Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][N:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]([CH3:33])=[N:26]1.O>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30]([C:29]5[N:25]([CH3:24])[N:26]=[C:27]([CH3:33])[CH:28]=5)=[O:31])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.65 mmol) in N,N-dimethylacetamide (2.0 mL) was added 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (185 mg, 1.16 mmol). After stirring at room temperature for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2→4-ethyl acetate) and precipitated from hexane/ethyl acetate to give the title compound (70 mg, 25%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15]3[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)=[O:7])=[CH:28][CH:29]=1
Reactant: CCOC(=O)/C=C/c1ccc(NC2CCN(C(=O)c3ccc(Cl)cc3)CC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/c1ccc(NC2CCN(C(=O)c3ccc(Cl)cc3)CC2)nc1
Temperature: 72.5 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A mixture of ethyl (2E)-3-(6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylate (190 mg) and 1N NaOH solution (1.0 ml) in MeOH (20 ml) was stirred at 70-75° C. for 2 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of AcOEt and water. The aqueous solution was adjusted to PH4.5 and extract with AcOEt and THF. The organic layer was washed with brine and dried over MgSO4. The solvent was concentrated in vacuo and the precipitate was collected by filtration to give (2E)-3-(6-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}-3-pyridyl)acrylic acid (85 mg)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13]>>[C:11]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)(=[O:15])[CH:12]([CH3:14])[CH3:13]
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)c1ccc2c(c1)CC(=O)N2

Procedure:
Prepared from 2-indolinone and isobutyryl chloride
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:28])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[CH:20][CH:19]=3)=[O:17])[CH:10]=2)[CH2:6]1>CS(C)=O.CC#N.CC#N.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:29])[CH:4]=[C:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:28])[C:16]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH:25]([F:26])[F:27])=[CH:22][CH:23]=3)=[O:17])[CH:10]=2)[CH2:6]1
Reactant: COC(=O)CC1CC(c2cccc(C(=O)C(=O)c3ccc(OC(F)F)cc3)c2)C1
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: CS(C)=O
Product: COC(=O)C=C1CC(c2cccc(C(=O)C(=O)c3ccc(OC(F)F)cc3)c2)C1
Temperature: 145 °C
Reaction time: 4 h
Yield: 79.8 %

Procedure:
In a 250 ml round bottom flask was dissolved (3-{3-[2-(4-Difluoromethoxy-phenyl)-2-oxo-acetyl]-phenyl}-cyclobutyl)-acetic acid methyl ester (1.348 g, 3.66 mmol) in DMSO (45 mL). Bis(acetonitrile)dichloropalladium was added and the flask heated (oil bath; 145° C.) for 4 hours. More Bis(acetonitrile)dichloro-palladium (90 mg) was added and heating was continued for another 4 hours. The crude material was partitioned between water (50 mls) and dichloromethane. Dichloromethane extracts (2×50 mls) were combined and concentrated onto silica gel. Purification by column chromatography (gradient; 10-20% EtOAc in hexanes) afforded 1.17 gm of a yellow oil (80%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.90-3.02 (m, 1H) 3.05-3.16 (m, 1H) 3.22-3.28 (m, 1H) 3.49-3.59 (m, 1H) 3.62-3.64 (m, 3H) 3.72-3.82 (m, 1H) 5.73-5.77 (m, 1H) 7.39 (dt, J=9.3, 2.5 Hz, 2H) 7.46 (t, J=73.0 Hz, 2H) 7.59 (t, J=7.8 Hz, 1H) 7.72-7.80 (m, 2H) 7.85 (t, J=1.9 Hz, 1H) 8.02 (dt, J=9.4, 2.6 Hz, 2H); MS (ES) m/z 401.1 [M+H]+
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:12]([NH:24][C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([NH2:30])=[O:29])[N:11]=1.CO.[OH-].[NH4+].[ClH:38]>CO>[ClH:9].[ClH:38].[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:12]([NH:24][C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=3)[C:28]([NH2:30])=[O:29])[N:11]=2)[CH2:4][CH2:3]1
Reactant: NC(=O)c1cccc(Nc2nc(Cl)nc3c2ncn3C2CCCC2)c1
Reactant: N[C@H]1CC[C@H](N)CC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3c2ncn3C2CCCC2)c1
Reaction time: 5 h

