Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8](C(O)=O)[C:7]2=[O:15]>C1(OC2C=CC=CC=2)C=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[CH:8][C:7]2=[O:15]
Reactant: O=C(O)c1c[nH]c2c(I)cccc2c1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cc[nH]c2c(I)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
8-Iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (15.69 g, 49.8 mmol) was suspended in phenylether (40 mL) and the mixture heated to boiling. After 30 min, reaction was completed by LCMS. The crude was transferred to a bequer and cooled to room temperature. Hexanes (500 mL) were added and the mixture was stirred for 10 min. The solid was retrieved by filtration, thoroughly washed with hexanes and purified by HPLC to afford 8-iodo-1H-quinolin-4-one as a brownish solid (4.4 g, 23%). 1H NMR (DMSO-d6, 400MHz) δ 6.14 (d, 1H), 7.09 (t, 1H), 7.88 (d, 1H), 8.08 (dd, 1H), 8.16 (dd, 1H). Exact mass calculated for C9H6INO 270.95, found 271.8 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([N:8]1[C:12](=[O:13])[CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[NH:10][C:9]1=[O:23])[CH:5]([CH3:7])[CH3:6]>Cl>[Br:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:11]2[C:12](=[O:13])[N:8]([CH:4]([CH:5]([CH3:6])[CH3:7])[C:3]([OH:24])=[O:2])[C:9](=[O:23])[NH:10]2)=[CH:21][CH:20]=1
Reactant: COC(=O)C(C(C)C)N1C(=O)NC(COc2ccc(Br)cc2)C1=O
Agent: Cl
Product: CC(C)C(C(=O)O)N1C(=O)NC(COc2ccc(Br)cc2)C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
A mixture of the compound obtained in step g above (22g) (759 mg, 1.907 mmol) and 3 N HCl (20 mL) was stirred at 80° C. for 2 h. The reaction mixture was cooled down and then extracted with EtOAc. The combined organic layers were dried and concentrated; the crude product was purified by silica gel column chromatography which gave the title compound as colorless oil (300 mg, 41%).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](C(N)CCBr)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:21]([O:20][C:18](=[O:19])[NH:10][CH2:9][CH2:8][CH2:7][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)([CH3:22])([CH3:23])[CH3:24]
Reactant: c1ccc(C2(c3ccco3)CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)C(N)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCN1CCC(c2ccccc2)(c2ccco2)CC1
Yield: 32 %

Procedure:
A solution of 4-phenyl-4-furan-2-yl-piperidine and 3-Boc-aminopropylbromide (0.30 g, 1.3 mmol) with 0.5 g of K2CO3 in 20 ml of dioxane was stirred at reflux for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic solution was dried over Na2SO4 and concentrated in vacuo to yield an oil which was subjected to column chromatography over silica gel (EtOAc) to provide 0.21 g (0.54 mmol, 32% for two steps) of 3-(4-phenyl-4-(furan-2-yl)piperidin-1-yl)propylcarbamic acid tert-butyl ester as a colorless oil. The ester in 5 ml of CH2Cl2 was added with 1 ml of CF3CO2H and resulting solution was stirred for 1 h at 25° C. The reaction mixture was concentrated in vacuo to yield oily mixture, which was dissolved in EtOAc and washed with aqueous NaHCO3. Concentration of the reaction mixture provided the desired product as an oil (0.13 g, 0.45 mmol, 84%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11](=[CH:13][CH2:14][CH2:15][CH:16]([CH2:18][CH2:19]O)[CH3:17])[CH3:12].S(=O)(=O)(O)O>O1CCCC1>[C:1]([O:9][CH2:19][CH2:18][CH:16]([CH3:17])[CH2:15][CH2:14][CH:13]=[C:11]([CH3:12])[CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)=CCCC(C)CCO
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)CCOC(=O)c1ccccc1
Yield: 19 %

