Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[CH:14]=[CH:15][NH:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=1[F:38]>CN(C=O)C.CC#N>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=3[F:38])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCc1ccccc1
Yield: 40.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 7-Benzyloxy-6-methoxy-1H-quinolin-4-one (12.2 g, 43.3 mmol, 1.0 eq.), acetonitrile (150 ml), DMF (150 ml) and cesium carbonate (28.2 g, 86.5 mmol, 2.0 eq). The mixture was stirred at room temperature for 30 minutes at which time 1,2-difluoro-4-nitro-benzene (7.57 g, 47.6 mmol, 1.1 eq) was added over a 10 minute period. After 2 hours the reaction was complete at which time 75% of the MeCN and DMF was removed and the resulting solution was poured over into ice water. The solid was filtered and dried and further columned with a biotage system. The eluent was 1:3 ethyl acetate/hexane. Removal of the solvent afforded 7-Benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline as a pale green solid (7.4 g, 41% yield). 1H NMR (400 MHz, CDCl3): 8.53 (d, 1H), 8.42 (dd, 1H), 8.16 (m, 1H), 7.5 (m, 8H), 6.76 (d, 1H), 5.31 (s, 2H), 3.92 (s, 3H); MS (EI) for C23H27FN2O5: 421 (MH+).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na+].Cl[CH2:29][CH2:30][CH2:31][CH2:32][OH:33].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCCCCCl
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCCCCO)cc1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 7.66 g of sodium 4-(n-hexadecylamino)benzoate, 7.55 g of 4-chloro-1-butanol, and 20.0 ml of hexamethylphosphoramide is stirred at 150° C for two hours, allowed to cool, and poured into water. The solid is collected by filtration and then is dissolved in methylene chloride. The solution is washed with water, dried, and evaporated. The residual solid is crystallized from hexane to yield 4-hydroxybutyl 4-(n-hexadecylamino)benzoate as a white solid, mp 61°-63° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]2=[N:14]1.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>CC(C)=O>[OH:1][C:2]1[C:7]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:6][C:5]([CH2:12][N:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]2=[N:14]1
Reactant: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reactant: OCCNCCO
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(CN(CCO)CCO)cc(-n2nc3ccc(Cl)cc3n2)c1O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
2-(2′-Hydroxy-3′-tert-butyl-5′-methylphenyl)-5-chlorobenzotriazole (3.95 g, 0.01 mole), diethanol amine (3.14 g, 0.03 mole) were dissolved in 100 mL of acetone. The reaction mixture was refluxed with constant stirring at 80° C. for 6 h. The solvent was then removed by rotary evaporation. Crude product was purified using silica gel column chromatography. Product was identified by 1H-NMR.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-4-methylbenzene (0.62 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.79 g, 61%).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:4]=1[C:5]#[N:6].[OH2:15].NN>C(O)C.[Ni]>[NH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:3]([N:2]([CH3:14])[CH3:1])[C:4]=1[C:5]([NH2:6])=[O:15]
Reactant: CN(C)c1cccc([N+](=O)[O-])c1C#N
Reactant: O
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: CN(C)c1cccc(N)c1C(N)=O
Temperature: 65 °C

