Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25].[CH3:26][N:27](C)C=O>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:26]#[N:27])=[C:3]([CH3:25])[CH:4]=3)[CH2:12]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C#N
Temperature: 115 °C

Procedure:
Zinc(II) cyanide (0.47 g) was added at ambient temperature to a solution of 3-(4-bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (3.0 g) (Example I4) in N,N-dimethylformamide (80 ml). Under an atmosphere of argon, tetrakis(triphenylphosphine) palladium(0) (0.46 g) was added. The mixture was heated to 115° C. for 27 hours. The reaction mixture was cooled to ambient temperature, diluted with toluene, washed with aqueous ammonium hydroxide (1M), then with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 4:1) to give 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzonitrile (2.26 g) as a white solid. 1H-NMR (CDCl3, 400 MHz): 7.65 (t, 2H), 7.57 (d, 1H), 7.5 (s, 1H), 7.42 (m, 2H), 4.08 (d, 1H), 3.7 (d, 1H), 2.58 (s, 3H) ppm.
Reaction SMILES: [ClH:1].[C:2]([O:5][CH:6]1[CH2:14][C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]2[CH:8]([CH2:9][N:10](C(OC=C)=O)[CH2:11]2)[C:7]1=[O:32])(=[O:4])[CH3:3]>O1CCOCC1>[ClH:1].[C:2]([O:5][CH:6]1[CH2:14][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]2[CH:8]([CH2:9][NH:10][CH2:11]2)[C:7]1=[O:32])(=[O:4])[CH3:3]
Reactant: C=COC(=O)N1CC2C(=O)C(OC(C)=O)CC(c3ccccc3)(c3ccccc3)C2C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)OC1CC(c2ccccc2)(c2ccccc2)C2CNCC2C1=O
Reaction time: 1 h

Procedure:
394 cm3 of a 5.2N solution of hydrochloric acid in dioxane are added to a solution of 51.2 g of (3aRS,5RS,7aRS)-5-acetoxy-7,7-diphenyl-2-vinyloxycarbonylperhydroisoindolin-4-one in 118 cm3 of dioxane at room temperature. The reaction mixture is stirred at this temperature for 1 hour and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from 200 cm3 of boiling ethanol. 13.4 g of (3aRS,5RS,7aRS)-5-acetoxy-7,7-diphenylperhydroisoindol-4-one hydrochloride are obtained in the form of white crystals which melt at a temperature above 300° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[F:10].[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([F:9])[C:3]=1[F:10]
Reactant: Cc1cc(F)c(F)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
1,2,3-Trifluoro-5-methylbenzene (40 mmol) was added to conc. H2SO4 (50 ml) at 0-5° C. Then the reaction mixture was slowly treated with conc. HNO3 (3.39 ml, 48.44 mmol, 90%) while maintaining the internal temperature below 20° C. The reaction mixture was stirred at room temperature for 16 h and poured onto ice (300 g) and the oily layer was extracted with CH2Cl2 (2×125 ml). The organic layer was washed with water (2×200 ml), brine (200 ml) and dried (MgSO4) and evaporated to obtain the crude product which was purified over flash silica gel chromatography to obtain the title product (6.5 g, 85%). 1H-NMR (300 MHz, CDCl3): δ 6.96 (septet, 1H), 2.39 (s, 3H). 19FNMR (CDCl3): δ−128.18, −141.50, −159.05.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH2:10][CH:9]1[C:18](O)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>O1CCCC1>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]([CH2:18][OH:19])[CH2:10]2
Reactant: CC(C)(C)OC(=O)N1c2ccc(Cl)cc2CC1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2ccc(Cl)cc2CC1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.8 %

