Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:15][CH:14]3[CH2:16][N:10]4[CH2:11][CH:12]([CH2:17][CH:8]2[CH2:9]4)[CH2:13]3)=[N:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[S:6][C:5]([N:7]3[CH2:15][CH:14]4[CH2:16][N:10]5[CH2:11][CH:12]([CH2:17][CH:8]3[CH2:9]5)[CH2:13]4)=[N:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Brc1cnc(N2CC3CC4CC2CN(C4)C3)s1
Reactant: OB(O)c1cccc(F)c1
Product: Fc1cccc(-c2cnc(N3CC4CC5CC3CN(C5)C4)s2)c1

Procedure:
The title compound was prepared from the product of Example 105A and 3-fluorophenylboronic acid according to General Method C: LC-MS Method D (ESI+) m/z 330.0 (M+H)+, retention time 1.55 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:11]2[CH2:15][CH:14]([OH:16])[CH2:12]2)([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(N)c1ccc(Br)cc1
Reactant: ClCC1CO1
Solvent: CCO
Product: CC(C)(c1ccc(Br)cc1)N1CC(O)C1
Yield: 38.8 %

Procedure:
1-(4-Bromophenyl)-1-methyl-ethylamine (1 g, 4.67 mmol) and epichlorohydrin (439 μl, 5.6 mmol) in EtOH (15 mL) were heated at 70° C. for 18 h. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC-MS to obtain 1-[1-(4-bromo-phenyl)-1-methyl-ethyl]-azetidin-3-ol as a white solid (489 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>C(OCC)(=O)C>[Cl:9][CH2:10][C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
p-Chloroaniline (3.82 g) was dissolved in ethyl acetate (30 ml), and chloroacetyl chloride (2.39 ml) was added at room temperature to stir the mixture for 1 hour. After the reaction mixture was heated and stirred at 60° C. for 3.5 hours, crystals deposited were collected by filtration to obtain the title compound (4.78 g). The filtrate was concentrated to about ¼, and crystals deposited were collected by filtration to obtain the title compound (1.01 g).
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1.[ClH:26]>CCOCC.O1CCOCC1>[ClH:17].[Cl:26][C:19]1[CH:20]=[C:21]([N:24]2[C:14](=[O:16])[CH2:13][CH:3]3[CH2:4][CH2:5][CH2:6][C:7]4[CH:12]=[CH:11][N:10]=[CH:9][C:8]=4[C:2]3=[N:25]2)[CH:22]=[CH:23][C:18]=1[Cl:17]
Reactant: O=C(O)CC1CCCc2ccncc2C1=O
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C1CC2CCCc3ccncc3C2=NN1c1ccc(Cl)c(Cl)c1

Procedure:
Prepared according to the method described in Example 1 from 9-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine-8-acetic acid and 4-chlorophenylhydrazine, the compound being dissolved in ether and hydrogen chloride in dioxan added to precipitate the hydrochloride salt.
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[O:9]=[C:10]1[C:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)=[C:14]([CH2:31][CH2:32][CH3:33])[N:13]2[N:34]=[CH:35][N:36]=[C:12]2[N:11]1[CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[CH2:39][CH2:38]1.Cl>BrCCBr.O1CCCC1>[OH:43][C:40]1([CH:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:41][CH2:42][CH:37]([N:11]2[C:10](=[O:9])[C:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:14]([CH2:31][CH2:32][CH3:33])[N:13]3[N:34]=[CH:35][N:36]=[C:12]23)[CH2:38][CH2:39]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: ClC1CCOCC1
Agent: Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)(C3CCOCC3)CC2)c2ncnn12
Temperature: 50 °C
Reaction time: 4 h
Yield: 52.5 %

Procedure:
To a mixture of magnesium (0.10 g) and tetrahydrofuran (1 mL) were added 4-chlorotetrahydro-2H-pyran (0.050 g) and 1,2-dibromoethane (10 drops) under an argon atmosphere. The mixture was heated to initiate the reaction, a solution of 4-chlorotetrahydro-2H-pyran (0.46 g) in tetrahydrofuran (5 mL) was added dropwise at 50° C., and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was cooled to 0° C., a solution of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.50 g) in tetrahydrofuran (5 mL) was added dropwise, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and HPLC to give the title compound as a colorless solid (0.12 g, 20%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]2[C:16]3[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:19]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccccc4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 469.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.C1(C)C=CC(S(O[CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][O:11][C:10]1[C:2]([O:1][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[CH:3][C:4]([N+:13]([O-:15])=[O:14])=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccncc2)cc1
Reactant: COc1cc(C(N)=O)c([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OCCOc1ccncc1
Temperature: 80 °C
Yield: 68.2 %