Procedure:
400 mg of trans-1,4-diaminocyclohexane and 250 mg of the product obtained in Stage 1 above are taken to approximately 150° C., the reaction medium is left under agitation for 5 hours then left to return to ambient temperature for 16 hours. 8 ml of methanol is added, chromatography on silica is carried out (eluent: MeOH/NH4OH 98/2). The residue is taken up in an ethanolic solution of hydrochloric acid, followed by evaporating the solvents, impasting in ether, separating, drying under reduced pressure at ambient temperature and 101 mg of expected product is recovered.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH:11]=[CH:10]2.CN([CH:32]=[O:33])C>>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=1)[CH:11]=[C:10]2[CH:32]=[O:33]
Reactant: CS(=O)(=O)c1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(Cn2cc(C=O)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DMF (10 mL) was cooled in an ice bath and phosphorus oxychloride (1.4 mL) added over 20 seconds. The solution was stirred for 10 minutes at room temperature then a solution of the product of step i) (2.0 g) in DMF (4 mL) was added over 5 minutes. The mixture was heated at 95° C. for 16 hours then allowed to cool and poured onto ice/water. The mixture was then extracted into ethyl acetate (100 mL) the organics combined and evaporated under reduced pressure. The residue was purified (SiO2 chromatography, eluting with 1:1 ethyl acetate:isohexane) to give the sub-titled compound (1.5 g).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:29][N+:30]1[CH:35]=[CH:34][C:33]([C:36]2C=CC=CC=2C=O)=[CH:32][CH:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:33]3[CH:34]=[CH:35][N+:30]([O-:29])=[CH:31][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccccc1-c1cc[n+]([O-])cc1
Product: [O-][n+]1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 1-oxidopyridin-4-yl benzaldehyde. MS (ESI) m/z 484.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=1>C1(C)C(C)=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[N:14][CH:15]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1C
Product: O=C1c2ccccc2C(=O)N1c1ccc(Cl)cn1
Temperature: 5 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a stirred solution at 120° C. containing 30 grams of phthalic anhydride in 500 ml. of xylene, 26 grams of 2-amino-5-chloropyridine was added in one portion. The stirred solution was heated at reflux for 4 to 5 hours during which time 3.6 ml. of water was removed. After stirring at 25°-30° C. for 18 hours, the slurry was cooled to 5° C., the solids collected by filtration and air dried at 25°-30° C. An 89 percent yield of N-(5-chloro-2-pyridyl)phthalimide, m.p. 153°-5° C., was obtained.
Reaction SMILES: C(=O)=O.CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:14]1([C:17]2[C:22]([CH2:23][OH:24])=[CH:21][N:20]=[C:19]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[N:18]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C>ClCCl.CCOCC>[CH:14]1([C:17]2[C:22]([CH:23]=[O:24])=[CH:21][N:20]=[C:19]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][CH:26]=3)[N:18]=2)[CH2:16][CH2:15]1
Reactant: OCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a dry ice cooled solution of 0.86 ml (12 mmol) DMSO in 10 ml dichloromethane was added 0.68 ml (7.79 mmol) oxalylchloride. After the reaction mixture was stirred for 5 min at −70° C., 1.8 g (5.99 mmol) of [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol, dissolved in 8 ml dichloromethane, was added by dropping within 5 min. The reaction mixture was then stirred for further ten minutes at −70° C. and after 4.17 ml (30 mmol) triethylamine was added, the reaction mixture was allowed to come to RT and it was stirred for 1 h at RT. The mixture was taken up in ether and washed with 1N HCl and water. The ether phase was concentrated under reduced pressure to give 1.75 g of pure 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbaldehyde.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].ClCCl>[Pd].C(OCC)(=O)C.C(O)(=O)C>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[C:15]([NH2:17])[CH:14]=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CCN(c2cc(-c3ccccc3)cc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2cc(N)cc(-c3ccccc3)c2)CC1
Reaction time: 1.5 h

Procedure:
Palladium on carbon (10 wt %, 13 mg, 0.012 mmol) was added to a solution of 1-(methylsulfonyl)-4-(5-nitrobiphenyl-3-yl)piperazine (44.1 mg, 0.122 mmol) in ethyl acetate (1 mL) and acetic acid (0.1 mL) and the reaction mixture was stirred under an atmosphere of H2 (balloon) for 90 minutes. Dichloromethane was added to the reaction mixture, and the mixture was filtered through CELITE, rinsed with ethyl acetate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) to provide 5-[4-(methylsulfonyl)piperazin-1-yl]biphenyl-3-amine as a white foam. 1H NMR (400 MHz, Acetone) δ 9.18 (s, 1H), 8.82 (d, J=4.9 Hz, 1H), 7.77-7.63 (m, 3H), 7.47 (dd, J=10.4, 4.7 Hz, 2H), 7.37 (t, J=7.4 Hz, 1H), 7.23 (d, J=4.9 Hz, 1H), 7.02 (d, J=1.5 Hz, 1H), 3.43 (dd, J=12.4, 5.3 Hz, 8H), 2.91 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:22]1[CH:23]=[C:24]([C:27]([OH:29])=[O:28])[S:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCOCC1.O>[N+:9]([C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:22]2[CH:23]=[C:24]([C:27]([OH:29])=[O:28])[S:25][CH:26]=2)[CH:5]=[CH:6][CH:7]=1)([O-:11])=[O:10]
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Reactant: O=C(O)c1cc(Br)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(-c2csc(C(=O)O)c2)cccc1[N+](=O)[O-]
Yield: 133.4 %

