Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([C:12]2[CH:21]=[C:20]([CH:22]([OH:36])[CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH3:37])[CH:18]=3)[N:13]=2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:49]([O-:53])([O-])(=[O:51])=S.[Na+].[Na+]>ClCCl>[O:51]=[S:49]1(=[O:53])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][N:4]([C:12]2[CH:21]=[C:20]([CH:22]([OH:36])[CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:27][CH2:28]3)[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH3:37])[CH:18]=3)[N:13]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc2nc(N3CCSc4ccccc4C3)cc(C(O)C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(C(O)C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-{[2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl](hydroxy)methyl}piperidine-1-carboxylate (519 mg, 1.0 mmol) in dichloromethane (10 mL) was added 3-chloroperbenzoic acid (537 mg, 70% purity, 2.2 mmol). After being stirred at room temperature for 4 hours, to the above mixture was added a saturated aqueous solution of sodium thiosulfate (3 mL). The separated organic layer was washed with a saturated aqueous solution of sodium carbonate (5 mL) and brine (5 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 20-50% ethyl acetate in petroleum ether) to afford 300 mg of the desired product. MS (ESI+) [(M+H)+] 552.
Reaction SMILES: C(O[CH:4]1[CH2:12][C:11]2[C:10](=O)[CH2:9][CH2:8][CH2:7][C:6]=2[O:5]1)C.[NH3:14]>>[O:5]=[C:6]1[CH2:7][CH2:8][CH2:9][C:10]2[NH:14][CH:4]=[CH:12][C:11]1=2
Reactant: N
Reactant: CCOC1CC2=C(CCCC2=O)O1
Product: O=C1CCCc2[nH]ccc21
Temperature: 100 °C
Yield: 54 %

Procedure:
96.5 mg of 2-ethoxy-4-oxo-2,3,4,5,6,7-hexahydrocoumarone and 1.5 ml of 28% aqueous ammonia were admixed in a glass tube which was sealed and heated at 100° C. for 14 hours. The reaction mixture was treated in the same manner as Example 11 to give 38.4 mg of 4-oxo-4,5,6,7-tetrahydroindole (yield 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-])=O)[CH:4]=1.[C:13]1(=O)[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH:18]=[CH:17][CH:16]=[C:15]3[C:14]1=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:8][CH:9]=1)[N:7]=[C:13]1[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:24]=3[C:15]([C:14]1=[N:10]2)=[CH:16][CH:17]=[CH:18]4
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C1C(=O)c2cccc3cccc1c23
Product: COc1ccc2nc3c(nc2c1)-c1cccc2cccc-3c12
Yield: 91 %

Procedure:
When 0.05 mole each of 4-methoxy-2-nitroaniline and acenaphthenequinone were reacted by the method of Example 1, 12.9 g (91 percent yield) of 9-methoxyacenaphtho[1,2-b]-quinoxaline, mp = 194°-195° C. were obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:12]([CH2:13][CH2:14]Cl)=[C:11](Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:19]=1[NH2:20]>CC(O)C>[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:19]=1[N:20]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([CH3:2])[C:12]=2[CH2:13][CH2:14]1
Reactant: Cc1nc2ccccc2c(Cl)c1CCCl
Reactant: Cc1cccc(C)c1N
Agent: Cl
Solvent: CC(C)O
Product: Cc1cccc(C)c1N1CCc2c(C)nc3ccccc3c21
Yield: 10.5 %

Procedure:
A mixture of 2-methyl-3-(2-chloroethyl)-4-chloroquinoline hydrochloride (13.8 g, 50 mmol), 2,6-dimethylaniline (12.5 ml, 100 mmol) and 2-propanol (400 ml) was heated to 140° for 5 days in a pressure vessel, then cooled and evaporated. The crude product was converted to free base and chromatographed (silica gel, methanolic ammonia in dichloromethane). Recrystallisation from aqueous methanol followed by aqueous ethanol gave 1-(2,6-dimethylphenyl)-4-methyl- 2,3-dihydropyrrolo[3,2-c]quinoline (1.52 g), m.p. 149°-152°.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][CH:14]([OH:29])[C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)=[CH:8][CH:7]=1)(=O)C.C1COCC1.[OH-].[Na+]>O>[OH:29][CH:14]([C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:13]#[C:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][OH:4])=[CH:11][CH:10]=1
Reactant: CC(=O)OCc1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(O)C#Cc3ccc(CO)cc3)ccc21
Reaction time: 0.5 h

