Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4](O)([C:19]([F:22])([F:21])[F:20])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[NH:7][C:6]=1[CH3:18].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[N:7]=[C:6]1[CH3:18])[C:19]([F:21])([F:20])[F:22]
Reactant: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(Cl)cc2)c1=O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(=C1C(=O)N(c2ccc(Cl)cc2)N=C1C)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 1-(4-chlorophenyl)-2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (182 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (173 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH:11]3[C:10]([CH3:30])([CH3:29])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(Cl)cc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(-c2ccc(Cl)cc2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 92.1 %

Procedure:
To a stirred mixture solution of 2-(4′-chloro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.5 g, 3.6 mmol) in methanol (15.0 mL) and tetrahydrofuran (16.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-(4′-chloro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.3 g, 90%) as a white solid: LC/MS m/e calcd for C24H22ClNO2 (M+H)+: 392.9, observed: 392.2.
Reaction SMILES: Cl.CN.C[O:5][C:6]([C:8]1[NH:9][C:10]2[CH:11]=[C:12]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:13]=[C:14]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:16]=1[C:15]=23)=O.[CH2:30]([N:32](CC)CC)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO>[C:26]([O:25][C:23](=[O:24])[NH:22][C:12]1[CH:13]=[C:14]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:16]3=[C:8]([C:6](=[O:5])[NH:32][CH3:30])[NH:9][C:10]([CH:11]=1)=[C:15]23)([CH3:28])([CH3:27])[CH3:29]
Reactant: COC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CN
Solvent: CO
Product: CNC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Yield: 29.1 %

Procedure:
Preparation of example 161 was carried out in a manner analogous to step 5 of Example 147, except that methylamine hydrochloride was substituted for methanol. Thus CO was bubbled through a mixture of Intermediate 147(d) from Example 147 (200 mg, 0.529 mmol), triethylamine (0.29 mL, 2.11 mmol), methylamine hydrochloride (71 mg, 1.06 mmol), and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (86 mg, 0.106 mmol). Reaction conditions, work up and silica gel chromatography (eluted with 46:4:25 dichloromethane:methanol:ethyl acetate) were also carried out in an analogous manner and afforded the title compound (55 mg, 0.154 mmol) in 29% yield.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[CH:13]=[N:12]2)[C:8]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 62 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 47) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (0.75 g, 62%); ES+-HRMS m/e calcd for C25H29N5O4F2 [M+H+] 502.2261 found 502.2258. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.09 (m, 1H), 1.24-1.75 (m, 8H), 1.93 (m, 1H), 2.28 (m, 1H), 3.89 (s, 2H), 4.68 (s, 1H), 5.47 (dd, J=4.2, J=10.9 Hz, 1H), 6.03 (d, J=3.0 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.34-7.51 (m, 3H), 7.53 (d, J=2.1 Hz, 1H), 8.28 (d, J=3.0 Hz, 1H), 10.86 (s, 1H).
Reaction SMILES: [CH2:1]([O:9][C:10]1[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.[BH:22]([OH:24])[OH:23]>C1COCC1.CCCCCC.C(OCC)C.[Cl-].[Cl-].[Zn+2]>[CH2:1]([O:9][C:10]1[N:11]=[N:12][C:13]([B:22]([OH:24])[OH:23])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(Cl)nn1
Reactant: OBO
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCCCOc1ccc(B(O)O)nn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
17.1 g (70.6 mmol) of 3-octyloxy-6-chloropyridazine are dissolved in 100 ml of absolute THF and cooled to -78° C. under a protective gas. 47.1 ml (75.2 mmol) of 1.6 molar n-butyllithium solution in hexane are then added dropwise over the course of 30 minutes. The mixture is stirred at -78° C. for a further 30 minutes. 216 ml (215.7 mmol) of 1.0 molar ZnCl2 solution in diethyl ether are subsequently slowly added dropwise, during which the temperature must not exceed -60° C. When the addition is complete, the mixture is stirred for a further 30 minutes. The crude boronic acid is employed directly, without isolation from the solution, for the subsequent couplings.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.Cl[CH:11]([F:13])[F:12]>CC(O)C.[OH-].[K+].O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:11]([F:13])[F:12])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: FC(F)Cl
Reactant: Oc1cc(Br)cc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: FC(F)Oc1cc(Br)cc(Br)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a tared, sealed 350 mL round-bottomed pressure flask containing a solution of 3,5-dibromophenol (10.0 g, 39.7 mmol; see Example 27(ii) above) in 2-propanol (100 mL) and 30% KOH (80 mL) at −78° C. was added chlorodifluoromethane via bubbling for 15 min through the septum. The septum was replaced with a Teflon stopper and the flask was then sealed and allowed to warm to room temperature where the flask was weighed and determined to contain 12.0 g (138 mmol) of chlorodifluoromethane. The solution was refluxed overnight in an oil bath set at 80° C. The flask was cooled to room temperature, the pressure cautiously released and the contents diluted with H2O (200 mL). The aqueous layer was extracted with CHCl3 (2×150 mL), then the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by Kugelrohr distillation at 80° C. at 0.2 mm Hg to afford the sub-title compound (9.6 g, 80%) as clear liquid.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31].[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:18][CH2:19]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(C2CCNCC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phenylmethyl 4-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)-1-piperazinecarboxylate from previous step was dissolved in DCM (60 mL) and cooled to 0° C. TFA (20 mL) was added. Reaction was stirred for 1 h. TLC showed no starting material remaining. Removed DCM and TFA on rotovap to give title compound of step B (presumed to be the bis-TFA salt) (14.0 g, 53% over 2 steps) which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.03-7.40 (m, 5H), 5.02 (s, 2H), 2.93-4.16 (m, 7H), 2.11-2.82 (m, 7H), 1.06-1.88 (m, 4H).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)=[N:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:11]=1[CH3:12].C(OCC)C>O.C(O)C.O1CCCC1>[C:1]([CH2:5][C:6]1[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)=[N:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:11]=1[CH3:12])#[N:2]
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CC#N
Temperature: 0 °C
Yield: 87.2 %