Procedure:
2-Amino-6-dimethylaminobenzamide is prepared by adding a suspension of 2-dimethylamino-6-nitrobenzonitrile and hydrazine hydrate in ethanol to a suspension of Raney nickel in ethanol while maintaining the reaction temperature at about 65° C. The mixture is then heated to reflux for about half an hour, filtered through Celite and evaporated to dryness. The solid product may be recrystallized from ethanol or used neat in the reaction with ethyl oxalyl chloride.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH:21]=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCC=O
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCC(O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (8.0 g, 27.1 mmol) in anhydrous THF (270 mL) was added dropwise a solution of phenylmagnesium bromide (27.08 mL of a 1 M solution in THF). After 30 minutes, the solution was quenched with saturated ammonium chloride (100 mL), diluted with ethyl acetate (300 mL), and the layers separated. The organic solution was washed successively with a saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated to a light orange oil. Chromatography on silica gel (elution with 5% methanol in dichloromethane) provided 4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-ol (4.3 g) as a light orange, gummy solid.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[OH:12][C:13](C(F)(F)F)=O.OC(C(F)(F)F)=O.[OH:26]/[N:27]=[C:28](\[NH2:57])/[C:29]([CH3:56])([NH:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([NH:44][C:45]3[N:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[CH:47][N:46]=3)[CH:41]=[C:40]([CH3:55])[CH:39]=2)=[CH:34][N:33]=1)[CH3:30].C1N=CN(C(N2C=NC=C2)=O)C=1>O1CCOCC1>[CH3:55][C:40]1[CH:39]=[C:38]([C:35]2[CH:36]=[CH:37][C:32]([NH:31][C:29]([C:28]3[NH:57][C:13](=[O:12])[O:26][N:27]=3)([CH3:30])[CH3:56])=[N:33][CH:34]=2)[CH:43]=[C:42]([NH:44][C:45]2[N:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[CH:47][N:46]=2)[CH:41]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(NC(C)(C)/C(N)=N/O)nc2)c1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(NC(C)(C)c3noc(=O)[nH]3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DBU (10.0 μL, 0.066 mmol) was added to a mixture of (1Z)—N′-hydroxy-2-methyl-2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}propanimidamide bis-TFA salt (14.0 mg, 0.025 mmol) and CDI (4.26 mg, 0.026 mmol) in dioxane (100 μL). The reaction was stirred at room temperature overnight. The reaction mixture was filtered, diluted with DMF (500 μL), and directly purified by reverse phase HPLC. The isolated material was repurified by silica gel chromatography (0-100% ethyl acetate in hexanes with 1% triethylamine and then 20% methanol in dichloromethane) to yield 3-(2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}propan-2-yl)-1,2,4-oxadiazol-5(4H)-one. MS APCI calc'd for C22H21F3N7O2 [M+H]+ 472. found 472. 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 7.79 (d, J=11.5 Hz, 2H), 7.41 (s, 1H), 7.31 (s, 1H), 7.05 (d, J=5.2 Hz, 2H), 6.64 (d, J=9.1 Hz, 1H), 2.43 (s, 3H), 1.80 (s, 6H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11](Br)=[C:10]([CH3:16])[CH:9]=1)(=[O:3])[CH3:2].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)=[C:10]([CH3:16])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(C)c(Br)c(C)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(C)c(-c2cccnc2)c(C)c1
Yield: 45 %

Procedure:
By carrying out the operation analogously to example 13, starting from 4-bromo-3,5-dimethylphenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation III, and 3-pyridineboronic acid, the expected product is obtained in the form of a colorless foam with a yield of 45%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH:30]=C)[CH2:10][N:11]2[C:17](=[O:18])[C:16]3[C:19]4[C:24]([CH:25]=[C:26]([C:27]#[N:28])[C:15]=3[S:14][CH2:13][CH2:12]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=[CH:6][C:7]=1[Cl:8].C1COCC1.[OH2:37].I([O-])(=O)(=O)=O.[Na+].[OH2:44]>[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH:30]=[O:44])[CH2:10][N:11]2[C:17](=[O:18])[C:16]3[C:19]4[C:24]([CH:25]=[C:26]([C:27]#[N:28])[C:15]=3[S@:14](=[O:37])[CH2:13][CH2:12]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O
Reactant: C=CC[C@H](CN1CCSc2c(C#N)cc3ccccc3c2C1=O)c1ccc(Cl)c(Cl)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: N#Cc1cc2ccccc2c2c1[S@](=O)CCN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C2=O
Temperature: 25 °C

Procedure:
To a solution of 2-[(2S)-2-(3,4-dichlorophenyl)pent-4-enyl]-1-oxo-1,2,3,4-tetrahydronaphtho[1,2-f][1,4]thiazepine-6-carbonitrile (Example 1, 225 mg, 0.50 mmol) in 3:1 THF/water (10 mL) under nitrogen at 0° C. was added osmium tetroxide (4% in water, 32.5 μL, 0.01 mmol) followed in 10 min by portion wise addition of sodium periodate over 5 min. The reaction mixture was allowed to warm to ambient temperature over 3 h and clarified by the addition of water. The products were extracted into ether and organic layer was washed with saturated NaHCO3 and brine, dried (Na2SO4), and evaporated to 230 mg of an oil which was chromatographed on silica gel in 10% MeOH/CHCl3 to give 40 mg of intermediate 78a, 22 mg of Intermediate 78b and 11 mg of Intermediate 78c.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)[CH:2]=1.[H][H]>C(O)C.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)[CH:2]=1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc(Oc2cccnc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Oc2cccnc2)cc1
Yield: 99 %

Procedure:
In 20 ml of ethanol was dissolved 2.0 g of ethyl (E)-3-[4-(pyridin-3-yloxy)phenyl]acrylate, and to the resulting solution was added 1.0 g of 5% palladiumcarbon, after which the resulting mixture was stirred in a hydrogen atmosphere at room temperature for 5 hours. The reaction mixture was filtered and the filtrate thus obtained was concentrated under reduced pressure to obtain 2.0 g (yield 99%) of colorless, oily ethyl 3-[4-(pyridin-3-yloxy)phenyl]propionate.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1)#[N:3].[C:12]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(=O)C>[C:12]([O:20][CH:21]1[CH2:22][C:23]2[C:8]3[C:7](=[CH:6][CH:5]=[C:4]([C:2]#[N:3])[CH:9]=3)[NH:10][C:24]=2[CH2:25][CH2:26]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(NN)cc1
Reactant: O=C(OC1CCCCC1)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: N#Cc1ccc2[nH]c3c(c2c1)CC(OC(=O)c1ccccc1)CC3
Yield: 47.8 %

