Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:3]=1[NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH2:6]1.[CH:34](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:33][S:30]([C:28]1[CH:27]=[CH:26][C:3]2[N:4]([CH:5]3[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][CH:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:9][CH2:10]3)[CH:34]=[N:1][C:2]=2[CH:29]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)c1ccc(NC2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c(N)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CS(=O)(=O)c1ccc2c(c1)ncn2C1CCN(CCC(c2ccccc2)c2ccccc2)CC1

Procedure:
A solution of 2-amino-4-methanesulphonyl-1-N-[-1-(3,3-diphenylpropyl)-piperidin-4-yl]aniline (prepared as described below) (50 mg, 0.1 mmol), trimethyl orthoformate (0.7 ml) and para-toluenesulphonic acid monohydrate (2 mg, 0.11 mmol) was stirred at 100° C. After 2.5 h the mixture was cooled and water (10 ml) was added. The solution was partitioned with EtOAc (2×40 ml) then the organics were combined, dried (MgSO4) and concentrated to give the title compound as an oil (47 mg, 0.1 mmol); MS: 474.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](SC)=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[C:14]#[N:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:22][CH:23]([NH2:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([NH:28][CH:23]([CH3:22])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[C:14]#[N:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(NC(SC)=C(C#N)S(C)(=O)=O)cc(OC)c1
Reactant: CC(N)C(C)(C)C
Product: COc1cc(NC(NC(C)C(C)(C)C)=C(C#N)S(C)(=O)=O)cc(OC)c1

Procedure:
3-(3,5-dimethoxyphenylamino)-2-methanesulfonyl-3-methylsulfanyl-2-propenenitrile (0.263 g, 0.8 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in Example 17, 2) gave the title compound as a syrup, 262 mg (86%). 1H NMR (200 MHz, CDCl3): δ=0.85 (s, 9H), 1.01 (d, 3H), 3.12 (s, 3H), 3.26 (m, 1H), 3.78 (s, 6H), 6.25 (d, 2H), 6.35 (t, 1H); EI SP/MS: 381 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1.[H-].[Na+].[CH3:16]I.CO>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:16])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: O=c1[nH]cnc2cc(Cl)nc(Cl)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5,7-dichloropyrido[4,3-d]pyrimidin-4(3H)-one (1 g, 4.65 mmol) was dissolved in anhydrous DMF 15 mL, and NaH (60% mineral oil, 205 mg, 5.11 mmol) was slowly added into the reaction solution. The reaction was stirred at room temperature for 15 minutes, then CH3I (730 mg, 5.11 mmol) in DMF was added drop-wise into the solution. The reaction was heated to 50° C. for 1 hour and then cooled down to room temperature. Methanol was then added to quench the reaction and the solvent was removed under the vacuum. The crude product was purified by silica column chromatography using hexane/ethyl acetate 1:1 to obtain the final compound 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one. 1H NMR (DMSO-d6) δ 8.64 (s, 1H), 7.74 (s, 1H), 3.46 (s, 3H); ESI-MS m/z 230.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.C(OO)(=[O:17])C>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][C:6]1[CH:7]=[N+:8]([O-:17])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)OO
Reactant: Fc1cccc(Oc2cccnc2)c1
Solvent: CC(=O)O
Product: [O-][n+]1cccc(Oc2cccc(F)c2)c1

Procedure:
A solution of 32 g of 3-(3-fluorophenoxy)pyridine [Fr. Pat. No. 1,472,619 (1967)] in 50 ml of glacial acetic acid is treated with 35 g of 40% peracetic acid in acetic acid and the mixture is refluxed 16 hours. The mixture is concentrated at reduced pressure and the oil is dissolved in 250 ml of dichloromethane. The dichloromethane solution is washed with excess 10% sodium hydroxide solution. The solution is dried and concentrated to dryness to yield 3-(3-fluorophenoxy)pyridine 1-oxide, m.p. 63°-66° C.
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[C:8]([C:14]([OH:16])=[O:15])[C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[CH2:4][CH2:3][O:2]1.C(OC(=O)C)(=O)C>>[CH2:1]1[C:6]2[CH:7]=[C:8]3[C:14](=[O:15])[O:16][C:11](=[O:13])[C:9]3=[CH:10][C:5]=2[CH2:4][CH2:3][O:2]1
Reactant: O=C(O)c1cc2c(cc1C(=O)O)COCC2
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc3c(cc21)CCOC3
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 82.6 %

