Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[N+:6]([C:9]1[CH:30]=[CH:29][C:12]([CH:13]=[C:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]2=3)=[CH:11][CH:10]=1)([O-])=O.Cl.[OH-].[Na+]>[Cl-].[Na+].O>[NH2:6][C:9]1[CH:30]=[CH:29][C:12]([CH:13]=[C:14]2[C:15]3[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=3[CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]2=3)=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(C=C2c3ccccc3C=Cc3ccccc32)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(C=C2c3ccccc3C=Cc3ccccc32)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To 150 ml of N,N-dimethylformamide, were added 10.0 g (30.7 mmol) of the above 5-(4-nitrobenzylidene)-5H-dibenzo[a,d]cycloheptene, 8.0 g (143 mmol) of reduced iron powder and 2.70 ml (30.6 mmol) of concentrated hydrochloric acid (d=1.18, 35%). The resulting mixture was heated to the inner temperature of about 70° C., and then heated and stirred for 3 hours at the same temperature. After the reaction was completed, the reaction mixture was cooled in an ice water bath, and about 12.4 ml of an aqueous 10% sodium hydroxide solution was added thereto, followed by stirring and thereafter suction filtration. The filtrate obtained was poured in about 1 liter of saturated brine, and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure. To thus obtained residue was added methanol, and the crystals precipitated were collected by filtration. The crystals were then recrystallized from methanol to give 8.41 g of 5-(4-aminobenzylidene)-5H-dibenzo[a,d]cycloheptene. Yield: 92.7%; m.p.: 119 to 120.0° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[C:11]C)[CH2:8][CH2:7][C@H:6]1[C:13]#[N:14])=[O:4].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:23])[CH2:18][CH2:17]1>C(#N)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]([N:19]2[CH2:18][CH2:17][CH:16]([NH:15][CH2:2][C:3]([N:5]3[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]3[C:13]#[N:14])=[O:4])[CH2:21][CH2:20]2)=[O:23])=[CH:25][CH:26]=1
Reactant: NC1CCN(C(=O)c2ccc(Cl)cc2)CC1
Reactant: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CCN(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-propynylpyrrolidine-2-carbonitrile (0.023 g, 0.118 mmol, Example 8D) in acetonitrile (1 mL) at room temperature was added (4-amino-piperidin-1-yl)-(4-chloro-phenyl)methanone (56 mg, 0.235 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (ESI) m/z 399 (M+H)+.
Reaction SMILES: C([O:4][C@H:5]1[C@H:14]([O:15]C(=O)C)[C@@H:13]([CH2:19][O:20]C(=O)C)[O:12][C@@H:7]([O:8][CH2:9][CH:10]=[CH2:11])[C@@H:6]1[NH:24][C:25](=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=O)C.[Na]>CO>[C:25]([NH:24][C@@H:6]1[C@@H:5]([OH:4])[C@H:14]([OH:15])[C@@H:13]([CH2:19][OH:20])[O:12][C@H:7]1[O:8][CH2:9][CH:10]=[CH2:11])(=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: C=CCO[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Agent: [Na]
Solvent: CO
Product: C=CCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Reaction time: 8 h

Procedure:
A solution of 6 grams of allyl 3,4,6-tri-O-acetyl-2-deoxy-2-palmitamido-β-D-glucopyranoside (Compound 1a) in 150 ml. of methanol was refluxed for about 30 minutes after the addition of a piece of sodium metal. A sulfonic cation exchange resin was added to remove the sodium, followed by hot filtration. The filtrate was concentrated on a hot plate and stored overnight in a freezer. It was then filtered to yield the desired compound as a gelatinous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:31])[N:17]3[C:22](=[C:23]([C:25](O)=[O:26])[CH:24]=2)[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][CH2:34][CH2:35][NH:36][C:37]1[S:41][N:40]=[C:39]([CH3:42])[CH:38]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[CH3:32][O:33][CH2:34][CH2:35][N:36]([C:37]1[S:41][N:40]=[C:39]([CH3:42])[CH:38]=1)[C:25]([C:23]1[CH:24]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)[C:16](=[O:31])[N:17]2[C:22]=1[C:21]1[S:28][CH:29]=[CH:30][C:20]=1[CH:19]=[CH:18]2)=[O:26]
Reactant: COCCNc1cc(C)ns1
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1cc(C)ns1

