Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=4)[C:13]([Cl:22])=[N:12][N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH2:26][CH2:25]1>>[ClH:22].[ClH:22].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=4)[C:13]([NH:23][CH:24]4[CH2:25][CH2:26][N:27]([CH2:30][C:31]5[CH:40]=[CH:39][C:38]6[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=6)[CH:32]=5)[CH2:28][CH2:29]4)=[N:12][N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc2c(-c3ccc4c(c3)OCO4)nnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1ccc2c(-c3ccc4c(c3)OCO4)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1
Product: Cl

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 4-(1,3-benzodioxol-5-yl)-1-chloro-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine. By treatment with a solution of hydrogen chloride in diethyl ether, a precipitate forms, which is filtered off, washed with diethyl ether and dried under reduced pressure. The hydrochloride obtained is in the form of a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][C@@H:23]([CH3:26])[CH2:24][OH:25]>>[OH:25][CH2:24][C@@H:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH3:26]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: C[C@H](N)CO
Product: C[C@@H](CO)Nc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 61 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (S)-2-amino-propan-1-ol according to the GPA affording 21.4 mg (61%) of a red powder. Rt=3.20 min.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:12][C:11]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.C(N(CC)CC)C.Cl[C:45]([O:47][CH3:48])=[O:46]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:18][CH2:19][N:20]([C:45]([O:47][CH3:48])=[O:46])[CH2:21][CH2:22]2)=[N:12][C:11]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(C3CCNCC3)[nH]c(=O)c2-c2nc3ccccc3s2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCC(c2nc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c(-c3nc4ccccc4s3)c(=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.9 %

Procedure:
Into a solution of tert-butyl (3R)-3-[[5-(1,3-benzothiazol-2-yl)-6-oxo-2-(piperidin-4-yl)-1,6-dihydropyrimidin-4-yl]amino]piperidine-1-carboxylate (100 mg, 0.20 mmol, 1.00 equiv) and triethylamine (29.7 mg, 0.29 mmol, 1.50 equiv) in dichloromethane (5 ml) was added methyl chloroformate (14.8 mg, 0.16 mmol, 0.80 equiv). The resulting mixture was stirred for 2 h at room temperature. Concentration under reducing pressure gave 100 mg of the title compound as a crude product, which was used directly for next step without further purification. MS m/z [M+H]+ (ESI): 569.
Reaction SMILES: [CH3:1][N:2]([CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[C:3]([C:5]1[CH:13]=[CH:12][C:8]2=[N:9][O:10][N:11]=[C:7]2[CH:6]=1)=[O:4].Cl.[NH2:22][OH:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:23][N:22]=[C:17]1[CH2:18][CH2:19][CH:14]([N:2]([CH3:1])[C:3]([C:5]2[CH:13]=[CH:12][C:8]3=[N:9][O:10][N:11]=[C:7]3[CH:6]=2)=[O:4])[CH2:15][CH2:16]1
Reactant: NO
Reactant: CN(C(=O)c1ccc2nonc2c1)C1CCC(=O)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc2nonc2c1)C1CCC(=NO)CC1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
N-Methyl-N-(4-oxocyclohexyl)-[2,1,3]-benzoxadiazole-5-carboxamide (0.41 g, 1.5 mmol) was dissolved in chloroform (10 ml), hydroxylamine hydrochloride (0.63 g) and triethylamine (1.6 ml) were added, and the mixture stirred overnight. Evaporation of the solvent and chromatography of the residue on silica gel, eluting with chloroform/ethyl acetate (3:2), gave a white solid (0.37 g). Mp=197-198° C., 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H); 7.93 (d, J=9.0 Hz, 1H); 7.86 (m, 1H); 7.43 (d, J=9.0 Hz, 1H); 4.90-4.70 and 3.80-3.35 (m, 1H); 2.99 and 2.88 (s+s, 3H); 2.80-1.50 ppm (s, 8H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]#[CH:19].[I-].[K+]>C(C(C)=O)C.C1(C)C=CC=CC=1>[CH2:19]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][OH:1])[C:18]#[CH:17]
Reactant: OCc1ccccc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCC(C)=O
Product: C#CCOc1ccccc1CO

