Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOP(OCC)([CH2:6][C:7]#[N:8])=O.[H-].[Na+].[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][C:24](=O)[CH2:23]2)[CH:18]=[CH:19][C:20]=1[Cl:21]>C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[C:24]([CH2:6][C:7]#[N:8])[CH2:23]2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=C1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC1=Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a stirred solution of diethyl cyanomethyl phosphonate EtO2POCH2CN (0.324 mL, 2 eq) in THF (2 mL) was added sodium hydride (60 mg, 60% in oil) in portions. After 30 minutes, 4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-2(1H)-one (beta-tetralone) (291 mg, 1 mmol) was added as a solution in THF (3 mL). After the mixture was stirred for two hours at 0° C., the reaction was quenched with ammonium chloride solution, extracted with MTBE, dried over sodium sulfate and evaporated. The residue was separated on silica to give the unsaturated nitrile (0.24 g, 77%) as a pale-green oil. GC-MS Rt=14.59 min, m/z=313 (M+). 1H NMR (CDCl3, δ): 7.37 (d, J=8.3 Hz, 1H), 7.3 (m, 2H), 7.2 (m, 2H), 7.00 (dd, J=2.1, 8.3 Hz, 1H), 6.84 (d, J=7.4 Hz, 1H), 6.64 (bs, 1H), 4.17 (t, J=8.1 Hz, 1H), 3.21 (bs, 2H), 2.69 (dd, J=6.9, 17.3 Hz, 1H), 2.52 (dd, J=8.4, 17.2 Hz, 1H). 13C NMR (CDCl3, δ, mult): 143.9(0), 135.2(0), 132.9(0), 132.5(0), 130.7(1), 130.5(1), 130.0(1), 128.2(1), 127.7(1), 127.5(1), 126.8(1), 126.4(1), 116.5(0), 43.1(1), 35.1(2), 25.1(2).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.[CH2:19]([O:22][NH2:23])[CH:20]=[CH2:21]>C(OCC)(=O)C>[CH2:19]([O:22][N:23]=[CH:13][C:12]1[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=1[NH:10][C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[Cl:1])[CH:20]=[CH2:21]
Reactant: C=CCON
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C=O)c1Cl
Solvent: CCOC(C)=O
Product: C=CCON=Cc1ccccc1Nc1c(Cl)ccc(C)c1Cl
Yield: 94 %

Procedure:
A solution in 3:1 ethanol-pyridine of 2-[(2,6-dichloro-3-methylphenyl)amino]benzaldehyde, prepared as in Example 1, steps 1-2, and O-allyl hydroxylamine(1.3 eq) was heated at reflux for 2 days. The reaction mixture was poured into ethyl acetate and the mixture was extracted with 10% aqueous HCl. Chromatography on silica gel (20% CH2Cl2 /hexanes) gave 2-[(2,6-dichloro-3-methylphenyl)amino]benzaldehyde-O-allyl oxime (1.13 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[C:34]([O-:37])(=[O:36])[CH3:35].[Na+]>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][O:37][C:34](=[O:36])[CH3:35])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCOC(C)=O)CC2)nc1N

Procedure:
[4-Amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) was reacted with sodium acetate in an analogous manner as described in Example 227 to give acetic acid 3-[4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-sulfonyl]-propyl ester. The crude acetic acid 3-[4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-sulfonyl]-propyl ester was hydrolyzed with 5% potassium hydroxide to give [4-amino-2-[1-(3-hydroxy-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone. HR-MS (ES, m/z) calculated for C20H26N5O5SF2 [(M+H)+] 486.1617, observed 486.1623.
