Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:14]2[CH:13]=[C:12]([C:15]([Cl:17])=[O:16])[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([C:18](Cl)=[O:19])=[CH:6][CH:7]=2.[CH2:21]([N:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][OH:29])[CH2:22][CH2:23][CH3:24]>C(Cl)(Cl)Cl>[ClH:17].[ClH:17].[CH2:21]([N:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][O:29][C:18]([C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:14](=[CH:13][C:12]([C:15]([O:29][CH2:28][CH2:27][CH2:26][N:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24])=[O:16])=[CH:11][CH:10]=3)[C:2](=[O:1])[C:3]=2[CH:4]=1)=[O:19])[CH2:22][CH2:23][CH3:24]
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)c1cc(C(=O)Cl)ccc1-2
Reactant: CCCCN(CCCC)CCCO
Solvent: ClC(Cl)Cl
Product: CCCCN(CCCC)CCCOC(=O)c1ccc2c(c1)C(=O)c1cc(C(=O)OCCCN(CCCC)CCCC)ccc1-2
Product: Cl
Temperature: 25 °C

Procedure:
A suspension of 30.5 g (0.10 mole) of 9-oxo-fluorene-2,7-dicarbonyl chloride in 1 liter of dry chloroform (ethanol free) is stirred and treated all at once with 37.5g (0.20 mole) of dry 3-dibutylamino-1-propanol causing a mildly exothermic reaction. The resulting mixture is stirred and refluxed for two hours, cooled to room temperature, filtered and the filtrate washed three times with 250 ml portions of a saturated sodium bicarbonate solution. The chloroform solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. Most of the solvent is removed from the filtrate on the steam bath in vacuo and the remaining residue dissolved in butanone. This solution is made acid to Congo red with ethereal HCl causing the desired product to precipitate as a yellow crystalline solid. The bis [3-(dibutylamino)propyl]9-oxo-fluorene-2,7-dicarboxylate dihydrochloride so obtained is filtered, recrystallized from a butanone-methanol mixture and dried. The compound on standing in the atmosphere forms a monohydrate having a m.p. 178.5°-179.5°C., λmaxH2O 276, and E1cm1% 1,370.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH:14]([S:16][CH2:17][CH3:18])[CH3:15])[CH2:8][C:7]1=[O:19])(=O)[CH2:2][CH2:3][CH3:4].[CH2:20]([O:22][NH2:23])[CH3:21].Cl>C(O)C>[CH2:20]([O:22][NH:23][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH:14]([S:16][CH2:17][CH3:18])[CH3:15])[CH2:8][C:7]1=[O:19])[CH2:2][CH2:3][CH3:4])[CH3:21]
Reactant: CCCC(=O)C1C(=O)CC(CC(C)SCC)CC1=O
Reactant: CCON
Agent: Cl
Solvent: CCO
Product: CCCC(NOCC)=C1C(=O)CC(CC(C)SCC)CC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.6 %

Procedure:
5.7 g of 2-butyryl-5-(2-ethylthiopropyl)-cyclohexane-1,3-dione was dissolved in 20 ml of ethanol, 1.4 g of ethoxyamine was added thereto, and the resulting solution was stirred at room temperature for 5 hours. After pouring the reaction solution into ice-cold water and acidifing the mixture with hydrochloric acid, the mixture was extracted with chloroform. The chloroform solution was washed with water, dried over anhydrous magnesium sulfate, and the removal of chloroform by distillation under reduced pressure gave 4.5 g of the desired product as colorless oily material. nD27.5 1.5229
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([CH2:13][C:14]([NH2:16])=[O:15])#[N:12].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[C:11]([C:13](=[C:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:9])[C:14]([NH2:16])=[O:15])#[N:12]
Reactant: CC(=O)Cc1ccccc1
Reactant: N#CCC(N)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(Cc1ccccc1)=C(C#N)C(N)=O

