Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][N:27]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][N:27]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccncn1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccncn1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 54A, 200 mg, 0.69 mmol) in methylene chloride (5 mL) was treated with 1 drop of N,N-dimethylformamide and then cooled to 0° C. The reaction mixture was then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.52 mL, 1.04 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 4-aminopyrimidine (131 mg, 1.38 mmol) in tetrahydrofuran (10 mL) and pyridine (0.28 mL, 3.45 mmol). The resulting reaction mixture was stirred at 23° C. for 14 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-pyrimidin-4-yl-propionamide (147 mg, 60%) as a white solid: mp 166.5-169.3° C.; EI-HRMS m/e calcd for C18H19Cl2N3O (M+) 363.0905, found 363.0909.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8](OC)=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)cc1F
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(CO)c(F)c2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A solution of 1.36 g (5.23 mmol) of methyl 3-fluoro-4′-methoxy-1,1′-biphenyl-4-carboxylate from Example 36A in 10 ml of anhydrous THF is added dropwise to 3.14 ml (3.14 mmol) of a 1 M solution of lithium aluminum hydride in anhydrous THF at 0° C. The mixture is stirred at 0° C. for 2 h. Then 10 ml of saturated ammonium chloride solution are cautiously added and, after dilution with ethyl acetate, the organic phase is separated off. The organic phase is washed successively with water and saturated sodium chloride solution, dried over sodium sulfate and, after filtration, freed of solvent. The resulting crude product is purified by flash chromatography (silica gel; mobile phase: cyclohexane/ethyl acetate 5:1). 914 mg (3.94 mmol, 73% yield) of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:4]([CH3:9])[CH2:5][C@H:6]([OH:8])[CH3:7])[CH:2]=[CH2:3].[Cl:10][C:11]1[CH:12]=[C:13]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][C:34]=3F)[N:29]=[CH:28][N:27]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.ClC1C=C(NC2C3C(=CC=CC=3OCCNC)N=CN=2)C=CC=1OCC1C=CC=CN=1>>[CH2:1]([N:4]([CH3:9])[CH2:5][C@@H:6]([CH3:7])[O:8][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:35]=1[C:26]([NH:25][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[C:11]([Cl:10])[CH:12]=1)=[N:27][CH:28]=[N:29]2)[CH:2]=[CH2:3]
Reactant: Fc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: C=CCN(C)C[C@@H](C)O
Agent: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C=CCN(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 53 %

Procedure:
(2R)-1-[allyl(methyl)amino]propan-2-ol was reacted with N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine using an analogous procedure to that described in Example 1 for the preparation of N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine, to give 5-{(1R)-2-[allyl(methyl)amino]-1-methylethoxy}-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine in 53% yield; NMR spectrum (DMSO-d6) 1.45 (d, 3H), 2.17 (s, 3H), 2.92-3.07 (m, 2H), 4.93 (m, 1H), 5.00 (d, 1H), 5.10 (d, 1H), 5.30 (s, 2H), 5.64 (m, 1H), 7.20-7.40 (m, 4H), 7.58 (m, 2H), 7.71 (dd, 1H), 7.85 (dd, 1H), 7.98 (m, 1H), 8.47 (s, 1H), 8.58 (d, 1H), 10.32 (bs, 1H).