Procedure:
To 2-(hydroxymethyl)phenol (10.0 g, 80.6 mmol) slurried in 300 ml of methyl ethyl ketone was added 1.2 equivalents of potassium carbonate. Then 3-bromopropyne (121 mmol, 18 g of an 80% solution in toluene) and potassium iodide (0.5 g) were added and the reaction was refluxed overnight. After cooling the salts were filtered off. The filtrate was concentrated and the residue was dissolved in water and extracted twice with ether. After washing with water and brine, the organic layer was dried over MgSO4 and concentrated to afford the subtitle compound.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][CH:3]([C:4]=23)[C:2]1=[O:13].[H-].[Na+].Br[CH:17]=[CH:18][CH2:19][CH2:20][CH3:21].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH2:21]([C:3]12[CH2:12][CH2:11][CH2:10][C:5]3[C:4]1=[C:9]([CH:8]=[CH:7][CH:6]=3)[NH:1][C:2]2=[O:13])[CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: O=C1Nc2cccc3c2C1CCC3
Reactant: CCCC=CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCC12CCCc3cccc(c31)NC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2a,3,4,5-Tetrahydro-1H-benz[cd]indol-2-one (4.0 g, 23 mmol) was dissolved in anhydrous N,N-dimethylformamide (100 ml), and the solution was mixed with sodium hydride (760 mg, 190 mmol) and stirred at 0° C. for 1 hour. The reaction solution was mixed with 1-bromopentene (3.8 ml, 25 mmol) and stirred at −40° C. for 2 hours. Ethyl acetate, water and hydrochloric acid (1 N) were added to the reaction solution. The reaction product was extracted with ethyl acetate, washed with saturated brine and then dried with anhydrous sodium sulfate, and the material obtained by evaporating the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 2.7 g (11 mmol, 49% in yield) of the title compound.
Reaction SMILES: Cl.N([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([CH3:31])[CH:25]=1>CN(C)C=O>[ClH:23].[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[C:26]([CH3:31])[CH:25]=1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: Cc1cc(Cl)ccc1N
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ccc(Cl)cc2C)c2c(ccc3nc[nH]c32)n1

Procedure:
A solution of 22 g. (0.1 m.) of the compound of Example I, C. and 14 g. (0.1 m.) of 4-chloro-2-methylaniline in 200 ml. of dimethylformamide was heated under reflux for 17 hours and filtered hot. The crystalline product which separated on cooling was filtered, washed with cold dimethylformamide, then ether and air-dried, giving 22 g. of straw-colored product. Recrystallization from 550 ml. of ethanol gave 14 g. m.p. 199°-206°.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)=[O:3].[Se](=O)=[O:16]>>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[O:16])=[CH:5][C:6]=1[C:11]([F:14])([F:12])[F:13]
Reactant: O=[Se]=O
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Product: O=CC(=O)c1ccc(F)c(C(F)(F)F)c1

Procedure:
4-Fluoro-3-(trifluoromethyl)acetophenone (2 g, 9.70 mmol) was reacted with selenium dioxide (1.6 g, 14.6 mmol) using the method described in Example 1 to give crude (4-fluoro-3-trifluoromethylphenyl)-oxoacetaldehyde as a yellow oil: m/z (ES+) 221.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>O.[Cu]>[F:10][C:8]1[CH:7]=[CH:6][C:5]([C:11](=[O:13])[CH3:12])=[C:4]([NH:2][CH3:1])[CH:9]=1
Reactant: CN
Reactant: CC(=O)c1ccc(F)cc1Cl
Agent: [Cu]
Agent: [Na+]
Agent: [S-2]
Solvent: O
Product: CNc1cc(F)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of a solution of methylamine in industrial methylated spirit (33% w/w; 120 ml), industrial methylated spirit (60 ml), 2'-chloro-4'-fluoroacetophenone (51.6 g) and copper powder (0.75 g), was charged to a pressure vessel and heated to 90° for 2 hours. After cooling in an ice bath to 30° the mixture was transferred to a second vessel, heated at 50° and then a solution of sodium sulphide nonahydrate (2.88 g) in water (30 ml) added. The mixture was heated to reflux with stirring for 10 minutes and then filtered. Water (300 ml) was added to the filtrate and the solution heated to reflux. Hydrochloric acid (5M; 90 ml) was added to the hot solution and the mixture heated to reflux for a brief period. The reaction mixture was cooled to ambient temperature and aqueous sodium hydroxide solution (5M; 30 ml) added. The mixture was extracted with dichloromethane (600 ml) and then further extracted with dichloromethane (200 ml). The combined dichloromethane extracts were dried (magnesium sulphate) and evaporated in vacuo to give a crude brown oil. The oil was distilled in vacuo (b.p. 90°, 1 mmHg) to give 4'-fluoro-2'-(methylamino)-acetophenone, m.p. 52°-53°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH:9]([NH2:12])(C)[CH3:10].[CH2:13](Cl)Cl>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:12]([CH3:13])[CH2:9][CH3:10])(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: ClCCl
Reactant: CC(C)N
Product: CCN(C)S(=O)(=O)CCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
3-Chloropropanesulfonyl chloride (2.54 g) is dissolved in methylene chloride and isopropylamine (1.90 g) is added dropwise under ice cooling. After stirring at room temperature for 2 hours, the solution is extracted with methylene chloride and water to give crude 3-chloropropanesulfonyl methylethylamine (2.54 g, 89%) as pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:25]1[O:34][C:33]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=2[O:26]1>C(OCC)(=O)C>[O:34]1[C:33]2[CH:32]=[CH:31][C:29]([NH:30][C:14]3[N:15]=[CH:16][C:11]4[CH:10]=[C:9]([C:3]5[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=5[Cl:8])[C:22](=[O:23])[N:21]([CH3:24])[C:12]=4[N:13]=3)=[CH:28][C:27]=2[O:26][CH2:25]1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: Nc1ccc2c(c1)OCO2
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc4c(c3)OCO4)nc21
Temperature: 200 °C

