Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:7][O:6][CH:5]([C:8]2[S:12][C:11]([C@H:13]([NH:23][S+]([O-])C(C)(C)C)[CH2:14][O:15][Si](C)(C)C(C)(C)C)=[CH:10][CH:9]=2)[O:4][CH2:3]1.[ClH:31]>CO>[ClH:31].[NH2:23][C@@H:13]([C:11]1[S:12][C:8]([CH:5]2[O:6][CH2:7][C:2]([CH3:30])([CH3:1])[CH2:3][O:4]2)=[CH:9][CH:10]=1)[CH2:14][OH:15]
Reactant: CC1(C)COC(c2ccc([C@@H](CO[Si](C)(C)C(C)(C)C)N[S+]([O-])C(C)(C)C)s2)OC1
Agent: Cl
Solvent: CO
Product: CC1(C)COC(c2ccc([C@H](N)CO)s2)OC1

Procedure:
A solution of ((6R)-6-[5-(5,5-dimethyl-1,3-dioxan-2-yl)thiophen-2-yl]-2,2,3,3,9,9-hexamethyl-4-oxa-8-thionia-7-aza-3-siladecan-8-olate (12.7 g, 26.7 mmol) in MeOH (26 mL) cooled to 0° C. was treated with a 4 N hydrogen chloride solution (46.7 mL, 187 mmol) for 2 hours. The solvent was evaporated under reduced pressure, after which toluene was added and the co-solvent mixture was evaporated under reduce pressure to afford a white solid characterized as the title compound. 1H NMR ((CD3)2SO) δ 8.50 (1H), 7.17 (1H), 7.04 (1H), 5.70 (1H), 5.65 (1H), 4.53 (1H), 3.80-3.71 (2H), 3.65 (4H), 1.15 (3H), 0.73 (3H).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]2[C:20]([C:21]([C:23]3[C:24]([C:33]4[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[C:36]([OH:42])=[C:35]([O:43]C)[CH:34]=4)=[N:25][C:26]4[C:31]([CH:32]=3)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:22])=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:4][C:3]=1[O:45]C.[BrH:47]>>[BrH:47].[OH:45][C:3]1[CH:4]=[C:5]([C:11]2[C:20]([C:21]([C:23]3[C:24]([C:33]4[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[C:36]([OH:42])=[C:35]([OH:43])[CH:34]=4)=[N:25][C:26]4[C:31]([CH:32]=3)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:22])=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[OH:1]
Reactant: COc1cc(-c2nc3ccccc3cc2C(=O)c2cc3ccccc3nc2-c2cc(OC)c(O)c([N+](=O)[O-])c2)cc([N+](=O)[O-])c1O
Agent: Br
Product: O=C(c1cc2ccccc2nc1-c1cc(O)c(O)c([N+](=O)[O-])c1)c1cc2ccccc2nc1-c1cc(O)c(O)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
820 mg of 4-hydroxy-3-methoxy-5-nitrophenyl(3-quinolinyl)ketone are treated with 50 ml of 48 percent hydrobromic acid and held at the reflux temperature for 3 hours. After distillation of the hydrobromic acid at 50°, the residue is treated with 70 ml of hot water and the insoluble constituent is filtered under suction. There is obtained 3,4-dihydroxy-5-nitrophenyl(3-quinolinyl)ketone hydrobromide in the form of yellow crystals of m.p. 270° (dec.).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][C@H:14]([C:16]2([NH:19]C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[C@H:13]([F:27])[CH2:12]1)=O)C1C=CC=CC=1.[NH2:28][C:29]1[C:38]([F:39])=C(F)[C:36]([O:41][CH3:42])=[C:35]2[C:30]=1[C:31](=[O:50])[C:32]([C:47]([OH:49])=[O:48])=[CH:33][N:34]2[C@@H:43]1[CH2:45][C@@H:44]1[F:46].C(N(CC)CC)C>C(O)C.[C].[Pd].CS(C)=O>[NH2:28][C:29]1[C:38]([F:39])=[C:9]([N:11]2[CH2:15][C@H:14]([C:16]3([NH2:19])[CH2:17][CH2:18]3)[C@H:13]([F:27])[CH2:12]2)[C:36]([O:41][CH3:42])=[C:35]2[C:30]=1[C:31](=[O:50])[C:32]([C:47]([OH:49])=[O:48])=[CH:33][N:34]2[C@@H:43]1[CH2:45][C@@H:44]1[F:46]
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CC(C)(C)OC(=O)NC1([C@H]2CN(C(=O)OCc3ccccc3)C[C@H]2F)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CS(C)=O
Product: COc1c(N2C[C@@H](F)[C@@H](C3(N)CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reaction time: 18 h
Yield: 42.7 %