Procedure:
4-Hydroxy-5-methoxy-2-nitrobenzamide (1.86 g, 9.5 mmol) and 2-(4-pyridyloxy)ethyl paratoluene sulphonate (3.3 g, 11.2 mmol) were mixed in the presence of potassium carbonate (1.7 g, 12.3 mmol) and anhydrous DMF (25 ml) and heated at 80° C. for 2 hours. The reaction mixture was allowed to cool overnight, the DMF was removed by evaporation and the residue was quenched into water (250 ml). The solid was collected by filtration and washed with a mixture of acetone/ether (1/1) to give 5-methoxy-2-nitro-4-(2-(4-pyridyloxy)ethoxy)benzamide as a cream solid (2.16 g, 68%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.C(=O)([O-])O.[Na+]>C(O)CO>[N:1]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1ccc2ccccc2n1
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Product: c1ccc2nc(N3CCNCC3)ccc2c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
To a solution formed by dissolving 4.31 g of anhydrous piperazine in 30 ml of ethylene glycol, 818 mg of 2-chloroquinoline was added, and stirred at 140° C. for 2 hours. After cooling, saturated aqueous sodium hydrogencarbonate solution was added, and the system was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (chloroform:methanol=2:1) to provide 1.09 g (100%) of 2-piperazin-1-ylquinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][NH:36][C:35](=[O:39])[CH:34]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:30][CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][NH:36][C:35](=[O:39])[CH:34]=4)=[O:23])=[CH:25][CH:26]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: NCCc1cc[nH]c(=O)c1
Reactant: COc1ccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)nc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Nc2cc(-c3ccc(C(=O)NCCc4cc[nH]c(=O)c4)cc3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.1 %

Procedure:
A mixture of 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (76 mg, 0.195 mmol), 4-(2-aminoethyl)pyridin-2(1H)-one (64 mg, 0.215 mmol), 1-methyl-1H-imidazole (96 mg, 1.17 mmol) and EDCI (223 mg, 1.17 mmol) in dichloromethane (10 mL) and DMF (0.5 mL) was stirred at room temperature for 16 h then dichloromethane (20 mL) was added. The mixture was washed with water (2×2 mL) and brine (2×2 mL) then dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, MeOH:dichloromethane=1:10) to afford 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)benzamide (44 mg, 44%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 11.35 (s, 1H), 9.94 (s, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.19 (s, 1H), 8.02-7.93 (m, 4 h), 7.66 (s, 1H), 7.40 (d, 1H, J=8.4 Hz), 7.26 (d, 1H, J=6.6 Hz), 7.10 (d, 1H, J=8.1 Hz), 6.16 (s, 1H), 6.08 (d, 1H, J=6.3 Hz), 4.00 (s, 3H), 3.76 (s, 3H), 3.50-3.40 (m, 2H), 2.69-2.67 (m, 2H). LC-MS: [M+H]+, 512, tR=1.412 min, HPLC: 98.19% at 214 nm, 97.49% at 254 nm, tR=7.244 min.
Reaction SMILES: [NH2:1][CH:2]([CH3:13])[CH:3]([OH:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26](I)=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([O:12][CH:3]([CH2:4][O:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:2]([NH2:1])[CH3:13])=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[CH:19][CH:20]=1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: CC(N)C(O)COc1ccccc1
Product: CC(N)C(COc1ccccc1)Oc1ccc2c(cnn2-c2ccc(F)cc2)c1