Reaction SMILES: N[C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[FH:12].N([O-])=O.[Na+].N#N.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>CS(C)=O>[F:12][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1S(N)(=O)=O
Reactant: F
Agent: N#N
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CS(C)=O
Product: NS(=O)(=O)c1ncccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
5.3 g (0.030 mol) of 3-aminopyridin-2-ylsulfonamide are dissolved in 12 ml of dimethyl sulfoxide, and the solution is added dropwise at 0° C. to 14.3 g (0.72 mol) of hydrogen fluoride (exothermal reaction). 2.4 g (0.035 mol) of sodium nitrite are then added in portions at 0° C. After one hour, the mixture is heated to 70° C. (evolution of N2). After the reaction mixture has cooled, it is added to an ice/water mixture, sodium bicarbonate and sodium chloride are added, and the mixture is then extracted with tetrahydrofuran and ethyl acetate. The combined extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, filtered and evaporated. The residue is stirred in diethyl ether/petroleum ether. Filtration gives 3.7 g of 3-fluoropyridin-2-ylsulfonamide (Compound No. 3.001) of a melting point of +124° to +125° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH:14]=[CH:13]1.Cl>CCOCC.[Cl-].[Cl-].[Zn+2]>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[O:18])=[CH:3][CH:4]=1
Reactant: O=C1C=CC(=O)O1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Product: O=C(O)C=CC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
Freshly fused ZnCl2 (82 g, 0.6 mole) was dissolved in dry Et2O (400 ml) and added dropwise to the Grignard reagent prepared from 4-bromobenzotrifluoride (112.5g, 0.5 mole) and Mg (12.2 g, 0.5 g-atom) in Et2O (600 ml). Maleic anhydride (44 g, 0.45 mole) in Et2O (400 ml) was added over 30 minutes with stirring at reflux. After 2 hours, the mixture was cooled and acidified to pH 2 with 10% HCl. The Et2O layer was separated and dried (MgSO4), and the Et2O evaporated. The residue was recrystallized from C6H6 (x3) to yield the title compound, 24.5 g (21%), mp 149°-151°. Anal. (C11H7F3O3) C, H, F. An alternative procedure is as follows. A mixture of 4-trifluoromethylacetophenone (18.8 g) glyoxylic acid monohydrate (18.8 g), Ac2O(20 ml) and a drop of Et3N was heated to 135°, internal temperature. More Et3N (2 ml) was added, and the mixture was held at 135° for 20 minutes. The mixture was cooled and evaporated to dryness in vacuo. The solid residue was digested with H2O, filtered, dried and recrystallized from C6H6 to give the title compound, 12.2 g (50%), mp 149°-151°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][O:22][CH:23]([CH3:27])[C:24](O)=[O:25]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:24](=[O:25])[CH:23]([O:22][CH3:21])[CH3:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: COC(C)C(=O)O
Solvent: CO
Product: COC(C)C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 2-methoxy-propanoic acid (CAN 4324-37-2) as starting materials; enantiomers were separated by chiral HPLC (ChiralPak AD, 10% ethanol/n-heptane); (+) enantiomer isolated; LC-MS (UV peak area/ESI) 100%, 389.0874 (M+H)+; αD20 (MeOH)=+37.5°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.9 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-propionic acid (49 mg, 0.21 mmol) in tetrahydrofuran (5 mL) was treated with N,N-diisopropylethylamine (0.04 mL, 0.25 mmol) and benzoyl chloride (0.02 mL, 0.21 mmol). The reaction mixture was stirred at 25° C. for 24 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 2-(4-benzoylamino-phenyl)-3-cyclopentyl-propionic acid (41 mg, 57.9%) as a white solid: mp 192.5-194° C.; EI-HRMS m/e calcd for C21H23NO3 (M+) 337.1677, found 337.1670.