Procedure:
A mixture of (phenyl)acetone (5 g), cyanoacetamide (3.15 g), ammonium acetate (0.29 g) and acetic acid (0.45 mL) was refluxed in toluene (50 mL) using a Dean and Stark head to remove water for 6 h. The mixture was cooled and the crystalline product was filtered off (3 g) and used without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].Cl.[CH:15]12[NH:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17][CH2:16]2.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH:19]12[N:22]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=3[C:10]([F:13])([F:12])[F:11])[CH:15]([CH2:21][CH2:20]1)[CH2:16][CH2:17][CH2:18]2
Reactant: C1CC2CCC(C1)N2
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(N2C3CCCC2CC3)c(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
4-Fluoro-3-(trifluoromethyl)benzonitrile (1.35 g, 7.14 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (1.26 g, 8.57 mmol), and N,N-diisopropylethylamine (1.79 g, 13.8 mmol) were combined in DMSO (15 mL) and heated at 120° C. for 24 hours. The mixture was allowed to cool to ambient temperature and partitioned between diethyl ether and saturated NaHCO3 solution. The separated aqueous phase was extracted with diethyl ether and the combined organic layers were washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [C:1]12([NH2:6])[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[NH2:7][C:8]1[CH:15]=[C:14](F)[C:11]([C:12]#[N:13])=[CH:10][N:9]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[NH2:7][C:8]1[CH:15]=[C:14]([NH:6][C:1]23[CH2:5][CH:3]([CH2:4]2)[CH2:2]3)[C:11]([C:12]#[N:13])=[CH:10][N:9]=1
Reactant: NC12CC(C1)C2
Reactant: N#Cc1cnc(N)cc1F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc(N)cc1NC12CC(C1)C2
Temperature: 80 °C

Procedure:
A mixture of bicyclo[1.1.1]pentan-1-ylamine (201 mg, 1.68 mmol), 6-amino-4-fluoronicotinonitrile (intermediate 21, 230 mg, 1.68 mmol) and diisopropylethylamine (1.47 ml, 8.39 mmol) in DMA (3 ml) was heated at 80° C. in a septum sealed reaction vessel for 48 h. The reaction mixture was heated for 5 h at 120° C. and 18 h at 80° C., then cooled, evaporated and purified twice by normal phase chromatography using 24 g RediSep® columns, eluting with gradients from heptane to EtOAc. Product containing fractions were combined and evaporated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[OH:11])=O)=[CH:4][CH:3]=1.[CH2:19]([CH2:21][NH2:22])[OH:20].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[BH4-].[Na+].C(Cl)(Cl)[Cl:40]>C(O)C>[ClH:40].[OH:20][CH2:19][CH2:21][NH:22][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[OH:11]
Reactant: Cc1ccc(C(=O)C(O)c2ccc(C)cc2)cc1
Reactant: ClC(Cl)Cl
Reactant: NCCO
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C(O)C(NCCO)c2ccc(C)cc2)cc1
Product: Cl
Temperature: 105 °C
Reaction time: 2 h

Procedure:
A mixture of 40.0 g (0.33 mole) of tolualdehyde, 10 ml ethanol and 10.84 g (0.17 mole) of potassium cyanide was refluxed overnight at 90° C. An additional 10.8 g (0.17 mole) of potassium cyanide was added and the mixture was refluxed for 5 hr more. Aqueous sodium bisulfite was added to remove unreacted aldehyde. The mixture was reheated, cooled and extracted with methylene chloride. The solvent was stripped off. On dissolving the residue in isopropyl alcohol, crystals were obtained in amount of 14.26 g which represents a 35% yield of 4,4'-dimethylbenzoin. A portion of the 4,4'-dimethylbenzoin, 4.74 g (0.19 mole), 3.84 g (0.063 mole) of ethanolamine and 2.5 g (0.018 mole) of phosphorus pentoxide were mixed and heated under nitrogen atmosphere by means of an oil bath for 4 hr at 105° C. The reaction mixture was cooled and 100 ml of chloroform was added to it with mixing. The chloroform layer was separated and washed twice with 100 ml of dilute hydrochloric acid each time. The aqueous layers were combined, basified and washed with chloroform. The chloroform layer was separated, concentrated and dissolved in 100 ml of ethanol to which 0.038 mole of sodium borohydride in aqueous solution was added. The mixture was stirred for 2 hr and concentrated to dryness. The residue was partitioned between 100 ml of 25% sodium hydroxide and 100 ml of methylene chloride. The methylene chloride layer was washed twice with 100 ml of water each time, concentrated and the residue was dissolved in hot isopropyl alcohol. A solution of hydrogen chloride in isopropyl alcohol was added to give, after filtration and drying, 1.25 g (48.8%) of the hydrochloride salt, m.p. 217°-220° C.
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=1.[SH:17][C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21].C(OCC)(=O)C>CN(C)C=O>[F:16][C:12]1[CH:11]=[C:10]([CH2:9][S:17][C:18]2[C:19]([C:20]([OH:22])=[O:21])=[CH:23][CH:24]=[CH:25][N:26]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Fc1cc(CCl)ccn1
Reactant: O=C(O)c1cccnc1S
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cccnc1SCc1ccnc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 53 %