Procedure:
1-Benzyloxycarbonyl-4-(R)-(1-tert-butoxycarbonylaminocyclopropyl)-3-(S)-fluoropyrrolidine (400 mg, 1.06 mmol) was dissolved in ethanol (20 ml). After adding a 5% palladium-carbon catalyst (moisture content: 55.6%, 500 mg), the mixture was stirred under a hydrogen atmosphere for 18 hours. After filtering off the catalyst through celite (washed with methanol), the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in dimethyl sulfoxide (8 ml) and 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (289 mg, 0.88 mmol) and triethylamine (2 ml) were added thereto. Then the mixture was stirred under a nitrogen atmosphere at 100° C. for 26 hours. After allowing it to cool, dimethyl sulfoxide was removed by evaporation. The residue was dissolved in chloroform (80 ml), and washed with a 10% aqueous solution of citric acid (80 ml). The organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography (eluent: chloroform:methanol=9:1) followed by concentration of the eluate under reduced pressure. Under ice cooling, concentrated hydrochloric acid (5 ml) was added dropwise into the residue followed by stirring at room temperature for 20 minutes. After adding 1 N hydrochloric acid (30 ml), the liquid reaction mixture was washed with chloroform (50 ml×2) and its pH value was adjusted to 12.0 with an aqueous solution of sodium hydroxide followed by washing with chloroform (100 ml×2). The pH value of this aqueous solution was adjusted to 7.4 with 1 N hydrochloric acid followed by extraction with chloroform (200 ml×3). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from ethanol and dried under reduced pressure to obtain 170 mg (42.6%) of the title compound as a yellow powder.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]([CH3:40])([OH:39])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH3:40][C:11]([OH:39])([CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:21][CH2:22][CH:23]([CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=3)[CH2:24][CH2:25]2)=[CH:18][CH:19]=1)[CH2:10][CH2:9][OH:8]
Reactant: [H][H]
Reactant: CC(O)(CCOCc1ccccc1)COc1ccc(N2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(O)(CCO)COc1ccc(N2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)cc1
Yield: 79.9 %

Procedure:
4-Benzyloxy-2-methyl-1-(4-{4-[4-(trifluoromethoxy)phenethyl]piperidin-1-yl}phenoxy)butan-2-ol (2.43 g, 4.5 mmol), ethanol (24 ml) and 20% palladium hydroxide on carbon (0.24 g) were mixed and stirred at 50 to 60° C. under the hydrogen pressure of 1 atm for 4 hours. The mixture was filtered through Celite to remove the catalyst, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→0:100) to afford the title compound as a colorless powder (1.68 g, 80%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=O)[CH2:11][C:12](=O)[CH:13]([F:15])[F:14].Cl.[S:19]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1)(=[O:22])(=[O:21])[NH2:20]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:29]([C:26]2[CH:25]=[CH:24][C:23]([S:19]([NH2:20])(=[O:22])=[O:21])=[CH:28][CH:27]=2)[N:30]=[C:12]([CH:13]([F:15])[F:14])[CH:11]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(CC(=O)C(F)F)c1nc2ccccc2s1
Agent: Cl
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2nc3ccccc3s2)cc1
Yield: 37 %