Reaction SMILES: Br.[C:2]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH:7](Br)[CH2:6]1)(=[O:4])[CH3:3].[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[C:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:13]=[C:14]([NH2:16])[S:15][C:7]=2[CH2:6]1)(=[O:4])[CH3:3]
Reactant: NC(N)=S
Reactant: CC(=O)N1CCC(=O)C(Br)C1
Agent: Br
Solvent: CCO
Product: CC(=O)N1CCc2nc(N)sc2C1
Reaction time: 1 h
Yield: 10.1 %

Procedure:
N-Acetyl-3-bromo-4-piperidone hydrobromide (3.0 g, 9.9 mmol) was added slowly to a solution of thiourea (756 mg, 9.9 mmol) in dry ethanol (13.5 ml) at 60°. After completion of the addition, the reaction mixture was allowed to stir at 40° for 1 hour; the ethanol was then distilled off at atmospheric pressure, and the residue was heated to 160°-170° for 20 minutes. The reaction mixture was then cooled and dissolved in water, neutralized with saturated aqueous sodium bicarbonate, and extracted three times with chloroform. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give an oil. Purification was effected by flash column chromatography (9:1 chloroform:methanol) to provide the title product as a solid (200 mg, 1.0 mmol, 10% yield).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[N:5][N:4]=1)[CH3:2].C([Li])CCC.[F:14][C:15]1[CH:29]=[CH:28][C:18]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1>O1CCCC1.CCCCCC>[F:14][C:15]1[CH:29]=[CH:28][C:18]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([OH:20])[CH:1]([C:3]2[N:7]([CH3:8])[N:6]=[N:5][N:4]=2)[CH3:2])=[CH:17][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCc1nnnn1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(c1nnnn1C)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
To a solution of 5-ethyl-1-methyl-1H-tetrazole (5.6 g, 0.05 mole) [prepared in Step A] in 60 mL of dry tetrahydrofuran was added 2.5M n-butyllithium (20 mL, 0.05 mole) in hexane over 5 minutes at -78° C. (bath temperature) under an inert atmosphere. The mixture was stirred for 30 minutes and a solution of 4,4'-difluorobenzophenone (10.8 g, 0.5 mole) in 25 mL of dry tetrahydrofuran was added over 5 minutes. This mixture was stirred for an additional 2 hours while the bath temperature was slowly warmed to -20° C. The reaction was quenched with 1N HCl and extracted with ethyl acetate (3×50 mL) and chloroform (3×50 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a white solid. The solid was purified by crystallization from ethanol-hexane to give 10.8 g (65%) of the title compound; m.p.=160°-161° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[N:19]([CH:27]([CH2:31][CH3:32])[C:28](O)=[O:29])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH3:14])[CH3:15])=[C:11]([NH:16][C:28](=[O:29])[CH:27]([N:19]3[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[N:22]=[C:18]3[CH3:17])[CH2:31][CH3:32])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCC(C(=O)O)n1cc(C(F)(F)F)nc1C
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCC(C(=O)Nc1cnn(-c2ccc(F)cc2)c1C(C)C)n1cc(C(F)(F)F)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (0.03 g, 0.14 mmol) in DMF (1.0 mL) was added 2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]butanoic acid (0.032 g, 0.14 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.057 g, 0.15 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.015 g, 0.034 mmol, 25%). 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.47 (q, J=1.2 Hz, 1H), 7.34-7.24 (m, 2H), 7.21-7.11 (m, 2H), 6.98 (s, 1H), 4.65 (dd, J=10.1, 5.3 Hz, 1H), 3.00-2.88 (m, 1H), 2.49 (ddd, J=14.4, 7.4, 5.3 Hz, 1H), 2.45 (s, 3H), 2.13-2.00 (m, 1H), 1.11-0.97 (m, 9H); MS: (ES) m/z calculated for C21H23F4N5O [M+H]+ 438.2, found 438.0.
