Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:23]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:15]=2)[CH2:8][C:9]([O:11]CC)=[O:10])[S:5][CH:6]=1>CO.C1COCC1.O>[CH3:1][C:2]1[N:3]=[C:4]([CH:7]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]3[CH:23]=[C:24]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=4)[CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:19]=2)[CH2:8][C:9]([OH:11])=[O:10])[S:5][CH:6]=1
Reactant: CCOC(=O)CC(c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1)c1nc(C)cs1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1csc(C(CC(=O)O)c2ccc(OCc3cccc(-c4ccc(C(F)(F)F)cc4)c3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
Compound 51.3 (50 mg, 0.1 mmol) was dissolved in MeOH/THF/H2O (1:1:1, 3 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to PH=4 and extracted with dichloromethane (3 mL×3). The product was purified on reverse phase HPLC to yield compound 51 (40 mg). MS ESI (pos.) m/e: 498 (M+H). 1H NMR (400 MHz) (DMSO) δ 7.92 (2H, d, J=8.1 Hz); 7.84 (3H, d, J=8.8 Hz); 7.71 (1H, t, J=5.1 Hz); 7.54 (2H, d, J=7 Hz); 7.29 (2H, d, J=8.7 Hz); 7.09 (1H, s); 7.01 (2H, d, J=8.7 Hz); 5.18 (2H, s); 4.66 (1H, m); 3.2 (1H, m); 2.93 (1H, m); 2.33 (3H, s).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:16]N)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12]N)[CH2:6][CH2:5]1.[C:19](=[O:30])([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[NH2:20].[NH3:31]>C(O)CCCCCCC>[CH2:22]([O:21][C:19]([NH:20][CH:3]([N:4]1[CH2:9][CH2:8][N:7]([CH:10]([NH:31][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:30])[C:11]([CH3:15])([CH3:14])[CH3:12])[CH2:6][CH2:5]1)[C:2]([CH3:18])([CH3:16])[CH3:1])=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCOC(N)=O
Reactant: CC(C)(CN)CN1CCN(CC(C)(C)CN)CC1
Reactant: N
Solvent: CCCCCCCCO
Product: CCCCCCCCOC(=O)NC(N1CCN(C(NC(=O)OCCCCCCCC)C(C)(C)C)CC1)C(C)(C)C

Procedure:
Agitated in a reaction vessel are 256 parts of N,N'-bis(2,2-dimethyl-3-aminopropyl)piperazine with 400 parts of O-octyl carbamate and 130 parts of n-octanol at a reflux temperature of 190° C.-200° C. for 1 hour while the ammonia is removed by distillation. At that point, an additional 650 parts of n-octanol are allowed to flow into the reaction mixture and the reaction is continued at reflux temperature for 7 hours. Unreacted octanol and O-octylcarbonate are removed by distillation up to a sump temperature of 180° C.-200° C. at 2 millibars. By transcrystallization of the residue from acetone/water, 506 parts of N,N'-bis(octoxycarbonylaminoneopentyl)piperazine, C32H64N4O4 (molecular weight 568), are obtained corresponding with 89 percent of theory relative to N,N'-bis(2,2-dimethyl-3-aminopropyl)piperaxine. The melting point is 66° C.-68° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16](C)(C)[CH3:17])=[O:14])[CH2:9][CH2:8]1)#[N:2].CCN(CC)CC.ClC(OCC)=O>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)c(C#N)c2)CC1
Agent: CCOC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(Cc2ccc(F)c(C#N)c2)CC1
Temperature: 0 °C

Procedure:
The tert-butyl 4-(3-cyano-4-fluorobenzyl)piperazine-1-carboxylate from the previous step (15.0 g, 47.0 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (150 mL), to which TFA (150 mL) was slowly added and the resultant mixture stirred for 10 minutes. CH2Cl2 and TFA were removed by concentration in vacuo. The resulting residue was dissolved in THF (170 mL) and Et3N (Aldrich, redistilled, 16.6 mL, 188.1 mmol, 4.0 equiv.). The reaction vessel was cooled to 0° C. and ethyl chloroformate (Aldrich, 4.7 mL, 49.4 mmol, 1.05 equiv.) was added dropwise via syringe under a nitrogen atmosphere. After 30 minutes the reaction was concentrated under reduced pressure, diluted with EtOAc, washed with sat. aq. NaHCO3 and brine, and dried over Na2SO4. The organic layer was removed in vacuo to yield 5.9 g of ethyl 4-(3-cyano-4-fluorobenzyl)piperazine-1-carboxylate.