Procedure:
To a solution of sodium cyanide (4.8 g) in water (50 ml) was added a suspension of 5-bromomethyl-6-methyl-2-phenyl-4-(3-nitrophenyl)pyrimidine (30 g) in a mixture of ethanol (180 ml) and tetrahydrofuran (180 ml), and the mixture was refluxed for 2 hours. The reaction mixture was poured into a mixture of ice-water (200 ml) and diethyl ether (200 ml). The precipitate was filtered, washed with water, dried in vacuo to give 5-cyanomethyl-6-methyl-2-phenyl-4-(3-nitrophenyl)pyrimidine (22.5 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][CH:14]([F:29])[C:15]1[CH:28]=[CH:27][C:18]([CH2:19][N:20]2[CH2:24][CH2:23][C@H:22]([OH:25])[C:21]2=[O:26])=[CH:17][CH:16]=1>ClCCl.O>[CH3:8][S:9]([O:25][CH:22]1[CH2:23][CH2:24][N:20]([CH2:19][C:18]2[CH:17]=[CH:16][C:15]([CH:14]([F:13])[F:29])=[CH:28][CH:27]=2)[C:21]1=[O:26])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1[C@@H](O)CCN1Cc1ccc(C(F)F)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCN(Cc2ccc(C(F)F)cc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Triethylamine (0.319 mL, 2.29 mmol) and methansulfonyl chloride (0.131 mL, 1.68 mmol) was added to a stirred solution of (S)-1-(4-(difluoromethyl)benzyl)-3-hydroxypyrrolidin-2-one (368 mg, 1.53 mmol) in dichloromethane (7.63 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The resulting mixture was diluted with water and the aqueous mixture was extracted with dichloromethane. The combined organic layers were washed with 10% sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified using silica gel column chromatography (0-100% EtOAc). The pure fractions were combined and concentrated in vacuo to afford 1-(4-(difluoromethyl)benzyl)-2-oxopyrrolidin-3-yl methanesulfonate (322 mg, 66% yield) as a white solid: LC-MS (M+H)+320.1; 1H NMR (500 MHz, chloroform-d) δ 7.53 (d, J=7.9 Hz, 2H), 7.38-7.33 (m, 2H), 6.67 (br. t, J=1.0 Hz, 1H), 5.27 (dd, J=8.2, 7.5 Hz, 1H), 4.60-4.49 (m, 2H), 3.41-3.35 (m, 1H), 3.33 (s, 3H), 3.27 (dt, J=9.9, 7.3 Hz, 1H), 2.64-2.55 (m, 1H), 2.27 (ddt, J=13.9, 8.9, 7.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]([CH:16]([CH3:18])[CH3:17])[NH2:15])[CH:3]=[N:4]O.N.[H][H].O>CO.[Ni]>[CH:16]([CH:14]([NH2:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:2]([CH3:1])([CH3:19])[CH2:3][NH2:4])([CH3:18])[CH3:17]
Reactant: [H][H]
Reactant: CC(C)C(N)CC=CCCC=CCC(C)(C)C=NO
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Product: CC(C)C(N)CCCCCCCCC(C)(C)CN
Temperature: 100 °C
Reaction time: 5 h
Yield: 92.7 %