Procedure:
The procedure of Example 9 was repeated using 1-(benzothiazol-2-yl)-4,4-difluorobutane-1,3-dione and 4-sulfamoylphenylhydrazine hydrochloride as the starting materials to obtain 4-[5-(benzothiazol-2-yl)-3-difluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide (yield, 37%). NMR(CDCl3 -DMSO-d6) δ: 6.86 (1H, t, J=54.5 Hz), 7.12 (2H, s), 7.25 (1H, s), 7.43-7.66 (4H, m), 7.92-8.06 (4H, m); mp 247-249° C. (DMF-ethanol)
Reaction SMILES: Cl[C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].[CH3:15]C1C(C(F)(F)F)=CC=CC=1C(O)=O.ClC1C(C(F)(F)F)=CC=CC=1C(O)=O>>[CH3:15][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5]
Reactant: Cc1c(C(=O)O)cccc1C(F)(F)F
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Agent: O=C(O)c1cccc(C(F)(F)F)c1Cl
Product: Cc1c(C(=O)Cl)cccc1C(F)(F)F

Procedure:
The title compound was prepared in a manner analogous to Intermediate 12 substituting 2-methyl-3-(trifluoromethyl)benzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[N+:13]([O-])=O)=[O:3].C(=O)(O)[O-].[Na+]>O.[Pd]>[NH2:13][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[C:2]([NH2:1])=[O:3])[C:8]([OH:10])=[O:9]
Reactant: NC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1ccc(C(=O)O)cc1N
Yield: 99.1 %

Procedure:
4-(aminocarbonyl)-3-nitrobenzoic acid (2.00 g, 9.52 mmol) was suspended in water (50 ml) and sodium bicarbonate (0.80 g, 9.52 mmol) was added. The resulting solution was hydrogenated in the presence of 10% palladium on carbon (300 mg) at 30 psi for 16 hours. The mixture was then filtered through Celite. The filtrate was acidified by addition of concentrated hydrochloric acid and the resulting solid was collected by filtration and dried in vacuo to afford 3-amino-4-(aminocarbonyl)benzoic acid (1.70 g, 99% yield). MS (EI) for C8H8N2O3: 179 (M−H).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[C:8]([Cl:11])[CH:7]=[C:6]([F:12])[C:5]=1[N:13]1[C:17](=[O:18])[C:16]2[CH2:19][CH2:20][CH2:21][CH2:22][C:15]=2[C:14]1=[O:23])[CH:2]=[CH2:3].C1C=C(Cl)C=C(C(OO)=[O:32])C=1.CC1C=CC(S(O)(=O)=O)=CC=1>ClCCCl>[Cl:11][C:8]1[C:9]2[O:10][CH:2]([CH2:3][OH:32])[CH2:1][C:4]=2[C:5]([N:13]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][CH2:22][C:15]=3[C:14]2=[O:23])=[C:6]([F:12])[CH:7]=1
Reactant: C=CCc1c(O)c(Cl)cc(F)c1N1C(=O)C2=C(CCCC2)C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Product: O=C1C2=C(CCCC2)C(=O)N1c1c(F)cc(Cl)c2c1CC(CO)O2
Temperature: 25 °C

Procedure:
A solution of 0.67 g of 19C and 475 mg of 80% MCPBA in 15 mL of 1,2-dichloroethane was heated on an oil bath at 70° C. for 2.5 hours. A few milligrams of PTSA was added, the mixture was cooled to room temperature, washed with a saturated aqueous solution of sodium sulfite, followed by a saturated aqueous solution of sodium bicarbonate, dried (Na2SO4), filtered and stripped of solvent. The residue was flash chromatographed on silica gel with a 40:60 v:v mixture of ethyl acetate and hexane as eluent, to give the title compound, as white crystals, m.p.: 193°-195° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[I:9]([O-])(=O)=O.[K+].[I-].[K+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: [O-][I+2]([O-])[O-]
Reactant: Nc1ccc(Br)cn1
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: Nc1ncc(Br)cc1I
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 179.8 %