Procedure:
To a mixture of 1.17 g of 1-(tert-butoxycarbonyl)-5-chloro-2,3-dihydro-1H-indole-2-carboxylic acid and 23 mL of tetrahydrofuran was added dropwise 15.7 mL of a 1 M solution of a borane-tetrahydrofuran complex in tetrahydrofuran under ice-cooling, followed by warming to room temperature and stirring overnight. After ice-cooling again, 15 mL of 1 M hydrochloric acid was added dropwise thereto, followed by extraction with chloroform. The obtained organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 1.18 g of tert-butyl 5-chloro-2-(hydroxymethyl)-2,3-dihydro-1H-indole-1-carboxylate as a pale yellow solid.
Reaction SMILES: [K].[O-]CCCC.[C:7]1([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>CN(C=O)C>[C:7]1([C:13]([CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: CCCC[O-]
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCOC1CCCCO1)(C(=O)OCC)c1ccccc1
Temperature: 70 °C
Yield: 96.4 %

Procedure:
Potassium t.butoxide (112 g, 1M) in DMF (800 ml) was treated with diethyl phenylmalonate (236 g, 1M) in DMF (200 ml) then with 1-bromo-2-tetrahydropyranyloxy-ethane (209 g, 1M) in DMF (200 ml). The reaction was heated to 70° C. After 5 hours the reaction was cooled to room temperature, quenched on to water (2.5 l) and 2N HCl (500 ml), and extracted with IPE (1 l, then 500 ml). The organic extracts were washed with water, dried and evaporated to give the title compound (351 g, 96%). Glc 93%+7% unchanged diethylphenylmalonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.[C:20](#[N:23])[CH:21]=[CH2:22]>O1CCOCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([S:17][CH2:22][CH2:21][C:20]#[N:23])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: C=CC#N
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#CCCSC1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Yield: 60.6 %

Procedure:
In 15 ml of dioxane was dissolved 2.1 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindole-1-on, and 1.5 g of acrylonitrile, together with several drops of triethylamine, was added, followed by heating at 85° to 90° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and the residual, oily substance was purified by means of column chromatography with the use of silica gel (acetone:hexane=1:3), thereby producing 1.5 g of the subject compound in white crystals, m.p. 101°-103° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].[NH4+].[OH-]>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:17]([O-:19])=[O:18])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccnc2ccccc12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
4-Chloroquinoline (10.0 g, 61.3 mmol) was added in small portions to sulfuric acid (45 mL) taking care to maintain the temperature at or below 15° C. Then the solution was cooled and maintained at −5° C. during the addition of fuming nitric acid (9 mL). The mixture was allowed to warm to room temperature and stirred for an additional 3 h. The reaction mix was poured on ice and basified (pH 9) with NH4OH. The resulting precipitate was filtered, washed well with water, dried, and recrystallized from methanol to provide 7.5 g (59%) of 6a as golden-brown needles; mp 128-129° C. (lit.32mp 129-130° C.); 1H NMR (CDCl3) δ 7.67 (d, 1H, J=4.5), 7.75 (dd, 1H, J=8.6, J=7.6), 8.10 (dd, 1H, J=7.6, J=1.3), 8.48 (dd, 1H, J=8.6, J=1.3), 8.94 (d, 1H, J=4.5); 13C NMR (CDCl3) δ 123.0, 124.4, 126.5, 127.5, 128.3, 140.6, 143.2, 148.7, 152.1. The mother liquor was evaporated and chromatographed in 19:1 hexanes-ethyl acetate, to provide 2.05 g (16%) of the 5-nitro isomer 6d as a very light yellow solid; mp 144-146° C. (lit.31 mp 150° C.); 1H NMR (CDCl3) δ 7.65 (d, 1H, J=4.7), 7.82 (m, 2H), 8.35 (dd, 1H, J=2.5, J=7.3), 8.90 (d, 1H, J=4.7); 13C NMR (CDCl3) δ 118.2, 123.4, 125.1, 128.8,134.2,135.6, 139.1,149.7,151.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][CH2:18][OH:19])=[CH:13][CH:14]=2)[CH:9]=[N:8]1>O=[Mn]=O.ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][CH:18]=[O:19])=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: OCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=CC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
A 500 mL three-necked round bottom flask was charged with 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)prop-2-yn-1-ol (11.4 g, 44.2 mmol; Intermediate 16), dichloromethane (300 mL) and MnO2 (38.4 g, 44.2 mmol). The resulting mixture was stirred at room temperature for 16 hours. Upon completion, the reaction mixture was filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1:100-1:20 EtOAc/petroleum ether) affording the title compound (6.4 g). 1H NMR (400 MHz, DMSO-d6): δ 9.45 (s, 1H), 8.27-8.25 (m, 2H), 7.87 (d, 1H), 7.66 (dd, 1H), 5.86 (dd, 1H), 3.91-3.87 (m, 1H), 3.79-3.72 (m, 1H), 2.40-2.36 (m, 1H), 2.05-1.96 (m, 2H), 1.78-1.72 (m, 1H), 1.61-1.56 (m, 2H); LCMS: 255 (M+H)+.
Reaction SMILES: [CH2:1]([CH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:9]=2[O:8][C:7]1=[O:23])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-:24].[K+]>CO>[OH:8][C:9]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]([OH:23])=[O:24]
Reactant: [OH-]
Reactant: CCCCCC1C(=O)Oc2c(Oc3ccccc3C)cccc21
Agent: [K+]
Solvent: CO
Product: CCCCCC(C(=O)O)c1cccc(Oc2ccccc2C)c1O