Procedure:
A mixture of benzoic acid (14.6 g, 0.12 mol) and citronellol (15.6 g, 0.1 mol) in tetrahydrofuran (THF) was heated on a water bath for 4 hours after the addition of concentrated sulfuric acid. The reaction was monitored by thin layer chromatography (TLC), and when the reaction was over, the reaction mixture was quenched over ice/water, extracted with THF or methylene chloride, washed with 5% sodium hydrogen carbonate, and dried over magnesium sulfate. The reaction mixture was concentrated under vacuum and purified by open column chromatography to yield 4.95 g (yield: 19%) of a product having the following physical properties.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24]Cl)[CH3:21].[OH-].[K+]>CC(C)=O>[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][N:4]([C:1](=[O:3])[CH3:2])[C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:7][CH:6]=1)[CH3:21]
Reactant: CC(=O)Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCN(CC)CCN(C(C)=O)c1ccc(C(=O)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
Combine N-acetyl-4-aminobenzophenone (4.0 g, 16.7 mmol), 2-diethylaminoethyl chloride hydrochloride (3.97 g, 23.1 mmol), and powdered potassium hydroxide (2.81 g, 50.1 mmol) in acetone (30 mL). Heat to reflux. After 2 hours, cool and decant the solvent. Evaporate the solvent in vacuo to give a residue. Partition the residue between water and ethyl acetate. Separate the organic layer and extract with water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf =0.0-0.14 (streaks on silica gel, ethyl acetate).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[CH:13]=1)[CH3:4].[C:29]([OH:39])(=O)[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:29](=[O:39])[CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:13]=1)[CH3:4]
Reactant: O=C(O)CCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Agent: Cl
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)CCc2ccccc2)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester, dihydrochloride and hydrocinnamic acid were reacted as described in Example 8, Step 6 to provide [5-(2-{[N-ethyl-N-(3-phenyl-propionyl)-amino]-methyl}-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([CH3:23])[N:11]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C>C1COCC1.O.O.[OH-].[Li+]>[CH2:16]([N:11]1[C:12]2[C:8](=[C:7]([O:6][CH2:5][C:4]([OH:24])=[O:3])[CH:15]=[CH:14][CH:13]=2)[CH:9]=[C:10]1[CH3:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)COc1cccc2c1cc(C)n2Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(OCC(=O)O)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1-benzyl-2-methyl-1H-indol-4-yloxy)-acetic acid ethyl ester (4) (0.80 g, 2.48 mmole) in THF:H2O (4:1, 10 mL), lithium hydroxide monohydrate was added (0.118 g, 4.96 mmole). The mixture was stirred at room temperature for 1 h. THF was evaporated and then crushed ice was added to the aqueous mixture; the resulting solid was collected by filtration to afford intermediate (5) as a solid. Yield: 0.67 g, 92% 1H NMR: 05-038-055
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH:9]2[CH2:11][CH2:10]2)[C:4](=[O:12])[CH:3]=1.[N:13]([O-])=[O:14].[Na+]>CC(O)=O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH:9]2[CH2:10][CH2:11]2)[C:4](=[O:12])[C:3]=1[N:13]=[O:14]
Reactant: Nc1cc(=O)n(C2CC2)c(=O)[nH]1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1[nH]c(=O)n(C2CC2)c(=O)c1N=O
Reaction time: 1 h

Procedure:
To a solution of 6-Amino-3-cyclopropyl-1H-pyrimidine-2,4-dione (5.0 g, 29.9 mmol, 1 eq) in 50% aq AcOH (10 ml) was added NaNO2 (4.13 g, 59.8 mmol, 2 eq) in small portions over a period of 10 min. The mixture was stirred for 1 hr. The purple precipitate was collected by filtration and washed with cold water to give 4.75 g, 81%, m/z (ES+) 197.17), which was used in the following step.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][C:5]1(C(O)=O)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CC#N>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([NH2:39])([CH2:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=2[CH3:1])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccccc1CC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccccc1CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C