Procedure:
A stirred solution of 5-bromo-pyridin-2-ylamine (50 g, 289 mmol) in 2M sulfuric acid (500 mL) was treated portionwise with potassium iodate (30.8 g, 144 mmol) and the mixture heated to 100° C. A solution of potassium iodide (26.5 g, 160 mmol) in water (50 mL) was added dropwise over ca. 1 hour. The mixture was allowed to stir for a further 30 minutes then cooled to ambient temperature. The pH of the aqueous phase was adjusted to 8-9 and the mixture extracted with ethyl acetate (×3). The combined organic layer was washed with aqueous sodium thiosulfate solution, water and brine, dried (Na2SO4) and evaporated to afford the title compound as a brown solid (77.4 g, 90%). 1H NMR (300 MHz, CDCl3): 8.06 (d, J=2.2 Hz, 1H), 7.96 (d, J=2.2 Hz, 1H), 4.96 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:8]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1.[CH2:28](I)[CH2:29][CH2:30][CH3:31]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:28][CH2:29][CH2:30][CH3:31])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:8]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1
Reactant: CCCCI
Reactant: COC(=O)c1cc2cc(O)c(OC)cc2c(-c2ccncc2)c1C(=O)OC
Product: CCCCOc1cc2cc(C(=O)OC)c(C(=O)OC)c(-c3ccncc3)c2cc1OC

Procedure:
1-(4-Pyridyl)-2,3-bis(methoxycarbonyl)-6-hydroxy-7-methoxynaphthalene and butyl iodide are treated in the same manner as in Reference Example 117-(2) to give 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6-butoxy-7-methoxynaphthalene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[CH:11][N+:12]([O-])=O.OS(O)(=O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][NH2:12]
Reactant: COc1ccc(C=C[N+](=O)[O-])c(F)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COc1ccc(CCN)c(F)c1

Procedure:
LiAIH4 (3.5 equivalents) was suspended in THF and brought to reflux. 2-fluoro-4-methoxy-1-(2-nitro-vinyl)-benzene (1 equivalent) was dissolved in THF and added dropwise to the LiAIH4. The reaction was allowed to proceed at reflux overnight. The reaction was then cooled in an ice bath and H2SO4 was added dropwise. The reaction was extracted with ether. The ether fractions were discarded. The aqueous layer was adjusted to pH 12 with 5% NaOH and extracted with ether (3×). Combined ether fractions were washed with brine and dried over Na2SO4. Solvent was removed to yield 2-(2-fluoro-4-methoxy-phenyl)-ethylamine as an oil, which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][CH2:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1>ClCCl>[CH3:7][O:8][CH2:9][C:10]1[N:15]=[C:14]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][N:11]=1
Reactant: C1CCNCC1
Reactant: COCc1nccc(Cl)n1
Solvent: ClCCl
Product: COCc1nccc(N2CCCCC2)n1
Reaction time: 8 h

Procedure:
Piperidine (6.17 ml) in dichloromethane (40 ml) was added dropwise to a solution of 2-methoxymethyl-4-chloropyrimidine (4.71 g) in dichloromethane (40 ml). After standing overnight at room temperature the mixture was heated under reflux for 1 hour. After cooling the solution was washed with water, dried and stripped. The residue was chromatographed (silica gel, CHCl3) to give 2-methoxymethyl-4-piperidinopyrimidine (4.49 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)[CH:16]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
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: [I-]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2ccc(C(F)(F)F)cc2)c1
Yield: 38.7 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(4-(trifluoromethyl)benzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.057 g; 0.164 mmol), 4-(trifluoromethyl)phenylboronic acid (0.031 g; 0.164 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.0082 mmol), sodium carbonate (0.035 g; 0.328 mmol), sodium iodide (0.049 g; 0.328 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.029 g (62%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:10](=[O:24])[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([S:19](Cl)(=[O:21])=[O:20])=[C:14]([Cl:23])[CH:13]=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:25]([NH2:28])[CH2:26][CH3:27]>C(#N)C.CCOCC>[CH2:1]([O:3][P:4]([C:9]1[C:10](=[O:24])[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([S:19]([NH:28][CH2:25][CH2:26][CH3:27])(=[O:21])=[O:20])=[C:14]([Cl:23])[CH:13]=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCCN
Reactant: CCOP(=O)(OCC)c1cc2cc(S(=O)(=O)Cl)c(Cl)cc2[nH]c1=O
Solvent: CCOCC
Solvent: CC#N
Product: CCCNS(=O)(=O)c1cc2cc(P(=O)(OCC)OCC)c(=O)[nH]c2cc1Cl
Reaction time: 3 h