Procedure:
3-(n-Pentyl)-7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one was treated with potassium hydroxide in methanol in a similar manner to that of Example 21-(10) to give 2-[2-hydroxy-3-(o-tolyloxy)phenyl]n-heptanoic acid, mp. 113°-114° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:12]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: Cc1ccc2c(c1)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(C)cc2C1=O
Yield: 83 %

Procedure:
A solution of 14.2 g of 6-methyl-1-indanone, 20.1 ml of 3-buten-2-ol and 140 mg of p-toluenesulfonic acid in 140 ml of 2,2-dimethoxypropane was boiled under reflux for 69 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 16.3 g (83%) of (RS)-2-(2-buten-1-yl)-6-methyl-1-indanone were obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:27]=1[CH3:36].CCOC(C)=O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[C:27]=3[CH3:36])[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
A suspension of 4-bromo-2-methyl-6-(4-morpholinyl)-1H-benzimidazole, prepared as described in Example 62 (500 mg, 1.688 mmol) and potassium carbonate (700 mg, 5.06 mmol) in N,N-Dimethylformamide (DMF) (6 mL) was stirred at rt for 15 min. 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (641 mg, 2.53 mmol) was added in and the resulting reaction mixture was stirred for 3 h at 80° C. It was then cooled to room temperature and poured into ice/water. The precipitate was collected by filtration, washed with water, then few mLs of hexanes and air dried. The crude material was purified on a silica gel column (ISCO, 0-80% EtOAc in hexanes) to the desired product (565 mg, 1.182 mmol, 70.0% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.59 (d, J=7.83 Hz, 1H), 7.16 (d, J=2.02 Hz, 1H), 7.10-7.15 (m, 1H), 6.46-6.52 (m, 2H), 5.25 (s, 2H), 3.75-3.89 (m, 4H), 3.05-3.14 (m, 4H), 2.55 (s, 3H), 2.51 (s, 3H). MS (ES+) m/e 468.9 [M+H]+.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]1[N:25]=[C:13]2[CH:14]=[CH:15][CH:16]=[C:17](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:12]2[N:11]=1.O>CS(C)=O>[CH3:9][C:10]1[N:25]=[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH:18]3[CH2:4][CH:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:12]2[N:11]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cccc2nc(C)nn12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1cccc2nc(C)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a suspension of sodium hydride (0.950 g, 24.8 mmol) in dimethyl sulfoxide (82 mL) was added a solution of trimethylsulfoxonium iodide (4.77 g, 21.8 mmol) in dimethyl sulfoxide (35 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-5-yl)acrylate (4.20 g, 18.2 mmol) in dimethyl sulfoxide (100 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (1.80 g, yield 40%).
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.Br.Br[C:8]1[S:9][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:11][N:12]=1.C(N(CC)CC)C>C(O)C>[CH:1]1([CH2:4][NH:5][C:8]2[S:9][C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: NCC1CC1
Reactant: Brc1nnc(-c2cccnc2)s1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1cncc(-c2nnc(NCC3CC3)s2)c1
Temperature: 125 °C
Yield: 26.4 %