Procedure:
To a mixture of 4-(2-methylbenzyl) N-t-butoxycarbonyl isonipecotic acid (1.0 g, 3.0 mmol) in CH3CN (20 ml) add diphenyl phosphoryl azide (0.99 g, 3.6 mmol) and triethylamine (0.50 ml, 3.6 mmol). After stirring at 55° C. (oil bath temp.) concentrate the reaction in vacuo and partion the residue between EtOAc and saturated aqueous NaHCO3. The organic phase is washed with brine, dried (MgSO4), and concentrated in vacuo to afford the crude product.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([O:15][CH2:16][CH2:17][OH:18])[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:5]1.CN(C=O)C.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>O>[CH2:31]([O:18][CH2:17][CH2:16][O:15][C:7]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:5][N:4]([CH3:3])[C:8]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: Cn1nc(-c2ccccc2)c(OCCO)c1-c1ccccc1
Reactant: CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCOCCOc1c(-c2ccccc2)nn(C)c1-c1ccccc1

Procedure:
Sodium hydride (0.89 g, 57%, 0.02 mole) is added to a solution of 2-[(1-methyl-3,5-diphenyl-4-pyrazolyl)oxy]ethanol (5.9 g, 0.02 mole) and dry DMF (50 ml). The reaction mixture is stirred and heated to 80°-90°C. The stirred mixture is allowed to cool. This mixture is added to a solution of 1-bromoheptane (9 g, 0.05 mole) and dry FMD (75 ml). After heating at 80°-90°C for 4 hours, the stirred reaction mixture is poured into water.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]3([C:34]#[N:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[N:6][C:7]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH3:21])=[CH:15][CH:14]=2)[CH:9]=1.[OH-:36].[Na+]>CO.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]3([C:34]([NH2:35])=[O:36])[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH:23]=2)=[N:6][C:7]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH3:21])=[CH:15][CH:14]=2)[CH:9]=1
Reactant: [OH-]
Reactant: CNCc1ccc(-c2cc(-c3nc(-c4ccnc(C5(C#N)CCOCC5)c4)cnc3N)on2)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1ccc(-c2cc(-c3nc(-c4ccnc(C5(C(N)=O)CCOCC5)c4)cnc3N)on2)cc1
Temperature: 100 °C

