Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[N:35]1([CH2:41][C:42]2[CH:47]=[CH:46][N:45]=[C:44]([O:48][CH2:49]/[CH:50]=[CH:51]\[CH2:52][NH2:53])[CH:43]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(OCC)(=O)C.CN(C)C=O>[N:35]1([CH2:41][C:42]2[CH:47]=[CH:46][N:45]=[C:44]([O:48][CH2:49]/[CH:50]=[CH:51]\[CH2:52][NH:53][C:7](=[O:9])[CH2:6][CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:43]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CC(=O)SCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)SCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.2 %

Procedure:
1.00 g of 3-(acetylthio)propionic acid, 1.39 g of dicyclohexyl carbodiimide, 1.05 g of 1-hydroxybenzotriazole and 1.76 g of 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine were added to 45 ml of dimethylformamide, and the solution was stirred for 5 hours at room temperature. At the end of this time, ethyl acetate was added to the reaction mixture, insoluble matter was filtered off, and the filtrate was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water. The reaction mixture was then condensed by evaporation under reduced pressure, and the resulting residue was subjected to silica gel chromatography, eluted with a 1:19 by volume mixture of methanol and ethyl acetate, to give 1.27 g (yield 48%) of the title compound as an oil.
Reaction SMILES: [OH:1][CH:2]([CH3:10])[CH2:3][NH:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7].ClC(Cl)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(N(CC)CC)C>[Cl:15][CH2:16][C:17]([O:1][CH:2]([CH3:10])[CH2:3][NH:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7])=[O:18]
Reactant: C=C(C)C(=O)NCC(C)O
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: C=C(C)C(=O)NCC(C)OC(=O)CCl

Procedure:
The compound was prepared by the method described in Example 7, using N-(2-hydroxypropyl)methacrylamide (14.3 g), dichloroethane (200 ml), chloroacetyl chloride (11.3 g) and triethylamine (10.1 g). The product distilled at 112° C./0.1 mm (12 g) and was obtained as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:33])[CH2:19][CH2:18]2)=[O:16])[C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[CH2:9][CH:10]([NH:14][C:15]([N:17]1[CH2:18][CH2:19][CH:20]([N:23]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]2=[O:33])[CH2:21][CH2:22]1)=[O:16])[C:11]([N:44]1[CH2:45][CH2:46][CH:41]([CH:38]2[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]2)[CH2:42][CH2:43]1)=[O:13]
Reactant: Cc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Reactant: CN1CCC(C2CCNCC2)CC1
Product: Cc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(C)CC3)CC2)cc1C

Procedure:
Prepared analogously to Example 83d) from 3-(3,4-dimethyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 1-methyl-[4,4′]bipiperidinyl.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:18])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].CCN(C(C)C)C(C)C.C(N[C@H:36]([C:47](O)=[O:48])[CH2:37]C1C=CC([N+]([O-])=O)=CC=1)(OC(C)(C)C)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl>C(#N)C>[C:47]([NH:1][C:2]1[C:3](=[O:18])[N:4]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH3:8])(=[O:48])[CH2:36][CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: COc1ccc(Cn2ccc(C)c(N)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCC(=O)Nc1c(C)ccn(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 157.3 %

