Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[CH2:25][N:26]2[CH:30]=[CH:29][CH:28]=[C:27]2[C:31](=[O:39])[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[CH:19][CH:18]=1)[C:11]([O:13][CH3:14])=[O:12])(C(C)(C)C)(C)C.O>C1COCC1>[OH:8][CH2:9][C@@H:10]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[CH2:25][N:26]2[CH:30]=[CH:29][CH:28]=[C:27]2[C:31](=[O:39])[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[CH:19][CH:18]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)OCc1ccc(/C=C/Cn2cccc2C(=O)c2ccc(C)cc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CO)OCc1ccc(/C=C/Cn2cccc2C(=O)c2ccc(C)cc2)cc1
Reaction time: 1 h

Procedure:
The compound of Example 68-4 (260 mg, 0.48 mmol) was dissolved in THF (5 ml), and thereto was added n-tetrabutylammonium fluoride (1 mol/liter in THF) (1.5 ml, 0.72 mmol) under ice-cooling. Under ice-cooling, the mixture was stirred for one hour, and thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([CH2:13][OH:14])[O:11][CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:15](Cl)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].N1C=CC=CC=1>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]([CH2:13][O:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:11][CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: COC(CO)CO[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(CO[Si](C)(C)C(C)(C)C)OC
Yield: 99 %

Procedure:
To a solution of alcohol Compound 42 (1.1 g, 5.0 mmol) in CH2Cl2 (10 mL) was added oleoyl chloride (1.8 mL, 5.5 mmol) followed, after 5 min, by the addition of pyridine (0.44 mL, 5.5 mmol). After TLC analysis indicated that the reaction had gone to completion, the mixture was partitioned between ethyl acetate (100 mL) and H2O (30 mL), the organic extract was dried (MgSO4) and concentrated to give 1-O-t-butyldimethylsilyl-2-O-methyl-3-O-oleoyl-rac-glycerol (Compound 43) (2.4 g, 99%) as a dark brown oil.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5]([CH3:8])[CH:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=2)[P:3]1(=[O:25])[O:18]C1C=CC=CC=1.C(#N)C.[OH2:29]>>[CH3:8][N:5]([CH:4]([P:3](=[O:25])([OH:18])[OH:29])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1)[C:6]([NH:2][CH3:1])=[O:7]
Reactant: O
Reactant: COc1cc(C2N(C)C(=O)N(C)P2(=O)Oc2ccccc2)ccc1O
Solvent: CC#N
Product: CNC(=O)N(C)C(c1ccc(O)c(OC)c1)P(=O)(O)O

Procedure:
A solution of 10.0g of 1,4-dimethyl-3-(4-hydroxy-3-methoxyphenyl)-2-phenoxy-1,4,2-diazaphospholidin-5-one-2-oxide in 90g of acetonitrile and 10g of water was warmed at reflux for 0.5 hr, and then most of the solvent was allowed to evaporate. The residue was recrystallized twice from ethanol to give 4.6g of white solid: mp 183°-184° (dec); 31P nmr (CD3SOCD3) -18.6 ppm (d, J= 24Hz), 1H nmr 10.0 (broad, 3, OH), 5.7 (d, 1, J = 24Hz, CH), 3.8 (s, 3, OCH3), 2.9 (s, 3, NCH3), 2.7 (s, 3, NCH3); 6.7-7.3 (m, 4, aryl and HN).
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[C:13](I)([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14].[CH2:27]=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38]>C(O)C.[Zn]>[C:13]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: C=CCCCCCCCCCO
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Zn]
Solvent: CCO
Product: OCCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
C4F9(CH2)11OAcr was prepared essentially as described above starting with the AIBN catalyzed addition of C4F9I to CH2═CH(CH2)9OH. The resulting iodohydrin was reduced with zinc in ethyl alcohol to give the desired C4F9(CH2)11OH and olefinic products in about an 80:20 ratio as follows.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[C:6](Cl)[CH:5]=[C:4]([CH3:14])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:22][SH:23]>C(#N)C.O.Cl>[Cl:1][C:2]1[C:7]2[C:8]([OH:10])=[C:22]([C:21]([O:25][CH2:26][CH3:27])=[O:24])[S:23][C:6]=2[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1sc2cc(C)nc(Cl)c2c1O
Reaction time: 15 h
Yield: 93.9 %