Procedure:
Prepared as described in Example 1 from (2RS,3RS)-3-amino-1-phenoxy-butan-2-ol (250 mg, 1.37 mmol), and 1-(4-fluorophenyl)-5-iodoindazole (557 mg, 1.64 mmol). Yield 157 mg (29
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1)[C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[BH4-].[Na+].O>C(O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][N:2]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:20]=1)[C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(CN(C)c2nc(-c3ccccc3)cs2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCc1ccc(CN(C)c2nc(-c3ccccc3)cs2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
To a solution of ethyl (E)-3-[4-[[methyl(4-phenyl-2-thiazolyl)amino]methyl]phenyl]propenoate (0.60 g, 1.6 mmol) and nickel chloride hexahydrate (0.41 g, 3.2 mmol) in ethanol (25 mL) was added sodium borohydride (0.30 g, 8.0 mmol), and the mixture was stirred at room temperature for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=18:1) to give the title compound (0.39 g, yield 64%). oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH2:27])[CH3:22].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH:27][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:16]([F:19])([F:18])[F:17])[CH3:22]
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[2-[N-(4-Fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.536 g (10 mmol) of β-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([OH:11])=O)[C:6](=[O:12])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:9]([C:7]2[C:6](=[O:12])[N:5]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:4](=[O:20])[N:3]([CH2:1][CH3:2])[CH:8]=2)=[O:11])=[CH:38][CH:37]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1cc(C(=O)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 4-(6,7-dimethoxy-quinazolin-4-yloxy)-phenylamine by the procedure for example 134. mp=238-241° C.; LCMS m/z=558 (M+H); 1H NMR (CDCl3): δ 10.82 (s, 1H), 8.63 (d, 2H J=6.5 Hz), 7.76 (d, 2H, J=9.0 Hz), 7.55 (s, 1H), 7.32 (s, 1H), 7.23 (d, 2H, J=8.9 Hz), 4.07 (s, 7H), 4.03 (q, 3H, J=7.2 Hz), 1.59 (s, 1H), 1.49 (s, 1H), 1.46 (t, 3H, 7.2 Hz), 1.20 (t, 1H, J=7.0 Hz), 1.03 (t, 1H, J=7.3 Hz).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C:27]1[CH:35]=[CH:34][C:30](C(Cl)=O)=[CH:29][CH:28]=1)#[N:26].[Cl:36][C:37]1[CH:38]=[C:39]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:40]=[CH:41][C:42]=1[Cl:43]>>[CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([C:30]2[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:35][CH:34]=2)=[O:17])[C@H:12]([C:22]([N:47]2[CH2:46][CH2:45][N:44]([C:39]3[CH:40]=[CH:41][C:42]([Cl:43])=[C:37]([Cl:36])[CH:38]=3)[CH2:49][CH2:48]2)=[O:24])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: N#Cc1ccc(C(=O)N2CC(=NOCc3ccccc3)C[C@H]2C(=O)N2CCN(c3ccc(Cl)c(Cl)c3)CC2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 1-(3,4-dichlorophenyl)piperazine the title compound was obtained in 43% purity by LC/MS. MS(ESI+): m/z=576.6.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:15]Br.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25]>CO.CCOCC>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:15][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=[C:2]1[NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:29])=[C:22]([F:21])[CH:23]=1
Reactant: Fc1ccc(CBr)cc1F
Reactant: Nc1ccc(F)c(F)c1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CO
Solvent: CCOCC
Product: Fc1ccc(Cn2c(Nc3ccc(F)c(F)c3)nc3ccccc32)cc1F

Procedure:
The title compound was prepared by Procedure B in two steps from 2-chloro-benzimidazole, 3,4-difluorobenzyl bromide and 3,4-difluoroaniline. The product was isolated by filtration and recrystallization (MeOH/Et2O) to give the title compound as its hydrochloride salt (white solid, mp 236-238° C.). MS(ES+) m/z 372 ([M+1]+, 100). 1NMR (DMSO-d6) δ 5.61 (s, 2H), 7.19-7.30 (m, 3H), 7.36-7.61 (m, 6H), 7.83-7.91 (m, 1H), 11.0 (br s, 1H).
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[CH:7]/[CH2:8][PH2:9])[C:3]([OH:5])=[O:4].Cl.[CH2:11](O)[CH3:12]>>[CH2:11]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[CH:7]/[CH2:8][PH2:9])[CH3:12]
Reactant: NC(/C=C/CP)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(N)/C=C/CP

Procedure:
1.0 g of E-2-amino-5-phosphino-3-pentenoic acid is suspended in 20 ml of ethanol and the suspension is saturated with hydrogen chloride gas for 2 hours at 65°. After concentration, the residue is dissolved in 10 ml of ethanol, 10 ml of propylene oxide are added and the precipitate is filtered off. Recrystallisation from water/acetone 1:1 yields E-2-amino-5-phosphino-3-pentenoic acid ethyl ester, m.p. 172°-173°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9](C(=O)C1C=CC=CC=1)[NH2:10].P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[C:26]1(O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:33](Cl)(Cl)(Cl)[Cl:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][N:10]=[C:33]([Cl:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Oc1ccccc1
Reactant: NN(C(=O)c1ccccc1)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: ClC(=NNc1cc(Cl)ccc1Cl)c1ccccc1