Procedure:
To a solution of 3-amino-1-(4-methoxybenzyl)-4-methyl-2-pyridone (5.03 g, 20.6 mmol), DIEA (3.76 mL, 21.6 mmol) and N-Boc-p-nitrophenylalanine (6.71 g, 21.6 mmol) in acetonitrile (100 mL) cooled on ice was added TBTU (7.94 g, 24.7 mmol). The mixture was stirred at rt overnight. Additional DIEA (3.76 mL, 21,6 mmol) was added, and the slurry was stirred for another 6 hours. 1N HCl (50 mL) was added, and the acetonitrile was removed under reduced pressure. Ethyl acetate (300 mL) was added, and the organic suspension was separated and washed with 1N HCl, 2.5N NaOH and brine. Ethyl acetate (50 mL) and THF (100 mL) were added to the suspension to dissolve all solids, and the organic phase was washed with brine, and dried (MgSO4/silica gel/charcoal). Evaporation of the solvent gave 3-2′-(S)-tbutoxycarbonylamino-3′-(4″-nitro)benzene]propanoylamino-1-(4-methoxybenzyl)-4-methyl-2-pyridone as a brown solid (9.73 g, 88%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C:7]([CH3:15])([CH3:14])[C:8]([F:13])([F:12])[CH2:9][CH2:10][OH:11])[CH3:5])[CH3:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:11][CH2:10][CH2:9][C:8]([F:12])([F:13])[C:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])([CH3:15])[CH3:14])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(C)OC(C)(C)C(F)(F)CCO
Solvent: c1ccncc1
Product: CCOC(C)OC(C)(C)C(F)(F)CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 1.00 g (0.0044 mol) of 4-(1-ethoxyethoxy)-3,3-difluoro-4-methyl-1-pentanol, 4 mL of pyridine and 1.27 g (0.0066 mol) of p-toluenesulfonyl chloride was stirred at 0° C. for 18 hr. The mixture was quenched with ice chips. The mixture was then poured into water and extracted with methylene chloride. The organic phase was sequentially washed with 10% aqueous sulfuric acid and saturated aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to yield oily 4-(1-ethoxyethoxy)-3,3-difluoro-4-methyl-1-pentanol 1-(4-methylbenzenesulfonate). NMR (CDCl3) δ4.93 (quartet, 1, J=7 Hz), 4.27 (triplet, 2, J=7 Hz), 3.45 (quartet, 2, J=7 Hz), 2.45 (singlet, 3), 2.36 (multiplet, 2), 1.27 (triplet, 6, J=1 Hz), 1.24 (doublet, 3 J=7 Hz), and 1.15 ppm (triplet, 3, J=7 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:12]1([CH3:27])[CH:17]=[CH:16][C:15]([C:18]2[N:22]=[C:21]([CH2:23][C:24](O)=[O:25])[O:20][N:19]=2)=[CH:14][CH:13]=1.N1CCCCC1>C(O)C>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:23]([C:21]3[O:20][N:19]=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([CH3:27])=[CH:13][CH:14]=4)[N:22]=3)[C:24](=[O:25])[O:1]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2noc(CC(=O)O)n2)cc1
Reactant: COc1ccc(C=O)c(O)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc2cc(-c3nc(-c4ccc(C)cc4)no3)c(=O)oc2c1

Procedure:
4.5 parts of 2-hydroxy-4-methoxy benzaldehyde and 7.38 parts of the ethyl ester of 3-p-tolyl-1,2,4-oxadiazol-5-acetic acid (melting point: 56° C) are dissolved in 80 parts of ethanol. 0.3 part of piperidine is added and the mixture is heated for 1 hour under reflux. After cooling, the crystalline precipitate obtained is filtered and washed in ethanol. Thus 8.5 parts of 7-methoxy-3-(3-p-tolyl-1,2,4-oxadiazol-5-yl) coumarin are obtained which melts at 227° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:17]2[C@:16]3([CH3:21])[C:18]([CH3:20])([CH3:19])[C@@H:13]([CH2:14][CH2:15]3)[C:12]=2[C:11](=[O:22])[N:10]1[CH2:23][C:24]1[C:25]([C:48]([F:51])([F:50])[F:49])=[N:26][N:27](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:28]=1.C([SiH](CC)CC)C>ClCCl>[CH3:8][N:9]1[C:17]2[C@:16]3([CH3:21])[C:18]([CH3:19])([CH3:20])[C@@H:13]([CH2:14][CH2:15]3)[C:12]=2[C:11](=[O:22])[N:10]1[CH2:23][C:24]1[C:25]([C:48]([F:49])([F:50])[F:51])=[N:26][NH:27][CH:28]=1
Reactant: Cn1c2c(c(=O)n1Cc1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc1C(F)(F)F)[C@@H]1CC[C@@]2(C)C1(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c2c(c(=O)n1Cc1c[nH]nc1C(F)(F)F)[C@@H]1CC[C@@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.3 %