Procedure:
A mixture of 0.113 g (0.29 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.50 g (3.70 mmol) of 3,4-methylenedioxyaniline was heated, with stirring, in a 200° C. oil bath. The resulting solution was heated for 5 minutes and cooled to room temperature. Ethyl acetate (2 mL) was added, and some traces of solids were filtered. The crystals that slowly developed in the filtrate were filtered and washed with 2 mL of ethyl acetate; wt 0.080 g. The solid was purified to remove dark colors by silica gel chromatography, eluting with chloroform and then 50% hexane/ethyl acetate to obtain pure crystalline product; wt 0.054 g; mp 240°-241° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[C:18]([C:22](Cl)=[O:23])[CH:17]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:22](=[O:23])[C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH3:25])[CH:17]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: Cc1cccc(C(=O)Cl)c1
Product: Cc1cccc(C(=O)NC2CCCc3c2[nH]c2ccc(Br)cc32)c1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methylbenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and m-toluoyl chloride in a similar manner as described above to give a tan solid (51% yield). 1H-NMR (CDCl3): δ 8.95 (s, 1H), 7.63-7.59 (m, 2H), 7.55 (m, 1H), 7.33 (m, 2H), 7.23 (m, 1H), 7.17 (d, 1H), 6.38 (d, 1H), 5.32 (m, 1H), 2.72 (m, 2H), 2.40 (s, 3H), 2.31 (m, 1H), 1.98 (m, 3H); MS m/z 383 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1C(C#N)=[N:11][S:10][N:9]=1.[OH-:15].[Na+].Cl.[CH2:18]([OH:20])[CH3:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:19]([C:18]([OH:15])=[O:20])=[N:11][S:10][N:9]=1
Reactant: [OH-]
Reactant: CCO
Reactant: N#Cc1nsnc1-c1ccccc1Cl
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1nsnc1-c1ccccc1Cl

Procedure:
In 1,3-dimethyl-2-imidazolidinone, were stirred 280 mg of 3-bromo-4-(2-chlorophenyl)-1,2,5-thiadiazole, and 180 mg of copper cyanide at 150° C. for 12 hours. After spontaneous cooling, the reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The diethyl layer was washed with dilute sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 120 mg of 3-(2-chlorophenyl)-4-cyano-1,2,5-thiadiazole. The obtained 3-(2-chlorophenyl)-4-cyano-1,2,5-thiadiazole (120 mg) was heated with 6 mL of 5% sodium hydroxide solution and 2 mL of ethanol, and refluxed for one hour. After spontaneous cooling, the reaction mixture was poured into a dilute hydrochloric acid solution, and the mixture was extracted with diethyl ether. The diethyl ether layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 100 mg of 4-(2-chlorophenyl)-1,2,5-thiadiazole-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[C:8]([OH:10])=O)=[O:5].[NH2:34][CH2:35][CH2:36][OH:37]>>[F:1][C:2]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:16][CH:17]=1)[C:8]([NH:34][CH2:35][CH2:36][OH:37])=[O:10])=[O:5]
Reactant: NCCO
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCC(F)(F)F)cc1F
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)c1ccc(OCCC(F)(F)F)cc1F