Procedure:
From 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid and (2-methoxy-ethyl)-(3-methyl-isothiazol-5-yl)-amine with triethylamine and diethyl cyanophosphonate in dimethylformamide.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[CH2:11]([O:13][C:14]([NH:16][C@@H:17]([C:21]([S:24][CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22])[C:18](O)=[O:19])=[O:15])[CH3:12].CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:18](=[O:19])[C@@H:17]([NH:16][C:14]([O:13][CH2:11][CH3:12])=[O:15])[C:21]([S:24][CH:25]([CH3:27])[CH3:26])([CH3:22])[CH3:23])=[O:10]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)(C)SC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CCOC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC)C(C)(C)SC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
A mixture of (L)-proline methyl ester hydrochloride (0.28 g), 2-(R)-ethoxycarbonylamino-3-isopropylsulfanyl-3-methyl-butyric acid (0.44 g), N-methyl morpholine (0.73 mL) and 0.54 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 10 mL of dry N,N-dimethylformamide was stirred for 16 h at ambient temperature. The volatiles were pumped off and water was added followed by extraction with ethyl acetate and concentration of the organic layer. The remaining residue was purified by silica chromatography (ethyl acetate/isohexane=1/1) to give 0.45 g (72%) of the title compound as a colorless oil. (+)-APCI-MS: 375 (MH+).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:18]=[CH:17][C:13]2[CH:14]=[N:15][S:16][C:12]=2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9])=C.Cl>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:18]=[CH:17][C:13]2[CH:14]=[N:15][S:16][C:12]=2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9]
Reactant: C=COCCONC(=O)c1ccc2cnsc2c1Nc1ccc(I)cc1F
Agent: Cl
Solvent: CO
Product: O=C(NOCCO)c1ccc2cnsc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a solution of 7-(2-fluoro-4-iodo-phenylamino)-benzo[d]isothiazole-6-carboxylic acid (2-vinyloxy-ethoxy)-amide (187 mg, 0.37 mmol) in MeOH (4 mL) was added a 1.0M aqueous solution of hydrochloric acid (0.75 mL). The reaction mixture was stirred at room temperature for 1 hour before being concentrated in vacuo. The resultant residue was taken up in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, then brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0% to 100%, ethyl acetate in DCM) to afford the title compound as a yellow solid (128 mg, 72%). LCMS (method A): RT=9.81 min, [M+H]+=474. 1H NMR (CDCl3, 400 MHz) 9.33 (1 H, s), 8.86 (1 H, s), 8.77 (1 H, s), 7.55-7.40 (4 H, m), 6.84 (1 H, t, J=8.30 Hz), 4.10 (2 H, t, J=4.16 Hz), 3.91 (1 H, t, J=6.45 Hz), 3.80 (2 H, t, J=4.55 Hz).
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:44]=[CH:43][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][C:31]([O:38]S(C)(=O)=O)=[C:32]([CH:37]=4)[C:33]([O:35][CH3:36])=[O:34])[O:25][C:26]=3[CH3:27])=[C:18]([O:45][CH3:46])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=[O:2].[OH-].[Na+].Cl.[C:50](=O)([O-])[O-].[K+].[K+].CI>O.CN(C)C=O.C(O)C.O1CCCC1>[CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:44]=[CH:43][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][C:31]([O:38][CH3:50])=[C:32]([CH:37]=4)[C:33]([O:35][CH3:36])=[O:34])[O:25][C:26]=3[CH3:27])=[C:18]([O:45][CH3:46])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=[O:2]
Reactant: COC(=O)c1cc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)ccc1OS(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)c1cc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)ccc1OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a mixture of methyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-(methanesulfonyloxy)benzoate (0.50 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (3 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give pale-yellow crystal. A mixture of the crystal, potassium carbonate (0.21 g), methyl iodide (0.55 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methoxybenzoate as pale-yellow crystals (0.30 g, yield 67%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 165-166° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1.[CH3:21][C:22]1([C:25](O)=[O:26])[CH2:24][CH2:23]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:25]([C:22]4([CH3:21])[CH2:24][CH2:23]4)=[O:26])[CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1
Reactant: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(Br)cc1
Reactant: CC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C(=O)N2CC[C@@H](Cc3n[nH]c(=O)n3-c3ccc(Br)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
Into a 5 mL microwave vial was placed 4-(4-bromophenyl)-5-[(3S)-3-pyrrolidinylmethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (0.473 mmol), 1-methylcyclopropanecarboxylic acid (0.499 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.200 mmol), 1-hydroxybenzotriazole (1.208 mmol), N,N-diisopropylethylamine (1.431 mmol), and N,N-dimethylformamide (2 mL). The vial was capped and the contents were stirred at room temperature for 4 h. Purification of the crude material by reverse phase HPLC (10-40% acetonitrile w/0.1% TFA/water w/0.1% TFA) followed by collection and concentration of the desired fractions provided the title compound (166 mg, 87%). MS(ES)+ m/e 405.0, 407.1 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH2:27]2)[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([N:26]4[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH2:27]4)[CH:23]=[N:22][CH:21]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: O=C1CN(c2cncc(Cl)n2)CCN1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: O=C1CN(c2cncc(-c3cnc4[nH]ccc4c3)n2)CCN1
Temperature: 100 °C