Procedure:
A suspension of the compound obtained in Step E (1.26 g, 3.0 mmol) with n-propylamine (9.0 mmol) in 30 ml of acetonitrile is stirred for 3 hours. Evaporation to dryness is carried out, the residue is then taken up in 1N HCl and extraction is carried out with ethyl acetate. Drying over MgSO4 and evaporation of the organic phase yield a residue which is taken up in ether and filtered to yield the title product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:46]=[CH:47][CH:48]=1)[C:24]([NH:26][C:27]1[C:28]([N:37]2[CH2:42][CH2:41][CH:40]([CH2:43][CH2:44]O)[CH2:39][CH2:38]2)=[N:29][CH:30]=[C:31]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:32]=1)=[O:25].C(Br)(Br)(Br)[Br:50]>C(Cl)Cl>[Br:50][CH2:44][CH2:43][CH:40]1[CH2:41][CH2:42][N:37]([C:28]2[C:27]([NH:26][C:24](=[O:25])[C:23]3[CH:46]=[CH:47][CH:48]=[C:21]([Cl:20])[CH:22]=3)=[CH:32][C:31]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:30][N:29]=2)[CH2:38][CH2:39]1
Reactant: CS(=O)(=O)c1cnc(N2CCC(CCO)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1cnc(N2CCC(CCBr)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a mixture of 0.300 g (1.14 mmol) of triphenylphosphine, and 0.500 g (1.14 mmol) of 3-chloro-N-[4-(2-hydroxy-ethyl)-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]benzamide in methylene chloride (20 mL), cooled to 0° C., is added 0.380 g (1.14 mmol) of carbon tetrabromide in multiple portions. The mixture is warmed to room temperature and stirred overnight then concentrated under reduced pressure and the residue purified by flash silica gel chromatography to provide 0.285 g (50% yield) of N-[4-(2-bromo-ethyl)-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-3-chloro-benzamide.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([C:10]2[C:14]([S:15][CH3:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:40])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:5]1[O:6][C:7]([C:10]2[C:14]([S:15]([CH3:16])=[O:40])=[C:13]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1c(-c2nnc(C(C)(C)C)o2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1c(-c2nnc(C(C)(C)C)o2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a solution of 2-tert-Butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(methylthio)-1H-pyrazol-3-yl)-1,3,4-oxadiazole (Ia-1) (150 mg, 0.30 mmol) in CH2Cl2 (5 mL) was added m-CPBA (77% Max, 74 mg, 0.33 mmol). The reaction mixture was stirred for 1 hr at room temperature. Saturated NaHCO3 was added to the reaction mixture, and the organic extract was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was subjected to silica gel column chromatography (eluent: hexane/EtOAc=½) to obtain 100 mg (65%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[NH2:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[C:4]=2[N:5]=[C:6]([NH:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29])[N:7]=1
Reactant: NC(CO)CO
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3ccc(C(F)(F)F)cc3)c2n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1ccc(C(F)(F)F)cc1
Yield: 45 %

