Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)=[CH:6][C:5]=1[OH:26].N12CCCN=C1CC[CH2:31][CH2:30][CH2:29]2.C(Br)C=C.O>C(O)C.C(OCC)(=O)C>[CH2:31]([O:26][C:5]1[CH:6]=[C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:1])[F:27])[CH:30]=[CH2:29]
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Solvent: C=CCBr
Solvent: CCOC(C)=O
Solvent: CCO
Product: C=CCOc1cc(-c2nc(CCC(=O)c3ncccc3C)co2)ccc1OC(F)F
Reaction time: 2 h

Procedure:
A 0.15 g quantity of the compound obtained in Example 327 and 0.18 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 3 ml of ethanol, 0.15 g of allyl bromide was then added to the obtained solution, and heating and refluxing were conducted for 2 hours. After cooling, water was added to the obtained reaction mixture, and ethyl acetate was performed. The organic layer was washed twice with water, concentrated, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1). The obtained crystals were recrystallized from aqueous 80% ethanol, thereby yielding 70 mg of white powdery 3-[2-(3-allyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:9]([O-])(=O)/C=C/C.CC1CC1C([O-])=O>CS(C)=O>[CH3:4][CH:3]1[CH2:9][CH:2]1[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C/C=C/C(=O)OCC
Reactant: C/C=C/C(=O)[O-]
Agent: CC1CC1C(=O)[O-]
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1C
Temperature: 17.5 °C
Yield: 26.8 %

Procedure:
To a solution of ethyl trans-crotonate (1.20 kg, 1.31 L, 1.00 equivalent) in DMSO (3.00 L) at ambient temperature is added the above preformed ylide solution over 30 min, while the temperature of the reaction mixture is maintained at about 15-20° C. The progress of the reaction is followed by analysis by gas chromatography (GC, conditions below) until only a small amount of residual crotonate relative to the 2-methylcyclo-propanecarboxylate is observed (about 20-24 h). The reaction mixture is split into two equal (8.5 L) portions for work-up; each portion is treated as follows: Methyl t-butyl ether (MTBE, 6 L) is added, and the biphasic mixture is cooled to 15° C. before the dropwise addition of water (6 L) over about 45 min while maintaining the temperature below 23° C. After the phases are separated, the organic phase is washed twice with 10% brine; and the solvent is gently removed under vacuum (400 mbar, bath temperature 35° C.) to afford the ethyl 2-methylcyclopropanecarboxylate (1.00 kg, 26.8%) containing about 3.3 equivalents of MTBE.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]3[N:25]=[CH:26][C:27]([C:28](O)=O)=[C:17]3[N:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[OH:33][NH:34][C:35](=[NH:46])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([S:42](=[O:45])(=[O:44])[NH2:43])[CH:37]=1>>[F:32][C:2]([F:1])([F:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[N:18]3[N:25]=[CH:26][C:27]([C:28]4[O:33][N:34]=[C:35]([C:36]5[CH:37]=[C:38]([S:42]([NH2:43])(=[O:44])=[O:45])[CH:39]=[CH:40][CH:41]=5)[N:46]=4)=[C:17]3[N:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)c(OCC(F)(F)F)c5)nc34)n2)c1