Procedure:
A mixture of 3,4-dihydro-1H-2-benzopyran-6,7-dicarboxylic acid (7.28 g, 32.8 mmol) and acetic anhydride is stirred for 3.5 hours at 100° C., allowed to stand overnight at room temperature and filtered. The filter cake is washed with ether and dried to give the title product as a white solid (5.53 g, 82.7%). Recrystallization gives mp 156°-158° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23]Br)[CH:7]=1)[CH3:2].[F:26][C:27]([F:31])([F:30])[CH2:28][SH:29]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[CH2:23][S:29][CH2:28][C:27]([F:31])([F:30])[F:26])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Reactant: FC(F)(F)CS
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1

Procedure:
As described for Example 21, [3-(2-bromomethyl-4-nitro-phenoxy)-4-chloro-phenyl]acetic acid ethyl ester and 2,2,2-trifluoroethanethiol were reacted to provide {4-chloro-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester, which was reduced to the amine and then treated with pivaloyl chloride to provide {4-chloro-3-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester provided the acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]3[CH2:22][CH2:21][N:20](C#N)[CH2:19][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#CN1CCC(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Yield: 75.6 %

Procedure:
A stirred mixture of 4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 102 (30 g, 0.094 moles) and 25% H2SO4 (225 ml) was refluxed for 20 hours. The mixture was cooled, poured into H2O, and basified with a 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 21 g (76%) of 1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indazole as an oil. To a stirred suspension of the indazole (3.5 g, 0.012 moles) and triethylamine (3.3 ml, 0.024 moles) in toluene (50 ml) was added methyl chloroformate (1.0 ml, 0.013 moles). The mixture was stirred for 17 hours at ambient temperature and was then poured into H2O. The product was extracted (ethyl acetate), dried (Mg SO4), and concentrated to yield 4.6 g of an oil. The product was purified on the HPLC (silica gel:ethyl acetate-hexane, 1:2) which produced 3.0 g (72%) of 4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carboxylic acid methyl ester, m.p. 95°-97° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([C:11]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(OCC)(=O)C>[CH2:5]([C:11]1[S:15][C:14]([N:16]=[C:1]=[O:2])=[N:13][N:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCc1nnc(N)s1
Solvent: CCOC(C)=O
Product: CCCCCCc1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-hexyl-2-amino-1,3,4-thiadiazole (40 grams) in ethyl acetate (300 ml) is added to the reaction vessel, and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-hexyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([OH:17])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O[C:19]1[CH:35]=[CH:34][C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH:31]([N:28]1[CH2:29][CH2:30][N:25]([C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([O:16][C:15](=[O:17])[CH:14]=[C:12]3[C:13]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:35][CH:34]=2)[CH2:26][CH2:27]1)([CH3:33])[CH3:32]
Reactant: CC(C)N1CCN(C(=O)c2ccc(O)cc2)CC1
Reactant: O=C(O)C=C1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc(OC(=O)C=C3c4ccccc4-c4ccccc43)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 20 ml chloroform solution containing 2.67 g (12 mmol) of 9-fluorenylidene acetic acid, 2.48 g (10 mmol) of 1-(4-hydroxybenzoyl)-4-isopropylpiperazine and 122 mg (1 mmol) of 4-dimethylaminopyridine was added 2.48 g (12 mmol) of dicyclohexyl carbodiimide, and the mixture was stirred at room temperature for 3 hours. Any insoluble matter which had formed was removed by filtration, and the filtrate was concentrated under reduced pressure. Thereafter, any insoluble matter was removed by filtration using 20 ml of ethyl acetate, and the filtrate was extracted up to 60 ml of 1N hydrochloric acid. After being washed with ethyl acetate, the extract was neutralized with sodium hydrogen carbonate and extracted up to 60 ml of chloroform. After being washed twice with water, the extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain yellow crystals. Recrystallization of the crystals from ethyl acetate-petroleum ether gave yellow prismatic crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].F[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17]>C1COCC1>[N+:16]([C:7]1[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:6]=1[NH:1][CH2:2][CH2:3][OH:4])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: NCCO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.9 %

Procedure:
To a stirred solution of 2-aminoethanol (5 ml, 150 mmol) in THF (20 ml), 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (6.9 ml, 50 mmol) was added slowly at 0° C. After the completion of the addition, the reaction mixture was stirred at RT for 24 hrs. THF was evaporated using a rotary evaporator and the residue was extracted using water and ethyl acetate. Ethyl acetate was washed with more water, dried and evaporated to give crystalline 2-aminoethanol derivative (10.0 g, 80%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH:13]([C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)[C:14]([O:16]C)=[O:15].Cl>>[NH2:3][CH2:12][CH:13]([C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)[C:14]([OH:16])=[O:15]
Reactant: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1ccsc1
Agent: Cl
Product: NCC(C(=O)O)c1ccsc1