Procedure:
4-[4-[5-amino-6-[3-[4-(methylaminomethyl)phenyl]isoxazol-5-yl]pyrazin-2-yl]-2-pyridyl]tetrahydropyran-4-carbonitrile (Trifluoroacetic Acid (1)) (18 mg, 0.03002 mmol) was dissolved in methanol (1 mL) and then 1 M sodium hydroxide solution (300.2 μL of 1 M, 0.3002 mmol) was added. The reaction mixture was heated in the microwave to 100° C. for 45 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracted organic layer was dried over MgSO4, filtered and concentrated in vacuo to a solid. Compound was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% trifluoroacetic acid in water; solvent B: acetonitrile) over 16 minutes at 25 mL/minutes], combined fractions were then freeze-dried to give 4-[4-[5-amino-6-[3-[4-(methylaminomethyl)phenyl]isoxazol-5-yl]pyrazin-2-yl]-2-pyridyl]tetrahydropyran-4-carboxamide Compound I-13 as a yellow solid (6 mg, 31.37%). 1H NMR (400.0 MHz, DMSO-d6) δ 2.2-2.25 (m, 2H), 2.45-2.5 (m, 2H), 2.65-2.7 (m, 3H), 3.6-3.75 (m, 4H), 4.28-4.33 (m, 2H), 7.18-7.2 (m, 1H), 7.27-7.3 (m, 1H), 7.35-7.39 (m, 1H), 7.7 (d, 2H), 7.85 (s, 1H), 8.05 (d, 1H), 8.1 (s, 1H), 8.18 (d, 2H), 8.7 (d, 1H), 8.88 (br s, 2H), 9.05 (s, 1H); LC/MS m/z 486.2 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[C:28]([Li])([CH3:31])([CH3:30])[CH3:29]>CCCCC>[C:28]([C:12]1([OH:15])[CH2:13][CH2:14][N:9]([CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C1CCN(CC(c2ccccc2)c2ccccc2)CC1
Reactant: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: c1ccccc1
Product: CC(C)(C)C1(O)CCN(CC(c2ccccc2)c2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a stirred solution of 2 parts of 1-(2,2-diphenylethyl)-4-piperidinone in 50 parts by volume of benzene under nitrogen atmosphere is added 30 parts of 1.6 M solution of tertiary-butyllithium in pentane. The resultant solution is stirred for about 24 hours and then quenched with the careful addition of 60 parts by volume of 10% ammonium chloride solution. After 1 hour, the organic layer is separated, washed with water and brine, dried with magnesium sulfate, and concentrated to give clear red oil. This oil is chromatographed on silica gel using successively methylene chloride and 10% ethanol-methylene chloride solution as eluents to give pale yellow solid which upon sublimation affords 4-tert-butyl-1-(2,2-diphenylethyl)-4-piperidinol. This compound melts at about 105°-110° C. and is represented by the following structural formula ##STR36##
Reaction SMILES: C([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25]/[CH:26]=[C:27](\[CH3:34])/[CH2:28][CH2:29][C:30]([O:32]C)=[O:31])C.[OH-:35].[Li+]>CO>[OH:35][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[C:4]=1[CH2:25][CH:26]=[C:27]([CH3:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: [OH-]
Reactant: CCc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Agent: [Li+]
Solvent: CO
Product: CC(=CCc1c(O)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2)CCC(=O)O

Procedure:
A solution of methyl (E) 6-(1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p-toluenesulfonyloxylisobenzofuran-5-yl)-4-methyl-4-hexenoate (3.16 g) and lithium hydroxide (1.2 g) in 1:1 aqueous methanol (40 ml) was heated at 62° C. for 18 hours. The solution was acidified and extracted with ethyl acetate. The extract was dried and evaporated and the residue chromatographed on silica gel, eluting wth ethyl acetate/hexane/acetic acid to afford (E) 6-(1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, m.p. 141°-142° C. (t-butylmethylether).
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.NCC[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1COCC1>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][CH2:4][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Reactant: NCCN1CCOCC1
Solvent: C1CCOC1
Product: COc1cc(COC(=O)NCCN2CCOCC2)ccc1OC(C)=O
Reaction time: 2 h
Yield: 71.2 %

Procedure:
Compound VII (219.1 mg, 0.642 mmol) was dissolved in anhydrous THF (3.2 mL, 5 mL/mmol of 6). To the yellow solution was added 4-(2-aminoethyl)morpholine (83.5 mg, 84 μL, 0.642 mmol). The reaction solution was stirred for two hours, after which time the solution was colorless. The solvent was removed under reduced pressure. The crude material was purified by column chromatography on silica gel using CH2Cl2/MeOH (96:4, v/v) to give 161 mg (71%) of 17 as a white solid: mp=82-83° C. (uncorrected); Rf=0.16 (CH2Cl2/MeOH, 96:4, v/v); 1HNMR (CDCl3) δ 6.99 (d, 3J=8 Hz, 1H), 6.96 (d, 4J=1.65 Hz, 1H), 6.94 (dd, 3J=8 Hz, 4J=1.8 Hz, 1H), 5.23 (bs, 1H), 5.05 (s, 2H), 3.82 (s, 3H), 3.67 (m, 4H), 3.29 (m, 2H), 2.46 (t, 3J=5.9 Hz, 2H), 2.42 (bs, 41-1) and 2.29 (s, 3H). Exact mass (ESI) calculated for C17H25N2O6 [M+H]=353.1707. found 353.1705.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][NH:35][C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:38]4[CH2:39][CH2:40][C@@H:36]([NH:35][CH3:34])[CH2:37]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CN[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CN[C@@H]1CCN(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (R)-3-methylaminopyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 3.66 (m, 2H), 3.49 (m, 2H), 3.32 (m, 2H), 2.36 (s, 3H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.30 (m, 2H). m/z: 437 [M+H]
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[C:26]([O:28]CC)=[O:27])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[C:26]([OH:28])=[O:27])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Yield: 55.9 %

