Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34]([NH2:36])=O)=[CH:32][N:33]=[C:27]2[N:26]=1>C1(C)C=CC=CC=1>[F:23][C:24]([F:38])([F:37])[C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34](=[S:10])[NH2:36])=[CH:32][N:33]=[C:27]2[N:26]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cnc2nc(C(F)(F)F)ccn12
Solvent: Cc1ccccc1
Product: NC(=S)c1cnc2nc(C(F)(F)F)ccn12
Yield: 92.8 %

Procedure:
Lawesson's reagent (281 mg, 0.7 mmol) was added to a stirred suspension of the foregoing amide (160 mg, 0.7 mmol) in toluene (16 ml). The resulting mixture was heated at reflux for 2.5 h and then concentrated under reduced pressure while dry loading onto silica. Subsequent purification by column chromatography on silica using firstly diethyl ether and then EtOAc/ether gave 7-trifluoromethylimidazo[1,2-α]pyrimidine-3-carbothioamide (160 mg, 93%): δH (360 MHz, d6-DMSO) δ 7.80 (1H, d, J 7.2), 8.70 (1H, s), 9.73 (1H, s), 9.82 (1H, s), 10.87 (1H, d, J 7.2).
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=[O:7].[Li+].[OH-]>C1COCC1>[F:1][CH:2]([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(C(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C(F)F)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of methyl 3-(difluoromethyl)benzoate (1 equiv.) in THF (0.25M) was added 1M LiOH (2.5 equiv.) and allowed to stir at RT. Upon initial addition of LiOH, the solution turned from clear to a burnt orange, and after 2 hrs the solution is light yellow. The reaction stirred for 18 hrs at RT. The volatiles were removed in vacuo, and the aqueous phase was acidified to ˜pH 3. A white precipitate was formed, filtered and dried. Isolated 3-(difluoromethyl)benzoic acid in 78% yield. LCMS (m/z) (M+H)=245.1, Rt=0.73). 1H NMR (400 MHz, <dmso>) δ ppm 6.97-7.30 (m, 1H) 7.63-7.71 (m, 1H) 7.83 (d, J=7.43 Hz, 1H) 8.06-8.16 (m, 1H)
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][CH3:20])=[CH:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[CH2:37][C:38]([NH:40][C:41]1[O:45][N:44]=[C:43]([C:46]([CH3:52])([CH3:51])[C:47]([F:50])([F:49])[F:48])[CH:42]=1)=[O:39].C([O-])([O-])=O.[Cs+].[Cs+]>O.O1CCOCC1.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]>[CH2:19]([O:18][C:3]1[CH:4]=[C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:6]=[CH:7][C:2]=1[C:26]1[CH:25]=[CH:24][C:23]([CH2:37][C:38]([NH:40][C:41]2[O:45][N:44]=[C:43]([C:46]([CH3:51])([CH3:52])[C:47]([F:50])([F:49])[F:48])[CH:42]=2)=[O:39])=[C:22]([F:21])[CH:27]=1)[CH3:20]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1Br
Reactant: CC1(C)OB(c2ccc(CC(=O)Nc3cc(C(C)(C)C(F)(F)F)no3)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cc(C(C)(C)C(F)(F)F)no2)c(F)c1
Yield: 32.4 %

Procedure:
To a mixture of 5-bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (74.1 mg, 0.219 mmol) and 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (100 mg, 0.219 mmol) in water (1 mL) and 1,4-dioxane (3 mL) was added Cs2CO3 (143 mg, 0.438 mmol) and PdCl2(dppf) (16.04 mg, 0.022 mmol) under N2. Then the mixture was stirred and irradiated in a microwave oven at 120° C. for 20 min. The mixture was then concentrated. The crude material was purified by preparative TLC (PE/EA=2:1, Rf=0.4) to yield an off white solid of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (70 mg, 0.071 mmol, 33% yield): 1H NMR (400 MHz, CD3OD) δ 7.40-7.34 (m, 2H), 7.30-7.17 (m, 4H), 6.92-6.88 (m, 2H), 6.45 (s, 1H), 6.38 (d, J=4.0 Hz, 1H), 5.27 (s, 2H), 4.13-4.10 (m, 2H), 3.83-3.82 (m, 2H), 3.79-3.77 (m, 3H), 1.53 (s, 6H), 1.37 (t, J=6.8 Hz, 3H); ES-LCMS m/z: 588 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]2[S:16][C:17]3[C:18](Cl)=[N:19][CH:20]=[CH:21][C:22]=3[N:23]=2)=[C:10]([Cl:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[CH:29]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]2[S:16][C:17]3[C:18]([NH:34][C:30]4[CH:29]=[C:28]([CH3:27])[N:33]=[CH:32][N:31]=4)=[N:19][CH:20]=[CH:21][C:22]=3[N:23]=2)=[C:10]([Cl:25])[CH:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc(N)ncn1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc3nc(-c4c(Cl)cc(NC(=O)OC(C)(C)C)cc4Cl)sc23)ncn1
Temperature: 85 °C
Yield: 67.8 %