Procedure:
Trifluoroacetic acid (4 mL) was added to a solution of (4R,7S)-1,7,8,8-tetramethyl-2-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (410 mg, 0.69 mmol) in dichloromethane (4 mL) and the yellow solution was stirred at room temperature for 4 h. Triethylsilane (110 μL, 0.69 mmol) was added and the solution was stirred at room temperature for 10 min. The solvent was evaporated using a rotary evaporator and the residue was held under high vacuum overnight. The residue was taken up in dichloromethane (50 mL), the solution was transferred to a separatory funnel and water (50 mL) was added. Aqueous saturated sodium hydrogen carbonate (1 Pasteur pipette) was added and the layers were separated. The organic layer was washed with brine (50 mL), dried (magnesium sulfate), filtered, evaporated, and purified using a Biotage 40S system, eluting with 1-3% methanol/ethyl acetate, to give (4R,7S)-1,7,8,8-tetramethyl-2-(3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (118 mg, 48%) as an off-white solid. APCI(+)-MS (M+H) 355.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>O>[Cl:13][S:14]([C:4]1[CH:5]=[C:6]([CH2:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:16])=[O:15]
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: COc1ccc(CC(C)=O)cc1S(=O)(=O)Cl

Procedure:
The (3-aminosulfonyl-4-methoxy)phenylacetone (4) is a novel compound and it may be prepared in analogy to a process described in U.S. Pat. No. 544,958 for related compounds. The starting compound is 4-methoxyphenyl acetone which is chlorosulfonated by chlorosulfonic acid at 0-5° C. After treating the reaction mixture with water, the resulting 3-chlorosulfonyl-4-methoxyphenylacetone (9) is formed in solid state and is isolated by filtration. The compound (9) is then treated in ethyl acetate solution with aqueous ammonia at 5° C. The formed crystals of crude (4) are recovered by filtration. The crude (4) may be purified by crystallization, e.g. from ethanol.
Reaction SMILES: [C:1](/[C:3](=[CH:9]\[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:17]([CH2:19][C:20](OCC)=O)#N.C1(C)C=CC(C=O)=CC=1.[N+](C(C)C)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:9]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[C:19]1([CH3:20])[CH3:17])#[N:2]
Reactant: CCOC(=O)/C(C#N)=C/c1ccc(C)cc1
Reactant: CCOC(=O)CC#N
Agent: Cc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)[N+](=O)[O-]
Solvent: CCO
Product: CCOC(=O)C1(C#N)C(c2ccc(C)cc2)C1(C)C
Yield: 74 %

Procedure:
A mixture of 576 mg (2.68 mmoles) of (E)-ethyl 2-cyano-3-(p-methylphenyl)-2-propenoate (7) [prepared from ethyl cyanoacetate and p-tolualdehyde (p-methylbenzaldehyde) using the procedure described in Example I for an analogous cyanoester], 0.25 ml (2.78 mmoles) of 2-nitropropane, 398 mg (2.88 mmoles) of anhydrous potassium carbonate, and 2.0 ml of absolute ethanol was heated at reflux for 7 hours. The product was isolated as described in the procedure of Example VIII, affording 511 mg (74% yield) of cyclopropanoid cyanoester 15: bp: 155°-183° C. (bath temperature, 0.15 mm).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[N:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=C(O)Cc1ccc(Br)cn1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Br)cn1

Procedure:
Key building block 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid (XII) can be prepared according to Scheme 8. Starting with commercially available 5-bromo-2-iodo-pyridine (XXXV), copper-catalyzed reaction with malonic acid diethyl ester furnishes 2-(5-bromo-pyridin-2-yl)-malonic acid diethyl ester (XXXVI). Hydrolysis and decarboxylation under basic conditions gives (5-bromo-pyridin-2-yl)-acetic acid (XXXVII), which subsequently can undergo nucleophilic acyl substitution with thionyl chloride in methanol to provide (5-bromo-pyridin-2-yl)-acetic acid methyl ester (XXXVIII). Deprotonation of XXXVIII with strong base followed by alkylation with 1-bromo-3-chloropropane gives 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid methyl ester (XXXIX), which can then be hydrolyzed under aqueous basic conditions to furnish key building block 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid (XII).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]([CH3:13])[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=1.[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]([CH3:13])[C:10](=[O:11])[O:23][C:20]2[CH:21]=[CH:22][C:17]([CH:14]([CH3:16])[CH3:15])=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(N(C)C(=O)Cl)n1
Reactant: CC(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: COc1cccc(N(C)C(=O)Oc2ccc(C(C)C)cc2)n1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A mixture of 2.01 g of N-(6-methoxy-2-pyridyl)-N-methylcarbamoylchloride, 1.36 g of 4-isopropylphenol, and 1.38 g of anhydrous potassium carbonate in 50 ml of methyl ethyl ketone was refluxed for 5 hours. After the reaction mixture was cooled to room temperature, it was poured into cold water and the product was extracted with benzene. The benzene solution, successively washed with water and brine, was dried over anhydrous magnesium sulfate. The residue obtained by the removal of benzene under reduced pressure was chromatographed through silica gel column using benzene as an eluent to give 2.56 g of pure 4-isopropylphenyl N-(6-methoxy-2-pyridyl)-N-methylcarbamate as solid in the yield of 85%. A part of the solid was recrystallized from hexane and crystals having melting point of 64° to 65° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15]([CH3:17])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>ClCCl>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15]([CH3:17])(=[O:28])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CS(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 58.9 %