Reaction SMILES: S(Cl)(Cl)=[O:2].C([O:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:16]=[C:15]([C:29]#N)[N:14]=1)C1C=CC=CC=1.[CH3:31][OH:32]>>[CH3:31][O:32][C:29]([C:15]1[N:14]=[C:13]([OH:12])[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:16]=1)=[O:2]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: N#Cc1nc(OCc2ccccc2)cc(-c2cccc(C(F)(F)F)c2)n1
Product: COC(=O)c1nc(O)cc(-c2cccc(C(F)(F)F)c2)n1
Reaction time: 0.5 h

Procedure:
To methanol (10 ml) at 0° C. was added thionyl chloride (500 ul). The mixture was stirred for 30 minutes then 4-benzyloxy-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (300 mg) was added and the reaction was heated to reflux for five hours. Solvent was evaporated under reduced pressure to yield crude product. Purification of the resulting residue by flash chromatography on silica afforded product 4-hydroxy-6-(3-trifluoromethylphenyl)-pyrimidine-2-carboxylic acid methyl ester (104 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH2:30][CH3:31])[C:26]([O:32][CH2:33][CH3:34])=[CH:25][C:24]=2[N:35]([S:37]([CH3:40])(=[O:39])=[O:38])[CH3:36])[C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].C([N:44](C(C)C)CC)(C)C.Cl.NO>C(O)C.CO.C(O)(=O)C.[Ni]>[C:17]1([S:14]([NH:13][C:11](=[O:12])[CH:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]([NH2:44])=[NH:2])=[CH:4][CH:5]=2)[C:23]2[CH:28]=[C:27]([O:29][CH2:30][CH3:31])[C:26]([O:32][CH2:33][CH3:34])=[CH:25][C:24]=2[N:35]([S:37]([CH3:40])(=[O:38])=[O:39])[CH3:36])(=[O:16])=[O:15])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOc1cc(C(Nc2ccc(C#N)cc2)C(=O)NS(=O)(=O)c2ccccc2)c(N(C)S(C)(=O)=O)cc1OCC
Agent: [Ni]
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(C(Nc2ccc(C(=N)N)cc2)C(=O)NS(=O)(=O)c2ccccc2)c(N(C)S(C)(=O)=O)cc1OCC
Temperature: 60 °C
Reaction time: 6 h

Procedure:
The N-{(4-cyanophenylamino)-[4,5-diethoxy-2-(methanesulfonyl-methyl-amino)-phenyl]-acetyl}benzenesulfonamide obtained above (126 mg, 0.21 mmole) was dissolved in ethanol (1.8 ml) and heated to 60° C. Diisopropylethylamine (DIPEA—260 ul, 1.5 mmole) was added followed by hydroxylamine-hydrochloride (74 mg, 1.04 mmole). The reaction was stirred at 60° C. under a nitrogen atmosphere for 6 hours. The reaction was then allowed to cool to room temperature. The solution was diluted with methanol (5 ml) and acetic acid (2 ml) and Raney Nickel 2800 (ca. 50 mg) added as a suspension. The reaction was then stirred vigorously under a hydrogen atmosphere for 1 hour. The catalyst was filtered off and the solvent removed. The crude product was purified by preparative reverse-phase HPLC using a water-acetonitrile (0.1% TFA) gradient to yield 40 mg of desired 4-{2-benzenesulfonylamino-1-[4,5-diethoxy-2-(methanesulfonyl-methyl-amino)phenyl]-2-oxo-ethylamino}benzamidine as its trifluoroacetic acid salt. MS: (M+H)=604.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C(CC(=O)C)(=O)C.[C:24]1(C)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[C:26]([CH3:27])=[CH:25][CH:24]=[C:29]2[CH3:28])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(N)c1
Solvent: CC(=O)CC(C)=O
Product: CCOC(=O)C(C)(C)Oc1cccc(-n2c(C)ccc2C)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
2-(3-Amino-phenoxy)-2-methyl-propionic acid ethyl ester (0.52 g, 2.36 mmol) was dissolved in Toluene (2 ml) and acetylacetone (0.53 m, 4.4 mmol) was added to the solution. The resulting mixture was refluxed for 6 h with a Dean-Stack apparatus. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material thus obtained was purified by flash column affording 2-[3-(2,5-Dimethyl-pyrrol-1-yl)-phenoxy]-2-methyl-propionic acid ethyl ester (0.5 g, 71%). 1H NMR (400 MHz, CDCl3): 1.): 1.24 (t, J=7.2 Hz, 3H), 1.57 (s, 6H), 2.02 (s, 6H), 4.23 (q, J=7.2 Hz, 2H), 5.88 (s, 2H), 6.71 (s, 1H), 6.83-6.91 (m, 2H), 7.26-7.33 (m, 1H); MS (EI) m/z: 302 (M+1).
