Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
A solution of diethyl (3-methoxy-4-nitrophenyl)propanedioate (3.8 g, 12.219 mmol) in 30 mL of methanol and 20 mL of water was added KOH (2.05 g, 36.657 mmol) and the mixture was heated to 70° C. for 4 hours. Cooled to ambient temperature and removed the solvents under reduce pressure. The residue was added 100 mL of water and adjusted to pH=2 with conc. HCl. Extracted with EtOAc and the organic layer was washed with water, brine and dried over anhydrous sodium sulfate, concentrated to give (3-methoxy-4-nitrophenyl)acetic acid. 1H-NMR (400 MHz, MeOD) δ ppm 7.75 (d, J=8.6 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 6.98 (dd, J=7.8 Hz, J=1.6 Hz, 1H), 3.93 (s, 3H), 3.70 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:11]([F:21])[CH:10]=2)[CH2:4]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:23][C:22]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[C:11]([F:21])[CH:10]=2)[CH2:4]1)=[O:24]
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
(S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (0.3 g, 1 mmol), acetic anhydride (0.12 g, 1.2 mmol) and triethylamine (0.5 g, 5 mmol) were added to 10 mL ethyl acetate and the reaction mixture was stirred at room temperature for 2 hours. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, most part of the solvent was evaporated, frozen crystallized and filtered to yield the crude product. The crude product was recrystallized with ethyl acetate to provide 0.30 g of linezolid in 88% yield.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=O>C(Cl)Cl>[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[CH:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccn1
Solvent: ClCCl
Product: COC(=O)C=Cc1ccccn1
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a solution of methyl triphenylphosphoranylideneacetate (31.2 g) in CH2Cl2 (120 mL) was added dropwise over 15 minutes 2-pyridine carboxaldehyde (8.9 mL, 0.093 mol) in CH2Cl2 (40 mL). The mixture was heated to reflux for 8 hours, additional ylide (3.1 g) was added and the mixture was refluxed overnight. The reaction mixture was cooled, concentrated to 1/2 value and allowed to stand for 2 hours. A solid was collected by filtration and was washed with CH2Cl2 /hexane. The filtrate was concentrated in vacuo and the residue was vacuum distilled at 80°-107° C. and 1.5 mm Hg to afford 12.2 g (80%) of methyl 3-(2-pyridyl)-2-propenoate.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[NH:10][C:11]1([C@H:14]([NH:18][C:19]2[CH:24]=[N:23][C:22]([C:25]#[N:26])=[C:21]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[N:39]=[CH:38][CH:37]=[CH:36][N:35]=4)[CH:29]=3)[N:20]=2)[CH:15]2[CH2:17][CH2:16]2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=[O:42].[K+].[K+]>CO.OO>[CH2:1]([O:8][C:9](=[O:40])[NH:10][C:11]1([C@H:14]([NH:18][C:19]2[CH:24]=[N:23][C:22]([C:25](=[O:42])[NH2:26])=[C:21]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[N:39]=[CH:38][CH:37]=[CH:36][N:35]=4)[CH:29]=3)[N:20]=2)[CH:15]2[CH2:17][CH2:16]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ncc(N[C@H](C2CC2)C2(NC(=O)OCc3ccccc3)CC2)nc1Nc1cccc(-c2ncccn2)c1
Agent: OO
Agent: [K+]
Solvent: CO
Product: NC(=O)c1ncc(N[C@H](C2CC2)C2(NC(=O)OCc3ccccc3)CC2)nc1Nc1cccc(-c2ncccn2)c1