Procedure:
A mixture of [3,5-dichloro-4-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-phenyl]-carbamic acid tert-butyl ester (0.30 g, 0.697 mmol), 6-methylpyrimidin-4-ylamine (0.073 g, 0.77 mmol), XantPhos (0.040 g, 0.0696 mmol) and Cs2CO3 (0.454 g, 1.39 mmol) in dioxane (10 mL) was degassed with a stream of argon. Pd2(dba)3 (0.032 g, 0.035 mmol) was added and the reaction mixture was heated at 85° C. for 18 hours. After cooling to room temperature, the crude reaction mixture was filtered through Celite® washing with EtOAc and the filtrate was concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-30% EtOAc in petroleum ether to afford the title compound as a yellow solid (0.238 g, 68% yield). LCMS (Method D): RT=3.14 min, m/z: 503 [M+H+].
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br:10][C:11]1[CH:12]=[N:13][C:14](Cl)=[N:15][CH:16]=1.[NH:18]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1>FC(F)(F)C1C=CC=CC=1.C(Cl)Cl>[Br:10][C:11]1[CH:12]=[N:13][C:14]([N:18]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2)=[N:15][CH:16]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)CC1CCNC1
Solvent: ClCCl
Solvent: FC(F)(F)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC1CCN(c2ncc(Br)cn2)C1
Temperature: 120 °C
Yield: 69 %

Procedure:
N-Ethyl-N,N-diisopropylamine (1.80 mL, 10.34 mmol) was added dropwise at room temperature to a solution of 5-bromo-2-chloropyrimidine B-5 (1.00 g, 5.17 mmol) and tert-butyl 2-(pyrrolidin-3-yl)acetate (1.00 g, 5.40 mmol) in anhydrous α,α,α-trifluorotoluene (10.2 mL) under an argon atmosphere, in a 20 mL microwave reactor vial. The reaction mixture was sealed and heated at 120° C. for 30 mins under microwave irradiation, then successively cooled to room temperature, diluted with methylene chloride (100 mL), quenched with a 1 N aqueous solution of hydrogen chloride (30 mL) and decanted. The aqueous layer was extracted with methylene chloride (2×150 mL); the combined extracts were sequentially washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes to ethyl acetate gradient) to give tert-butyl 2-(1-(5-bromopyrimidin-2-yl)pyrrolidin-3-yl)acetate B-6 (1.22 g, Yield=69%). MS (ESI), [M+1]+ 342, 344.
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)=[CH:25][CH:24]=2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[ClH:37]>>[ClH:37].[ClH:37].[CH3:36][O:35][C:31]1[CH:30]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]([CH:8]([C:2]3([OH:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:9][N:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)=[CH:28][CH:27]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: COc1cccc(-c2ccc(C(CN3CCN(C(=O)OC(C)(C)C)CC3)C3(O)CCCCC3)cc2)c1
Agent: Cl
Product: COc1cccc(-c2ccc(C(CN3CCNCC3)C3(O)CCCCC3)cc2)c1