Procedure:
2-(2-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4d (0.81 g, 2.9 mmol), 4-bromo-thiophene-2-carboxylic acid (0.3 g, 1.45 mmol), tetrakis (triphenylphosphine)palladium (80 mg, 0.073 mmol) and sodium carbonate (0.31 g, 2.9 mmol) were dissolved in a solvent mixture of 20 mL of 1,4-dioxane and 10 mL of water. The reaction was heated to reflux for 0.5 hours. The mixture was adjusted to pH 3 with 1 N hydrochloric acid and extracted with ethyl acetate (20 mL×3). The combined organic extracts were concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound 4-(3-nitro-2-methoxy-phenyl)-thiophene-2-carboxylic acid 19a (0.54 g) as a brown oil, which was directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]#[N:19])[CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C(O)=C>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[CH:4][C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])[C:18]#[N:19])[CH:12]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: N#CCc1cccnc1
Agent: C=CO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#CC(=Cc1ccc(Cl)cc1Cl)c1cccnc1
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
To a stirred solution of 2,4-dichlorobenzaldehyde (5.0 g, 29 mmole) and 3-pyridylacetonitrile (3.05 ml, 29 mmole) in 150 ml absolute ethenol were added 3.95 g K2CO3. After stirring for about 15 minutes, a white solid precipitated out of the reaction mixture. The reaction mixture was stirred overnight and filtered. The filter cake was washed with absolute ethanol and dissolved in CH2Cl2. The CH2Cl2 solution was filtered and concentrated in vacuo. The resulting white solid was recrystallized from 3:2 hexane/ethyl acetate to give 6.0 g (76%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]#[N:14])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][C:18]([N+:35]([O-])=O)=[C:19]([NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=3)=O)[CH:20]=2)[CH:9]=1>C1COCC1.O.[Fe].CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]#[N:14])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][C:18]3[N:35]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=4)[CH2:23][C:22](=[O:34])[NH:21][C:19]=3[CH:20]=2)[CH:9]=1
Reactant: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3cc(C#N)c(-c4ccccc4Cl)c3)ccc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cccc(C2=Nc3ccc(-n4cc(C#N)c(-c5ccccc5Cl)c4)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from N-{5-[3-(2-chloro-phenyl)-4-cyano-pyrrol-1-yl]-2-nitro-phenyl}-3-(3-cyano-phenyl)-3-oxo-propionamide (Example M6) by reductive cyclization with Fe/HOAc in THF/H2O at 80° C. according to the general procedure J (method d). Obtained as a brown solid (164 mg).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][C:4]2[C:9]=1[CH:8]=[CH:7][C:6](=O)[N:5]=2.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:6]1[N:5]=[C:4]2[CH:3]=[CH:2][NH:1][C:9]2=[CH:8][CH:7]=1
Reactant: O=C1C=CC2=NC=CC2=N1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2[nH]ccc2n1