Procedure:
The starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.205 mmol, 1 eq) and 4-(6-chloropyrazin-2-yl)piperazin-2-one (132) (33 mg, 0.184 mmol, 0.9 eq) in DME (8 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.409 mmol, 2 eq) followed by addition of Pd(dpp)Cl2 (6 mg, 0.00819 mmol, 0.04 eq) and degassing and purging under argon for additional 10 min. The reaction mixture was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound 4-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)piperazin-2-one 133 in 9 mg quantity. The compound 133 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 11.84 (s, 1H), 8.95 (d, J=2.07, 1H), 8.64 (d, J=1.95, 1H), 8.57 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H, 7.53 (m, J=2.92, 1H), 6.56 (m, J=1.70, 1H), 4.18 (s, 2H), 3.89 (m, J=5.36 2H); MS m/z 294.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:15][N:16]=[C:17]=[O:18]>C(N(CC)CC)C.C1C=CC=CC=1>[CH3:15][NH:16][C:17](=[O:18])[O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])=[CH:7][CH:8]=1
Reactant: CN=C=O
Reactant: COC(COc1ccc(O)cc1)OC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1ccc(OCC(OC)OC)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-(2,2-Dimethoxyethoxy)phenol (5.0 grams) and benzene were charged into a glass reaction vessel equipped with a mechanical stirrer. Methyl isocyanate (3.5 ml) and 4 drops of triethylamine were then added, and the reaction mixture was stirred at room temperature for a period of about 6 hours. After this time the reaction mixture was filtered, and the filtrate was concentrated to 10 ml by partially stripping the solvent under reduced pressure. Cyclohexane (10 ml) was then added to the concentrate, resulting in the formation of a precipitate. The precipitate was recovered by filtration to yield the desired product O-[4-(2,2-dimethoxyethoxy)phenyl] N-methylcarbamate as a slightly pink solid melting at 79° to 81° C.
Reaction SMILES: [F:1][C:2]1[N:3]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH2:7][OH:8].C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[N:3]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc(CO)c1F
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.5 %

Procedure:
To a solution (20 mL) of [2-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (330 mg) in acetonitrile were added tetra-n-propylammonium perruthenate (53 mg), N-methylmorpholine N-oxide (270 mg) and molecular sieves 4A powder (500 mg), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→4:1) to give the title compound as a colorless oil (yield 110 mg, 34%).
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH2:23])[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:24]([N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(Cl)Cl>[C:27]([O:26][C:24]([N:31]1[CH2:36][CH2:35][CH:34]([NH:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:13])=[O:12])[CH2:33][CH2:32]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: Nc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A mixture of [3-(1-naphthylsulfonyl)-1H-indazol-5-yl]amine (400 mg, 1.24 mmol), 1-Boc-4-piperidone (493 mg, 2.47 mmol), sodium triacetoxyborohydride (524 mg, 2.47 mmol), and acetic acid (149 mg, 2.47 mmol) in 1,2-dichloroethane was stirred at room temperature overnight, diluted with CH2Cl2, washed with water, dried over Na2SO4 and concentrated in vacuo. The resultant residue was purified by column chromatography with 1% MeOH in CH2Cl2 as eluent to provide the title compound, 390 mg (62% yield), characterized by HNMR and mass spectral analyses.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([F:14])[C:5]=1[N:15]1[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=[CH:16]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:3][C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:11])[F:13])[CH:7]=[C:6]([F:14])[C:5]=1[N:15]1[C:20](=[O:21])[C:19]([Br:1])=[C:18]([C:22]([F:24])([F:25])[F:23])[N:17]=[CH:16]1
Reactant: BrBr
Reactant: O=c1cc(C(F)(F)F)ncn1-c1c(F)cc(C(F)(F)F)cc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1c(Br)c(C(F)(F)F)ncn1-c1c(F)cc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of bromine (146 mg) in acetic acid (1 ml) was added dropwise to a solution of compound 11 (in Table I) (285 mg) and sodium acetate (204 mg) in acetic acid (3 ml). After stirring at the ambient temperature for 16 hours, the solvent was removed by evaporation under reduced pressure and the residue dissolved in aqueous sodium bicarbonate solution. After extraction with ethyl acetate, the organic layer was washed with aqueous sodium thiosulphate solution, dried and filtered, and concentrated under reduced pressure to qive a pale yellow solid. Recrystallization from a mixture of ethyl acetate and petroleum ether (boiling range 60°-80° C.) gave 1-(2,6-difluoro-4-trifluoromethylphenyl)-5-bromo-4-trifluoromethylpyrimidin-6-one;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:5][NH:6][C:7](=[O:11])[CH2:8][C:9]#[N:10].CO[CH:18]=[CH:19][C:20](=O)[CH3:21].N12CCN(CC1)CC2>COCCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:5][N:6]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:8]([C:9]#[N:10])[C:7]1=[O:11]
Reactant: COC=CC(C)=O
Reactant: N#CCC(=O)NCc1ccc(Cl)c(Cl)c1
Agent: C1CN2CCN1CC2
Solvent: COCCO
Product: Cc1ccc(C#N)c(=O)n1Cc1ccc(Cl)c(Cl)c1
Yield: 62 %