Procedure:
A solution of 4-Chloro-2-methylsulfinyl-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (0.29 g, 0.75 mmol) in dichloromethane (30 mL) was mixed with a solution of serinol (0.075 g, 0.82 mmol) in DMF (0.75 mL). The resultant mixture was stirred at room temperature for 1 hour before concentrated under vacuum. Flash chromatography (EtOAc:Hexane, 3:1) then provided the title compound (0.14 g, 45%): MS (ES) m/z 415 (M+H)+; 1H-NMR(CDCl3) δ 2.25 (s, br, 2H), 3.66 (m, br, 5H), 6.15 (m, br, 1H), 6.55 (d, J=9.2 Hz, 1H), 7.36 (m, 2H), 7.81 (d, J=8.1 Hz, 2H), 7.92 (d, J=9.2 Hz, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[C:6](O)(=[O:15])[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)O.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:20][CH:19]=1>>[O:15]=[C:6]1[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:23]2[CH:22]=[C:21]([CH2:24][C:25]([NH2:27])=[O:26])[CH:20]=[CH:19][C:18]=2[O:17]1
Reactant: O=C(O)C(O)c1ccccc1
Reactant: NC(=O)Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: NC(=O)Cc1ccc2c(c1)C(c1ccccc1)C(=O)O2
Temperature: 80 °C
Yield: 20 %

Procedure:
190 ml of 80% strength sulfuric acid solution are added to a mixture of 16 g of mandelic acid and 15 g of 4-hydroxyphenylacetamide [J. Am. Chem. Soc. (1946) p. 2633]. The medium is heated very rapidly to 80° C. and immediately hydrolyzed using 600 g of ice. The aqueous phase is extracted with 3 times 200 ml of chloroform and the organic phase washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product obtained is recrystallized in chloroform.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([NH:12][C:13](=[O:20])[CH2:14][C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[CH:14]([C:15]3[CH:19]=[CH:18][S:17][CH:16]=3)[C:13](=[O:20])[NH:12]2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1ccsc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2C(=O)C1c1ccsc1
Reaction time: 2 h

Procedure:
To a solution of thiophene-3-acetic acid (1.4 g, 10 mmol) in dichloromethane (40 ml) was added oxalyl chloride (1.74 ml, 20 mmol) and dimethylformamide (catalytic, 3 drops) and the reaction stirred for 1 h. The solvent was evaporated and the residue co-evaporated with toluene (3×20 ml). The resulting acid chloride was dissolved in 1,2-dichloroethane (40 ml), methyl 2-amino-4-chlorobenzoate (1.5 g, 8 mmol) added and the reaction refluxed for 2 h. The residue remaining on evaporation of the solvent was triturated with diethyl ether to afford methyl 4-chloro-2-(3-thienyl)acetamidobenzoate as a tan solid (1 g), m.p. 96°-97° C. To a solution of the foregoing amide (0.5 g, 1.6 mmol) in tetrahydrofuran (25 ml) was added a solution of potassium hexamethyldisilazide in toluene (0.5M, 4 mmol) and the reaction stirred for 2 h. Methanol (5 ml) was added and the solvent evaporated. The residue was partitioned between aqueous sodium hydroxide (1M, 20 ml) and diethyl ether (20 ml), and the aqueous layer acidified with hydrochloric acid (5M). The resultant precipitate was collected and recrystallised from dimethylformamide/water to afford the title compound as a white solid; m.p. 341°-344° C. (from DMF/H2O) (Found: C, 55.07; H, 2.86; Cl, 12.94; N, 5.16; S, 11.42; C13H8ClNO2S, 0.5 H2O requires C, 55.32; H, 3.03, Cl, 12.56; N, 4.96; S, 11.36%); δ(DMSO-d6) 7.22 (1H, dd, J=8.6 and 2 Hz, 6-H), 7.31 (1H, s, 8-H), 7.43 (1H, d, J=4.9 Hz, 5'-H), 7.49-7.51 (1H, m, 4'-H), 7.76 (1H, s, 2'-H), 7.98 (1H, d, J=8.6 Hz, 5-H), 11.55 (1H, s, NH); m/z 277 (M+).