Procedure:
4-Cyanophenyl hydrazine hydrochloride (20.2 g) and 4-benzoyloxy-cyclohexane (25.9 g) were dissolved in glacial acetic acid (400 ml) and the mixture was heated under reflux for 1.5 hr. After allowing to cool, the mixture was filtered, and the filtrate was evaporated to dryness, and neutralized with aqueous sodium bicarbonate solution to give a solid precipitate, which was purified by chromatography (SiO2 ; hexane/ethyl acetate) to give 3-benzoyloxy-6-cyano-1,2,3,4-tetrahydrocarbazole (18 g). This product (11.6 g) was suspended in ethanol (230 ml) and treated with 2.5% aqueous potassium hydroxide solution (120 ml), and heated under reflux for 1 hr. The cooled mixture was neutralized with glacial acetic acid and evaporated to a solid residue which was washed with water, and dried to give 3-hydroxy-6-cyano-1,2,3,4-tetrahydrocarbazole (6.6 g).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:13][O:14][CH:15]2[CH2:17][CH2:16]2)[C:8]([O:10]CC)=[O:9])[N:3]=1.Cl>[OH-].[Na+]>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:13][O:14][CH:15]2[CH2:17][CH2:16]2)[C:8]([OH:10])=[O:9])[N:3]=1
Reactant: CCOC(=O)C(=NOC1CC1)c1nsc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(C(=NOC2CC2)C(=O)O)ns1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.2 %

Procedure:
A suspension of ethyl 2-(5-amino-l,2,4-thiadiazol-3-yl)-2-(cyclopropyloxyimino)acetate (syn isomer)(763 mg) in 1N sodium hydroxide (6 ml) was stirred at ambient temperature for 2 hours to give a clear solution. The mixture was adjusted to pH 4.5 with 1N hydrochloric acid and washed with ethyl acetate. The aqueous solution was adjusted to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and crystallized from diethyl ether to give 2-(5-amino-l,2,4-thiadiazol-3-yl)-2-cyclopropyloxyiminoacetic acid (syn isomer) (110 mg) as a crystal.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([NH2:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]2[C:18]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=3)[NH:9][C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)CCC#Cc1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)nc1I
Product: COC(=O)CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)nc12

Procedure:
Prepared from 6-chloro-2-iodo-3-pyridinamine (Description 14) and methyl 5-(4-chlorophenyl)-4-pentynoate (Description 2) according to the method of Description 4. 1H NMR (500 MHz, CDCl3) δ 8.20 (1H, br s), 7.56 (1H, d, J 8.4 Hz), 7.52 (2H, d, J 8.5 Hz), 7.47 (2H, d, J 8.5 Hz), 7.11 (1H, d, J 8.4 Hz), 3.61 (3H, s), 3.21 (2H, t, J 7.8 Hz), and 2.85 (2H, t, J 7.8 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[N:5]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH:19]=O)=[CH:12][CH:11]=2)[C:4](=[S:21])[N:3]1[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=1.[CH2:34]([NH2:37])[CH2:35][NH2:36].BrN1C(=O)CCC1=O>ClCCl>[NH:36]1[CH2:35][CH2:34][N:37]=[C:19]1[CH2:18][CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([N:5]2[C:4](=[S:21])[N:3]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=3)[C:2](=[O:1])[C:6]32[CH2:7][CH2:8][CH2:9]3)=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC=O)cc3)C2=S)cc1C(F)(F)F
Reactant: NCCN
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC4=NCCN4)cc3)C2=S)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
The mixture of 4-(8-Oxo-5-(4-(4-oxobutyl)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile (68) [ND-10] (15 mg, 0.03 mmol) and ethylene diamine (2 μL, 0.04 mmol) in dry dichloromethane (3 mL) was stirred at 0° C. for 30 min under argon. N-Bromosuccinimide (NBS, 6 mg, 0.04 mmol) was added to the mixture and the resulting solution was stirred overnight at 21° C. Reaction was quenched by the addition of saturated NaHCO3 solution. The mixture was extracted with dichloromethane. The organic layer was dried over MgSO4, and evaporated in vacuo. The residue was purified by flash column chromatography (ethanol:ethyl acetate, 1:4) to give 4-(5-(4-(3-(4,5-Dihydro-1H-imidazol-2-yl)propyl)phenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile (65) [ND-11] (6 mg, 35%): 1H NMR δ 7.98 (d, 1H, J=1.9 Hz) 7.97 (d, 1H, J=8.3 Hz) 7.85 (dd, 1H, J=8.3, 1.9 Hz), 7.46 (d, 1H, J=8.2 Hz) 7.25 (d, 1H, J=8.2 Hz), 4.72 (br s, 1H), 3.67-3.80 (m, 4H), 2.85-3.05 (m, 2H), 2.57-2.70 (m, 2H), 2.43-2.57 (m, 4H), 2.15-2.30 (m, 1H), 1.63-1.80 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=O)[CH2:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:6][C:5]=2[NH:4][N:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:9]1[CH2:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:6][C:5]2[NH:4][N:3]=[C:2]([CH3:1])[C:10]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1ccccc1C1CC(=O)c2c(C)n[nH]c2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C)n[nH]c2C1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 86.6 %