Procedure:
To a mixture of (R)-benzyl-1-((5-cyano-6-(3-(pyrimidin-2-yl)phenylamino)pyrazin-2-ylamino)(cyclopropyl)methyl)cyclopropylcarbamate in methanol (2 ml) was added K2CO3 (excess) and H2O2 (50%, a few drops). After completion, it was concentrated to give (R)-benzyl-1-((5-carbamoyl-6-(3-(pyrimidin-2-yl)phenylamino)pyrazin-2-ylamino)(cyclopropyl)methyl)cyclopropylcarbamate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=O)[CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.O[N:34]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.O.N>CN(C)C=O.O>[NH2:34][C:30]([CH:27]1[CH2:26][CH2:25][N:24]([C:21]2[N:20]=[C:19]([N:16]3[CH2:17][CH2:18][N:13]([C:11]([NH:10][C:3]4[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][N:2]=4)=[O:12])[CH2:14][CH2:15]3)[S:23][N:22]=2)[CH2:29][CH2:28]1)=[O:32]
Reactant: O=C(O)C1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)C1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A solution of 1-(5-{4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazin-1-yl}-1,2,4-thiadiazol-3-yl)piperidine-4-carboxylic acid (70.0 mg, 0.153 mmol), 1-hydroxybenzotriazole (23.4 mg, 0.153 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44.1 mg, 0.230 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 1 hour. 25% Ammonia water (33.8 mg, 0.497 mmol) was added thereto under ice-cooling, and the resulting mixture was stirred at room temperature for 0.5 hour. The reaction mixture was poured to water, and a solid was separated by filtration, which was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to give 52.3 mg (74.9%) of the desired product as a solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 62 %

Procedure:
4.65 g (3.10 mmol) of 2-fluoro-5-nitrotoluene, 6.71 g (3.60 mmol) of tert-butyl 1-piperazinecarboxylate and 10.4 g (7.50 mmol) of potassium carbonate are solubilized under an argon atmosphere, in dry DMF (50 ml), then the reaction medium is taken to 80° C. for 18 hours. The reaction medium is then cooled down using an ice bath then poured into ice-cold water. The product is extracted using 3 times 50 ml of ethyl acetate. The organic solution is dried over magnesium sulphate, followed by filtration and concentration under vacuum. Purification is then carried out by crystallization from diisopropyl ether and the solid obtained is filtered and rinsed with isopentane in order to obtain, after drying, 5.9 g of a yellow solid product (yield 62%). Melting point: 121.8-123.4° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[O:13][C:9]1([CH2:12][CH2:11][CH2:10]1)[CH2:8][C:7]2=O.[OH2:18]>O1CCCC1.CO>[Cl:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[O:13][C:9]1([CH2:12][CH2:11][CH2:10]1)[CH2:8]/[C:7]/2=[CH:8]\[C:9]([O:13][CH2:14][CH3:6])=[O:18]
Reactant: O
Reactant: O=C1CC2(CCC2)Oc2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)/C=C1\CC2(CCC2)Oc2ccc(Cl)cc21

Procedure:
Triethyl phosphonoacetate (4.03 g, 17.897 mmol) was added over 15 min to a stirred and cooled mixture of sodium hydride (431 mg, 17.897 mmol) in anhydrous tetrahydrofuran (25 ml). The reaction mixture was stirred for 30 min and then added 6-Chlorospiro[chromene-2,1′-cyclobutan]-4(3H)-one (2 g, 8.948 mmol) in anhydrous tetrahydrofuran. The reaction mixture was stirred at the same temperature under nitrogen for 24 h. The reaction mixture was diluted with methanol and water and the product was extracted into ethyl acetate (3×100 ml). The organic layer was washed with water (100 ml), brine, dried (Na2SO4) and concentrated to give 3.54 g of the crude product which was used as such for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[C:11]([Cu])#[N:12]>CN1C(=O)CCC1>[F:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:11]#[N:12]
Reactant: N#C[Cu]
Reactant: O=Cc1ccc(F)c(Br)c1
Solvent: CN1CCCC1=O
Product: N#Cc1cc(C=O)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.3 %