Procedure:
780 mg (2 mmol) of 4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzyl acetate and 30 ml of THF were introduced into a round-bottomed flask. 5 ml of a 2N methanolic sodium hydroxide solution were added and stirring was carried out for 30 min. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was triturated in heptane and filtered, 419 mg (60%) of the expected compound, with a melting point of 85°-86° C., were recovered.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH:14]([CH3:18])[C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[O:28][CH3:29]>>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:15](=[O:17])[CH:14]([C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH3:18])=[CH:23][C:22]=1[O:28][CH3:29]
Reactant: CC(C(=O)[O-])c1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COc1cc(N)ccc1F
Agent: [Na+]
Product: COc1cc(NC(=O)C(C)c2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Yield: 21.9 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 100 mg of sodium 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]propanoate and 195 mg of 4-fluoro-3-methoxyaniline in place of the 2,4-difluoroaniline. 30 mg of N-(4-fluoro-3-methoxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]propanamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>C1(C)C=CC=CC=1>[C:13]1([CH3:18])[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]1
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccccc2C)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccccc1O[C@H]1CC[C@H](C(=O)NN)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-o-tolyloxy-cyclohexanecarboxylic acid methyl ester (0.091 g, 0.36 mmol) and hydrazine hydrate (0.02 ml, 0.36 mmol) was heated at 120° C. for 22 h. After cooling to room temperature the reaction mixture was suspended in toluene. After evaporation of the solvent the residue was dried in high vacuo (1-2 mbar) to give the crude title compound (0.73 g, 81%) as white solid, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14](=[S:16])[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=O.C(=O)([O-])[O-].[Ca+2]>C(O)(C)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[S:16][C:18]2[CH2:26][C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:19]=2[N:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2CC1Br
Reactant: CC(C)(C)OC(=O)NC1CCCC1C(N)=S
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1CCCC1c1nc2c(s1)Cc1ccccc1-2
Yield: 12.1 %

