmol), 3,5-bis-trifluoromethylbenzylamine (3.0 g, 12.5 mmol) and N-methylmorpholine (2.2 mL, 20 mmol) in 25 mL dimethylsulphoxide are kept for 6 h at 60-100° C., diluted with 150 mL ethyl acetate, washed with water, dilute hydrochloric acid and water again, dried and concentrated by evaporation until not quite dry. The residue is combined with 80 mL EtOH and evaporated down to a residual volume of about 50 mL. The crystals precipitated after cooling are filtered off and washed with EtOH and petroleum ether.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[C:5]([F:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[C:5]([F:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[C:11]=1[CH3:12]
Reactant: OB(O)c1cccnc1
Reactant: Cc1c(Cl)nc2c(F)cccc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccnc2)nc2c(F)cccc2c1Cl

Procedure:
Prepared according to general Procedure F using 2,4-dichloro-8-fluoro-3-methylquinoline (250 mg, 1.1 mmol), 3-pyridylboronic acid (134 mg, 1.1 mmol), tetrakis(triphenylphosphine)palladium(0) (126 mg, 0.11 mmol), sodium carbonate (202 mg, 1.90 mmol) in toluene:water (5 mL:2 mL) and heating at 130° C. overnight. After purification 4-chloro-8-fluoro-3-methyl-2-(pyridin-3-yl)quinoline was obtained as a white solid. Mass Spectrum (ESI) m/e=273.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8]C(=O)[N:6]3[N:13]=[C:14]([CH2:16][O:17][CH3:18])[N:15]=[C:5]3[C:4]=2[CH:3]=1.ClC1C=CC2NC(=O)N3N=C(C4CC4)N=C3C=2C=1>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:8])=[C:4]([C:5]2[NH:6][N:13]=[C:14]([CH2:16][O:17][CH3:18])[N:15]=2)[CH:3]=1
Reactant: COCc1nc2c3cc(Cl)ccc3[nH]c(=O)n2n1
Agent: O=c1[nH]c2ccc(Cl)cc2c2nc(C3CC3)nn12
Product: COCc1n[nH]c(-c2cc(Cl)ccc2N)n1
Yield: 92.3 %

Procedure:
As described for example 1b) 9-chloro-2-methoxymethyl-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one (73.4 g, 277 mmol), instead of 9-chloro-2-cyclopropyl-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one, was converted to the title compound (61.0 g, 92%) which was obtained as a brown solid. MS: m/e=238.9 [M+H]+.
Reaction SMILES: [CH:1]1([C@@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2C(OC)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Br>[CH:1]1([C@@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1C1CCCCC1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@H](C3CCCCC3)C2)o[nH]1
Yield: 33.8 %

Procedure:
(2S,4S)-Methyl 2-cyclohexyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (79 mg, 0.26 mmol) was stirred in HBr (33% in AcOH) overnight. Evaporation of solvents and the residue purified by preparative HPLC (Instrument: FractionLynx I, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm.) to yield 5-((2S,4S)-2-cyclohexylpiperidin-4-yl)isoxazol-3(2H)-one 22 mg (35%). 1H NMR (400 MHz, cd3od) δ 1.00-1.39 (m, 5H), 1.51-1.64 (m, 1H), 1.64-1.93 (m, 6H), 1.96-2.11 (m, 1H), 2.15-2.25 (m, 1H), 2.26-2.35 (m, 1H), 2.92-3.02 (m, 1H), 3.03-3.16 (m, 1H), 3.22-3.33 (m, 2H), 5.57 (s, 1H). HRMS Calcd for [C14H22N2O2+H]+: 251.1760. Found: 251.1754.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[I:11].BrC1C=C(C=CC=1F)C([Cl:18])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:18])=[O:7])=[CH:4][C:3]=1[I:11]
Reactant: O=C(O)c1ccc(Cl)c(I)c1
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Product: O=C(Cl)c1ccc(Cl)c(I)c1

Procedure:
4-Chloro-3-iodobenzoylchloride was prepared from 4-chloro-3-iodobenzoic acid according to the procedure described in Example 183 for the synthesis of 3-bromo-4-fluorobenzoyl chloride.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:18][CH2:19][C:20](Br)=[O:21]>Cl>[Br:18][CH2:19][C:20]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:21]
Reactant: CC(C)Nc1ccccc1
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
Isopropyl aniline (8.00 g, 59.2 mmol) and triethylamine (8.26 mL, 59.2 mmol) are combined in anhydrousDCM (75 mL) under nitrogen and cooled to 0°-5° C. with an ice-water bath. Bromoacetyl bromide (5.16 mL, 59.2 mmol) is added dropwise over approximately 10 min. and the reaction is allowed to stir to ambient temperature overnight. The mixture is combined with aqueous HCl (50 mL 1N) and transferred to a separatory funnel. The organic layer is separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to provide the title compound as a brown solid (15.13 g, 59.1 mmol). 1H NMR (300 MHz, CDCl3) δ=1.08 (d, J=6.8 Hz, 6H); 3.53 (s, 2H); 4.92-5.01 (m, 1H); 7.18-7.54 (m, 5H). TLC Rf=0.22 (3:17 ethyl acetate: hexane).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[CH2:10]Cl)([CH3:6])([CH3:5])[CH3:4].[CH:20](=[O:23])[CH2:21][CH3:22].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.O>[C:3]([C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[CH2:10][CH:21]([CH3:22])[CH:20]=[O:23])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1O
Reactant: CCC=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: c1ccccc1
Product: CC(C=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A mixture of 30 grams of sodium hydroxide, 5 grams of tetrabutylammonium bromide, 60 milliliters of water and 250 milliliters of benzene is heated to 70° C. and to it is added over a period of 5 hours a solution of 127.5 grams of 3,5-di-t-butyl-4-hydroxybenzyl chloride and 17.5 grams of propionaldehyde in 125 milliliters of benzene. The reaction mixture is stirred for an additional 30 minutes at 70° C. and is then neutralized by the addition of a solution of 50 milliliters of concentrated hydrochloric acid in 100 milliliters of water. The layers are separated and benzene is removed from the organic layer on a rotary evaporator. The viscous residue crystallizes on mixing with hexane and the solid is separated by filtration. There is obtained 67.5 grams of 2,2-bis(3,5-ditert.butyl-4-hydroxybenzyl propionaldehyde.
Reaction SMILES: Cl.[C:2]1(/[C:8](/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][CH3:29])=[CH:21][CH:20]=2)=[C:9](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[CH2:10]CO)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]([Cl:53])(Cl)(Cl)Cl>C(#N)C>[Cl:53][CH2:49][CH2:10][C:9]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[C:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][CH3:29])=[CH:21][CH:20]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CNCCOc1ccc(/C(=C(/CCO)c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CNCCOc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture containing 41.0 g of (Z)-1,2-diphenyl-1-[4-[2-(N-methylamino)ethoxy]phenyl]-1-buten-4-ol hydrochloride, 57.4 g of triphenyl phosphine, 61.6 g of carbon tetrachloride and 500 ml of acetonitrile is refluxed for 1 h. On cooling the product crystallizes out and is collected for filtration. The yield of the hydrochloride is 25.3 g (59%) and m.p. 206°-8° C. The base is liberated from its salt by conventional means giving an oil.