Procedure:
A solution of triethylamine (7.0 mL, 50 mmol) in N,N-dimethylformamide (20 mL) was added to a solution of 4-chloromethyl-2-fluoropyridine (Reference compound No. 1-1, 5.5 g, 38 mmol) and 2-mercaptonicotinic acid (6.2 g, 40 mmol) in N,N-dimethylformamide (40 mL) under ice-cooling, then the mixture was stirred for 12 hours at room temperature. Ethyl acetate (50 mL) was added to the reaction mixture, the whole was extracted with 0.1 N aqueous sodium hydroxide solution (100 mL). 1 N hydrochloric acid was added to the aqueous layer to adjust to pH 5, and the precipitated crystal was filtered off. The crystal was dried at 80° C. under reduced pressure to give 5.3 g of the title reference compound as a brown solid. (Yield 53%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-])=O)=[CH:15][CH:16]=2)[N:11]([CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>CCOCC.[Zn]>[NH2:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][N:11]2[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(Cn2nc(OCc3ccccc3)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)c1ccc(Cn2nc(OCc3ccccc3)c3ccc(N)cc32)c(OC)c1
Reaction time: 2 h
Yield: 84.7 %

Procedure:
Zinc dust (0.065 g.) was added to a stirred mixture of methyl 4-(3-benzyloxy-6-nitroindazol-1-ylmethyl)-3-methoxybenzoate (CC) (0.043 g.) and acetic acid (0.9 ml.). The mixture was stirred for 2 hours, diluted with ether, and filtered. The filtrate was washed with water, brine, dried (MgSO4), and evaporated to give methyl 4-(6-amino-3-benzyloxyindazol-1-ylmethyl)-3-methoxybenzoate (DD) (0.034 g., 85%) as a brown oil, and was used without further purification as described below.
Reaction SMILES: [O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:28][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][O:14][C:10]2[CH:9]=[CH:8][C:7]3[N:6]=[C:5]4[NH:21][C:2](=[O:1])[NH:3][C:4]4=[CH:13][C:12]=3[CH:11]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Reactant: NC1CCCCC1
Product: O=C(CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)NC1CCCCC1

Procedure:
This compound, m.p. >320° C., was prepared analogous to Example 15 from 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid and cyclohexylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:27][CH2:28][C:29](O)=[O:30])[C:10]=2[CH:9]=1.[C:32](Cl)(=O)C(Cl)=O.[CH3:38][C@H:39]1[CH2:44][NH:43][CH2:42][C@@H:41]([CH3:45])[NH:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:32])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:27][CH2:28][C:29]([N:43]3[CH2:42][C@H:41]([CH3:45])[NH:40][C@H:39]([CH3:38])[CH2:44]3)=[O:30])[C:10]=2[CH:9]=1
Reactant: O=C(O)CCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=C(Cl)C(=O)Cl
Product: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCC(=O)N1C[C@@H](C)N[C@@H](C)C1)C(=O)NC3=O
Yield: 76 %

Procedure:
Reaction of acid (117) prepared as described in example 230 with oxalyl chloride followed by cis-2,6-dimethylpiperazine using the procedure described in example 207 gave the amide (126) (76%) as a yellow powder, mp 168–173° C. (dec). 1H NMR δ [(CD3)2SO] 11.13 (br, 1H), 8.52 (d, J=2.6 Hz, 1H), 7.80 (s, 0.5H), 7.76 (s, 0.5H), 7.71 (m, 1H), 7.58 (m, 1H), 7.54–7.43 (m, 3H), 7.31 (dd, J=9.0, 2.6 Hz, 1H), 4.71 (m, 2H), 4.17 (m, 1H), 3.89 (s, 3H), 2.94 (m, 1H), 2.75 (m, 1H), 2.23 (m, 1H), 2.08 (m, 1H), 1.87 (m, 2H), 0.88, 0.86 (2d, J=5.9 Hz, 3H), 0.67 (d, J=6.1 Hz, 3H). Found: C, 64.03; H, 5.47, N, 9.72. C30H29ClN4O4.H2O requires C, 64.00; H, 5.55; N, 9.95.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:11]3[CH2:14][O:13][CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:17][S:18]([C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][N:22]=1)(=[O:20])=[O:19].CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:11]3[CH2:14][O:13][CH2:12]3)[C:7]([CH2:9][N:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:21]([S:18]([CH3:17])(=[O:19])=[O:20])=[N:22]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Reactant: ClCc1nc2cc(Cl)ccc2n1C1COC1
Agent: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2COC2)c2ccccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-oxetan-3-yl-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[N+:5]([C:8]1[CH:9]=[C:10](/[CH:14]=[N:15]/[C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6]>C(#N)C.B(F)(F)F.CCOCC>[CH3:1][C:2]1([CH3:4])[C:17]2[C:16](=[CH:23][CH:22]=[C:19]([C:20]#[N:21])[CH:18]=2)[NH:15][CH:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=2)[CH2:3]1
Reactant: N#Cc1ccc(/N=C/c2cccc([N+](=O)[O-])c2)cc1
Reactant: C=C(C)C
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: CC1(C)CC(c2cccc([N+](=O)[O-])c2)Nc2ccc(C#N)cc21
Temperature: 30 °C
Reaction time: 10 h
Yield: 27.7 %