Procedure:
4-Chloro-4'-methylsulfinylmethylbenzophenone (2.9 g) and m-chloroperbenzoic acid (2.5 g) were dissolved in dichloromethane, and the mixture was stirred for 12 hours at 0° C. After the precipitated crystals were filtered off, the filtrate was successively washed with aquous sodium bicarbonate solution, aqueous 5% sodium thiosulfate solution and water, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:5) to obtain 4-chloro-4'-methylsulfonylmethylbenzophenone (1.8 g).
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(Cl)Cl.[O-]Cl.[Na+].[C:16](=S)=[S:17]>O>[CH2:1]([N:7]=[C:16]=[S:17])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=S
Reactant: NCc1ccco1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: S=C=NCc1ccco1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Furfurylamine (9.71 g) is added over 30 minutes to a stirred, cooled mixture of 8.84 g of NaOH, 20 ml of CH2Cl2, 15 ml of H2O and 7.5 ml of CS2. The mixture is stirred 55 minutes in the ice bath and 600 ml of 5.25% aqueous NaOCl solution is added over 1 hour and 45 minutes (temperature is maintained at 8° C. or less). After stirring 16 hours at 20° C., the reaction mixture is extracted three times with CH2Cl2 (total volume of combined CH2Cl2 extracts is 600 ml). The CH2Cl2 extract is washed with 2×100 ml of H2O, dried with Na2SO4 and evaporated to give 12.4 g of crude furfurylisothiocyanate.
Reaction SMILES: N1C=CC=N1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([O:13]C)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:11]([C:10]2[CH:15]=[C:16]([CH3:18])[CH:17]=[C:8]([O:7][CH3:6])[CH:9]=2)=[O:13])=[CH:22][N:21]=1
Reactant: Cc1ccc(Cl)nc1
Reactant: COC(=O)c1cc(C)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: c1cn[nH]c1
Product: COc1cc(C)cc(C(=O)Cc2ccc(Cl)nc2)c1

Procedure:
For the synthesis of the pyrazole derivative, first, as illustrated in Reaction Scheme 10, methyl 3-methoxy-5-methylbenzoate of Formula 2a is allowed to undergo a nucleophilic attack at its carboxylic carbon by the activated methylene group of 2-chloro-5-methylpyridine in the presence of lithium hexamethyldisilazide to afford 2-(2-chloropyridin-5-yl)-1-(3-methoxy-5-methylphenyl)ethanone, represented by Formula 28. The compound of Formula 28 is converted into a pyrazole derivative through two successive steps. In this regard, the ethanone compound of Formula 28 is heated with N,N-dimethylformamide dimethylacetal, successively followed by cyclization with hydrazine hydrate into 4-(2-chloropyridin-5-yl)-3-(3-methoxy-5-methylphenyl)-1H-pyrazol, represented by Formula 29. The reaction of the pyrazole compound of Formula 29 with iodoacetonitrile in the presence of potassium carbonate produces two regioisomers 4-(2-chloropyridin-5-yl)-3-(3-methoxy-5-methylphenyl)-1H-pyrazol-1-yl)acetonitrile, represented by Formula 30, and 4-(2-chloropyridin-5-yl)-5-(3-methoxy-5-methylphenyl)-1H-pyrazol-1-yl)acetonitrile, represented by Formula 31. In the presence of a palladium catalyst, the regioisomers of Formulas 31 and 32 are subjected to nucleophilic substitution with various arylboronic acids to synthesize various compounds represented by Formulas 32a-c and 33a-c. Finally, these compounds are demethylated with boron trifluoride dimethyl sulfide to synthesize target pyrazole derivatives of Formulas 34a-c and 35a-c.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8](=O)[CH2:9][CH3:10])[CH2:3]1.Cl.[C:13]1([CH2:19][O:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:19][O:20][N:21]=[C:8]([C:4]2[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][CH:5]=2)[CH2:9][CH3:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NOCc1ccccc1
Reactant: CCC(=O)C1=CCCN(C)C1
Agent: Cl
Product: CCC(=NOCc1ccccc1)C1=CCCN(C)C1
Yield: 82 %