Procedure:
To methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(thiophen-3-yl)propanoate (E429) was added 6 N HCl and the solution was refluxed for 4 h. The solvents were evaporated to give 3-amino-2-(thiophen-3-yl)propanoic acid (E430).
Reaction SMILES: [CH3:1][C:2]12[CH2:18][CH2:17][CH:16]([O:19][C:20](=[O:60])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]3[CH2:33][CH:32]([OH:34])[CH2:31][CH:30]3[CH:35]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[O:36][CH:37]([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)=[O:28])[CH2:15][C:14]1=[CH:13][CH2:12][CH:11]1[CH:3]2[CH2:4][CH2:5][C:6]2([CH3:69])[CH:10]1[CH2:9][CH2:8][CH:7]2[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68].[C:70]1(=[O:76])[O:75][C:73](=[O:74])[CH2:72][CH2:71]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([CH:37]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[O:36][CH:35]([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:30]2[N:29]([C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]([O:19][CH:16]3[CH2:15][C:14]4[C:2]([CH3:1])([CH:3]5[CH:11]([CH2:12][CH:13]=4)[CH:10]4[C:6]([CH3:69])([CH:7]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:8][CH2:9]4)[CH2:5][CH2:4]5)[CH2:18][CH2:17]3)=[O:60])[CH2:33][CH:32]([O:34][C:70](=[O:76])[CH2:71][CH2:72][C:73]([OH:75])=[O:74])[CH2:31]2)=[CH:47][CH:48]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCCC1CCC2C3CC=C4CC(OC(=O)NCCCCCC(=O)N5CC(O)CC5C(OC(c5ccc(OC)cc5)c5ccc(OC)cc5)c5ccccc5)CCC4(C)C3CCC12C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC1CCC2C3CC=C4CC(OC(=O)NCCCCCC(=O)N5CC(OC(=O)CCC(=O)O)CC5C(OC(c5ccc(OC)cc5)c5ccc(OC)cc5)c5ccccc5)CCC4(C)C3CCC12C
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
Referring to scheme 3, Compound 6 (22 g, 23.2 mmol) was mixed with succinic anhydride (3.48 g, 34.8 mmol) and DMAP (0.283 g, 2.32 mmol) and dried in a vacuum at 40° C. overnight. The mixture was dissolved in anhydrous dichloromethane (50 mL), triethylamine (7 g, 9.6 mL, 70 mmol) was added and the solution was stirred at room temperature under argon atmosphere for 16 h. It was then diluted with dichloromethane (100 mL) and washed with ice cold aqueous citric acid (5% wt., 100 mL) and water (2×100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography to afford compound 8 as white solid (21.7 g, 89% yield; Rf=0.5 in 10% MeOH/CHCl3).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].CN(C=O)C.[CH2:12]([C:17]1[CH:22]=[CH:21][C:20](/[C:23](/C)=[CH:24]/C(O)=O)=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH2:15][CH3:16]>ClCCl>[CH2:12]([C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[CH3:24])=[CH:1]/[C:2]([Cl:4])=[O:3])=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCc1ccc(/C(C)=C/C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCc1ccc(/C(C)=C/C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Oxalyl chloride (3.2 mL, 36.60 mmol) and DMF (50 μL) were added drop wise to a solution of compound 1003 (5.0 g, 21.52 mmol) in dichloromethane (100 mL) at 0° C. The reaction solution was warmed up to room temperature and stirred for 4 hours. The reaction mixture was concentrated in vacuum and the residue was dried under hi-vacuum for 3 hours. The crude product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:14].[CH3:15][C:16]1[CH:36]=[CH:35][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:24]=2)=[O:21])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>CC(O)C>[N:29]1([C:25]2[CH:24]=[C:23]([NH:22][C:20]([C:19]3[CH:35]=[C:36]([C:2]4[CH:7]=[CH:6][C:5]([C:8]5[N:12]=[C:11]([CH3:13])[O:10][N:9]=5)=[CH:4][C:3]=4[CH3:14])[C:16]([CH3:15])=[CH:17][CH:18]=3)=[O:21])[CH:28]=[CH:27][CH:26]=2)[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: Cc1nc(-c2ccc(Br)c(C)c2)no1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Solvent: CC(C)O
Product: Cc1nc(-c2ccc(-c3cc(C(=O)Nc4cccc(N5CCOCC5)c4)ccc3C)c(C)c2)no1