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 2-{[2-fluoro-4-(3,3,3-trifluoropropoxy)benzoyl]amino}-3-[4-(trifluoromethoxy)phenyl]propanoic acid (145 mg) prepared in Example 84 (84b) and 2-aminoethanol (22 μL) to give 128 mg of the title compound (white powder).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)=[N:26][CH:27]=1>>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:29]4[CH:30]=[CH:31][N:32]=[C:28]4[C:25]4[CH:24]=[CH:23][C:22]([F:21])=[CH:27][N:26]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: Fc1ccc(-c2ncc[nH]2)nc1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3ccc(F)cn3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 77, with Intermediate B instead of Intermediate C and with 5-fluoro-2-(1H-imidazol-2-yl)pyridine instead of 2-phenyl-1H-imidazole. LCMS: 422.3 m/z (M+H)+; ret. Time: 6.73 min (Analytical Method C).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[N:6]1[C:13](Cl)=[N:12][C:10](Cl)=[N:9][C:7]=1Cl.C([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])C>C(#N)C>[CH2:20]([N:17]([CH2:18][CH3:19])[C:7]1[N:9]=[C:10]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[N:12]=[C:13]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[N:6]=1)[CH3:21]
Reactant: CC(C)=NO
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)c1nc(ON=C(C)C)nc(ON=C(C)C)n1
Temperature: 45 °C
Reaction time: 21 h
Yield: 50.3 %

Procedure:
To a solution of acetone oxime (4.68 g, 0.063 mol) and cyanuric chloride (3.69 g, 0.020 mol) in dry acetonitrile (40 ml) is at room temperature added triethylamine (6.38 g, 0.063 mol). The temperature of the reaction mixture at the end of the addition rises up to 44° C. The mixture is then stirred for 21 h at 45° C., cooled to 8° C., the precipitated solid is filtered off and the filtrate is evaporated under reduced pressure. The residue is washed thoroughly with water and dried to afford 2.96 g of the title compound as a white solid, mp. 111-113° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:41][C:42]1[C:43]([CH3:59])=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47](O)=[O:48]>CN(C)C=O>[Br:41][C:42]1[C:43]([CH3:59])=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47]([NH:7][C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)=[O:48]
Reactant: Cc1cc(OCc2ccccc2)c(C(=O)O)cc1Br
Reactant: Nc1ccnnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCc2ccccc2)c(C(=O)Nc2ccnnc2)cc1Br
Reaction time: 0.17 h

Procedure:
4-Pyridazinamine (207 mg, 2.18 mmol), diisopropylethylamine (0.52 ml, 2.97 mmol) and HATU (904 mg, 2.38 mmol) were added to a solution of 5-bromo-4-methyl-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 9; 636 mg, 1.98 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred for 2 hours, after 10 minutes a solid had crashed out of solution. The solid was filtered and washed with ethyl acetate (10 ml) to yield the title compound. 475 mg.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].[CH2:9]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)[CH3:10].[CH:19]1([N+:24]#[C-:25])[CH2:23][CH2:22][CH2:21][CH2:20]1.Cl(O)(=O)(=O)=O>CO>[CH:19]1([NH:24][C:25]2[N:6]3[N:5]=[CH:4][C:3]([C:7]#[N:8])=[C:2]3[NH:1][C:15]=2[C:14]2[CH:17]=[CH:18][C:11]([CH2:9][CH3:10])=[CH:12][CH:13]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: [C-]#[N+]C1CCCC1
Reactant: CCc1ccc(C=O)cc1
Reactant: N#Cc1cn[nH]c1N
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: CCc1ccc(-c2[nH]c3c(C#N)cnn3c2NC2CCCC2)cc1
Reaction time: 0.08 h
Yield: 18.5 %