Procedure:
490 g (1.84 mols) of 2,2-dimethyl-11-isopropyl-11-amino-undeca-4,8-dienal-oxime is dissolved in 2.4 liters of methanol, and the solution is transferred, together with about 200 g of liquid ammonia, with the addition of 150 g of Raney nickel, to a 6.3-liter steel autoclave. Hydrogen is subsequently injected up to a pressure of 100 bars, and the temperature is raised to 100° C. with stirring. Hydrogenation is performed for about 5 hours under these conditions; the mixture is then cooled, and the ammonia and excess hydrogen are released. Subsequent distillation under high vacuum yields 436 g (1.705 mols) of 1-isopropyl-10,10-dimethyl-1,11-diaminoundecane in the form of colourless liquid clear as water; yield 92.6% of theory; b.p. 87° C./4 Pa; nD20 =1.4619.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[N+]([O-])(O)=O.[O:14]([CH2:18][CH2:19][NH2:20])[N+:15]([O-:17])=[O:16].C(OC(C)C)(C)C>>[O:14]([CH2:18][CH2:19][NH:20][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])=[O:9])[N+:15]([O-:17])=[O:16]
Reactant: NCCO[N+](=O)[O-]
Reactant: Cc1ccsc1C(=O)O
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: Cc1ccsc1C(=O)NCCO[N+](=O)[O-]
Yield: 42.8 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.60 g of 3-methyl-2-thiophenecarboxylic acid and 0.60 g of nitroxyethylamine nitrate, 0.35 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].I[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH:17]([C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)[CH3:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(I)c1ccc([N+](=O)[O-])cc1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: CC(c1ccc([N+](=O)[O-])cc1)N(c1ccc(C#N)cc1)c1cncnc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 1-(1-iodoethyl)-4-nitrobenzene
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[Si:5]([Cl:9])(Cl)(Cl)[Cl:6].Cl>>[CH:2]([O:4][Si:5]([O:4][CH:2]([CH3:3])[CH3:1])([Cl:9])[Cl:6])([CH3:3])[CH3:1]
Reactant: CC(C)O
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: Cl
Product: CC(C)O[Si](Cl)(Cl)OC(C)C

Procedure:
This material is prepared after the manner of Chappelow et al. (J. Org. Chem. 1960, 25, 435-459.) 2-Propanol (887 g, 14.8 mol) was added slowly over a period of three hours under an atmosphere of Ar to SiCl4 (1475 g, 8.7 mol) at 0° C. The vented HCl gas from the reaction was neutralized by bubbling through a 25% (w/v) solution of KOH in water. The solution was allowed to react for 3 h whereupon, Ar was bubbled through the solution for 30 min. The solution was then distilled through a 30 cm Hemple column packed with 3 mm glass beads (Pot Temp: 180° C., Vapor Temp: 120° C.). The resulting fractions were analyzed by 1H NMR. Fraction A: 411 g (95% Mono: 5% Di); Fraction B: 184 g (22% Mono, 76% Di, 2% Tri); Fraction C: 511 g—27% yield, (95% Di, 5% Tri); and Fraction D: 393 g (50% Di, 50% Tri). Fractions B and D were pooled with other impure cuts from other runs and redistilled at a latter date. 1H NMR (CDCl3, 300 mHz) δ Mono: 4.53 (h, J=6.2 Hz, 1 H), 1.31 (d, J=6.2 Hz, 6 H). Di: 4.41 (h, J=6.2 Hz, 2 H), 1.26 (d, J=6.2 Hz, 12 H); Tri: 4.29 (h, J=6.2 Hz, 3 H), 1.21 (d, J=6.2 Hz, 12 H). 13C NMR (CDCl3, 75.5 mHz) δ Di: 69.27, 24.85.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:25][N:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[C:28]([F:31])([F:30])[F:29]>C(OCC)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([C:27]([C:28]([F:29])([F:31])[F:30])([NH:26][CH3:25])[C:32]([F:35])([F:34])[F:33])[S:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: CN=C(C(F)(F)F)C(F)(F)F
Reactant: Fc1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CNC(c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)s1)(C(F)(F)F)C(F)(F)F
Reaction time: 3 h

Procedure:
A solution of 2,3-bis(4-fluorophenyl)thiophene (5.4 g, 20 mmole) in 150 ml diethyl ether/30 ml toluene was cooled to 10° and treated with 1.6M n-butyl lithium (15 ml, 1.2 equiv.). The reaction mixture was heated at reflux for 1.5 hours, cooled to 0° and treated dropwise with a solution of N-methyl hexafluoroacetone imine (4.3 g, 1.2 equiv.) in 10 ml diethyl ether. The reaction mixture was stirred for 3 hours at 0° and then quenched with water.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[N:11]=[C:10]2[O:23][CH2:24][CH3:25])=[C:4]([F:26])[CH:3]=1.S(OC)(O[CH3:31])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:24]([O:23][C:10]1[N:9]([C:5]2[CH:6]=[C:7]([O:8][CH3:31])[C:2]([Cl:1])=[CH:3][C:4]=2[F:26])[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:21])([F:22])[C:17]([F:20])([F:18])[F:19])[N:11]=1)[CH3:25]
Reactant: COS(=O)(=O)OC
Reactant: CCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(OC)c(Cl)cc1F