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[C:10]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:11]([CH3:13])[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[I:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:49]=1[CH:48]=[C:47]([S:50]([NH2:53])(=[O:52])=[O:51])[CH:46]=[CH:45]2>>[CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[C:10]([C:14]2[CH:22]=[CH:21][C:17]([C:18](=[O:19])[NH:53][S:50]([C:47]3[CH:46]=[CH:45][C:44]4[C:49](=[C:40]([I:39])[CH:41]=[CH:42][CH:43]=4)[CH:48]=3)(=[O:51])=[O:52])=[CH:16][C:15]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:11]([CH3:13])[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: NS(=O)(=O)c1ccc2cccc(I)c2c1
Reactant: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)n1
Product: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(I)c4c3)cc2C(=O)N2CCc3ccccc3C2)n1
Yield: 14.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 265, 4-(4-(dibutylcarbamoyl)-1-methyl-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoic acid (Intermediate 264L, 45 mg, 0.09 mmol) and 8-iodonaphthalene-2-sulfonamide (Intermediate 6, 72 mg, 0.21 mmol) were converted to the title compound (11 mg, 15%). 1H NMR (CD3OD, 1:1 mixture of amide rotamers) δ 8.93 (s, 1H), 8.26 (d, J=7.2 Hz, 1H), 8.15 (dd, J=8.8, 1.6 Hz, 2H), 8.05-8.02 (m, 3H), 7.69 (dd, J=15.6, 8.0 Hz, 1H), 7.58 (s, 0.5H), 7.46 (br s, 0.5H), 7.40 (t, J=7.2 Hz, 1H), 7.23-7.11 (m, 3.5H), 6.91 (d, J=7.2 Hz, 0.5H), 4.76 (s, 1H), 4.45 (s, 1H), 3.73 (s, 3H), 3.63-3.52 (m, 6H), 2.82-2.78 (m, 2H), 1.56-1.46 (m, 2H), 1.45-1.27 (m, 4H), 1.20-1.00 (m, 2H), 1.00-0.92 (m, 3H), 0.85-0.75 (m, 3H); MS(ESI+) m/z 832.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].CO>C(#N)C>[Si:15]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
4-hydroxybenzaldehyde (8.21 g, 67.2 mmol) was dissolved in acetonitrile (164 ml) in nitrogen atmosphere, and imidazole (6.87 g, 100.8 mmol) was added at room temperature. Tert-butyldimethylsilyl chloride was added under cooling with ice, followed by stirring for 30 minutes. Methanol was added to terminate the reaction, the reaction solution was subjected to filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 4-(tert-butyldimethylsilyloxy)benzaldehyde (15.23 g, 96%) as a pale yellow oily substance.