Procedure:
To a clear colorless solution of 5-amino-1H-pyrazole-4-carbonitrile (161 mg, 1.49 mmol) in methanol (3 mL) were added 4-ethylbenzaldehyde (200 mg, 204 μL, 1.49 mmol) followed by cyclopentyl isonitrile (143 mg, 167 μL, 1.49 mmol) and perchloric acid (29.9 mg, 26.7 μL, 0.298 mmol) at RT under nitrogen atmosphere. The resulting brown solution was stirred for 15 h and during this period (within 5 min) lot of solids were formed. The solids were collected by filtration and washed with methanol. After air drying, 88 mg (18.5% yield) of 3-(cyclopentylamino)-2-(4-ethylphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile was isolated as an off-white solid. LC/MS calcd. for C19H21N5 (m/e) 319.4, obsd. 320.1 (M+H, ES+).
Reaction SMILES: [K].[S:2]([CH2:6][CH2:7][NH:8][C:9](=[S:12])SC)([OH:5])(=[O:4])=[O:3].[N-:13]=[N+:14]=[N-:15].[Na+].O>CC(C)=O>[S:2]([CH2:6][CH2:7][N:8]1[C:9]([SH:12])=[N:15][N:14]=[N:13]1)([OH:5])(=[O:4])=[O:3]
Reactant: CSC(=S)NCCS(=O)(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [K]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)(O)CCn1nnnc1S

Procedure:
A mixture of 21.5 g. (0.087 mol.) of methyl 2-sulfoethyldithiocarbamate potassium salt (0.5 hydrate) and 7.16 g. (0.11 mol.) of sodium azide in 200 ml. of water was refluxed for two hours. The solution was cooled to 25° and extracted with ethyl acetate. The aqueous phase was treated with Amberlite IR-120H resin, washed with ether and evaporated to give an oil. The oil was dissolved in acetone, the solution was filtered and the filtrate was evaporated to dryness to give 1-(2-sulfoethyl)-tetrazole-5-thiol. The thiol was dissolved in isopropanol, cyclohexylamine was added until pH 8-9 and acetonitrile was added to give 1-(2-sulfoethyl)tetrazole-5-thiol as the di-cyclohexylamine salt.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[O:3].[NH2:8][CH2:9][C@@H:10](O)[CH3:11].[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([N:23]2[N:27]=[CH:26][CH:25]=[N:24]2)=[C:18]([CH:22]=1)[C:19](O)=[O:20]>C1(C)C=CC=CC=1>[CH3:11][C@@H:10]1[O:3][CH:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[N:8]([C:19](=[O:20])[C:18]2[CH:22]=[C:14]([CH3:13])[CH:15]=[CH:16][C:17]=2[N:23]2[N:27]=[CH:26][CH:25]=[N:24]2)[CH2:9]1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: C[C@H](O)CN
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1O[C@@H](C)CN1C(=O)c1cc(C)ccc1-n1nccn1

Procedure:
By using ethyl glyoxylate (polymer type, a solution of 47% toluene) (0.5 mL, 2.4 mmol), (2S)-1-aminopropan-2-ol (0.18 mL, 2.4 mmol) and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (0.20 g, 0.98 mmol), the same procedure as in Reference Example 1 was carried out to obtain the title compound (0.11 g) (colorless oil).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH2:25]O)[CH:20]=3)[N:15]=2)=[CH:10][C:9]=1[C:27]([F:30])([F:29])[F:28].CCN(C(C)C)C(C)C.CS([Cl:44])(=O)=O.O>C(Cl)Cl>[Cl:44][CH2:25][C:21]1[CH:20]=[C:19]([C:16]2[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([N:3]4[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]4[CH3:1])=[C:9]([C:27]([F:30])([F:28])[F:29])[CH:10]=3)[O:18][N:17]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CC1CCCCN1c1ccc(-c2nc(-c3ccnc(CO)c3)no2)cc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCCN1c1ccc(-c2nc(-c3ccnc(CCl)c3)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of (4-(5-(4-(2-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)methanol (0.125 g; 0.30 mmol) and DIEA (0.10 mL; 0.60 mmol) in DCM (2.5 mL) was added methanesulfonyl chloride (0.026 mL; 0.33 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. Water was added to the reaction mixture and the mixture poured through a hydrophobic frit. The solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with iso-hexane/EtOAc (100% iso-hexane to 100% EtOAc) to afford the title product (0.129 g, 98%). 1H NMR (CDCl3, 400 MHz) δ 8.77 (1 H, dd, J=5.1, 0.9 Hz), 8.51 (1 H, d, J=2.1 Hz), 8.34 (1H, dd, J=8.4, 2.1 Hz), 8.23 (1 H, s), 7.99 (1 H, dd, J=5.1, 1.6 Hz), 7.56 (1 H, d, J=8.4 Hz), 4.78 (2 H, s), 3.12-3.03 (2 H, m), 2.59 (1 H, td, J=11.0, 3.1 Hz), 1.86-1.62 (4 H, m), 1.53-1.38 (2 H, m), 0.86 (3 H, d, J=6.2 Hz).