Procedure:
The title compound was prepared from 5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) (237 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/hexane) and crystallization (dichloromethane) as a light yellow solid (220 mg, 67%). MS (EI) 652.2 [(M)+]; mp 250° C.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[C:33]([N:40]1[C@@H:45]([CH:46]=O)[CH2:44][CH2:43][CH2:42][C@@H:41]1[CH3:48])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].CCOC(C)=O.CCCCCC>C1COCC1.O>[C:33]([N:40]1[C@@H:41]([CH:48]=[CH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:42][CH2:43][CH2:44][C@@H:45]1[CH3:46])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@H]1CCC[C@H](C=O)N1C(=O)OC(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@H]1CCC[C@H](C=Cc2ccccc2)N1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
A suspension of benzyltriphenylphosphonium bromide (10.3 g, 26.5 mmol) in 54 mL of THF was cooled to −30° C. and treated with n-BuLi (11.2 mL, 26.88 mmol) dropwise. The deep red solution was slowly warmed to 0° C., stirred for 30 min, and then cooled to −78° C. The ylide was treated with a solution of trans-N-Boc-2-Methyl-6-Piperidinecarboxaldehyde (4.00 g, 18.93 mmol) in 6 mL of THF, and the mixture was slowly warmed to room temperature. The mixture was diluted with water, and the organic layer was separated. The aqueous layer was extracted with ether and the combined extracts were dried over K2CO3 and then concentrated to give a crude product as an oil. Chromatography on silica with 5% EtOAc/hexane afforded 3.8 g (66%) of the product which was homogeneous by TLC analysis. 1H NMR (250 MHz) δ 7.35-7.19 (m, 5H), 6.38-6.34 (m, 1H), 5.80-5.76 (m, 1H), 4.74-4.67, (m, 1H), 4.35-4.18 (m, 1H), 1.80-0.88 (m, 18H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][NH:26][C:25]=3[CH:24]=[N:23]2)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][N:26]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:14])[F:13])[C:25]=3[CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Product: O=C(Cc1ccccc1C(F)(F)F)N1CCCc2c1cnn2-c1ccc(F)cc1
Yield: 59 %