Procedure:
A mixture of pyrrolo[3,2-b]pyrid-5-one (prepared according to the procedure described in J. Med. Chem. 1990, 33, 2087) (1.33 g, 9.91 mmol) and 20 mL of phosphorous oxychloride is heated in a sealed Parr high pressure stainless steel vessel at 180° C. for 2.5 hours. After cooling, excess phosphorous oxychloride is removed in vacuo. The residue is cooled in an ice bath and quenched with ice water. The resulting mixture is neutralized by addition of saturated NaHCO3 solution and extracted with EtOAc (3×). The combined organic layers are dried over MgSO4, filtered and concentrated in vacuo. The crude product (1.07 g, 7.01 mmol) is used in the subsequent step without further purification.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1.O.[NH2:38][NH2:39].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:21][C:19]([F:20])([F:22])[O:18][C:14]1[CH:13]=[C:12]([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:38][N:39]=[C:24]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=4)[C:3]=3[C:4]2=[O:23])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cc1ccc(C(F)(F)F)cc1)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccc(C(F)(F)F)cc3)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
To a suspension of 4-hydroxy-1-(3-trifluoromethoxyphenyl)-3-(4-trifluoromethylphenylacetyl)-1,8-naphthyridine-2(1H)-one (508 mg, 1.0 mmol) produced in Synthesis Example 22 in DMF (8 mL) was added hydrazine monohydrate (purity of 80%, 194 μL), and the mixture was stirred at 100 to 110° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 5-(3-trifluoromethoxyphenyl)-3-(4-trifluoromethylbenzyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (162 mg, yield 32%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][CH:37]([NH:39][CH2:40][CH2:41][NH2:42])[CH3:38]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:42][CH2:41][CH2:40][NH:39][CH:37]([CH3:38])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: CC(C)NCCN
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCNC(C)C)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 46.5 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (30 mg, 0.06 mmol) in DCM (5 mL) was added N-(1-methylethyl)-1,2-ethanediamine (0.037 mL, 0.30 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (15 mg, 46%). LC-MS m/z 538 (M+H)+; 1H-NMR (MeOD) δ 1.00 (m, 9H), 1.65 (m, 2H), 2.31 (s, 3H), 2.61 (m, 2H), 2.73 (m, 2H), 3.20 (m, 2H), 3.40 (m, 1H), 4.11 (s, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)/[C:5](=[N:7]/[OH:8])/[NH2:6].[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[C@@H:23]([CH3:27])[C:24](O)=O.C(=NC1CCCCC1)=NC1CCCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:27]([C@@H:23]([N:14]3[C:15](=[O:22])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]3=[O:12])[CH3:24])[O:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: N/C(=N\O)c1cccc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: C[C@@H](c1nc(-c2cccc(Cl)c2)no1)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
To a stirred solution of (Z)-3-chloro-N′-hydroxybenzimidamide (500 mg, 2.93 mmol) and (S)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (642 mg, 2.93 mmol) was added N,N′-methanediylidenedicyclohexanamine (1.1 eq, 665 mg, 3.22 mmol) and allowed to reflux at 100° C. for 12 hours. Concentrate in vacuo, dilute w/EtOAc, filter washing w/EtOAc, wash w/water, brine, concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting w/0-10% EtOAc/DCM afforded 300 mg. HRMS m/z 353.0567
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C:11]([CH2:13][CH3:14])=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:9]2=[O:22])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24].B.[Na].CO.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][CH3:14])[CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:9]2=[O:22])=[CH:4][C:3]=1[C:23]([F:25])([F:26])[F:24]
Reactant: CCC1=C(c2cccc(F)c2)C(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: CCC1CN(c2ccc(Cl)c(C(F)(F)F)c2)C(=O)C1c1cccc(F)c1
Reaction time: 1 h
Yield: 95.4 %

Procedure:
14.0 g (36.4 mmol) of 1-(4-chloro-3-trifluoromethylphenyl)-4-ethyl-3-(3-fluorophenyl) -3-pyrroline-2-one synthesized in Example 5 and 1.10 g (29.1 mmol) of sodium boron hydride were dissolved in 120 ml of tetrahydrofuran, and 22 ml of methanol were slowly added to the solution over about 1.5 hours, while the solution was heated under reflux. Reaction was allowed to proceed at the same temperature for further 1 hour, and the reaction mixture was then poured into 1 N hydrochloric acid, followed by extraction with ethyl acetate. The resultant organic layer was washed with water, an aqueous saturated sodium bicarbonate solution and water in this order, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and n-hexane was then added to the resultant residue to achieve crystallization, followed by recrystallization from ether-n-hexane, thereby obtaining 13.4 g of the desired product in the state of colorless crystals (yield 95%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]([CH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>ClCCCl>[Cl:18][CH2:19][C:20]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:12][C:13]2[NH:17][N:16]=[N:15][N:14]=2)=[CH:7][CH:8]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: c1ccc(OCc2nnn[nH]2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCl)c1ccc(OCc2nnn[nH]2)cc1
Reaction time: 8 h

Procedure:
Aluminium chloride (30.3 g) was added to a stirred mixture of the product of step (i) above (10 g) and chloroacetyl chloride (19.3 g) in dry 1,2-dichloroethane and stirring continued overnight. The mixture was concentrated to about half volume on the steam bath, cooled and added to an ice/hydrochloric acid mixture. After stirring for 15 minutes the solid was collected and, on recrystallisation from methanol/water, gave 5-(4-chloroacetylphenoxymethyl)tetrazole, 7.5 g: m.p. 194°-196° C.; NMR (d6DMSO) δ 7.99 (2H, d), 7.20 (2H, d), 5.61 (2H, s), 5.11 (2H, s); m/e 251 (M-H)-, 1 Cl pattern; calculated for C10H9ClN4O2 : C, 47.5; H, 3.6; N, 22.2. found: C, 47.3; H, 3.7; N, 22.2%.