Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(=O)([O-])O[C:3]([CH2:8][CH3:9])([CH2:6][CH3:7])[C:4]#N.[H-].[Na+].C(C1C=C(C(C)C)[C:19]([O:25][S:26](=[O:47])(=[O:46])[NH:27][C:28](=[O:45])[CH2:29][C:30]2[C:35](C(C)C)=[CH:34][C:33]([CH:39]([CH3:41])[CH3:40])=[CH:32][C:31]=2[CH:42]([CH3:44])[CH3:43])=C(C(C)C)C=1)=O>O1CCCC1>[C:28]([CH:29]=[CH:4][C:3]1[CH:8]=[C:9]([CH:30]([CH3:31])[CH3:35])[C:19]([O:25][S:26](=[O:47])(=[O:46])[NH:27][C:28](=[O:45])[CH2:29][C:30]2[C:35]([CH:39]([CH3:41])[CH3:40])=[CH:34][C:33]([CH:39]([CH3:41])[CH3:40])=[CH:32][C:31]=2[CH:42]([CH3:44])[CH3:43])=[C:7]([CH:33]([CH3:34])[CH3:32])[CH:6]=1)#[N:27]
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(C=O)cc2C(C)C)c(C(C)C)c1
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(C=CC#N)cc2C(C)C)c(C(C)C)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
Diethylcyanomethyl phosphonate (1.49 mL, 9.2 mmol) was added dropwise to a suspension of sodium hydride (0.37 g, 9.2 mmol) in 20 mL tetrahydrofuran at 0° C. After 15 minutes, the reaction was cooled to -78° C. and a solution of [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 4-formyl-2,6-diisopropyl-phenyl ester (2.32 g, 4.4 mmol) in 75 mL tetrahydrofuran was added dropwise. The reaction was allowed to warm to room temperature overnight and then concentrated in vacuo and partitioned the residue between 1 M HCl and dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give an oily solid. Chromatography on silica gel (20% ethyl acetate/hexanes) gave 1.16 g of the title compound as a white solid; mp 157-160° C.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].[F:15][C:16]([F:20])([F:19])[CH2:17]I.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:17][C:16]([F:20])([F:19])[F:15]
Reactant: FC(F)(F)CI
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1OCC(F)(F)F
Temperature: 130 °C
Reaction time: 6 h
Yield: 71.9 %

Procedure:
To dry N,N-dimethylformamide (10 ml) were added 2-methoxyphenol (150 mg), 2,2,2-trifluoroethyl iodide (584 mg) and potassium carbonate (400 mg), and the mixture was stirred vigorously at 130° C. for 6 hours. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and chloroform (5/2) as eluent to give 179 mg of 1-methoxy-2-(2,2,2-trifluoroethoxy) benzene as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[OH:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[CH:23][CH:22]=1>CS(C)=O>[N+:16]([C:10]1[CH:11]=[CH:12][C:13]([O:20][C:21]2[CH:36]=[CH:35][C:24]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[CH:23][CH:22]=2)=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:18])=[O:17]
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Agent: [K]
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
24.7 g of 5-fluoro-2-nitrophenyl benzyl ether (0.1 mol) are dissolved in 250 ml of dimethyl sulfoxide, and a solution of 26.6 g of the potassium salt of benzyl 4-hydroxybenzoate (0.1 mol) in 250 ml of dimethyl sulfoxide is then slowly added drop wise with stirring at room temperature. The mixture is then stirred first at room temperature for 1 hour and then at 50° C. for 24 hours. The reaction solution is then allowed to cool to room temperature and is filtered through a fluted filter, the filtrate is diluted with 700 ml of water, and the crude product is extracted by shaking with 300 ml of ethyl acetate. The organic phase is then washed three times with water, dried over sodium sulfate and evaporated in a rotary evaporator until the reaction product precipitates out. The reaction product is stirred in petrol ether (boiling range 40 to 60° C.) for 2 hours, filtered off via a Büchner funnel and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 91%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][C:6]1([CH3:16])[O:11][CH2:10][C:9]([CH2:14][CH3:15])([CH:12]=[O:13])[CH2:8][O:7]1.[Cl-].[NH4+]>O1CCCC1>[CH3:5][C:6]1([CH3:16])[O:7][CH2:8][C:9]([CH2:14][CH3:15])([CH:12]([OH:13])[CH2:1][CH3:2])[CH2:10][O:11]1
Reactant: CC[Mg]Br
Reactant: CCC1(C=O)COC(C)(C)OC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)C1(CC)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl magnesium bromide (70 ml, 1.3M in tetrahydrofuran) was stirred at 0°, under nitrogen. 2,2-Dimethyl-5-ethyl-5-formyl-1,3-dioxane (10.3 g.) in dry tetrahydrofuran (20 ml.) was added and the mixture was stirred at room temperature for three hours. The mixture was then refluxed, with stirring, for one hour. Saturated aqueous ammonium chloride solution was added to the cooled reaction mixture. The aqueous mixture was extracted with ether. The ether extracts were washed with water, dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel, eluting with 40% ether hexane. 2,2-Dimethyl-5-ethyl-5-(1-hydroxy propyl)-1,3-dioxane was obtained as a colourless oil (10.0 g.).