Reaction SMILES: [S:1]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6](Cl)=[O:7])([OH:4])(=[O:3])=[O:2].[NH2:18][CH:19]1[C:25](=[O:26])[N:24]2[CH:20]1[S:21][C:22]([CH3:31])([CH3:30])[CH:23]2[C:27]([OH:29])=[O:28].O>CCOCC.C(=O)(O)[O-].[Na+]>[S:1]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6]([NH:18][CH:19]1[C:25](=[O:26])[N:24]2[CH:20]1[S:21][C:22]([CH3:31])([CH3:30])[CH:23]2[C:27]([OH:29])=[O:28])=[O:7])([OH:4])(=[O:3])=[O:2]
Reactant: O=C(Cl)C(c1ccc2c(c1)CCO2)S(=O)(=O)O
Reactant: CC1(C)SC2C(N)C(=O)N2C1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC1(C)SC2C(NC(=O)C(c3ccc4c(c3)CCO4)S(=O)(=O)O)C(=O)N2C1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sulfo(2,3-dihydro-5-benzofuranyl)acetyl chloride (5 mmole) in 10 ml of ether is added to 5 mmole of 6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid dissolved in 10 ml of water containing 10 mmole of sodium bicarbonate. The temperature is maintained at about 0° C. during the addition. The reaction mixture is stirred for about 30 minutes at 0° C. The organic phase is separated from the aqueous phase. The pH of the aqueous phase is adjusted to 6.5 to 7.0. The aqueous phase is extracted with ethyl acetate. The ethyl acetate is dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]#[N:12])=[N:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:5]2=[N:6][CH:7]=1.C[O-].[Na+].[Cl-].[NH4+:25].[C:26]([OH:29])(=[O:28])[CH3:27]>CO>[C:26]([OH:29])(=[O:28])[CH3:27].[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](=[NH:25])[NH2:12])=[N:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:5]2=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: N#Cc1nn(Cc2ccccc2F)c2ncc(F)cc12
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncc(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.1 g (41.07 mmol) of 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (Example 8A) were added to 2.22 g (41.07 mmol) of sodium methoxide in methanol (270 ml), and the mixture was stirred at RT for 2 h. 2.64 g (49.29 mmol) of ammonium chloride and acetic acid (9.17 ml) were then added, and the mixture was heated to reflux overnight. It was then concentrated to dryness and the residue was taken up in water (100 ml) and ethyl acetate (100 ml) and adjusted to a pH of 10 using 2N aqueous sodium hydroxide solution. The mixture was stirred vigorously at RT for about 1 h. The resulting suspension was filtered with suction and washed through with ethyl acetate (100 ml), with water (100 ml) and once more with ethyl acetate (100 ml). The residue was dried under high vacuum over phosphorus pentoxide.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[S:8][C:4]=2[CH:3]=1.C[O:13][C:14](=O)[CH2:15][N:16]=[C:17]=[S:18]>N1C=CC=CC=1>[SH:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]3[C:14](=[O:13])[CH2:15][NH:16][C:17]3=[S:18])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: COC(=O)CN=C=S
Reactant: Nc1ccc2nc(S)sc2c1
Solvent: c1ccncc1
Product: O=C1CNC(=S)N1c1ccc2nc(S)sc2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
Into a 13×100 mm screw cap Pyrex® vial were added 6-amino-1,3-benzothiazole-2-thiol (108 mg, 0.59 mmol), methyl-2-isothiocyanatoacetate (94.8 mg, 0.72 mmol), and pyridine (2 ml). The vial was purged with Ar, capped, and shaken in an oven at 60° C. for 8 h. The solution was concentrated, and the residue was triturated with Et2O to give a rusty brown powder (59 mg, 35%). 1H NMR (DMSO-d6) δ=4.27 (s, 2H), 7.26 (d, 1H), 7.35 (d, 1H), 7.61 (s, 1H), 10.40 (s, 1H), 13.86 (br s, 1H); ESIMS: m/z 280 (M−H); mp>266° C.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[C:10]=1[CH3:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:36](O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[C:1]([C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]([CH3:19])[C:16]([O:18][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:17])[C:10]=1[CH3:20])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)c2ccccc2)c(C)n1C(C)C(=O)O
Reactant: OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)c2ccccc2)c(C)n1C(C)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 62.7 %

Procedure:
In 5 ml of methylene chloride was dissoved 2-(3-benzoyl-2,5-dimethylpyrrol-1-yl)propionic acid (500 mg, 1.85 mmoles), and 257 μl (1.85 mmoles) of triethylamine was added. The mixture was stirred at -15° C. for 5 minutes. Isobutyl chloroformate (243 μl, 1.85 mmoles) was added to the solution, and the mixture stirred at -15° C. for 10 minutes. Then, 190 μl (1.85 mmoles) of benzyl alcohol was added. The mixture was stirred at room temperature for 20 hours, and 50 ml of methylene chloride was added. The organic layer was washed with water, dilute hydrochloric acid and an aqueous solution of sodium hydrogen carbonate in this order, dried, and concentrated to afford 543 mg of a crude product. The product was chromatographed on a column of silica gel using benzene/ethyl acetate as an eluent to afford compound (720)(421 mg, 1.16 mmoles, 63%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=2)[C:10]([NH:12][CH3:13])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Ni]>[NH2:17][C:15]1[CH:14]=[C:9]([CH:8]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:16]=1)[C:10]([NH:12][CH3:13])=[O:11]
Reactant: [H][H]
Reactant: CNC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCO
Product: CNC(=O)c1cc(N)cc(N2CCOCC2)c1

Procedure:
A solution of 3-(4-morpholinyl)-5-nitro-N-(methyl)-benzamide (Example 86d; 300 mg, 1.12 mmol) in ethanol (20 mL) is hydrogenated at atmospheric pressure over Raney nickel (0.2 g) at 25° C. The calculated amount of hydrogen is taken up in 19 hours. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate to give the title compound as a beige crystalline solid, m.p. 201–204° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:30][CH2:31][N:32]([CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:6]4[C:5]5[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=5[O:8][N:7]=4)=[CH:14][CH:13]=3)[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-(4-chlorophenyl)-4-hydroxypiperidine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=497.