Procedure:
To a suspension of ethyl 2,4-dichloro-6-methylpyridine-3-carboxylate (10.0 g, 42.7 mmol) in acetonitrile (45 mL) were added potassium carbonate (8.85 g, 64.1 mmol) and ethyl thioglycolate (4.68 mL, 42.7 mmol), and the mixture was stirred for 15 hr under refluxing conditions. The reaction mixture was diluted with water (150 mL), 6N hydrochloric acid (15 mL) was added and the mixture was stirred for 30 min. The precipitated solid was collected by filtration, washed with water and ethanol-diisopropyl ether (1/1), and dried under reduced pressure to give the title compound (10.9 g, 94%) as a white powder.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[C:30](Cl)[N:29]=[CH:28][N:27]=4)[CH2:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:35][NH2:36]>C(O)C>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[C:30]([NH:36][CH3:35])[N:29]=[CH:28][N:27]=4)[CH2:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(N1CCN(c2cc(Cl)ncn2)CC1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: CN
Solvent: CCO
Product: CNc1cc(N2CCN(C(=O)N3CCN(S(=O)(=O)c4ccc(C(F)(F)F)cc4)CC3)CC2)ncn1

Procedure:
A solution of 1-(4-triflouromethylphenylsulphonyl )-4-[1-(6-chloro-pyrimidin-4-yl)piperazin-4-ylcarbonyl]piperazine (26.0 g) in 33% methylamine in ethanol (400 ml) was heated at 110° C. in a Carius tube for 8 hours. The mixture was evaporated to dryness and the residue recrystallised from methanol to give, as a solid 1-(4-triflouromethylphenylsulphonyl)-4-[1-(6-metliylamino-pyrimidin-4-yl)piperazin-4-ylcarbonyl]piperazine (13.67 g), mp 230-231° C. Found C, 49.10; H, 4.90 and N, 19.00%. C21H26F3N7O3S requires C, 49.12; H, 5.10 and N, 19.09% NMR (CDCl3): 2.85 (d, 3H), 3.10 (m, 4H), 3.30 (m, 4H), 3.40 (m, 4H), 3.60 (m, 4H), 4.75 (m, 1H), 5.40 (s, 1H), 7.80 (d, 2H), 7.90 (d, 2H) and 8.15 (s, 1H); m/z 154 (M+1).
Reaction SMILES: Cl.Cl.[C:3]1([NH2:10])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[CH3:11][CH:12]1[CH2:17][CH2:16][O:15][C:13]1=O>Cl>[NH:9]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[N:10]=[C:11]1[CH:12]([CH3:13])[CH2:17][CH2:16][OH:15]
Reactant: CC1CCOC1=O
Reactant: Nc1ccccc1N
Agent: Cl
Product: CC(CCO)c1nc2ccccc2[nH]1
Yield: 126.9 %

Procedure:
Following the general procedure described in A. R. Friedman, D. S. Payne and A. R. Day, J. Heterocyclic Chemistry, 3:257-259(1966), a mixture of 9 g of 1,2-phenylenediamine dihydrochloride and 7 g of 2-methylbutyrolactone in 60 mL of 4N hydrochloric acid was heated to reflux for 4 days, 1 teaspoon of decolorizing carbon added, and after another 15 min reflux, filtered hot. The filtrate was concentrated under reduced pressure to near dryness, the residue made basic (pH=8) with ammonium hydroxide and extracted into 3×100 mL of ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. After drying under vacuum, 12 g of 3-(1H-benzimidazol-2-yl)-butan-1-ol was obtained as a resin.
Reaction SMILES: [CH2:1]([C:3]1([C:11](Cl)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH3:10])C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>CCOCC>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:11]([C:3]2([CH2:9][CH3:8])[CH2:1][CH2:7][CH2:6][CH2:5][CH:4]2[CH3:10])=[O:12])=[CH:18][CH:17]=1
Reactant: CCC1(C(=O)Cl)CCCCCC1C
Reactant: COc1ccc(N)cc1
Solvent: CCOCC
Product: CCC1(C(=O)Nc2ccc(OC)cc2)CCCCC1C