Procedure:
In 50 ml of isopropanol, 0.63 g of 2-(tert-butoxy-carbonylamino)cyclopentanecarbothioamide and 0.54 g of 2-bromo-1-indanone were dissolved. Then, 0.26 g of calcium carbonate was added, followed by heating under reflux for 3 hours. After cooling, the insoluble matter was removed by filtration, and the solvent was evaporated. The resulting residue was subjected to silica gel column chromatography eluted with chloroform-methanol-29% aqueous ammonia (100:10:1). The resulting crystals were recrystallized from diethyl ether, whereby 0.11 g of 2-[2-(tert-butoxycarbonylamino)cyclopentyl]-8H-indeno[1,2-d]thiazole was obtained.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:22])[CH:6]([NH2:21])[C:7](=[O:20])[CH2:8][CH2:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)[CH3:3].[CH3:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>CN(C=O)C.C1COCC1>[CH2:2]([O:4][C:5](=[O:22])[CH:6]([NH:21][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[CH3:23])[C:7](=[O:20])[CH2:8][CH2:9][C:10]12[CH2:17][CH:16]3[CH2:18][CH:12]([CH2:13][CH:14]([CH2:15]3)[CH2:19]1)[CH2:11]2)[CH3:3]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCOC(=O)C(N)C(=O)CCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(=O)c1ccccc1C)C(=O)CCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
5-Adamantan-1-yl-2-amino-3-oxo-pentanoic acid ethyl ester hydrochloride (prepared using the method of T. W. von Geldem & C. Hutchins et al, J. Med. Chem. 1996, 39, 957) (3.30 g, 10.0 mmol) was suspended in DMF (15 ml) and a solution of 2-methylbenzoyl chloride (1.55 g 10.0 mmol) in THF (15 ml) was added. The mixture was stirred at room temperature and a solution of N,N-diispropylethylamine (3.48 ml 20.0 mmol) in THF (10 ml) was added dropwise over 30 min. After stirring for 2 h the THF was evaporated and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, washed with water, 2M HCl, brine, dried (MgSO4), and the solvent was evaporated. The residue was purified by flash column chromatography (silica, DCM/hexane/ethyl acetate 9:9:2) to afford the product as a pale yellow oil. (2.08 g, 60%). 1NMR (300 MHz, CDCl3) 7.49-7.23 (4H, m), 6.97 (1H, d), 5.45 (1H, d), 4.30 (2H, m), 2.77 (2H, m), 2.47 (3H, s), 1.97 (3H, s) 1.67 (6H, m), 1.47 (8H, m), 1.34 (3H, t).
Reaction SMILES: [CH3:1][NH2:2].CS[C:5]([NH:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[C:20]([O:21][CH2:22][CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=1)=[CH:6][N+:7]([O-:9])=[O:8]>C(O)C>[CH3:1][NH:2][C:5]([NH:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[C:20]([O:21][CH2:22][CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=1)=[CH:6][N+:7]([O-:9])=[O:8]
Reactant: CN
Reactant: CCOc1cccnc1CSCCNC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CCOc1cccnc1CSCCNC(=C[N+](=O)[O-])NC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylamine in ethanol (33%, 25 cc) was added to 1-methylthio-1-[2-(3-ethoxy-2-pyridylmethylthio)ethylamino]-2-nitro ethylene (1.32 g) and the mixture was stirred at 40° for 1 hour and 1 hour at room temperature. Nitrogen was bubbled through the mixture for 1 hour and the precipitate was recrystallised from ethanol/ether to give the title product (0.52 g) m.p. 130°-131°.
Reaction SMILES: [N:1]([CH2:4][CH:5]([CH2:24][CH:25]([O:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:26])[CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N+]=[N-].C(OC(C)CC(COC(=O)NCCCCCCCCCCCCCCCCCC)CN)(=O)C1C=CC=CC=1>[Pd].CO>[C:28]([O:27][CH:25]([CH3:26])[CH2:24][CH:5]([CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:4][NH2:1])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCCCCCCCCCCCCCCSCC(CN=[N+]=[N-])CC(C)OC(=O)c1ccccc1
Agent: [Pd]
Agent: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)CC(C)OC(=O)c1ccccc1
Solvent: CO
Product: CCCCCCCCCCCCCCCCSCC(CN)CC(C)OC(=O)c1ccccc1

Procedure:
A mixture of 1.291 g (2.56 mM) of 1-azido-2-(2-benzoyloxypropan-1-yl)-3-n-hexadecylthiopropane m12b, 130 mg of 10% palladium on charcoal in 130 ml of methanol is hydrogenated by the same procedure as described in (129) and crude product of the titled compound m13 is obtained.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[N:12]=1.C1COCC1.[OH-].[Na+]>CCO>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[N:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:20])=[O:2])[O:9][CH:10]=1
Reactant: COC(=O)CCCCc1nc(-c2ccccc2N)co1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccccc1-c1coc(CCCCC(=O)O)n1