Procedure:
To NMP (40 ml) were added 3-bromo-4-fluorobenzaldehyde (10 g, 0.05 mol) and CuCN (5 g, 0.055 mol). The resulting mixture was heated at 170 for 24 h until the reaction finished (monitored by TLC), and cooled to 80, 10 g of celite was added and stirred for 1 h at this temperature. The reaction mixture then was cooled to room temperature, and partitioned between ethyl acetate (250 ml) and water (125 ml), the organic phase was washed with water and brine, dried, filtered, and concentrated to give the crude. Then the crude was purified by column chromatography on silica gel (Petroleum ether:Ethyl Acetate=4:1) to afford target compound (8 g, 100%) as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:14]([O:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirred solution of 3,4-dinitrophenol (1 g) in dimethylformamide (30 mL) was treated with benzyl bromide (723 μL) and potassium carbonate (1.13 g). The reaction mixture was stirred at ambient temperature for 24 hours and then partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:4, v/v) to give 4-benzyloxy-1,2-dinitrobenzene (1.30 g) as a yellow solid. LC-MS (METHOD B): RT=3.31 minutes. 1HNMR [(CD3)2CO, ppm): δ 5.28 (s, 2H), 7.26-7.42 (m, 61), 7.57 (d, 1H), 8.12 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]O)[C:6]=2[CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:42]I>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14][I:42])[C:6]=2[CH:17]=1
Reactant: II
Reactant: C[C@H](CO)CN1C(=O)COc2ccc(F)cc21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Yield: 100.5 %

Procedure:
The compound (S)-6-Fluoro-4-(3-hydroxy-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (111MF03) (2.63 g, 11.0 mmol), triphenylphosphine (6.35 g, 24.2 mmol), imidazole (1.8 g, 26.4 mmol) and I2 (7.81 g, 30.8 mmol) were mixed according to GP9. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (111MF04) (3.86 g, 100%). 1H NMR (CDCl3) δ 6.97-6.93 (m, 1H), 6.82-6.78 (m, 1H), 6.73-6.68 (m, 1H), 4.63-4.53(m, 2H), 3.90 (d, J=6.8 Hz, 2H), 3.20-3.16 (m, 2H), 2.15-2.04 (m, 1H), 1.06 (d, J=6.4 Hz, 3H); 13C NMR (CDCl3) δ 165.0, 158.5 (d, J=240.2 Hz), 141.7 (d, J=2.3 Hz), 129.6 (d, J=10.4 Hz), 118.1 (d, J=9.2 Hz), 110.1 (d, J=23.4 Hz), 103.1 (d, J=28.7 Hz), 67.8, 46.3, 33.5, 18.9, 11.6.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:5]=[CH:4][N:3]=1.[N:21]1([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:33][C:30]1[CH:29]=[CH:28][C:27]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:32][C:31]=1[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cc(N3CCCCC3)ccc2N)OC1(C)C
Reactant: O=C(Nc1ccnc(Cl)c1)c1cccc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(N2CCCCC2)cc1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N-(2-chloropyridin-4-yl)-3-(trifluoromethyl)benzamide (350 mg, 1.16 mmol, 1.00 equiv), 4-(piperidin-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (430 mg, 1.42 mmol, 1.20 equiv), Pd(PPh3)2Cl2 (81.7 mg, 0.12 mmol, 0.10 equiv), K3PO4.7H2O (790 mg, 2.33 mmol, 2.00 equiv), X—PHOS (91.6 mg, 0.23 mmol, 0.20 equiv) in DME/H2O (10:1) (30/3 mL). The resulting solution was stirred for 2 h at 80° C. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residual solution was diluted with 50 mL of water. The resulting solution was extracted with 2×50 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (100˜100:1˜40:1). This resulted in 350 mg (67%) of N-(2-(2-amino-5-(piperidin-1-yl)phenyl)pyridin-4-yl)-3-(trifluoromethyl)benzamide as a yellow solid
Reaction SMILES: [CH:1]1([N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:17]C#N)=[C:14]([CH3:16])[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:1]1([N:7]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:17][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:14]([CH3:16])[N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClCCN1CCCC1
Reactant: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SC#N
Product: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SCCN1CCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(4-methyl-5-thiocyanato-thiazol-2-yl)-urea and N-(2-chloroethyl)pyrrolidine.
Reaction SMILES: O=O.[NH3:3].O.[NH3:5].[CH3:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[CH3:13]>>[CH:10]1[CH:11]=[C:12]([C:13]#[N:3])[C:7]([C:6]#[N:5])=[CH:8][CH:9]=1
Reactant: N
Reactant: Cc1ccccc1C
Agent: O=O
Solvent: O
Product: N#Cc1ccccc1C#N
Temperature: 470 °C