Procedure:
1-Ethyl-2-methylcycloheptanecarbonyl chloride (1.5 g, 0.007 mole) in ether (10 ml.) was added to a stirred solution of p-anisidine (0.01 mole) in ether (30 ml.). A further quantity of ether (100 ml.) was added and the solution was washed with dilute hydrochloric acid, dilute sodium hydroxide and then with water. The ether solution was dried (MgSO4) and the solvent was removed by distillation. The residue was recrystallised from 40-60 petroleum ether to give N-(p-Methoxyphenyl)-1-ethyl-2-methylcyclohexanecarboxamide, mp. 107°.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=2)[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:38](Cl)(=[O:44])[O:39][CH2:40][CH2:41][O:42][CH3:43]>C1COCC1>[C:1]1([CH2:7][C:8]([NH:9][C:38](=[O:44])[O:39][CH2:40][CH2:41][O:42][CH3:43])([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:29])([F:30])[F:31])[CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(Cc1ccccc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reactant: COCCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCCOC(=O)NC(Cc1ccccc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To a solution of 2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethanamine (20 mg, 0.045 mmol) in THF (6 mL) was added 1M K2CO3 (20 mg in 0.1 mL), followed by 2-methoxyethyl carbonochloridate (0.106 mL, 0.91 mmol). The resulting mixture was stirred at rt for 16 h. The crude product was purified by prep HPLC (phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford 2-methoxyethyl 2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethylcarbamate (Example 283) as white lyophillate (12 mg, 51% yield). LCMS: RT=4.19 min [M+H] 544.2 (4 min Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.ClC1C=C([N:16]2N=[N:19][C:18]([C:21]([OH:23])=[O:22])=[N:17]2)C=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:16]=[N:17][C:18]([C:21]([OH:23])=[O:22])=[N:19]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1nnn(-c2cccc(Cl)c2)n1
Reactant: Nc1ccc(F)cc1
Product: O=C(O)c1nnn(-c2ccc(F)cc2)n1

Procedure:
This intermediate was prepared from 4-fluoro-phenylamine in four steps according to the preparation of 2-(3-chloro-phenyl)-2H-tetrazole-5-carboxylic acid.
Reaction SMILES: C(OC(=O)/C=C/[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]([C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:22]([O:24][CH3:25])=[O:23])[C:12]2=[O:30])(C)(C)C.I([O-])(=O)(=O)=O.[Na+].C1C[O:41][CH2:40]C1>O.C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[CH:40]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]([C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:22]([O:24][CH3:25])=[O:23])[C:12]2=[O:30])=[O:41]
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(/C=C/C(=O)OC(C)(C)C)cc3c2=O)c1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)c1ccc(C)c(-n2cnc3ccc(C=O)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of methyl 3-[6-[(1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl]-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate (1.11 g) and sodium periodate (1.24 g) in THF (20 ml) and water (6 ml) was added 2.5% wt solution of osmium tetroxide in tert-butanol (0.34 ml). The reaction was stirred at room temperature for 72 hours, diluted with THF (30 ml) and the precipitate removed by filtration. The resultant solution was concentrated and the residue dissolved in ethyl acetate, washed water/brine mixture, 10% aqueous solution of sodium thiosulfate (×2) and brine. The organic layers were concentrated to give a solid which was triturated with iso-hexane and collected by filtration to give methyl 3-(6-formyl-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate as a solid (0.54 g). NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 3.88 (s, 3H), 7.64 (d, 1H), 7.93 (d, 1H), 8.05 (m, 1H), 8.11 (d, 1H), 8.32 (m, 1H), 8.48 (s, 1H), 8.77 (d, 1H), 10.19 (s, 1H); Mass Spectrum: M+H+ 323.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[F:12][C:13]([F:23])([F:22])[C:14](=O)[CH2:15][C:16](OCC)=[O:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([OH:17])[C:6]2[C:4](=[C:3]([O:2][CH3:1])[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=2)[N:5]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(OC)c2nc(C(F)(F)F)cc(O)c2c1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
2,4-Dimethoxyaniline (30 g) was dissolved in benzene (400 mL), and ethyl trifluoroacetoacetate (34 mL) and p-toluenesulfonic acid monohydrate (3.7 g) were added. The mixture was refluxed for 21 hr. The reaction solution was concentrated under reduced pressure, and a saturated a aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The extract solution washed with saturated brine, dried and concentrated under reduced pressure. 75% Polyphosphoric acid (150 mL) was added to the residue and the mixture was stirred at 130° C. for 2 hr. The reaction solution was poured onto ice, and the mixture was extracted with ethyl acetate. The extract solution washed successively with a saturated a aqueous sodium hydrogen carbonate solution, 1 mol/L hydrochloric acid and saturated brine, dried and concentrated under reduced pressure. Ethanol was added to the residue and the precipitate was filtered off. The filtrate was concentrated under reduced pressure to give 2-trifluoromethyl-4-hydroxy-6,8-dimethoxyquinoline (12 g) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:24][CH2:25][CH2:26][NH:27][C:28]2[C:29](=[O:45])[N:30]([C:41]([CH3:44])([CH3:43])[CH3:42])[S:31](=[O:40])(=[O:39])[C:32]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=O)=O)=CC=1>>[C:41]([N:30]1[C:29](=[O:45])[C:28]([NH:27][CH2:26][CH2:25][CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=2)=[C:32]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[S:31]1(=[O:39])=[O:40])([CH3:42])([CH3:43])[CH3:44]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Product: COC(=O)Cc1ccc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Yield: 75 %