Reaction SMILES: C(Cl)Cl.[F:4][C:5]1[N:10]=[C:9]([F:11])[C:8]([F:12])=[C:7](F)[C:6]=1[F:14].[CH3:15][NH:16][CH3:17]>O>[CH3:15][N:16]([CH3:17])[C:7]1[C:6]([F:14])=[C:5]([F:4])[N:10]=[C:9]([F:11])[C:8]=1[F:12]
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: CNC
Solvent: O
Solvent: ClCCl
Product: CN(C)c1c(F)c(F)nc(F)c1F
Reaction time: 0.5 h

Procedure:
To methylene chloride (50 mL) cooled in an ice bath was added pentafluoropyridine (2.0 g, 11.8 mmol) and dimethylamine (2.97 mL of a 40% solution in water, 24 mmol). After stirring for 30 minutes the solution was washed with water, and dried over basic alumina. The solvent was removed in vacuo to give 4-dimethylamino-2,3,5,6-tetra-fluoropyridine; NMR (CDCl3) 3.13 (m,6) ppm.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([CH3:12])=[C:7]([C:9]([CH3:11])=O)[N:8]=1)[CH2:2][CH3:3].[C:13](OCC)(=[O:16])[NH:14][NH2:15]>C(O)(=O)C.C(O)CCC>[CH3:11][C:9]1[C:7]2[N:8]([C:4]([CH2:1][CH2:2][CH3:3])=[N:5][C:6]=2[CH3:12])[C:13](=[O:16])[NH:14][N:15]=1
Reactant: CCCc1nc(C(C)=O)c(C)[nH]1
Reactant: CCOC(=O)NN
Solvent: CCCCO
Solvent: CC(=O)O
Product: CCCc1nc(C)c2c(C)n[nH]c(=O)n12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 59.7 g. of methyl 2-n-propyl-5-methyl-4-imidazolyl ketone, 41.14 g. of ethyl carbazate, 200 ml. of n-butanol and 4 drops of glacial acetic acid is warmed until solution is complete and then heated under reflux for 5 hours. The solution is concentrated in vacuo to an oily residue, 250 ml. of diphenyl ether are added and the resulting solution is heated with stirring in an oil bath for 30 minutes after the start of gas evolution. The temperature is maintained as closely as possible to the point at which gas evolution starts (150°-250°C.). The reaction is removed from the oil bath, cooled to 50° C. and diluted with 1-2 volumes hexane. The product is collected, washed with petroleum ether and then dissolved in 200 ml. of chloroform. This solution is filtered through 250 ml. of Magnesol® followed by an 800 ml. chloroform wash. The filtrate is concentrated in vacuo and the residue is recrystallized from 250 ml. of ethyl acetate, giving 48.2 g. of the desired product as off-white crystals, m.p. 154°-155° C.
Reaction SMILES: C1([C@@H]([N:9]2[CH2:13][CH:12]([C:14]3([NH:18]C(OC(C)(C)C)=O)[CH2:17][CH2:16][CH2:15]3)[CH:11]([F:26])[CH2:10]2)C)C=CC=CC=1.[NH2:27][C:28]1[C:37]([F:38])=[C:36](F)[C:35]([CH3:40])=[C:34]2[C:29]=1[C:30](=[O:48])[C:31]([C:45]([OH:47])=[O:46])=[CH:32][N:33]2[C@@H:41]1[CH2:43][C@@H:42]1[F:44].C(N(CC)CC)C>C(O)C.[C].[Pd]>[NH2:27][C:28]1[C:37]([F:38])=[C:36]([N:9]2[CH2:13][C@H:12]([C:14]3([NH2:18])[CH2:17][CH2:16][CH2:15]3)[C@H:11]([F:26])[CH2:10]2)[C:35]([CH3:40])=[C:34]2[C:29]=1[C:30](=[O:48])[C:31]([C:45]([OH:47])=[O:46])=[CH:32][N:33]2[C@@H:41]1[CH2:43][C@@H:42]1[F:44]
Reactant: C[C@@H](c1ccccc1)N1CC(F)C(C2(NC(=O)OC(C)(C)C)CCC2)C1
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1c(N2C[C@@H](F)[C@@H](C3(N)CCC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 50 °C
Reaction time: 18 h
Yield: 11.2 %

Procedure:
Cis 1-[(1-(S)-phenylethyl]-4-(1-tert-butoxycarbonylaminocyclobutyl)-3-fluoropyrrolidine (optical isomer B; 1.13 g, 3.12 mmol) was dissolved in ethanol (20 ml), and the solution was mixed with a 10% palladium-carbon catalyst (water content, 55.6%; 1.0 g) and stirred at 50° C. for 18 hours under a hydrogen atmosphere. The catalyst was removed by celite filtration (methanol washing), and the filtrate was concentrated under reduced pressure. The thus obtained residue was dissolved in dimethyl sulfoxide (10 ml), and the solution was mixed with 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (1.18 g, 3.78 mmol) and triethylamine (5 ml) and stirred at 140° C. for 4 days under a nitrogen atmosphere. After cooling, dimethyl sulfoxide was evaporated under reduced pressure, the thus obtained residue was dissolved in chloroform (50 ml) and washed with a 10% citric acid aqueous solution (50 ml) and saturated brine (100 ml) in that order and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to flash silica gel chromatography and eluted with an eluant of chloroform:methanol 9:1. The eluate was concentrated under reduced pressure. To the thus obtained residue, which was cooled in an ice bath, was added dropwise concentrated hydrochloric acid (5 ml), followed by 30 minutes of stirring at room temperature. After adding 1 N hydrochloric acid (30 ml) to the reaction solution, the aqueous solution was washed with chloroform (50 ml×2) and adjusted to pH 12.0 with a sodium hydroxide aqueous solution. The aqueous solution was washed with chloroform (100 ml), adjusted to pH 7.4 with 1 N hydrochloric acid and then extracted with chloroform (150 ml×3). The organic layers were combined, dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to preparative TLC (development with the bottom layer of a mixture of chloroform:methanol:water=7:3:1) to obtain a crude title compound, and this was recrystallized from a mixture of ethanol and ether to obtain 157 mg (17%) of the title compound.