Procedure:
A mixture of (1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethoxycarbonylpiperidine (trans isomer) (0.50 g) and 1N aqueous sodium hydroxide solution (5 ml) in methanol (5 ml) was refluxed for 3 hours. The reaction mixture was evaporated to remove methanol, neutralized with 10% hydrochloric acid and extracted with chloroform. The extract was washed with saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (20 g) with chloroform as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give 1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]piperidine-2-carboxylic acid (trans isomer) (0.26 g) as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8](F)=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[CH:5]=[C:4]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:3]=1.[CH3:25][CH:26]([OH:28])[CH3:27]>>[CH:26]([O:28][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:9]([CH3:10])[CH3:8])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[CH:5]=[C:4]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:3]=1)([CH3:27])[CH3:25]
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1F
Reactant: CC(C)O
Product: COCCOc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1OC(C)C

Procedure:
Similar procedure as described in example 10 was used, starting from [1-Chloro-6-fluoro-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine and 2-propanol to give [1,6-Diisopropoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 415(MH+).
Reaction SMILES: FC(F)(F)C([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[OH-].[Na+]>CO>[C:13]1([CH:12]=[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]2[NH2:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(NC1CCCCC1=Cc1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC1CCCCC1=Cc1ccccc1
Yield: 100.4 %

Procedure:
A mixture of 1.4 g (5 mmole) of the 2,2,2-trifluoro-N-[2-(phenylmethylene)cyclohexy]acetamide, Z isomer from step (c) above, 7 ml of 20% w/v aqueous sodium hydroxide solution and 7 ml of methanol was heated on a steam bath for 5 min. The methanol was evaporated and the residue was extracted with diethyl ether. The ether extract was washed with saturated sodium chloride solution, dried with magnesium sulfate and evaporated to leave 0.94 g of the N-[2-(phenylmethylene)cyclohexyl]amine, Z isomer, as a colorless oil. The NMR spectrum was consistent; the CH--N coupling pattern suggests that this H is equatorial. The GC analysis, 1% QF-1, 99.7%, retention time 2.36 min UV λmax(ε)243(12,000). The mass spectrum and IR were also consistent. The hydrochloride salt of this amine was formed in ethereal hydrogen chloride and crystallized from a methanol/diethyl ether mixture, mp 214°-215° C. The mass spectrum and IR spectrum were consistent with this sub-titled hydrochloride salt.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[C:13]=1[C:14]#[N:15]>C(Cl)Cl.N1C=CC=CC=1>[Br:20][C:16]1[C:13]([C:14]#[N:15])=[C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#Cc1c(N)cccc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1c(Br)cccc1NS(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 28 %

Procedure:
Benzenesulfonyl chloride (0.53 g) was added to a solution of 2-amino-6-bromobenzonitrile (Intermediate 22, 0.5 g) in DCM (15 mL) and pyridine (1 mL). The mixture was stirred for 2 hours, then a further aliquot of benzenesulfonyl chloride (0.53 g) was added and the mixture was stirred overnight. The reaction mixture was diluted with DCM, washed with 1N hydrochloric acid, and the organic solution was dried with sodium sulfate and filtered. The filtrate was evaporated under vacuum and the residue was purified by flash chromatography on silica, eluting with a mixture of DCM and methanol. The fractions containing the desired product were combined and evaporated to give the title compound as a white powder (0.24 g).