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-ethoxy-4-pentafluoroethyl-6(1H)-pyrimidinone and dimethyl sulphate with sodium carbonate in acetone there is obtained 2-ethoxy-1-(4-chloro-2-fluoro-5 -methoxyphenyl)-4-pentafluoroethyl-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 400 MHz): 7.33 ppm (d,1H), 6.79 ppm (d,1H), 6.65 ppm (s,1H), 4.48 ppm (m,2H), 3.89 ppm (s,3H), 1.29 ppm (t,3H);
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:27])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=O)(C)(C)C.[ClH:28]>C(O)C>[ClH:28].[F:24][C:23]([F:25])([F:26])[C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][CH2:15][C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][NH2:8])=[O:27]
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)COc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: NCCCCNC(=O)COc1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
A mixture of 9.8 g of the product of Step D, 90 ml of ethanol and 28 ml of ethanolic 2N hydrogen chloride was refluxed with stirring for one hour and then evaporated to dryness under reduced pressure to obtain 11.9 g of product which was crystallized from ethyl acetate to obtain 7.55 g of the desired product melting at 90° C.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(N(CC)CC)C.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C1(C)C(C)=CC=CC=1>[N:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:19]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])=[CH:22][CH:23]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCc1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: O=C1c2ccccc2C(=O)N1Cc1ccncc1
Yield: 78.9 %

Procedure:
To a mixture of 148.0 g (1.0 mol) of phthalic anhydride and 15 mL of triethylamine in 1.5 L of xylene was slowly added 108.0 g (1.0 mol) of 4-(Aminomethyl)pyridine with mechanical stirring. The resulting solid was collected by filtration. The N-Pyridin-4-ylmethyl-phthalamic acid was then cyclized, by heating 235 g (0.88 mol) to the melt stage for 15 min. The mixture was allowed to cool slightly and 2.5 L of ethanol was added to the warm reaction mixture, and the solution filtered. Upon cooling, the mixture crystallized to give 188.0 g of 2-Pyridin-4-ylmethyl-isoindole-1,3-dione (m.p. 166-167.5° C.). A mixture of 23.8 g (0.1 mol) of 2-Pyridin-4-ylmethyl-isoindole-1,3-dione and 1.3 g of platinum oxide in 400 mL of methanolic HCl was reduced at 50 psi until no starting material could be detected by TLC. The mixture was filtered through celite and concentrated to give 22.0 g of 2-Piperidin-4-ylmethyl-isoindole-1,3-dione hydrochloride as a white solid. A small sample was recrystallized from ethanol to give an analytically pure sample of 16A (m.p. 241-242.5° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:6][CH2:7][C:8]([NH:10][NH:11][C:12]([C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:6][CH2:7][C:8]1[S:40][C:12]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:11][N:10]=1
Reactant: COc1ccc(OCC(=O)NNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(OCc2nnc([C@@H]3CCCN3C(=O)OC(C)(C)C)s2)cc1OC
Temperature: 90 °C
Reaction time: 6 h
Yield: 54.1 %

Procedure:
To a toluene (30 ml) solution of the compound (540 mg) obtained in Example 8-(1), Lawesson's reagent (750 mg) was added and the mixture was stirred at 90° C. for 6 hours. After adding water, extraction was conducted with AcOEt. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (AcOEt/hexane) to give the titled compound (291 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.C(OCC)(=O)C>[C:25]([O:24][C:23]([NH:22][C:20]1[N:21]=[C:16]([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[CH:17]=[CH:18][C:19]=1[C:30](=[O:35])[C:31]([F:32])([F:33])[F:34])=[O:29])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1nc(NC2CCCN(C(=O)OC(C)(C)C)C2)ccc1C(=O)C(F)(F)F
Temperature: 90 °C

Procedure:
561 mg (2.8 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate, 700 mg (2.16 mmol) of tert-butyl [6-chloro-3-(trifluoroacetyl)pyridin-2-yl]carbamate (Example 7A) and 0.56 ml (3.23 mmol) of diisopropylethylamine were suspended in 14 ml of DMSO and heated to 90° C. in a microwave reactor for 45 min. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous ammonium chloride solution (3×40 ml) and then with saturated aqueous sodium hydrogencarbonate solution (40 ml). The organic phase was dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel (eluent: cyclohexane/ethyl acetate 5:1 to 1:1). 670 mg (63% of theory) of the product were isolated.