Procedure:
750 ml of a catalyst having a particle size of from 0.05 to 0.3 mm are introduced into a quartz reactor which has a diameter of 60 mm and a length of 1000 mm and is provided with an external heater and a quartz frit for uniformly distributing the reaction gas. The catalyst is composed of 5.0% by weight of V2O5, 5.9% by weight of Sb2O3 0.24% by weight of K2O, 0.56% by weight of BaO and 88.3% by weight of γ-Al2O3. The reactor is heated to 470° C. and a gas mixture consisting of 3.25% by volume of o-xylene, 13% by volume of oxygen and 83.75% by volume of ammonia is passed through. The hot reaction gases are cooled to 70° C. with ammonia water in two wash towers arranged in series. An aqueous suspension of crystals is formed, from which the o-phthalodinitrile is isolated by filtration. 2,687 parts of o-xylene give 2,581 parts of o-phthalodinitrile and 195 parts of o-tolunitrile. By reacting the 195 parts of o-tolunitrile again with ammonia and oxygen, a further 170 parts of o-phthalodinitrile are obtained. The total yield of o-phthalodinitrile is 84.8 mol %, based on converted o-xylene.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32]Br.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32][N:9]1[CH:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)ccc1CN1C(c2ncccc2C)CCCC1c1ncccc1C
Yield: 96.1 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.260 g, 0.98 mmol), 2-bromomethyl-5-cyano-benzoic acid methyl ester (0.360 g, 1.42 mmol), KI (37 mg, 0.22 mmol), and DIPEA (0.35 mL, 2.01 mmol) in DMF (5 mL) was heated at 60° C. for 17 hours. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 415 mg (96%) of 5-cyano-2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester as a tan solid. To a cold (0° C.) solution of 5-cyano-2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester (0.409 g, 0.937 mmol) in THF (4.5 mL) and MeOH (9 mL) was added LiBH4 (229 mg, 10.52 mmol) and the mixture was allowed to warm to room temperature overnight. The mixture was diluted with 1.0 N NaOH (10 mL) and extracted with CH2Cl2 (5×25 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.332 g (87%) of COMPOUND 29 as a white foam. 1H NMR (CDCl3) δ 1.61-1.77 (m, 3H), 2.05-2.14 (m, 1H), 2.30-2.44 (m, 2H), 2.51 (s, 6H), 3.71 (s, 2H), 4.11 (d, 2H, J=10.8 Hz), 4.46 (s, 2H), 4.94 (br s, 1H), 6.87-6.96 (m, 4H), 7.22-7.27 (m, 3H), 8.21 (d, 2H, J=4.2 Hz). 13C NMR (CDCl3) δ 19.35, 25.70, 28.19, 51.31, 62.24, 67.36, 109.58, 119.48, 122.56, 129.25, 130.02, 132.00, 132.24, 138.53, 139.79, 145.29, 146.76, 159.25; ES-MS m/z 413 (M+H). Anal. Calcd. For C26H28N4O.1.0H2O2: C, 72.53; H, 7.02; N, 13.01. Found: C, 72.46; H, 6.73; N, 12.91.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)[CH:5]=[N:6][C:7]=1[C:8]#[N:9].[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>ClCCl>[OH:31][C:25]([C:27]([F:30])([F:29])[F:28])=[O:26].[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:4]1[CH:3]=[C:2]([Br:1])[C:7]([C:8]#[N:9])=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Br)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ncc(N[C@@H]2CCCC[C@@H]2N)cc1Br
Temperature: 25 °C