Procedure:
Example 32 was prepared using 3-(4-bromo-3-methylphenyl)-5-methyl-[1,2,4]oxadiazole and 4-methyl-N-(3-morpholin-4-yl-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) -benzamide (Intermediate 5) with propan-2-ol as the solvent.
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[CH2:18]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22])[CH3:19]>CS(C)=O>[CH2:18]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH3:19]
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Reactant: CCc1ccccc1N
Solvent: CS(C)=O
Product: CCc1ccccc1Nc1c(Nc2ccccc2O)c(=O)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2-ethylaniline (0.024 mL, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 309 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:22]1([NH:32]N)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:32]([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(Br)c2)ccc1=O
Reactant: NNc1cccc2ccccc12
Product: O=c1ccn(-c2cccc(Br)c2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
The product was obtained starting from 1-(3-Bromo-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-18) and naphthalen-1-yl-hydrazine according to the method described for example 1. MS: M=443.2 (M+H)+
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6](F)[CH:7]=[CH:8][CH:9]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>CS(C)=O.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: Fc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Brc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an amount of 400 mg of imidazole was dissolved in 7.5 ml of dimethyl sulfoxide under argon atmosphere, added with 255 mg of 60% sodium hydride, and stirred at room temperature. After 1 hour, the reaction mixture was added with 0.8 ml of 3-bromofluorobenzene, and stirred at 140° C. for 21 hours. The reaction mixture was diluted with 50 ml of ethyl acetate, and washed with 20 ml of saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate (3:1 to 1:1)) to obtain 1.1 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:35]([NH:37]O)=[NH:36])=[CH:31][N:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:27][N:37]=[C:35]([C:32]5[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=5)[N:36]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Reactant: N=C(NO)c1cnc(N)nc1
Product: Nc1ncc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)c(Cl)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.17) (205 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example B.5) (115 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (150 mg, 57%). MS (EI) 526.1 [(M)+]; mp 279° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].[NH2:24][CH2:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH:24][CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Reactant: NC[C@H]1CC[C@H](CCO)CC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CCO)CC4)cc3)oc12

Procedure:
The title compound was prepared from 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (INTERMEDIATE 2), and 2-[trans-4-(aminomethyl)cyclohexyl]ethanol (INTERMEDIATE 8) as described in EXAMPLE 1. Mass spectrum (ESI) 446.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][N:16]=2)[N:12]=[CH:11]1.C1C(=O)N([Br:30])C(=O)C1>C(Cl)Cl>[Br:30][C:14]1[N:10]([CH2:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:11]=[N:12][C:13]=1[C:15]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][N:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccnc(-c2cn(CCc3ccccc3Cl)cn2)c1
Solvent: ClCCl
Product: N#Cc1ccnc(-c2ncn(CCc3ccccc3Cl)c2Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 2-[1-[2-(2-chlorophenyl)ethyl]imidazol-4-yl]pyridine-4-carbonitrile (1 eq) in DCM (10 mL) was added NBS (1.05 eq) at rt and stirred for 3 hr at rt. Washed by H2O, dried and concentrated to afford the title compound (95%). [M+H] Calc'd for C17H12BrClN4, 387. Found, 387.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([Br:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][C:32]([F:35])([F:34])[F:33])[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([Br:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][C:32]([F:33])([F:34])[F:35])[N:17]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2Br)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
(4-{[5-Bromo-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester (75 mg, 0.13 mmol) was dissolved in CH2Cl2 (2 mL). To this solution was added TFA (2 mL) and the reaction was stirred at 25° C. for 1 h. The volatiles were removed in vacuo. The crude was redissolved in CH2Cl2 and poured into 10% aqueous NaHCO3. The aqueous phase was separated and extracted two more times with CH2Cl2. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The crude was purified via flash chromatography (SiO2, 2-10% (NH4OH:CH3OH:CH2Cl2—CH2Cl2)) to afford 45 mg (73%) of the target compound, m/z 474.38 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)=[CH:4][CH:3]=1.CO>O1CCCC1.[Pt].[C]>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[CH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc(Oc2ccc(Br)cc2)nc1
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cnc(Oc2ccc(Br)cc2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
Under an argon atmosphere, to a solution of 2-(4-bromophenoxy)-5-nitropyrimidine (400 mg) in tetrahydrofuran (20 mL)/methanol (20 mL) was added 3% platinum-carbon (200 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered through Celite® to give the titled compound (363 mg) having the following physical data.