Procedure:
To a small reactor, isobutene (100 mL, 1.19 mol) was added to a mixture of boron trifluoride etherate (12 mL, 0.96 mmol) and 4-{[1-(3-nitro-phenyl)-meth-(E)-ylidene]-amino}-benzonitrile (30 g, 0.12 mol) in dry acetonitrile (300 mL), sealed. The resultant mixture was allowed to stir at 30° C. for 10 h. The reaction mixture was washed by brine and dried over anhydrous sodium sulfate. It was filtered and concentrated to provide the crude product (30 g). The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford 4,4-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonitrile as yellow solid (10.2 g, yield: 27.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1C(O)=O.C([N:15](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.FC(F)(F)C(O)=O>C(O)(C)(C)C.O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[NH2:15]
Reactant: CCN(CC)CC
Reactant: CSc1ccc(Cl)c(C(=O)O)c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccc(Cl)c(N)c1
Product: Cl
Temperature: 25 °C

Procedure:
To a stirred solution of 2-chloro-5-(methylthio)benzoic acid (5 g, 24.67 mmol) in t-butanol (20 mL) was added triethylamine (5.25 mL, 37.8 mmol). After stirring briefly, diphenylphosphoryl azide (6 mL, 27.60 mmol) was added drop wise. The reaction mixture was slowly heated to reflux for 6 hours and then cooled to room temperature. The solvent was removed under reduced pressure and the crude reaction mixture was dissolved in tetrahydrofuran (12.5 mL) followed by the addition of 12.5 mL trifluoroacetic acid (1:1). The reaction mixture was heated to reflux for 6 hours and the solvent was evaporated after cooling to room temperature. The reaction mixture was treated with NaOH (25%) to bring the pH to 12 while cooling in an ice water bath. The product was repeatedly extracted into ethylacetate (4×25 mL) and the organic layer washed with water (10 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo to afford yellow oil. The product was purified by column chromatography (SiO2, gradient of hexanes/EtOAc) and the collected samples dissolved in ether and treated with HCl/ether (10 mL, 1M) to provide white crystals. The title product was a white solid (3.73 g, 87% yield): mp: 180-181° C.; TLC: hexanes/EtOAc (9:1) Rf=0.51; MS (Cl) m/e 174 (M+1 for C7H8ClNS) and m/e 191 (M+NH3), 1H-NMR (CDCl3) δ (ppm) 7.2-6.7 (m, 3H, Ar—H), 2.5 (s, 3H, S—CH3).
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18]>C(O)C>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2][C:3]1=[O:11])=[O:18]
Reactant: O=C(Cl)c1ccco1
Reactant: O=C1Cc2ccccc2N1
Agent: [Na]
Solvent: CCO
Product: O=C1Nc2ccccc2C1C(=O)c1ccco1
Reaction time: 0.21 h
Yield: 36.5 %

Procedure:
To a stirred solution of 5.5 g (0.24 mole) of sodium in 150 ml of ethanol was added 13.3 g (0.10 mole) of 2-oxindole at room temperature. The resulting slurry was cooled to ice-bath temperature, and then 15.7 g (0.12 mole) of 2-furoyl chloride was added, dropwise, during 10-15 minutes. The ice-bath was removed, and an additional 100 ml of ethanol was added and then the reaction mixture was heated under reflux for 7 hours. The reaction mixture was allowed to stand overnight and then the solid was filtered off. The solid was added to 400 ml of water and the resulting mixture was acidified using concentrated hydrochloric acid. The mixture was cooled with ice and the solid was collected by filtration. The solid residue was recrystallized from 150 ml of acetic acid, affording 8.3 g of yellow crystals, m.p. 209°-210° C. (dec.). Analysis: Calcd. for C13H9O3N: C, 68.72; H, 3.99; N, 6.17%. Found: C, 68.25; H, 4.05; N, 6.20%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15][CH2:16][Cl:17])[O:8][CH2:7][C:6]2([CH3:19])[CH3:18].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>C(O)CO>[ClH:17].[ClH:17].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15][CH2:16][N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:34])([F:35])[F:20])[CH:23]=3)[CH2:33][CH2:32]1)[O:8][CH2:7][C:6]2([CH3:19])[CH3:18]
Reactant: COc1cc2c(cc1OC)C(C)(C)COC2CCCl
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Solvent: OCCO
Product: COc1cc2c(cc1OC)C(C)(C)COC2CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Product: Cl