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][C@H:26]1[NH:31][CH2:30][CH2:29][NH:28][CH2:27]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:28]3[CH2:29][CH2:30][NH:31][C@H:26]([CH3:25])[CH2:27]3)=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(N2CCN[C@H](C)C2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 112 mg of R-(+)-2-methylpiperizine in 1 mL of BuOH. Purified by reverse phase HPLC to yield (R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methylpiperazin-1-yl)nicotinamide. MS (Q1) 422.3 (M)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=1[O:18][CH3:19])=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1>>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:32]2[CH:33]=[N:34][CH:35]=[C:30]([F:29])[CH:31]=2)=[CH:13][C:12]=1[O:18][CH3:19])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(Br)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: OB(O)c1cncc(F)c1
Product: COc1cc(-c2cncc(F)c2)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared rac-[2-(4-bromo-2-methoxy-phenyl)-1-(3,4-dichloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 5-fluoropyridine-3-boronic acid in analogy to Example 1b): MS (ISP): 507.4 (M+H)+ (100%) and 522.7 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])=[CH:9][S:8][C:7]=1[N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2Cl)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2cccc(Cl)c2Cl)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(2,3-dichlorophenyl)thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 25, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([O:3]CC1C=CC=CC=1)=[O:2].[Li]CCCC.CCCCCC.[Cl-].[NH4+].[O:32]1[CH2:36][CH2:35][CH2:34]C1>>[F:18][C:14]1[CH:13]=[C:12]([N:11]2[CH2:34][C@H:35]([CH2:36][OH:32])[O:3][C:1]2=[O:2])[CH:17]=[CH:16][CH:15]=1
Reactant: C1CCOC1
Reactant: O=C(Nc1cccc(F)c1)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
132 g of N-carbobenzyloxy-3-fluoroaniline 132 g prepared in the Preparation example 1 was dissolved in 1.3 L of tetrahydrofuran and the solution was cooled to −78° C. 370 ml of n-buthyllitium (n-BuLi, 1.6M/n-hexane) was slowly added to the solution in a nitrogen atmosphere, followed by stirring for 10 min. And 84 ml of (R)-(−)-glycidylbuthylate was slowly added to the reaction mixture, stirred at the same temperature for 2 hours and allowed to react for 24 hours at room temperature. After completion of the reaction, the solution was added with ammonium chloride (NH4Cl) solution and extracted with 0.5 L of ethyl acetate at room temperature. The organic layer, thus separated, was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate and washed with n-hexane to give white crystals, which were purified to the title compound. 80 g. Yield 70%.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][C@H:25]3[O:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)[C:20]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)=[CH:19][N:18]=2)=[N:14][CH:15]=1)#[N:9]>ClCCl>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([C:20]2[C:21]([NH:23][CH2:24][C@H:25]3[O:30][CH2:29][CH2:28][NH:27][CH2:26]3)=[CH:22][C:17]([NH:16][C:13]3[N:14]=[CH:15][C:10]([C:8]#[N:9])=[N:11][CH:12]=3)=[N:18][CH:19]=2)=[CH:39][CH:40]=1
Reactant: COc1ccc(-c2cnc(Nc3cnc(C#N)cn3)cc2NC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cnc(Nc3cnc(C#N)cn3)cc2NC[C@@H]2CNCCO2)cc1
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
TFA (0.2 mL) was added to a solution of (R)-tert-butyl 2-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)morpholine-4-carboxylate (0.014 g, 0.027 mmol) dissolved in dichloromethane (2 mL) at room temperature. The reaction mixture was stirred for 20 min. Solvent was removed in vacuo and the mixture was purified by ion exchange on SCX-II acidic resin (500 mg), eluting with methanol then 2M ammonia-methanol. The basic fractions were combined and solvent was removed in vacuo. The crude product was purified by preparative thin layer chromatography, eluting with methanol/dichloromethane (1/19), to give the title compound as a yellow solid (0.007 g, 62%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:20][C:21]([OH:23])=O)([C:17](O)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:39][N:40]([CH3:42])[NH2:41]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2([C:17](=[O:18])[N:41]([N:40]([CH3:42])[CH3:39])[C:21](=[O:23])[CH2:20]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC1(C(=O)O)CCN(C(=O)OCc2ccccc2)CC1