Reaction SMILES: [CH2:1]([C:4]1([CH:27]([CH3:29])[CH3:28])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.[O:30]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C:4]([CH2:1][CH2:2][OH:30])([CH:27]([CH3:29])[CH3:28])[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: C=CCC1(C(C)C)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C1(CCO)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-isopropyl-1,3-oxazinan-2-one (60 mg, crude) in dry CH2Cl2 (10 mL) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to remove excess ozone. NaBH4 (29 mg, 0.75 mmol) was added to the mixture in portions at rt. The mixture was stirred overnight at rt. The mixture was quenched with water, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC to give two isomers.
Reaction SMILES: [NH2:1][CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][C@@H:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)=[O:4].C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[C:27]([NH:1][CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][C@@H:6]1[CH:11]2[CH2:10][CH2:9][N:8]([CH2:13][CH2:12]2)[CH2:7]1)=[O:4])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.5 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate (I30) (100 mg, 0.38 mmol) in DCM (4 ml) and triethylamine (0.08 ml, 0.58 mmol), was added benzoyl chloride (58.0 μl, 0.50 mmol). The reaction was stirred at RT for 1.5 hours, and then the volatiles were evaporated. The crude was purified by flash chromatography (DCM/MeOH/NH4OH=95/5/0.3) to obtain (R)-quinuclidin-3-yl 2-benzamido-2-phenylacetate (70 mg; 50% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][C@@H:19]([C:21]2[CH:32]=[CH:31][C:24]3[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=3[CH:22]=2)[O:18][C:17]1=[O:33].[CH:37]1([N:43]=[C:44]=[O:45])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(O)(C)C>ClCCl>[CH:37]1([NH:43][C:44]([NH:1][C:2]2[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][C@@H:19]([C:21]4[CH:32]=[CH:31][C:24]5[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=5[CH:22]=4)[O:18][C:17]3=[O:33])[CH:3]=2)=[O:45])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C=NC1CCCCC1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)NC5CCCCC5)c4)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
A solution of (5R)-3-(6-{2-[(3-aminobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3oxazolidin-2-one (0.209 g) in dichloromethane (4 ml) was treated with cyclohexyl isocyanate (0.075 g) and the mixture stirred under nitrogen at 20° C. for 3 h. At this point further cyclohexyl isocyanate (0.150 g) was added, and the reaction mixture stirred for a further 65 h. Isopropanol (15 ml) was added to quench excess isocyanate, and the mixture stirred for 3 h. The solvents were removed in vacuo to give a residue which was purified by Biotage. Elution with 6:4 EtOAc/cyclohexane followed by solvent evaporation in vacuo gave the title compound (0.212 g). LCMS RT=3.77 min, ES+ve 624 (MH)+.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:8]([CH3:16])=[N:9][C:10]([CH3:15])=[C:11]([Br:14])[C:12]=1[Cl:13].Cl[C:18](=[O:25])[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20]>C1COCC1>[Br:14][C:11]1[C:12]([Cl:13])=[C:7]([C:18](=[O:25])[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[C:8]([CH3:16])=[N:9][C:10]=1[CH3:15]
Reactant: Cc1nc(C)c(Br)c(Cl)c1Br
Reactant: CC(C)OC(=O)C(=O)Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 75.4 %

Procedure:
A solution of 2M isopropyl magnesium chloride (84 mL, 168 mmol) was added drop wise over 20 min to a cold (−70° C.), nitrogen purged solution of 3,5-dibromo-4-chloro-2,6-dimethylpyridine (48 g, 160 mmol) and copper(I)bromide-dimethyl sulfide complex (1.65 g, 8.02 mmol) in THF (240 mL), which was then allowed to warm to −10° C. over 60 min. The reaction mixture was transferred via cannula into a 1 L RB-flask containing isopropyl 2-chloro-2-oxoacetate (26.6 g, 176 mmol) in THF (160 mL) maintained at −60° C., and the reaction stirred an additional 2.5 h while being allowed to warm to −10° C. The reaction was quenched upon diluted with a mixture of 10% NH4Cl solution (80 mL) in ether (320 mL). The organic layer was washed with 160 mL of sat'd NaHCO3/10% NH4Cl solution (1:1), brine, and dried (Na2SO4). The crude product was charged (DCM solution) to a 330 g ISCO silica gel cartridge and gradient eluted (5-20% EtOAc/hexanes) using an Isolera chromatography station gave isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate 40.38 g (76%). 1H NMR (500 MHz, CDCl3) δ 5.28-5.21 (m, 1H), 2.77 (s, 3H), 2.47 (s, 3H), 1.40 (d, J=6.3 Hz, 6H). LCMS (M+H)=336.04.
Reaction SMILES: [OH:1][C@H:2]([C:5]1[C:6]([F:16])=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][OH:4].O.[C:18]1(C)[CH:23]=CC(S(O)(=O)=O)=C[CH:19]=1.C(=O)(O)[O-].[Na+]>COC(OC)(C)C>[CH3:19][C:18]1([CH3:23])[O:1][C@H:2]([C:5]2[C:6]([F:16])=[C:7]([CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][O:4]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)c1cccc([C@@H](O)CO)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)OC
Product: CCOC(=O)c1cccc([C@@H]2COC(C)(C)O2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A 5.71 g portion of ethyl 3-[(1R)-1,2-dihydroxyethyl]-2-fluorobenzoate was dissolved in 30 ml of 2,2-dimethoxypropane, mixed with 476 mg of p-toluenesulfonic acid monohydrate and stirred at room temperature for 30 minutes. This was mixed with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate, the organic layer was washed with saturated brine, dried with sodium sulfate and concentrated, and then the thus formed residue was purified by a silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 5.46 g (81%) of ethyl 3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluorobenzoate (Reference Example 16-1). FA: 269
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1)=[O:5])C.[OH-].[Na+]>O.C(O)C>[Cl:12][C:11]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][CH:8]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:10]=1
Reactant: CCOC(=O)c1ncc(C(F)(F)F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 3 h
Yield: 84.5 %

Procedure:
423 g of 3-chloro-5-trifluoromethyl-2-pyridinecarboxylic acid ethyl ester (Example P2) is placed in a mixture of 800 ml of water and 160 ml of ethanol. 800 ml of a 2N sodium hydroxide solution are added dropwise at below 35° C. After 3 hours, the mixture is washed twice with dichloromethane and then rendered acidic with excess concentrated hydrochloric acid while cooling with an ice-bath. The resulting slurry is filtered, washed with water and dried in vacuo. 318 g of the desired product are obtained in the form of a white solid having a melting point of 135° C. (decomposition).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[CH:13]1[C:26]2[C:17](=[N:18][C:19]([CH2:27][NH2:28])=[C:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:8][CH2:9][C:10]([NH:28][CH2:27][C:19]1[N:18]=[C:17]2[C:26](=[C:25]3[C:20]=1[CH:21]=[CH:22][CH:23]=[CH:24]3)[CH:13]=[CH:14][CH:15]=[CH:16]2)=[O:11]
Reactant: NCc1nc2ccccc2c2ccccc12
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)NCc1nc2ccccc2c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (460 μL, 3.30 mmol), followed by a solution of chloroacetyl chloride (175 μL, 2.20 mmol) in CH2Cl2 (5 mL) were added dropwise over 5 minutes to a solution of the amine 8 (229 mg, 1.10 mmol) dissolved in CH2Cl2 (15 mL) at 0° C. The reaction mixture was then allowed to warm to ambient temperature and stirred for 2 hours. The solvent was removed under reduced pressure and the reaction crude purified via flash chromatography over silica eluting with a gradient of CH2Cl2 to 1% MeOH/99% CH2Cl2. Evaporation of the solvents under reduced pressure yielded the chloro 9 as an off-white solid (177 mg, 56.5% over three steps).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[S:4][N:3]=1.C(N(CC)CC)C.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>C(OCC)(=O)C>[CH2:17]([NH:21][C:7]([C:5]1[S:4][N:3]=[C:2]([CH3:1])[CH:6]=1)=[O:9])[CH2:18][CH2:19][CH3:20]