Procedure:
Examploying the general method of Example 5 above, but starting with 1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-1-propanone and O-(phenylmethyl)hydroxylamine hydrochloride, the title compound was prepared in 82% yield and isolated as the ethanedioate salt, mp 137°-139° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([N:23]1[CH:27]([C:28]([OH:30])=O)[CH2:26][S:25][CH:24]1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH3:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.ON1C2C=CC=CC=2N=N1>O1CCCC1.C(OCC)(=O)C>[CH3:37][CH:38]1[CH2:43][CH2:42][N:41]([C:28]([CH:27]2[CH2:26][S:25][CH:24]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[N:23]2[C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])=[O:30])[CH2:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Reactant: CC1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1CCN(C(=O)C2CSC(c3cccnc3)N2C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
A solution of 540 mg of dicyclohexylcarbodiimide in 5 ml of tetrahydrofuran was added dropwise to a mixture of 810 mg of N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid, 260 mg of 4-methylpiperidine, 530 mg of 1-hydroxybenzotriazole and 10 ml of tetrahydrofuran with ice cooling, and the mixture was stirred with ice cooling for 1 hour and then at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-methyl-1-[3-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperidine. Trifluoroacetic acid (5 ml) was added to the thus-obtained compound, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and the solution was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure The residue thus obtained was purified by silica gel column chromatography (eluent: ethyl acetate) to give 4-methyl-1-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperidine. This compound was dissolved in ethyl acetate, and 3 ml of 2N hydrogen chloride solution in dioxane was added The resultant solid was collected by filtration, washed with ethyl acetate and dried to give 530 mg of 4-methyl-1-(3-pyridyl)thiazolidin-3-ylcarbonyl]piperidine dihydrochloride. Melting point 130° C.
Reaction SMILES: [C:1]([N:5]([NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=3)[NH:22][CH:21]=2)[N:14]=1)[CH2:6][C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([N:5]([CH2:6][C:7]([OH:9])=[O:8])[NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]([F:32])([F:30])[F:31])[CH:27]=3)[NH:22][CH:21]=2)[N:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CN(Nc1nc(-c2c[nH]c3ncc(C(F)(F)F)cc23)ncc1F)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)N(CC(=O)O)Nc1nc(-c2c[nH]c3ncc(C(F)(F)F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-[tert-butyl-[[5-fluoro-2-[5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]amino]acetate, 155a, (0.200 g, 0.440 mmol) in THF (40 mL) was added a solution of lithium hydroxide hydrate (0.074 g, 1.760 mmol) in H2O (4 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture concentrated in vacuo to remove the THF. The remaining aqueous phase was diluted to 8 mL and the solution was used directly in a preparatory HPLC. The product precipicated when the fraction was concentrated on rotavaporator. The solid was filtered and dried in desiccator with P2O5 to afford 120 mg of the desired product: 1H NMR (400 MHz, d6-DMSO) δ 12.65 (s, 1H), 12.41 (s, 1H), 9.28 (s, 1H), 8.86 (s, 1H), 8.65 (s, 1H), 8.30 (d, J=3.5 Hz, 2H), 3.97-3.70 (m, 1H), 3.51 (s, 1H), 1.18 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.92 min, (M+H) 427.40
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[Cl:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:29]4[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:28]=4[Cl:27])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: COc1ccc(B(O)O)c(Cl)c1
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Product: COc1ccc(-c2ccc(C(=O)Nc3ccc4nc(N(C)CCN(C)C)sc4c3)cc2)c(Cl)c1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.05 g, 0.12 mmol) and 2-chloro-4-methoxy-phenyl boronic acid (0.026 g, 0.14 mmol) to afford 0.036 g (60%). LC/MS, Retention time=4.53 min; (m/z): calcd for C26H27ClN4O2S (M+H)+: 496.1; found: 496.0.