Reactant: CN(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CN(C)N1C(=O)CC2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-benzyloxycarbonyl-4-carboxy-piperidin-4-yl)acetic acid (1.28 g) in dimethylformamide (10 ml) was added dicyclohexylcarbodiimide (0.82 g), and this was followed by 30 minutes of stirring at room temperature. 1,1-Dimethylhydrazine (0.62 ml) was then added, and this was also followed by 30 minutes of stirring at room temperature. The solvent was then evaporated under reduced pressure. To the resulting residual oily compound were added acetic anhydride (10 ml) and then anhydrous sodium acetate (0.33 g), and this was followed by stirring at 100° C. for 30 minutes. The solvents were then evaporated under reduced pressure. The resulting residual substance was dissolved in ethyl acetate (50 ml), and it was washed with a saturated aqueous solution of sodium hydrogen-carbonate and then with water. The organic layer was then dried with anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure to yield an oily substance. This oily substance was separated by silica gel column chromatography (eluent; methanol-dichloromethane=1:19 (v/v)), and the solvent for the solution containing the desired product was evaporated to obtain 0.71 g of a colorless oil.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([OH:15])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:19])=O>CCCCCC>[C:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([Cl:19])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)c1ccc(C2CC2C(=O)O)s1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(C2CC2C(=O)Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
A mixture of 2-(5-t-butylthiophen-2-yl)-cyclopropanecarboxylic acid (3.38 g, 0.015 mol) and oxalyl chloride (2.65 g, 0.021 mol) in hexane (35 ml) was stirred at room temperature for 2 hours and then warmed at 60° C. for 3 hours. The hexane and excess oxalyl chloride were removed in vacuo to give 2-(5-t-butylthiophen-2-yl)-cyclopropanecarbonyl chloride (3.59 g, 99%) as a pale yellow liquid which was used in the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]O)[C:5]([I:10])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][Cl:13])[C:5]([I:10])=[CH:4][CH:3]=1
Reactant: OCc1nc(Cl)ccc1I
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1nc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (6-chloro-3-iodo-pyridin-2-yl)-methanol (2.5 g, 9.3 mmol, 1 eq) in DCM (25 mL) was added thionyl chloride (0.68 mL, 9.3 mmol, 1 eq) in drop wise manner at 0° C. under nitrogen atmosphere. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, reaction mixture was cooled to 0° C. and quenched by aqueous sodium bicarbonate (25 mL), extracted with DCM (3×70 mL). Combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown semisolid (2.5 g, crude). Crude title compound was used as such for the next reaction. 1H NMR not clean. LC-MS: No ionization.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]C)=[O:8])[N:4]([CH3:11])[N:3]=1.O.[Li+].[OH-]>O1CCOCC1>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([CH3:11])[N:3]=1
Reactant: COC(=O)c1cc(Cl)nn1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc1C(=O)O
Reaction time: 16 h
Yield: 90.5 %

Procedure:
To a solution of methyl 3-chloro-1-methyl-1H-pyrazole-5-carboxylate (6.0 g, 34.4 mmol) in dioxane (10 ml) was added H2O (10 ml) and LiOH (1.65 g, 68.7 mmol). After stirring for 16 h, the reaction mixture was washed with CH2Cl2 and then the aqueous phase acidified by drop wise addition of conc. HCl. The resulting residue was filtered off, washed with water and dried to yield the title compound (5.0 g, 91%). [1H-NMR (DMSO-d6, 360 MHz) δ 13.77 (br. s, 1H), 6.88 (d, 1H), 4.05 (s, 3H); HPLC-MS RtJ=0.47 min; [M+H]+=160.9, 163.0]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N:25]1([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)[CH:29]=[N:28][CH:27]=[N:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:34][C:33]3[CH:32]=[CH:31][C:30]([N:25]4[CH:29]=[N:28][CH:27]=[N:26]4)=[CH:37][CH:36]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=Cc1ccc(-n2cncn2)cc1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3ccc(-n4cncn4)cc3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared by coupling 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Step 1 of Example B(13), to 4-[1,2,4]Triazol-1-yl -benzaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31).ESIMS (MH+): 509.1.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(Nc1nc2cccc(Br)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A3), 5.0 g; 23.5 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (8.36 g; 47.0 mmol; 2.0 eq.) as a grey powder (5.86 g, 78%). HPLC, Rt: 1.24 min. (purity 97.4%). LC/MS, M+(ESI): 319.0, M−(ESI): 318.3.