Procedure:
The compound was prepared from 2-trifluoromethylphenylacetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 1 M NaHSO4. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-50% EtOAc in hexanes) to provide 72 mg (59%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.46 (s, 0.8H), 7.70 (m, 1H), 7.55 (m, 1.2H), 7.41-7.50 (m, 4H), 7.15 (m, 2H), 4.19 (s, 0.3H), 4.06 (s, 1.7H), 3.95 (m, 0.3H), 3.76 (m, 1.7H), 2.82-2.88 (m, 2H), 2.03 (m, 2H); MS: (ES) m/z calculated for C21H18F4N3O [M+H]+ 404.1, found 404.1.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.FC1C=C([C:31]2[C:36](=[O:37])[N:35]3[CH:38]=[CH:39][S:40][C:34]3=[N:33][C:32]=2[CH3:41])C=C(F)C=1>C1(C)C=CC=CC=1.CC1N=C2SC=CN2C(=O)C=1C1C=CC(C#N)=CC=1.O>[CH3:41][C:32]1[N:33]=[C:34]2[S:40][CH:39]=[CH:38][N:35]2[C:36](=[O:37])[C:31]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=1
Reactant: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1nc2sccn2c(=O)c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared by coupling reaction of Step 2 intermediate from Intermediate 4 (600 mg, 2.001 mmol) with 3-(trifluoromethyl)phenyl boronic acid (585 g, 3.020 mmol) in the presence of Pd[(C6H5)3P]4 (92 mg, 0.0812 mmol) and sodium carbonate (1.27 g, 12.061 mol) in a mixture of toluene, ethanol and water according to the procedure described in Intermediate 3, step 3 1.21 g yielded 18.5 g of the desired compound as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 7.53-7.59 (m, 4H), 7.58-7.80 (m, 1H), 8.01 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 311.28 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[CH:38][C:39]([O:46][CH3:47])=[C:40]([CH:45]=4)[C:41]([O:43]C)=[O:42])[O:33][C:34]=3[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[CH:38][C:39]([O:46][CH3:47])=[C:40]([CH:45]=4)[C:41]([OH:43])=[O:42])[O:33][C:34]=3[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(OC)c(C(=O)OC)c3)oc2C)c(OC)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(OC)c(C(=O)O)c3)oc2C)c(OC)c1)OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a mixture of methyl 5-{4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl}-2-methoxybenzoate (0.10 g), tetrahydrofuran (1 mL) and ethanol (1 mL) was added 1N aqueous sodium hydroxide solution (0.5 mL); and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (1 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 5-{4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl}-2-methoxybenzoic acid as colorless crystals (0.08 g, yield 80%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 171-172° C.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH:9](O)[C:10]([Cl:14])([Cl:13])[CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH:9]([NH:29][C:28]2[CH:30]=[CH:31][C:25]([Cl:24])=[CH:26][CH:27]=2)[C:10]([Cl:14])([Cl:13])[CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: CCC(Cl)(Cl)C(O)NC(=O)c1ccc(Br)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCC(Cl)(Cl)C(NC(=O)c1ccc(Br)cc1)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromo-N-(2,2-dichloro-1-hydroxybutyl)benzamide 119 (0.84 g, 2.48 mmol) in chloroform (15 mL) was reacted with PCl5 (0.54 g, 2.46 mmol) at 50° C. for 30 minutes. The mixture was cooled to room temperature and quenched with ice. The aqueous layer was extracted with ether. The organic solution was dried over MgSO4, filtered, and reacted with 4-chloroaniline (0.66 g, 5.17 mmol). The mixture was stirred for 18 hours at room temperature. An acidic, (HCl) aqueous workup and ether extraction preceded chromatographic purification on silica gel (7:3 hexane:CH2Cl2). 4-Bromo-N-(2,2-dichloro-1-(4-chlorophenylamino)butyl)benzamide (Compound-15) was obtained as a white solid (701 mg, 62%). 1H NMR (300 MHz, CDCl3): δ=7.64-7.56 (m, 4H), 7.16 (d, J=9.0 Hz, 2H), 6.73 (d, J=8.7 Hz, 2H), 6.48 (d, J=9.6 Hz, 1H), 6.01 (d, J=9.0 Hz, 1H), 2.50-2.27 (m, 2H), 1.27 (t, J=7.2 Hz, 3H).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)=O.[CH2:19]([NH2:22])[CH2:20][CH3:21]>C1(C)C=CC=CC=1>[CH2:19]([NH:22][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:20][CH3:21]
Reactant: CCCN
Reactant: CC(C)(C)OC(=O)N1CCCC1COS(C)(=O)=O
Solvent: Cc1ccccc1
Product: CCCNCC1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of tert-butyl 2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (5.0 g, 18 mmol) and propan-1-amine (20.0 g, 339 mmol) in toluene (50 mL) was heated at 100° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude tert-butyl 2-((propylamino)methyl)pyrrolidine-1-carboxylate that was used directly without further purification. LCMS ESI (+) m/z 243 (M+1) detected.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C@H:11]2[CH3:23])=[O:9])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[K+].[K+]>ClCCl>[F:24][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@@H:11]2[CH3:23])=[O:9])[CH2:6][CH2:7]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)C1CCC(F)(F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CNCCN1C(=O)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(R)-tert-butyl 4-(4,4-difluorocyclohexanecarbonyl)-3-methylpiperazine-1-carboxylate 54 (1.89 g, 5.46 mmol) was dissolved in dichloromethane (30 ml). Trifluoroacetic acid (4.20 ml, 54.6 mmol) was added and the reaction stirred at RT for 1.5 hours. The reaction was added to aqueous K2CO3 (100 ml) and extracted three times with dichloromethane (50 ml). The combined organic extracts were dried (MgSO4) and evaporated to give (S)-(4,4-difluorocyclohexyl)(2-methylpiperazin-1-yl)methanone 55 as a yellow oil, 1.35 g. LC/MS m/z=247 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([N:12]([CH3:14])[CH3:13])[N:7]=1.[H-].[Na+].[CH3:18][N:19]([CH3:23])[C:20]([Cl:22])=[O:21].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:36].Cl>C1(C)C=CC=CC=1.C(O)C>[ClH:22].[ClH:36].[CH3:18][N:19]([CH3:23])[C:20]([N:5]([CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])[C:6]1[CH:11]=[N:10][CH:9]=[C:8]([N:12]([CH3:14])[CH3:13])[N:7]=1)=[O:21]
Reactant: CN(C)C(=O)Cl
Reactant: CN(C)CCNc1cncc(N(C)C)n1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)CCN(C(=O)N(C)C)c1cncc(N(C)C)n1
Reaction time: 0.5 h