Procedure:
Combine 5-[4-(2-amino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (2.5 g, 9.1 mmol) with THF (3 mL), EtOH (3 mL) and 1N NaOH (15 mL) and stir until hydrolysis is complete. Concentrate the mixture, dilute the residue with water and adjust the pH to 2.5-3.5 with aq HCl. Extract the mixture with EtOAc and dry the extracts over Na2SO4 before concentrating. Chromatograph the residue over silica gel (EtOAc) to allow for recovery of 5-[4-(2-amino-phenyl)-oxazol-2-yl]-pentanoic acid (2.03 g, 86%). MS (ES): (M+1)+ 261.1 m/z.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C:18]3([OH:32])[CH2:23][CH:22]4[CH2:24][CH2:25][CH:19]3[CH:20]=[C:21]4[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:8][C:7]=2[C:6]([O:34][CH3:35])=[CH:5][CH:4]=1.CCN(CC)CC.[C:43](Cl)(=[O:47])[CH:44]([CH3:46])[CH3:45]>C(Cl)Cl>[CH3:35][O:34][C:6]1[C:7]2[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C@:18]3([O:32][C:43](=[O:47])[CH:44]([CH3:46])[CH3:45])[CH2:23][C@H:22]4[CH2:24][CH2:25][C@@H:19]3[CH:20]=[C:21]4[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:10][C:11]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CC(C)C(=O)Cl
Reactant: COc1ccc(OC)c2[nH]c(CCCN(C)CCC3(O)CC4CCC3C=C4c3ccccc3)nc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OC)c2[nH]c(CCCN(C)CC[C@]3(OC(=O)C(C)C)C[C@H]4CC[C@@H]3C=C4c3ccccc3)nc12
Reaction time: 8 h

Procedure:
To a solution of 199 mg of rac-(1R*,2R*,4R*)-2-(2-{[3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol in 4 mL DCM were added 0.2 mL of NEt3 and 0.1 mL of isobutyrylchloride at 0° C. The reaction mixture was stirred overnight allowing the temperature to reach slowly rt. The reaction was quenched with sat. aq. NaHCO3, the phases were separated and the water phase was re-extracted with DCM. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was redissolved in 3 mL EtOAc, silica gel and 1.5 mL MeOH were added and the mixture was stirred vigorously for 7 d. The mixture was filtered, thouroughly washed with EtOAc-MeOH (2:1) and evaporated. Purification by CC using EtOAc-MeOH (5:1 to 3:1+0.1% NEt3) yielded 186 mg of rac-isobutyric acid (1R*,2R*,4R*)-2-(2-{[3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester as beige foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[C:14]([CH3:20])=[N:15][N:16]([CH3:19])[C:17]=1[CH3:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:12][C:13]2[C:14]([CH3:20])=[N:15][N:16]([CH3:19])[C:17]=2[CH3:18])=[S:10])[CH:7]=1
Reactant: Cc1nn(C)c(C)c1N
Reactant: Cc1ccc(Cl)cc1N=C=S
Product: Cc1ccc(Cl)cc1NC(=S)Nc1c(C)nn(C)c1C
Yield: 71.4 %

Procedure:
Prepared using Method A from 4.5 g (24.5 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 3.06 g (24.5 mmol) of 4-amino-1,3,5-trimethylpyrazole to give 5.4 g of title compound as a white solid, m.p. 176-177° C. (71% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9].[N:21]([O-])=O.[Na+].[Na]>Cl.O.C(OCC)(=O)C>[F:19][C:17]([F:20])([F:18])[C:13]1[CH:12]=[C:11]([C:3]2[C:2]3[N:1]=[N:21][NH:10][C:8](=[O:9])[C:7]=3[CH:6]=[CH:5][N:4]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1ccnc(-c2cccc(C(F)(F)F)c2)c1N
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]nnc2c(-c3cccc(C(F)(F)F)c3)nccc12
Yield: 68.5 %