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])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[C:23]([NH:33][CH3:34])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([CH3:32])=[CH:27][CH:26]=2>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[C:23]([NH:33][CH3:34])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([CH3:32])=[CH:27][CH:26]=2
Reactant: CNc1nc2ccc(C)cc2cc1CCl
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CNc1nc2ccc(C)cc2cc1Cc1c(O)nc(C)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (40 mg, 182 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 2 N aq. KOH solution (0.17 mL, 0.34 mmol) at RT followed by 3-(chloromethyl)-N,6-dimethylquinolin-2-amine hydrochloride MDE 32062 (39 mg, 152 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before to be extracted with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6 to 90:10) gave 12 mg of 6,7-dimethoxy-1-methyl-4-((6-methyl-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-((6-methyl-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 33 as a brown solid (14 mg, 19% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[H-].[Na+].[CH3:15]I>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CI
Reactant: O=C1NCCc2cc(F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCc2cc(F)ccc2C1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a stirred solution of 6-fluoro-3,4-dihydroisoquinolin-1(2H)-one (102 mg, 0.62 mmol) in THF (5 ml) was added NaH (49 mg of a 60% dispersion in mineral oil, 1.23 mmol) giving a thick white precipitate. After 30 minutes, methyl iodide (76 μl, 1.23 mmol) was added and the reaction was heated at 50° C. for 1 hour. Complete conversion was observed by TLC and the reaction was concentrated, diluted with dichloromethane (30 ml), washed with saturated NaHCO3 (15 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by FCC (using a gradient of eluents 1:1 Hexane/EtOAc to EtOAc) to provide the title compound as colourless oil (106 mg, 96%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[N:13]=2)=[N:6][CH:7]=1.O.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:13]=2)=[N:6][CH:7]=1
Reactant: COC(=O)CCc1csc(Nc2ncc(Br)cc2Sc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1csc(Nc2ncc(Br)cc2Sc2ccccc2)n1
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a mixture of methyl 3-(2-(5-bromo-3-(phenylthio)pyridin-2-ylamino)thiazol-4-yl)propanoate (1.40 g, 3.11 mmol) in 50 mL THF was added 25 mL water followed by sodium hydroxide (0.249 g, 6.22 mmol) and the mixture was stirred overnight. The mixture was concentrated to dryness, water added and acidified with NH4Cl. The mixture was then extracted with THF. The organics were dried over Na2SO4 and concentrated to give the title compound (1.38 g, 102% yield) that was used as the crude material.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[C:24](=[O:34])([O:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:25][CH:26](Cl)[CH3:27]>>[CH2:30]([O:29][C:24]([O:25][CH:26]([O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])[CH3:27])=[O:34])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOC(=O)OC(C)Cl
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Product: CCCCOC(=O)OC(C)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the procedure of Example 6, piroxicam (3.00 g, 9.1 mmol) and alpha-chloroethyl butyl carbonate (5.30 g, 29.3 mmol) were converted to title product, 600 mg yellow solid (1.3 mmol, 13.9%) which was recrystallized from isopropyl alcohol to give 325 mg white crystals: mp 132°-133° C.; IR (KBr) 1758, 1681 cm-1 ; 1H NMR (CDCl3) delta 0.87 (t, J=7 Hz, 3H), 1.18-1.35 (m, 2H), 1.42-1.58 (m, 2H), 1.76 (d, J=6 Hz, 3H), 3.11 (s, 3H), 4.01 (t, J=7 Hz, 2H), 6.35 (q, J=6 Hz, 1H), 7.05-7.15 (m, 1H), 7.65-7.82 (m, 3H), 7.82-7.95 (m, 2H), 8.30-8.40 (m, 2H), 9.39 (br s, 1H): precise mass calcd for C22H25N3O7S m/e 475.1413, found 475,1425.