Procedure:
A quantity (16.87 g., 0.06 mole) benzoic acid (2,5-dichlorophenyl)hydrazide (Preparation VI, above) was added to a solution of 12.50 g. ((0.06 mole) phosphorus pentachloride in 50 ml. carbon tetrachloride, and the resulting suspension was allowed to react at 25° C. until evolution of hydrogen chloride gas slowed. The reaction mixture was then heated at the reflux temperature for 15 minutes, chilled in ice, and 17.8 g. (0.19 mole) phenol in 75 ml. carbon tetrachloride was added. After the reaction was completed, the carbon tetrachloride was removed by evaporation under reduced pressure at 30° to 32° C. The resulting suspension was filtered, and the filter cake was washed with 50 ml. cold methanol. Two recrystallizations from Skellysolve B gave benzoyl chloride (2,5-dichlorophenyl)hydrazone melting at 84.5° to 86° C.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:14]([CH3:16])([CH3:15])[C:13]2[CH:12]=[C:11]([CH:17]=[O:18])[C:10]([Br:19])=[CH:9][C:8]=2[C:7]([CH3:21])([CH3:20])[CH2:6]1)(=[O:3])[CH3:2].[CH2:22](O)[CH2:23][OH:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.ClCCl>[C:1]([O:4][CH:5]1[C:14]([CH3:15])([CH3:16])[C:13]2[CH:12]=[C:11]([CH:17]3[O:24][CH2:23][CH2:22][O:18]3)[C:10]([Br:19])=[CH:9][C:8]=2[C:7]([CH3:21])([CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: OCCO
Reactant: CC(=O)OC1CC(C)(C)c2cc(Br)c(C=O)cc2C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC(=O)OC1CC(C)(C)c2cc(Br)c(C3OCCO3)cc2C1(C)C

Procedure:
7-Acetoxy-3-bromo-2-formyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (0.3 g, 0.849 mmol) from the preceding reaction was dissolved in 2 mL of benzene. Ethylene glycol (0.104 mL, 1.87 mmol) and p-toluenesulfonic acid monohydrate (0.024 g, 0.127 mmol) were added. A Dean-Stark apparatus was attached to the reaction flask and the reaction was brought to reflux for several hours. When the reaction was judged complete by TLC (SiO2, 20% ethyl acetate/hexanes), dichloromethane (25 mL) and sodium bicarbonate solution (50 mL) were added and the layers were separated. The aqueous layer was extracted one more time with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give 7-Acetoxy-3-bromo-2-(1,3-dioxolane-2-yl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as an oily residue that was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([OH:26])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22]C(=O)C)[CH2:8][CH2:7]1>Cl>[ClH:1].[ClH:1].[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][CH:13]([OH:26])[CH2:12][N:9]1[CH2:8][CH2:7][CH:6]([O:5][C:4]2[CH:27]=[CH:28][C:29]([Cl:30])=[C:2]([Cl:1])[CH:3]=2)[CH2:11][CH2:10]1
Reactant: CC(=O)Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Product: Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Yield: 165.3 %

Procedure:
N-(2-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide (1.418 g, 3.13 mmol) was dissolved in 50 ml-HCl (35%/aq, puriss) and refluxed overnight. The product precipitated and was filtered and dried to give 0.835 g (65%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:33]B(O)O.C(=O)([O-])[O-].[K+].[K+].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.O.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH3:33])=[CH:10][CH:9]=2)=[O:4]
Reactant: CB(O)O
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(C)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Temperature: 100 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
A mixture of 6-bromo-2-(2,3-dihydrobenzofuran-5-ylmethyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), methylboronic acid (180 mg), tetrakis(triphenylphosphine)palladium(0) (70 mg), potassium carbonate (250 mg), toluene (6 ml) and THF (3 ml) was stirred at 100° C. under a nitrogen atmosphere for 12 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=2:1) and recrystallized (ethyl acetate-hexane) to give the title compound (230 mg).