Procedure:
The title compound was prepared as described for Example 12 from methyl (4-hydroxyphenyl)acetate and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 30 mins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using 25% EtOAc in hexane as eluent to give the title compound (0.079 g, 75%). 1H NMR (500 MHz CDCl3): δ 7.52-7.44 (m, 2H), 7.14-7.38 (m, 3H), 7.17 (d, 2H), 6.78 (d, 2H), 5.72 (t, 1H), 3.85 (t, 2H), 3.68 (s, 3H), 3.56 (s, 2H), 3.10-3.00 (m, 2H), 1.84-1.78 (m, 2H), 1.72 (s, 9H); 13C NMR (125 MHz CDCl3): δ 172.5, 159.8, 157.7, 135.3, 131.8, 130.7, 130.5, 129.7, 128.8, 126.8, 125.3, 115.7, 114.7, 107.2, 66.1, 61.7, 52.2, 42.4, 40.5, 28.9, 27.8; Mass Spectrum: M+H+ 487.
Reaction SMILES: [S:1]1CS[C:2]1=[C:5]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=O.O.[NH2:24][NH2:25]>C(O)C>[N+:14]([C:10]1[CH:9]=[C:8]([C:6]2[C:5]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:2]([SH:1])[NH:24][N:25]=2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: NN
Reactant: O=C(C(=C1SCS1)c1ccncc1)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2n[nH]c(S)c2-c2ccncc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
2-[1,3]-Dithietan-2-ylidene-1-(3-nitro-phenyl)-2-pyridin-4-yl-ethanone (5.2 g, 15.7 mmol) was suspended in absolute ethanol (60 mL) and heated to 60° C. Hydrazine monohydrate (3.05 mL, 63 mmol, 4 eq) was added dropwise and the mixture was stirred at 60° C. for 2 hours. The suspension was concentrated to about ¼ of the original volume, diluted with THF (30 mL) and stirred for 5 minutes. The solid was filtered, washed with THF and dried at 50° C. for 2 hours. 3.92 g of 5-(3-nitro-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol were obtained as an orange solid (84%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:20]([NH2:22])=O)[CH:3]=1>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)([CH3:12])[CH3:11])=[C:4]([C:20]#[N:22])[CH:3]=1
Reactant: CC(C)(CNc1nnc(Cl)cc1C(N)=O)c1ccc(F)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(CNc1nnc(Cl)cc1C#N)c1ccc(F)cc1
Yield: 17.9 %

Procedure:
To a portion of 6-chloro-3-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-4-carboxamide (3.4 g, 11 mmol, 1.0 equiv) was added POCl3 (10 mL) at room temperature. The mixture was stirred at reflux for 3 hours and then quenched by pouring it into ice water containing NaHCO3. Dioxane and EtOAc were added to facilitate mixing of the layers. The layers were allowed to separate and the aqueous layer was extracted with EtOAc and the combined organic phases were washed with saturated NaCl. The organics were dried over Na2SO4 and evaporated to dryness in vacuo. Purification over silica gel using a gradient of 10-20% EtOAc/hexanes yielded the desired product (0.60 g, 19%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)cnn1-c1cccc(Cl)c1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1cccc(Cl)c1
Yield: 23.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (2.0 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (2.4 g), the title compound (1.0 g) was obtained, melting point: 210° C.
Reaction SMILES: [CH2:1]([O:5][P:6]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH2:8]/[CH:9]=[CH:10]/[CH2:11][C:12]1([C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[C:24]2[CH:23]=[C:22]([F:25])[CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][C:15]([F:26])=[CH:16][CH:17]=2)=[O:7])[CH2:2][CH2:3][CH3:4]>C(O)C.[Pd]>[CH2:36]([O:35][P:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])([CH2:8][CH2:9][CH2:10][CH2:11][C:12]1([C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[C:13]2[CH:14]=[C:15]([F:26])[CH:16]=[CH:17][C:18]=2[C:19]2[C:24]1=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:7])[CH2:37][CH2:38][CH3:39]
Reactant: CCCCOP(=O)(C/C=C/CC1(C(=O)NCC(F)(F)F)c2cc(F)ccc2-c2ccc(F)cc21)OCCCC
Agent: [Pd]
Solvent: CCO
Product: CCCCOP(=O)(CCCCC1(C(=O)NCC(F)(F)F)c2cc(F)ccc2-c2ccc(F)cc21)OCCCC
Reaction time: 24 h
Yield: 94 %