Procedure:
A solution of 49.7 g. (0.204 mole) of N-(3,4-dichlorobenzyl)-2-cyanoacetamide, 48.0 g (0.48 mole) of 4-methoxy-3-buten-2-one, and 4 g. of 1,4-diazabicyclo (2.2.2)octane (DABCO) in 160 ml. of 2-methoxyethanol is refluxed for 4 hr. The dark reaction mixture is then concentrated in vacuo and the crude solid is isolated by filtration from the resulting slurry and washed with ether. The crude product is dissolved in methylene chloride and the organic solution is washed with water, 2N--HCl and finally with more water. The methylene chloride is removed and the product is obtained in 62% yield by ether tirituration.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)=O.CC(C)=O.[F:20][C:21]1[C:26]([C:27](Cl)=[O:28])=[C:25]([F:30])[C:24]([F:31])=[C:23]([F:32])[C:22]=1[F:33]>C(O)C.CCOCC.C(Cl)(Cl)(Cl)Cl>[F:20][C:21]1[C:26]([C:27]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:28])=[C:25]([F:30])[C:24]([F:31])=[C:23]([F:32])[C:22]=1[F:33]
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C=O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)c(F)c(F)c(F)c1F
Yield: 99.6 %

Procedure:
A 7.35 g portion of magnesium chips, 1.5 ml of carbon tetrachloride and 15 ml of absolute ethanol were added to a dry flask. A solution of 48.1 g of diethyl malonate in 30 ml of absolute ethanol and 120 ml of anhydrous ether was added dropwise over a one hour period. When addition was complete, the mixture was stirred at reflux for 3 hours then cooled to -10° C. with dry ice/acetone. A solution of 70 g of pentafluorobenzoyl chloride in 120 ml of ether was added over 2 hours, maintaining the temperature at not more than -5° C. The mixture was then stirred overnight at room temperature, partially evaporated, cooled in crushed ice and an ice cold solution of 7.5 ml of concentrated sulfuric acid in 300 ml of water was added at a rate such that the internal temperature did not go above 5° C. The mixture was extracted several times with ether, the extracts combined, washed with saturated sodium chloride, dried and concentrated, giving 106 g of (pentafluorobenzoyl)propanedioic acid, diethyl ester as a yellow oil.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:16].[CH3:25][C:26]1[N:27]=[C:28]([N:41]2[C:45](=[O:46])[NH:44][N:43]=[CH:42]2)[S:29][C:30]=1[C:31]([NH:33][CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)=[O:32]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[CH2:14][N:44]2[C:45](=[O:46])[N:41]([C:28]3[S:29][C:30]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[C:26]([CH3:25])[N:27]=3)[CH:42]=[N:43]2)=[CH:19][CH:20]=1
Reactant: Cc1nc(-n2cn[nH]c2=O)sc1C(=O)NCc1cccnc1
Reactant: O=C(CBr)Nc1ccc(Cl)cc1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: Cc1nc(-n2cnn(CC(=O)Nc3ccc(Cl)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 25 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 2-bromo-N-(4-chlorophenyl)acetamide to react with 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 25% yield: mp 255-256° C. (ethyl acetate/hexane); 1H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.90 (t, J=5.8 Hz, 1H), 8.79 (s, 1H), 8.52 (br s, 1H), 8.44 (br s, 1H), 7.75-7.65 (m, 1H), 7.61-7.49 (m, 2H), 7.39-7.28 (m, 3H), 4.67 (s, 2H), 4.40 (d, J=5.8 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 484.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N.Cl>N1CCCCC1.O.N1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5](/[CH:7]=[CH:10]/[C:11]([OH:13])=[O:12])[CH:4]=[N:3]1
Reactant: Cn1cc(C=O)cn1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: N
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cn1cc(/C=C/C(=O)O)cn1
Temperature: 110 °C
Yield: 41.8 %

Procedure:
A mixture of 1-methyl-1H-pyrazole-4-carbaldehyde (13 g, 118 mmol), malonic acid (12.29 g, 118 mmol), pyridine (65 ml) and piperidine (0.234 ml, 2.361 mmol) was heated to 110° C. under argon for 4 h. After cooling, water (100 ml) was added, followed by aqueous ammonia (12 ml) to obtain a clear solution, which was acidified to pH˜1 with hydrochloric acid. The precipitate was collected by filtration, washed with water and dried to obtain the title compound (7.5 g, 40.5% yield). LCMS: rt=0.92 min, [M+H+]=153