Procedure:
A mixture of 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindazol-4-one (0.15 g), aminoguanidine hydrochloride (0.072 g), concentrated hydrochloric acid (0.062 ml), water (0.062 ml) and ethanol (30 ml) was stirred at 50° C. for 3 hours and at 80° C. for 1.5 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with diethylether. To the aqueous layer was added sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and to the residue was added 1N hydrochloric acid (1.5 ml). Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindazole hydrochloride (Compound 20) (0.18 g) as colorless crystals.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)C=O)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].CO[CH:29]([O:32][CH3:33])[O:30][CH3:31].C(=O)(O)[O-].[Na+]>CO>[CH3:33][O:32][CH:29]([O:30][CH3:31])[C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][C:12](=[O:17])[C:13]([CH3:15])([CH3:14])[CH3:16])[CH:20]=1
Reactant: COC(OC)OC
Reactant: CC(C)(C)C(=O)Oc1cccc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1cccc(OC(=O)C(C)(C)C)c1
Reaction time: 1 h

Procedure:
Four hundred mg of p-toluenesulfonic acid dissolved in 25 ml of methanol was added, with stirring, to the 3-pivaloyloxybenzaldehyde of Example I. Trimethylorthoformate (224 ml; 2.05 mol) was then added dropwise. The minor exotherm that resulted was allowed to proceed unchecked while the mixture was stirred for 1 hour. One half gram of sodium bicarbonate was added, and the flask was placed on the rotary evaporator (bath temperature40° C.) to remove all volatiles. The resulting oil was passed through a short silica gel column under nitrogen pressure to give an orange-brown oil which was pumped under vacuum (1.0 mm Hg) with stirring to yield 426 g of crude 3-pivaloyloxybenzaldehyde dimethyl acetal. Infrared analysis revealed no aldehyde carbonyl absorption (1695 cm-1).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]([Cl:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[Br:1][C:2]1[C:3]([F:13])=[C:4]([Cl:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([Cl:17])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Br)c(F)c(Cl)c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)c(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A quantity of 5.2 g of 5-bromo-3-chloro-2,4-difluorobenzoic acid is suspended in 30 ml of dichloromethane; then 2.92 g of oxalyl chloride is added, and 3 drops of dry DMF are added. The mixture is stirred at room temperature for 3 hours and the desired compound is isolated after evaporation of the solvent.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[F:15][C:16]1([F:24])[CH2:20][NH:19][C@H:18]([C:21]([OH:23])=[O:22])[CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.O.C(O)C>[F:15][C:16]1([F:24])[CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=2)[C@H:18]([C:21]([OH:23])=[O:22])[CH2:17]1
Reactant: O=C(O)[C@@H]1CC(F)(F)CN1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1CC(F)(F)CN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 90 °C
Yield: 88.2 %

Procedure:
To 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (416 mg, 2 mmol), (S)-4,4-difluoropyrrolidine-2-carboxylic acid (301 mg, 2 mmol), and sodium carbonate (633 mg, 574 μL, 6.0 mmol) was added 1:1 water/Ethanol (8 mL) and the reaction mixture was heated at 90° C. for 72 h. The reaction mixture was diluted with water (50 mL) then acidified with 1 N HCl and the product was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield (S)-4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine-2-carboxylic acid as a brown oil (600 mg, 89%), which was used directly in the next reaction. LC/MS: m/z 341.00 (M+H)+ at 1.49 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:24]([O:28][C:29]([N:31]1[CH2:35][C:34](=[O:36])[NH:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:35][C:34](=[O:36])[N:33]([C:20]2[CH:21]=[CH:22][C:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=4)[CH2:10][CH2:11]3)=[O:16])=[CH:18][CH:19]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CNC(=O)C1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CN(C(=O)OC(C)(C)C)CC4=O)cc3)CC2)c(C)c1
Yield: 87.7 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (211 mg) described in Preparation Example 113 and 4-oxoimidazolidine-1-carboxylic acid tert-butyl ester (93 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (210 mg) was obtained.