Reaction SMILES: [NH2:1]CC(N1CCC(C)CC1)=O.[CH2:12]([O:19]C1(OC)C=CC(C(O)=O)=CC1OC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:12]([NH2:1])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1CCN(C(=O)CN)CC1
Reactant: COC1C=C(C(=O)O)C=CC1(OC)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2-amino-1-(4-methylpiperidin-1-yl)ethanone represented by Formula 120 (24 mg, 0.15 mmol) was slowly added to 4-benzyloxy-3,4-dimethoxybenzoic acid represented by Formula 89 (48.72 mg, 0.17 mmol) prepared in Preparative Example 1 and diisopropylethylamine (0.11 mL, 0.61 mmol) in DMF (3 mL) at room temperature. After cooling the reaction mixture to 0° C. and adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 58.41 mg, 0.15 mmol) thereto, the mixture was agitated for 24 hours. The reaction solvent was removed under reduced pressure and chloroform (5 mL) was added to the remaining concentrate to prepare a solution. The solution was washed with a potassium carbonate solution, followed by separation to form an organic layer. After drying the organic layer with sodium sulfate (Na2SO4), the solvent was removed again under reduced pressure and the concentrate mixture was recrystallized using chloroform and hexane, resulting in a benzamide compound represented by Formula 37 as a desired product (VVZ-040; 27.2 mg, 42% yield).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(N(CC)CC)C.CS(C)=O>O>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:9][C:6]=1[C:7]#[N:8])([O-:12])=[O:11]
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: c1nc[nH]n1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1cc(-n2cncn2)ccc1[N+](=O)[O-]
Temperature: 85 °C
Yield: 48.9 %

Procedure:
A mixture of 5-fluoro-2-nitrobenzonitrile (3 g), 1,2,4-triazole (4.92 g), triethylamine (9.9 ml) and DMSO (50 ml) was stirred and heated to 85° C. for 16 hours. The mixture was cooled to ambient temperature and water was added. The precipitate was isolated and dried to give 2-nitro-5-(1,2,4-triazol-1-yl)benzonitrile (1.9 g) which was used without further purification.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH3:16])=[N:13][CH:14]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH3:16])=[N:13][CH:14]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(=O)c1ccc(Br)cn1
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: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C(C)=O)nc2)cc1
Reaction time: 5 h
Yield: 88 %

Procedure:
To a stirred solution of toluene and ethanol (9 mL, 2:1) of 1-(5-bromopyridin-2-yl)ethanone (200 mg, 1 mmol) was added (4-methoxyphenyl) boronic acid (304 mg, 2 mmol), 2M Na2CO3 (2.84 mL), and Pd(PPh3)4 (11 mg, 0.01 mmol) under argon atmosphere and heating was continued for 5 hours at 70° C. The reaction mixture was concentrated under vacuum and diluted with water (100 mL) and extracted with EtOAc (2×200 mL). The combined extracts were washed with brine solution (20 mL), and organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. This, on purification by flash chromatography (silica gel, 60-120μ) using 10% ethyl acetate in hexane eluent, afforded 1-(5-(4-methoxyphenyl)pyridin-2-yl)ethanone as off-white solid (200 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.99 (d, 1H), 8.20 (dd, 1H), 7.97 (d, 1H), 7.76 (d, 2H), 7.07 (d, 2H), 3.81 (s, 3H), 2.63 (s, 3H); LC-MS m/z calculated for [M+H]+ 228.27, found 228.4.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[CH3:9][O:10][N:11]=[C:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:29]([OH:34])[C:30](=[O:33])[O:31][CH3:32])=[CH:20][C:15]=2[O:14][CH2:13]1>CN(C)C=O.C(OCC)C>[CH3:9][O:10][N:11]=[C:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:29]([O:34][CH3:3])[C:30](=[O:33])[O:31][CH3:32])=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: O=C([O-])[O-]
Reactant: CON=C1COc2cc(OCc3ccccc3N(O)C(=O)OC)ccc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CON=C1COc2cc(OCc3ccccc3N(OC)C(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
1.1 g of methyl iodide and 0.88 g of anhydrous potassium carbonate were added to a solution of 1.9 g of methyl N-[2-(3-methoxyimino-2,3-dihydro-benzofuran-6-yloxymethyl)phenyl]-N-hydroxycarbamate in 20 ml of N,N-dimethylformamide, and they were stirred at room temperature for 24 hours. The reaction solution was diluted with 200 ml of diethyl ether, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate) to obtain 1.5 g of the title compound (having a m. p. of 102-103° C. and 1H-NMR data shown in the following table].