Procedure:
A suspension of cyclopropylmethanamine (0.528 g, 0.743 mmol), 2-bromo-5-(3-pyridyl)-1,3,4-thiadiazole hydrobromide (0.2 g, 0.619 mmol) and triethylamine (0.3 ml, 2.16 mmol) in ethanol (20 mL) was heated to 125° C. for 42 minutes in a microwave reaction vessel, cooled to room temperature, concentrated under reduced pressure and resuspended in 2:1 saturated aqueous sodium bicarbonate:ethyl acetate (100 mL). The suspension was shaken vigorously and the organic extract collected and washed with water (50 mL) and brine (30 mL) before drying over magnesium sulfate. The solution was concentrated under reduced pressure and purified by silica column chromatography, eluting with a gradient of methanol in ethyl acetate. The slower eluting fraction was concentrated under reduced pressure to afford the title compound as a yellow solid (38 mg, 26%): mp 162-165° C.; IR (ATR) 1573(s), 1549(s), 1464(m), 1063(m) cm−1; 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J=1.6 Hz, 1H), 8.63 (dd, J=4.8, 1.6 Hz, 1H), 8.18 (ddd, J=8.0, 2.2, 1.7 Hz, 1H), 7.38 (ddd, J=8.0, 4.8, 0.7 Hz, 1H), 5.68 (s, 1H), 3.29 (d, J=7.1 Hz, 2H), 1.26-1.09 (m, 1H), 0.72-0.53 (m, 2H), 0.42-0.25 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 170.01, 154.19, 150.61, 147.94, 133.64, 127.47, 123.76, 52.20, 10.76, 3.73; ESIMS m/z 231.8 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].FC1C(F)=C(OCCCCCCCC)C=CC=1C1N=CC(Br)=CN=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.COCCOC>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Brc1cnc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: FC(F)(F)c1ccc(-c2ncc(Br)cn2)cc1
Yield: 56.3 %

Procedure:
--Quantities: 5-bromo-2-iodopyrimidine 2 (2.64 g, 9.26 mmol), 4-(trifluoromethyl)phenylboronic acid 9 (2.29 g, 12.0 mmol), tetrakis(triphenylphosphine)palladium (53 mg, 0.046 mmol), DME (50 ml), 2M aqueous sodium carbonate (50 ml). The experimental procedure was as described for compound 4 to yield the trifluoromethylphenylpyrimidine 10 (1.58 g, 56%) (from MeOH), m.p. 167° C.; νmax /cm-1 (KBr) 1530, 1420, 1320s, 1165, 1120, 1070 and 1010; δ 7.74 (2H, d, J 8, 3'- and 5'-H), 8.52 (2H, d, J 8, 2'- and 6'-H) and 8.86 (2H, s, 4- and 6-H); m/z 304 (M+), 302 (M+),196 and 171.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]([N:19]2C(=O)C3=CC=CC=C3C2=O)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:8]=[CH:9][CH:10]=1>C(O)C>[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]([NH2:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1C(Cc1ccccn1)c1cccc(Cl)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NC(Cc1ccccn1)c1cccc(Cl)c1

Procedure:
150 ml of a solution of 5.25 g of hydrazine hydrate in ethanol was added to 12.7 g of the N-{1-(3-chlorophenyl)-2-(pyridin-2-yl)ethyl}phthalimide prepared in the Preparative Example 22. The obtained mixture was heated under reflux for 2 hours. The precipitated crystals were filtered out and the filtrate was concentrated, followed by the addition thereto of ethyl acetate. The precipitated impurities were filtered out and the filtrate was concentrated to give the title compound. Yield: 7.9 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](B(O)O)[CH:29]=2)[CH:24]=[N:23]1>>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:28]3[CH:29]=[C:30]4[C:25]([CH:24]=[N:23][N:22]4[CH3:21])=[CH:26][CH:27]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: Cn1ncc2ccc(B(O)O)cc21
Product: C[C@@H](Oc1nc(-c2ccc3cnn(C)c3c2)cc2ncn(C)c12)[C@H]1CNC(=O)C1