Procedure:
2-(2-Dimethylaminoethylamino)-6-dimethylaminopyrazine (16.5 g., (0.079 mole) is dissolved in 150 ml dry toluene under nitrogen and sodium hydride (50% in mineral oil) (4.17 g., 0.087 mole) is added. The mixture is heated with stirring at 90°-98° C. for 1/2 hour and then refluxed for 1/2 hour. After cooling to 35° C. dimethylcarbamoylchloride (9.35 g., 0.087 mole) is added and the mixture is refluxed for 3 hours and cooled. Ethanol, 5 ml is added and the solvents are removed under reduced pressure. The residue is dissolved in dilute hydrochloric acid and extracted with ether. The aqueous layer is made alkaline with aqueous sodium hydroxide with a cooling bath to maintain the temperature below 35° C. The alkaline solution is extracted with methylene chloride. The organic extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under vacuum. The residual oil is dissolved in isopropanol, 50 ml and diethyl ether, 300 ml and then gaseous hydrogen chloride is passed into the solution. The product dihydrochloride crystallizes, is filtered, and washed with 100 ml of 1:1 acetone: isopropanol. Recrystallization from 150 ml isopropanol and 75 ml of diethyl ether yields 8 g. (0.029 mole) of the dihydrochloride salt, melting point 189° C. (dec).
Reaction SMILES: C([O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][C:8]([CH:9]=[O:10])=[C:7](Br)[C:6]=1[O:16][CH3:17])(=O)C.[CH2:18]([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[C:24]([C:7]2[C:8]([CH:9]=[O:10])=[CH:11][C:12]([O:13][CH3:14])=[C:5]([OH:4])[C:6]=2[O:16][CH3:17])=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19]
Reactant: COc1cc(C=O)c(Br)c(OC)c1OC(C)=O
Reactant: CCOC(=O)c1ccccc1B(O)O
Product: CCOC(=O)c1ccccc1-c1c(C=O)cc(OC)c(O)c1OC

Procedure:
6′-Formyl-3′-hydroxy-2′,4′-dimethoxy-biphenyl-2-carboxylic acid ethyl ester was prepared from 4-acetoxy-2-bromo-3,5-dimethoxybenzaldehyde (Example 162, step a) and 2-ethoxycarbonylphenyl boronic acid using the protocol described in Example 147, step a. Mass Spectrum: 331 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH:13]=1)([CH3:7])[CH3:6])C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[CH2:14]([N:11]1[CH2:10][CH:9]=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][OH:3])[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(C)(C)C1=CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CO)C1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
Step C To a solution of 2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propionic acid ethyl ester (6 g, 21 mmol) in anhydrous tetrahydrofuran 75 mL) at 0° C. was added a tetrhydrofuran solution (1 M) of LiAlH4 (84 mL, 84 mmol) under nitrogen. The reaction mixture was heated at reflux for 3 h, then cooled to room temperature. Water and aqueous NaOH solution (2N) was added. The mixture was filtered to remove the precipitate, and the filtrate was concentrated. Water was added, and the mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HCl solution, brine, dried over MgSO4, and concentrated to give 2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propan-1-ol as a brown oil (4.73 g, 77%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([S:20][CH3:21])[CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:22][CH:23]([CH3:25])[CH3:24].ClC1C=CC=C(C(OO)=[O:34])C=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([S:20]([CH3:21])=[O:34])[CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:22][CH:23]([CH3:25])[CH3:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cncc(COc2cc3ncnc(NC(C)C)c3cc2Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)Nc1ncnc2cc(OCc3cncc(S(C)=O)c3)c(Br)cc12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74 %

Procedure:
6-Bromo-N-isopropyl-7-{[5-(methylsulphanyl)pyridin-3-yl]methoxy}quinazolin-4-amine (430 mg, 1.03 mmol) is presented as an initial charge in 20 mL of chloroform and at 0° C. and at 0° C. admixed with meta-chloroperbenzoic acid (260 mg, 1.13 mmol). The batch is subsequently stirred at 0° C. for 45 minutes. The batch is introduced into 2N aqueous sodium hydroxide solution. The mixture is extracted with dichloro-methane, the organic phase is dried over sodium sulphate and the solvent is concentrated. Chromatography (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 74% yield (330 mg).
Reaction SMILES: O[CH:2]=[C:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[CH:9]=2)[C:4]1=O.Cl.[NH2:16][CH:17]([CH3:21])[CH2:18][NH:19][NH2:20].C([O-])(O)=O.[Na+]>C(O)C.CO>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]1[N:19]([CH2:18][CH:17]([NH2:16])[CH3:21])[N:20]=[CH:2][C:3]=1[CH2:11]2
Reactant: COc1ccc2c(c1)CC(=CO)C2=O
Reactant: CC(N)CNN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COc1ccc2c(c1)Cc1cnn(CC(C)N)c1-2
Yield: 19.7 %