Procedure:
A mixture of 1.50 g. (0.0053 m) of 2-(6,7-dimethoxy-4,4-dimethyisochroman-1-yl)ethyl chloride, 2.48 g. (0.011 m) of 3-trifluoromethylphenylpiperazine and 30 ml of ethylene glycol is stirred at 55° for 24 hr. The mixture is partitioned between methylene chloride and sodium bicarbonate. The organic phase is concentrated and chromatographed. The salt of the title compound is prepared from ethereal hydrogen chloride. The yield is 0.83 g., mp 162°-163.5° C.
Reaction SMILES: [CH:1]([C:4]1[C:12]([C:13](=O)[CH:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].Cl.[NH2:19][OH:20].[OH-].[Na+].Cl>CCO.O>[CH:1]([C:4]1[C:12]([C:13](=[N:19][OH:20])[CH:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)C(=O)c1c(C(C)C)nn2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(=NO)c1c(C(C)C)nn2ccccc12
Temperature: 0 °C
Yield: 48.9 %

Procedure:
To a solution of 2.3 g (10 mmol) of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one in 32 ml of anhydrous EtOH was added hydroxylamine hydrochloride 1.5 g (20 mmol), followed by dropwise addition of 2.4 g NaOH in 6 ml of water. The mixture was stirred and refluxed over night. After cooling, the solution was poured into a solution of 8.3 ml of 6N HCl and 380 ml ice water with stirring for 30 minutes. The precipitate was filtered and washed with ethyl ether-hexane to furnish 1.2 g (74.5%) of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime (as a mixture of cis- and trans-isomers), which was separated on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to yield 0.3 g (cis-) and 0.325 g (trans-) isomers of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime. Compound 1012.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([CH2:9][OH:10])[CH:5]=1.F[C:12]1[CH:19]=[CH:18][CH:17]=[C:16](F)[C:13]=1[C:14]#[N:15].O>CN(C=O)C>[CH3:3][C:4]1[O:8][N:7]=[C:6]([CH2:9][O:10][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]#[N:15])[CH:5]=1
Reactant: N#Cc1c(F)cccc1F
Reactant: Cc1cc(CO)no1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccccc2C#N)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a mixture of 60% sodium hydride (0.164 g; 4.10 mmol) in DMF (5 mL) at 0° C. was added dropwise (5-methylisoxazol-3-yl)methanol (0.456 g; 4.00 mmol) and stirred at 0° C. for 30 minutes. The mixture was added to a solution of 2,6-difluorobenzonitrile (0.556 g, 4.00 mmol) in DMF (5 mL) at 0° C. and stirred for 18 hours at ambient temperature. The solution was poured into a mixture of ice and water. The solid was collected by filtration and dried in a 40° C. vacuum oven to yield 540 milligrams of (5-methylisoxazole-3-ylmethoxy)benzonitrile.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:18][CH3:19])[C:13]=2[Cl:17])[C:8]=1[Cl:20])(=O)=O.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[Cl:17][C:13]1[C:14]2[C:9](=[C:8]([Cl:20])[C:7]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][C:12]=1[O:18][CH3:19]
Reactant: COc1ccc2c(Cl)c(OS(=O)(=O)C(F)(F)F)ccc2c1Cl
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc3c(Cl)c(OC)ccc3c2Cl)cc1

Procedure:
The title compound was prepared by 1,5-dichloro-6-methoxy-2-naphthyl trifluoromethanesulfonate (0.32 g, 0.85 mmol) with 4-methoxyphenyl boronic acid (0.18 g, 1.2 mmol) according to method A to yield 0.27 g (95%) of a white solid mp 146–149° C.;1H NMR (CDCl3): δ 3.88 (3H, s), 4.07 (3H, s), 7.02 (2H, d, J=8.73 Hz), 7.41 (1H, d, J=9.52 Hz), 7.46 (2H, d, J=8.83 Hz), 7.53 (1H, d, J=8.73 Hz), 8.19 (1H, d, J=8.73 Hz), 8.36 (1H, d, J=9.12 Hz);