Procedure:
Following General Procedure B, beginning with crude (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (35 mg, 0.119 mmol) and 1-methyl-1H-indazol-6-ylboronic acid (23 mg, 0.131 mmol), (R)-4-((R)-1-(3-methyl-6-(1-methyl-1H-indazol-6-yl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3B.30 was isolated, following column chromatography.
Reaction SMILES: [OH:1]S(O)(=O)=O.[C:6]([C@:8]([NH:19][C@H:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21]([NH2:23])=[O:22])([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)#[N:7]>C(Cl)Cl>[C:21]([C@H:20]([NH:19][C@@:8]([CH3:18])([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:6]([NH2:7])=[O:1])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:22])[NH2:23]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(C[C@@](C)(C#N)N[C@@H](C(N)=O)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(C[C@](C)(N[C@@H](C(N)=O)c2ccccc2)C(N)=O)cc1
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Into a 10 L reactor equipped with anchor stirrer was charged CH2Cl2 (1.64 L). The solvent was cooled to 15° C., then 95% H2SO4 (492 mL) and 2-[1-(S)-cyano-2-(4-methoxyphenyl)-1-methylethylamino]-2-(R)-phenylacetamide 2 (410 g, 1.27 mol) were added alternately in 9 portions over approximately 45 min (specifically: 164 mL of H2SO4 then 82 g of 2; subsequently, at approximately 5 min intervals, 8×[41 mL of H2SO4 then immediately 41 g of 2]). On addition of each portion, the suspension of 2 in the dense oily phase slowly dissolved (1-2 min) to provide a biphasic mixture. The resulting biphasic mixture (a red-brown dense oil with a pale yellow supernatant CH2Cl2 layer) was stirred for 0.5 h at 25° C. Ice-cold water (4.1 L) was added over 30 min, very slowly initially (200 mL dropwise over 15 min) due to a violent exotherm, and the biphasic mixture was stirred for 0.5 h. The phases were separated and the organic phase discarded. The combined aqueous phases were washed with CH2Cl2 (450 mL), and residual CH2Cl2 was stripped from the aqueous phase by distillation under vacuum at 55° C. (20-30 mBar). The aqueous solution was then cooled to 20° C. and was basified with 32% aq NH3 (1150 mL) to pH 8-9 at such a rate that the temperature was kept below 28° C. (approximately 120 min). The suspension was stirred for 30 min to ascertain a stable pH. The white solid which formed was separated by filtration, washed with H2O (2×2050 mL), and was thoroughly drained of water (but was not dried) to provide 2-[(R)-(carbamoylphenylmethy)-amino]-3-(4-methoxyphenyl)-2-(S)-methylpropionamide 3 (1087 g (391 g theoretical, the sample contains 64% w/w of H2O), yield 90%, 97% HPLC purity, 96% de) as a wet white solid. HPLC (Luna C18, H2O/MeCN 95:5 to 0:100 30 min, 254 nm, sample 2 mg/mL in MeOH). tR(3)=15.3 min, 96% de. (2 degrades under these conditions: 3 peaks are detected at 17.7, 18.9 and 19.9 min). HPLC (R,R/S,S)-diastereoisomer of 3, tR=15.0 min. de determination: HPLC comparing integration of peaks at tR=15.3 min (97.3 area % 3) and tR=15.0 min (1.6 area % (R,R)-diastereoisomer of 3 (reference (R,R/S,S) prepared from nearly rac-phenylglycinamide).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[N+:17]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>O1CCCC1.[Pd]>[CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(NC2CCCCC2)c(N)c1
Yield: 100 %

Procedure:
60.0 g (0.23 mol) of N-cyclohexyl-2,4-dinitroaniline were dissolved in 500 ml of tetrahydrofuran and, after addition of 3 g of palladium/carbon (10%), were hydrogenated. The mixture was then filtered and the filtrate was concentrated under reduced pressure to yield 47.2 g (100%) of the product.