Procedure:
To a solution of the product from Step A (1.9 g, 10 mmol) in ethanol (20 mL) was added a 1 N solution of HCl in a 1:1 mixture of methanol and ethanol followed by 2-aminopropylhydrazine (0.9 g, 10 mmol) and the solution was heated to reflux for 16 h. The solution was allowed to cool, poured into aqueous NaHCO3, extracted with ethyl acetate (2×20 mL), dried (Na2SO4) and concentrated. The crude material was taken up in 0.1 N HCl and washed with ether (2×20 mL), basified by the addition of NaHCO3 and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated to a residue, which was purified by chromatography (silica, 10% methanol in dichloromethane) to furnish an oil (0.48 g, 20%); MS m/z 244 [M+H]+.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:26][C@@H:27]([C:29]([OH:31])=[O:30])[CH3:28]>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][C@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:7]
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: C[C@@H](N)C(=O)O
Product: C[C@@H](NC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)C(=O)O

Procedure:
Prepared in analogy to Example A-63 g) by reacting 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester with D-alanine at the reflux condition for 5 days. MS-(−)-ion: M−1=351.1.
Reaction SMILES: O1CC1COC1C=CC=C2C=1OCC=C2.Cl.[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH:18]1[NH:27]CC(O)COC1C=CC=C2C=1OCC=C2>C(O)C>[NH2:27][CH:18]1[CH2:19][CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17]1
Reactant: OC(CNC1CCc2ccccc2C1)COc1cccc2c1OCC=C2
Agent: C1=Cc2cccc(OCC3CO3)c2OC1
Agent: Cl
Solvent: CCO
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure of Example 27, but starting from 8-(2,3-epoxypropoxy)-2H-chromene (20.4 g) and 2-aminotetralin (14.85 g) in absolute ethanol (120 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2H-chromen-8-yloxy)-propanamine hydrochloride is obtained ((i): R=H, Ar=radical 44, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([C:18]([Cl:23])=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)nc2ccccc12
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(-c2ccc(F)cc2)nc2ccccc12

Procedure:
A mixture of 16.5 g of 2-(4-fluorophenyl-4-quinolinecarboxylic acid, 100 ml of thionyl chloride, and 50 ml of toluene was stirred and heated under reflux for 4 hr. The reaction mixture was the concentrated in vacuo, the residue was treated with more toluene, and the mixture again concentrated n vacuo. The residue was washed with ether to give 16 g of the above-named compound as a yellow solid.
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH2:19][C@:18]([OH:24])([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:25][CH2:26][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[N:27]1([C:38](=[O:39])[C:37]2[N:36]([CH2:40][C:41]([OH:43])=[O:42])[CH:35]=[N:34][C:33]=2[N:31]([CH3:32])[C:29]1=[O:30])[CH3:28]>>[CH3:1][CH2:2][C@:3]12[CH2:19][C@:18]([OH:24])([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:25][CH2:26][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[N:27]1([C:38](=[O:39])[C:37]2[N:36]([CH2:40][C:41]([O-:43])=[O:42])[CH:35]=[N:34][C:33]=2[N:31]([CH3:32])[C:29]1=[O:30])[CH3:28]
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Agent: CC[C@]12CCCN3CCc4c(n(c5ccccc45)[C@@](O)(C(=O)OC)C1)[C@@H]32
Product: Cn1c(=O)c2c(ncn2CC(=O)[O-])n(C)c1=O

Procedure:
The salt is prepared, likewise the preceding examples, from 7.08 g (2.10-2 moles) of vincamine and 4.77 g (2.10-2 moles) of theophylline-7-acetic acid. There are obtained 12 g of a crystalline product having melting point of 188° C., which is soluble in alcohol and insoluble in water and in the common organic solvents.