Reaction SMILES: [Br:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1>>[C:4]([C:3]1[C:2]([Br:1])=[C:11]([CH:10]=[CH:9][CH:8]=1)[NH:12][C:13]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH:14]=1)([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(N)c1Br
Reactant: O=C1CCCC(=O)C1
Product: COC(=O)c1cccc(NC2=CC(=O)CCC2)c1Br
Temperature: 125 °C
Yield: 92.5 %

Procedure:
A mixture of methyl 2-bromo-3-aminobenzoate (13.2 g, 60.0 mM) and 1,3-cyclohexanedione (8.4 g, 75 mM) was heated at 125° C. under a stream of nitrogen for 4 h. The resultant solid was purified by HPLC on silica gel (elution with methylene chloride/ethyl acetate) to afford 17.2 g (88%) of 3-(3-carbomethoxy-2-bromoanilino)cyclohex-2-en-1-one as a tan foam. 1H NMR (DMSO-d6) δ 8.75 (s, 1H), 7.6-7.4 (m, 3H), 4.65 (s, 1H), 3.85 (s, 3H), 2.6 (t, 2H, J=6 Hz), 2.15 (t, 2H, J=6 Hz), and 1.9 (m, 2H). IR (CHCl3, cm−1) 3400, 3004, 2954, 1732, 1607, 1588, 1573, 1513, 1464, 1436, 1412, 1308, 1249, 1177, and 1144. MS (ES) m/e 322, 324, 326.
Reaction SMILES: Cl.C(OCC)C.[NH2:7][C:8]1[CH:22]=[CH:21][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.Cl[CH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O>C(O)C.[Cl-].[Cl-].[Zn+2]>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([C:11]2[CH:21]=[C:22]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:24][CH:25]=[C:26]3[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:13])=[CH:15][CH:16]=1
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: O=C(CCCl)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)c1ccc2nccc(-c3ccccc3)c2c1
Reaction time: 0.25 h
Yield: 37.4 %

Procedure:
HCl/diethyl ether (30.8 ml) was added to a solution of 4-amino-4'-chlorobenzophenone (35 g) in ethanol (250 ml) at room temperature and the mixture was stirred for 15 minutes. FeCl3.6H2O (69.4 g) and then ZnCl2 (2.05 g) were added portionwise and the mixture was stirred at 65° C. for 30 minutes. 3-Chloro-1-phenyl-1-propanone (25.46 g) was added and the mixture was stirred and refluxed for one night. The mixture was poured into ice and extracted with DCM. The organic layer was washed with K2CO3 10%, dried (MgSO4), filtered off and evaporated. The residue was crystallized from ACN. The mother layers were purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 99/1). The pure fractions were collected and evaporated, yielding 19.4 g (37%) of (4-chlorophenyl)(4-phenyl-6-quinolinyl)methanone (interm. 8-a).