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>>[CH3:1][N:2]([CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(C)NC
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCN(C)C(C)CC(=O)OCC
Temperature: 110 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
A mixture of 54.4 gm (0.374 mole) ethyl 3-(N-methyl-amino)butanoate and 100 gm (0.999 mole) ethyl acrylate was heated at 110° C. with stirring for 18 hours. The reaction mixture was cooled to room temperature and then distilled under reduced pressure to provide 61.7 gm (67.1%) of the desired compound.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[S:6])[CH:2]=[CH2:3].[CH3:7][NH:8][C:9](=S)[NH:10][NH2:11].C(O)C.NC(NNC(=O)N)=O>P(Cl)(Cl)(Cl)=O>[CH2:1]([NH:4][C:5]1[S:6][C:9]([NH:8][CH3:7])=[N:10][N:11]=1)[CH:2]=[CH2:3]
Reactant: CNC(=S)NN
Reactant: C=CCN=C=S
Agent: NC(=O)NNC(N)=O
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCNc1nnc(NC)s1
Temperature: 2 °C
Yield: 21.4 %

Procedure:
A stirred suspension of allyl isothiocyanate (19.8 g, 0.2 mole) and of 4-methyl-3-thiosemicarbazide (21.0 g, 0.2 mole) in 150 ml denatured ethanol (5% methanol) was refluxed for one hour. The crystalline suspension was briefly chilled, and the 1-allyl-6-methyl-2,5-dithiobiurea was collected and vacuum dried. A stirred solution of this biurea (30.6 g, 0.15 mole) in phosphorous oxychloride (150 ml) was refluxed for 11/2 hours. Unreacted phosphorus oxychloride was removed in vacuo, and the residue carefully partitioned between 1.2 M hydrochloric acid (150 ml) and chloroform (150 ml) while maintaining this mixture at 2° C with ice-bath cooling. The chloroform phase was extracted with another portion of 1.2 M hydrochloric acid (100 ml), and the combined acid layer was carefully made alkaline with conc. ammonium hydroxide. The resultant alkaline suspension was extracted with two portions of chloroform, and the combined chloroform extract was washed with a small portion of distilled water. After drying this chloroform extract over magnesium sulfate, the solvent was removed under reduced pressure to yield a colorless solid. Crystallization of the product from ethyl acetate gave 7.3 g (29 percent) of 2-allylamino-5-methylamino-1,3,4-thiadiazole (a colorless solid). Analysis confirmed the desired product.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>C1(C)C=CC=CC=1>[CH3:28][O:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:33]
Reactant: COc1ccccc1C(=O)Cl
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g) and triethylamine (0.4 ml), and 2-methoxybenzoyl chloride (0.7 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][C:15]3=[N:18][NH:19][C:20]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])=[C:14]3[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[C:35](Cl)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[F:8][C:6]1[CH:5]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][C:15]3[N:18]([C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[N:19]=[C:20]([NH:21][C:22](=[O:27])[C:23]([F:24])([F:25])[F:26])[C:14]=3[CH2:13]2)(=[O:11])=[O:10])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(Nc1[nH]nc2c1CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2)C(F)(F)F
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2c1CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-[5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl]-2,2,2-trifluoro-acetamide (43.76 g, 106.65 mmol) and triethylamine (44.6 mL, 319.95 mmol) in dichloromethane (1 L), at room temperature, trityl chloride (31.22 g, 111.98 mmol) was added. The reaction was stirred at room temperature for 1 hour. The organic phase was washed with NaHCO3 satured solution, water and brine, dried over sodium sulfate filtered and evaporated to dryness affording the crude title compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:15][O:16]C1C=CC(N)=CC=1.C(O)(=O)CC(O)=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]([O:16][CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc2nc(Cl)cc(Cl)c2c1
Agent: C[O-]
Agent: O=C(O)CC(=O)O
Agent: [Na+]
Solvent: CO
Product: COc1ccc2nc(Cl)cc(OC)c2c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of 2,4-dichloro-6-methoxyquinoline (0.97 g) synthesized from p-anisidine and malonic acid according to the method of WO200226713 in methanol (20 mL) was added sodium methoxide (1.37 g), and the mixture was stirred at 70° C. for 3 h. The reaction solution was added dropwise to ice water, and the resulting solids were collected by filtration. The resulting solids were purified by silica gel column chromatography (hexane/ethyl acetate=5:1) to obtain 2-chloro-4,6-dimethoxyquinoline (0.61 g) as white solids.
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].COC(OC)[N:20]([CH3:22])C.O.[NH2:26]N>>[C:11]1([CH2:10][CH2:9][C:2]2[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:22][NH:20][N:26]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)CCc1ccccc1
Reactant: NN
Solvent: O
Product: CCOC(=O)c1c[nH]nc1CCc1ccccc1

Procedure:
Using ethyl 3-oxo-5-phenylpentanoate (5.8 g), dimethylformamide dimethylacetal (3.6 mL) and hydrazine monohydrate (1.3 mL) and in the same manner as in Example 1(3), a crude product of ethyl 3-(2-phenylethyl)-1H-pyrazole-4-carboxylate was obtained. This was dissolved in dimethylformamide (30 ml), potassium carbonate (5.5 g) and 2-chloro-5-trifluoromethylpyridine (4.8 g) were added, and the mixture was stirred at 100° C. overnight. In the same manner as in Example 1(4), the title object compound (5.2 g, 50%) was obtained as a white solid.