Procedure:
A solution of Example 203 compound (574 mg, 1 mmol) in 25 ml of absolute ethanol containing 250 mg of 10% Pd on carbon as catalyst was stirred under a hydrogen atmosphere (balloon) for 48 hours. The reaction was filtered after stirring 24 hrs and fresh catalyst added. The reaction was filtered through a 0.45 μm nylon filter and the solvent evaporated yielding 538 mg (94%) of title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(SCC(CCC(=O)O)C(=O)O)cc1C
Solvent: CO
Product: COC(=O)CCC(CSc1ccc(C)c(C)c1)C(=O)O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 1423.5 %

Procedure:
A mixture of 2-(3,4-dimethylphenylthiomethyl)glutaric acid (1.16 g), methanol (20 ml), and p-toluenesulfonic acid (0.04 g) was stirred at 40° C. for 1.5 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica by eluting with chloroform/ethanol (10:1) to give 0.98 g of 3-(3,4-dimethylphenylthio)-2-(2-methoxycarbonylethyl)propionic acid as an oil.
Reaction SMILES: CC([Mg]Cl)C.I[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[F:17][C:18]([F:26])([CH3:25])[C:19](N(OC)C)=[O:20]>C1COCC1>[F:17][C:18]([F:26])([CH3:25])[C:19]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=[O:20]
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: CON(C)C(=O)C(C)(F)F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(F)(F)C(=O)c1cccc(C(F)(F)F)c1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A solution of 2-propylmagnesium chloride in THF (1.3 M, 7.5 ml) was cooled to −15° C. and admixed with 1-iodo-3-(trifluoromethyl)benzene (2.80 g, 10.2 mmol). The reaction mixture was stirred at −15° C. for 1 h, warmed to room temperature and admixed dropwise with a solution of 2,2-difluoro-N-methoxy-N-methylpropanamide (1.43 g, 9.35 mmol: prepared according to Synth. Comm. 2008 (38), 1940-1945), and stirred at room temperature overnight. Then the mixture was added to ice-cold dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by means of silica gel chromatography with the eluent cyclohexane/ethyl acetate (EA) (0% FA to 30% EA).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17](Br)=[N:18][CH:19]=3)[CH:11]=[N:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:23][C:24]1[CH:25]=[C:26]([SH:30])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C.N#N>>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([S:30][C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=4)=[N:18][CH:19]=3)[CH:11]=[N:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccc(Br)nc2)cc1
Reactant: Cc1cccc(S)c1
Agent: N#N
Solvent: CCN(CC)CC
Product: Cc1cccc(Sc2ccc(Cn3cncc3Cc3ccc(C#N)cc3)cn2)c1
Temperature: 105 °C

Procedure:
The compound from Step 3 (0.28 mmol, 0.164 g), 3-methyl thiophenol (0.85 mmol, 0.106 g) and triethylamine (3.59 mmol, 0.36 g) were placed in an N2 purged sealed tube. This was heated at 105° C. for 15 hr. The residue was dissolved in methanol and purified on a C18 preperative hplc column. Lyophilized from dioxane/HCl to provide the title compound. FAB-MS: calc: 396.4 found: 397.2 1H-NMR (CD3OD): 2.4 ppm (s, 3H); 4.2 ppm (s, 2H); 5.4 ppm (s, 2H); 7.2-7.6 ppm (1OH); 8.1 ppm (s, 1H); 9.1 ppm (s, 1H).