Procedure:
tert-Butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate (PrepEx 1.1) (100 mg, 0.253 mmol) was suspended in dichloromethane (1 mL). TFA (0.390 mL, 5.06 mmol) was added, and the reaction mixture was maintained at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-bromopyridine-2-carbonitrile TFA salt. The material was used without further purification in the subsequent transformation. MS ESI calc'd. for C12H16BrN4 [M+H]+ 295 and 297. found 295 and 297.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=O)[NH:8][C:7]1=[O:20])[CH2:2][CH2:3][CH2:4][CH3:5].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>O1CCOCC1>[CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=[S:22])[NH:8][C:7]1=[O:20])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCCn1c(=O)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Solvent: C1COCCO1
Product: CCCCCn1c(=O)[nH]c(=S)c2[nH]c(C(F)(F)F)nc21
Temperature: 100 °C
Yield: 17.5 %

Procedure:
A mixture of 3-pentyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione (0.81 g, 2.8 mmol) and phosphorus pentasulfide (1.2 g, 2.8 mmol) in 1,4-dioxane (20 mL) was heated at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography twice (0-50% MeOH in CH2Cl2) to yield 0.15 g of pure product as a yellow solid (0.15 g, 18% yield). LCMS calculated for C11H14F3N4OS (M+H): 307.1. found: 307.1.
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH2:4][N:3]3[C:2]1=[O:13].CC(C)([O-])C.[K+].C1COCC1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([N:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH2:4][N:3]3[C:2]1=[O:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c2cccc3c2n1CC=C3
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1n(Cc2ccccc2)c2cccc3c2n1CC=C3
Reaction time: 0.17 h

Procedure:
A mixture of 4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (I, J. Heterocyclic Chem., 19, 837-49 (1982), 1.0 g, 5.8 mmol) in DMF (10 (1) is cooled to 0° and treated with potassium t-butoxide in THF (1.98 M, 3.2 ml, 6.3 mmol) maintaining the reaction temperature at 0°. The resulting mixture is stirred at 0° for 10 minutes. Benzyl bromide (0.73 ml, 6.1 mmol) is then added while maintaining the reaction temperature at 0°. After 1 hr, the mixture is partitioned with methyl t-butyl ether (MTBE) from water followed by several water washes. The MTBE phase is concentrated under reduced pressure. The concentrate is cooled to 0°, filtered and washed two times with 0° MTBE. The product is dried at 50° under reduced pressure with a nitrogen purge to give the title compound, CMR (CDCl3, 100 MHz) L 153.78, 136.44, 128.69, 127.67, 127.60, 126.73, 125.86, 122.90, 122.78, 121.28, 116.92, 116.17, 108.36, 44.95 and 42.37.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1>C(Cl)Cl>[N+:14]([C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C1CNCCN1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccnc1N1CCNCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
Anhydrous piperazine (60 g) was dissolved in methylene chloride (400 ml) and then, 2-chloro-3-nitropyridine (40 g) was added slowly at 10~20° C. and the mixture was stirred at 20° C. for 2 hours. After completion of the reaction, the reaction mixture was washed with water (300 ml) three times and the separated organic layers were concentrated under reduced pressure. The precipitate was washed with water and small amount of ethanol and dried in vacuo to give 46 g (yield: 87.5%) of the desired compound.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([OH:29])=[C:24]([F:30])[CH:23]=1)=[O:17])C>>[F:28][C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([F:30])[C:25]=1[O:29][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH2:21][CH:19]1[CH2:20][CH:18]1[C:16]([OH:17])=[O:15]
Reactant: CCCSc1ncccc1CCl
Reactant: CCOC(=O)C1CC1Cc1cc(F)c(O)c(F)c1
Product: CCCSc1ncccc1COc1c(F)cc(CC2CC2C(=O)O)cc1F
Yield: 76.2 %

Procedure:
3-chloromethyl-2-propylsulfanyl-pyridine (0.016 g, 0.08 mmol) obtained in Step C of Preparation Example 14 and 2-(3,5-difluoro-4-hydroxy-benzyl]-cyclopropane carboxylic acid ethyl ester (0.02 g, 0.08 mmol) obtained in Step D of Preparation Example 49 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.024 g, 77%).