Procedure:
562 mg of 3-amino-2-(3-trifluoromethylphenyl)-4-pyridinecarboxamide were stirred at 0° C. in 5 ml of concentrated hydrochloric acid during the addition of 160 mg of sodium nitrite in 1 ml of water. After 0.5 hour the mixture was diluted with water and ethyl acetate and made basic with sodium hicarbonate. The organic phase was separated, dried over sodium sulphate and evaporated, and the residue was purified by chromatography on silica gel using ethyl acetate/petroleum ether (1:1) for the elution. There were obtained 400 mg of 8-(3-trifluoromethylphenyl)pyrido[3,4-d]-1,2,3-triazin-4(3H)-one in the form of a solid of melting point 192°-193° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:23]=O)=[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl.[NH2:26]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([C:23]#[N:26])=[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: NO
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccco1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1=C(C)NC(C#N)=C(C(=O)OCC)C1c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
A mixture of diethyl 2-methyl-4-(2-furyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.6 g), hydroxylamine hydrochloride (383.6 mg) and sodium acetate (787.6 mg) in acetic acid (14 ml) was stirred for 30 minutes at room temperature. To the mixture, acetic anhydride (1 ml) was added and stirred for 1.5 hours at room temperature and further stirred for an hour under reflux. After removal of the acetic acid from the reaction mixture, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution and water and dried, and then the solvent was distilled off under reduced pressure. The resultant brown oil (1.8 g) was purified by column chromatography on silica gel by an eluent (a mixture of 15 parts of chloroform and one part of ethyl acetate by volume). The concentrate (920 mg) of the fraction of the eluate which showed one spot on thin-layer chromatography and the concentrate of one (450 mg) which showed plural spots respectively gave crystals (totally 875 mg) and these were recrystallized from a mixture of diethyl ether and n-hexane to give pure crystals (818 mg) of diethyl 2-methyl-4-(2-furyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 139° to 141° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:13]([CH3:16])([O-:15])=[O:14].C(N(CC)CC)C>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([OH:12])([CH2:16][N+:13]([O-:15])=[O:14])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: C[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(O)(C[N+](=O)[O-])C1
Yield: 97 %

Procedure:
3-Oxoazetidine-1-carboxylic acid tert-butyl ester (500 mg, 2.9 mmol) was dissolved in ethanol (1.5 mL) and to this was added nitromethane (0.6 mL) and triethylamine (cat.). The reaction was stirred for eighteen hours and the solvent was then removed under reduced pressure to yield the title compound as a white solid (650 mg, 97%). δH (d6-DMSO) 6.42 (1H, s), 4.86 (2H, s), 4.04 (2H, d, J 9.2 Hz), 3.75 (2H, d, J 9.2 Hz), 1.39 (9H, s). LCMS (ES+) RT (pH 10) 1.73 min (M−H)− 231.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[N:33]=[C:32]([CH3:34])[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[C:32]([CH3:34])=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c(C)n1
Temperature: 80 °C
Yield: 76.1 %

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in a reaction tube. 6-Methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (65 mg, 0.26 mmol), 0.2 mL of an aqueous 2 M sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol) were added and the reaction mixture was heated at 80° C. overnight. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexane to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,3-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (69 mg, 76%). ESI-MS m/z calc. 453.4. found 454.3 (M+1)+. Retention time 1.98 minutes.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].Cl.[NH2:31][CH:32]1[CH2:37][CH:36]2[CH2:38][CH:33]1[CH2:34][CH2:35]2.C(N(CC)CC)C>CN(C=O)C>[CH:33]12[CH2:38][CH:36]([CH2:35][CH2:34]1)[CH2:37][CH:32]2[NH:31][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28]
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(-c2ccc(F)cc2)cc1
Reactant: NC1CC2CCC1C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)c1ccc(NC2CC3CCC2C3)c([N+](=O)[O-])c1)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 16 h

Procedure:
A solution of Example 1D (50 mg, 0.12 mmol), 2-aminonorbornane hydrochloride (106 mg, 0.58 mmol), and triethylamine (0.08 ml, 0.58 mmol) in DMF (2 mL) were heated to 120° C. in a sealed vial with shaking for 16 hours, then concentrated. The concentrate was dissolved in 1:1/DMSO:methanol (1.0 ml) and purified by reverse phase preparative HPLC with 0.1% TFA in H2O/CH3CN to provide the desired product. MS (APCI(+)) m/e 510 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.45 (br s, 1H), 8.67 (d, 1H), 8.48 (d, 1H), 7.99 (dd, 1H), 7.95 (d, 2H), 7.78 (2d, 4H), 7.32 (t, 2H), 7.24 (d, 1H), 4.04 (m, 1H), 2.58 (m, 1H), 2.27 (m, 1H), 2.24-2.21 (m, 1H), 1.59-1.29 (m, 6H), 0.97 (dt, 1H).