Reactant: Cc1cc(C(=O)O)sn1
Reactant: CCCCN
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCNC(=O)c1cc(C)ns1
Reaction time: 0.5 h

Procedure:
3-Methyl-5-isothiazolecarboxylic acid (2.3 g) was dissolved in 40 ml of ethyl acetate. After 2 g of triethylamine were added, the resultant mixture was cooled over an ice-water bath and, at 5°-10° C., 1.5 g of n-butylamine were gradually added dropwise. After completion of the dropwise addition, stirring was continued for 30 minutes. The reaction mixture was washed successively with an aqueous solution of sodium hydrogencarbonate and then with water. After dried over sodium sulfate, the solvent was distilled off so that 2.60 g of N-n-butyl-3-methyl-5-isothiazolecarboxylic acid amide were obtained as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:25][N:26](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([C:2]1[N:3]=[C:4]([O:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)#[N:26]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(Cl)cc3ccccc23)C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccccc23)C1
Yield: 83 %

Procedure:
A solution of (S)-tert-butyl 3-((3-chloroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (4.430 g, 12.70 mmol), zinc cyanide (2.980 g, 25.40 mmol) and Pd(PPh3)4 (1.468 g, 1.27 mmol) in DMF (36.3 mL) was heated at 160° C. for 20 minutes in a microwave reactor. The reaction mixture was filtered, diluted with water (400 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica column chromatography to give the title compound as a white-to-pale-yellow solid (3.570 g, 83%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (d, J=13.18 Hz, 9H), 2.23 (d, J=11.23 Hz, 2H), 3.42-3.59 (m, 3H), 3.65-3.75 (m, 1H), 5.68-5.80 (m, 1H), 7.82-7.89 (m, 1H), 7.91-7.98 (m, 1H), 8.06 (d, J=8.79 Hz, 1H), 8.21-8.30 (m, 2H); ESI-MS m/z [M+H-tert-butyl]+ 284.6.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([OH:11])=O)[C:5]([F:12])=[C:4]([F:13])[C:3]=1[CH3:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[NH2:43]>C(Cl)Cl.CN(C=O)C>[F:12][C:5]1[C:4]([F:13])=[C:3]([CH3:14])[C:2]([F:1])=[C:7]([F:8])[C:6]=1[C:9]([NH:43][CH:38]1[CH2:39][CH2:40][CH2:41][CH2:42][CH:37]1[CH3:36])=[O:11]
Reactant: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Reactant: CC1CCCCC1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(F)c(F)c(C(=O)NC2CCCCC2C)c(F)c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
2,3,5,6-tetrafluoro-p-toluic acid acid (4.00 g, 19.22 mmol), HOBt (5.19 g, 38.44 mmol) and EDCI (4.42 g 23.06 mmol) were mixed in 200 ml of anhydrous DCM and 30 ml of anhydrous DMF. The mixture was cooled to 0° C. and allowed to stir under Ar for 15 minutes. To the mixture was added 2-methylcyclohexanamine (3.05 mL, 23.06 mmol) and the reaction mixture was allowed to slowly warm to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM, washed with 1N HCl, water, aqueous NaHCO3, water and brine, drying over MgSO4, filtration and removal of solvent in vacuo, afforded the crude product as a pale yellow solid Recrystallization (EtOH/H2O) and drying in vacuo gave 5.23 g of the title compound as a white solid (mixture of 2 diasteromers, 90%). 1H NMR (CDCl3) δ 0.95, 1.01 (d, J=7.0, 6.6 Hz, 3H) 1.1-2.1 (m, 9H), 2.29 (m, 3H), 3.70, 4.29 (m, 1H), 5.65, 5.92 (m, 1H). MS (304.1, M+H). m.p. 202-204° C.