Procedure:
In an analogous manner to Example 135, step 4,1-[1-(3′-methoxy-1,1′-biphenyl-4-yl)-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride was prepared from tert-butyl 4-[2-(1-hydroxycyclohexyl)-2-(3′-methoxy-1,1′-biphenyl-4-yl)ethyl]piperazine-1-carboxylate. MS (ES) m/z 395.4 ([M+H]+); HRMS: calcd for C25H34N2O2.2.00 HCl, 466.2154; found (ESI), 395.2697.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1([C:16]([OH:18])=[O:17])[CH2:12][CH:11]1[CH:13]([CH3:15])[CH3:14])=O)(C)(C)C.[ClH:19].CCOCC>O1CCOCC1>[ClH:19].[NH2:8][CH2:9][C:10]1([C:16]([OH:18])=[O:17])[CH2:12][CH:11]1[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)C1CC1(CNC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)C1CC1(CN)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-2-isopropyl-cyclopropanecarboxylic acid (2.05 g, 8.0 mmol) in dry 1,4-dioxane (40 mL) was added 4N HCl (40 mL, in 1,4-dioxane). The reaction mixture was stirred at room temperature overnight and ether was added (100 mL). The white solid was collected and dried to give 1-aminomethyl-2-isopropyl-cyclopropanecarboxylic acid hydrochloride (1.35 g, 88%): mp: 245–246° C.; 1H NMR (300 MHz, D2O) δ 0.94 (d, J=6.5 Hz, 3H), 0.96 (m, 1H), 1.05 (d, J=6.4 Hz, 3H), 1.23–1.31 (m, 1H), 1.49–1.59 (m, 2H), 2.85 (d, J=13.7 Hz, 1H), 3.83 (d, J=13.7 Hz, 1H); 13C NMR (75 MHz, D2O) δ 22.3, 23.9, 27.8, 30.8, 39.6, 41.7, 179.6; MS (APCI) m/z 158 [M+H]+. Anal. Calcd. For C8H15NO2—HCl: C, 49.61; H, 8.33; N, 7.23; Cl, 18.31. Found: C, 49.76; H, 8.44; N, 7.11; Cl, 18.48.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]([C:12]#[N:13])[C:9]([OH:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([NH:25][NH2:26])=O)=[CH:18][CH:17]=1.O1CCOCC1>C(O)(=O)C>[Br:1][C:2]1[N:11]=[C:10]([C:12]2[NH:13][C:23]([CH2:22][C:19]3[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=3)=[N:25][N:26]=2)[C:9]([OH:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: NNC(=O)Cc1ccc(F)cc1
Reactant: N#Cc1nc(Br)c2cccnc2c1O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Oc1c(-c2nnc(Cc3ccc(F)cc3)[nH]2)nc(Br)c2cccnc12
Temperature: 200 °C
Yield: 21.2 %

Procedure:
A suspension of 5-bromo-8-hydroxy-1,6-naphthyridine-7-carbonitrile (0.25 g, 9.99 mmol), 2-(4-fluorophenyl)acetic hydrazide (0.34 g, 2 mmol), 1,4-dioxane (2 mL) and acetic acid was heated at 200° C. for 10 minutes in a microwave chamber. The mixture was allowed to cool to room temperature, the precipitate was filtered and washed with dichloromethane. The filtrate was concentrated in vacuo, 1 N sodium hydroxide and ethyl acetate were added and the aqueous layer was washed with ethyl acetate. The aqueous layer was then acidified to pH 5 and the solids formed were collected. This material was azeotroped with methanol to provide 5-bromo-7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol (0.17 g, 42%) as a yellow solid. 1H NMR (CDCl3/CD3OD): δ 9.07 (dd, J=4.0, 1.2 Hz, 1 H), 8.50 (dd, J=8.4, 1.2 Hz, 1 H), 7.65 (dd, J=8.4, 4.0 Hz, 1 H), 7.26 (m, 2 H), 6.95 (m, 2 H), 4.11 (s, 2 H); MS m/z 400 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:46]=[CH:45][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:20][C:19]=3[N:36](C)[C:37](=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.Cl.O1CCOCC1>>[CH3:37][N:36]1[C:19]2[CH:20]=[C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[CH:22]=[CH:23][C:18]=2[N:17]=[C:15]1[CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])=[CH:46][CH:45]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCCC2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccccc3N3CCCC3)cc21
Yield: 92 %

Procedure:
In a similar manner to that described in Example (2-2a), a reaction was carried out using t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-[2-(pyrrolidin-1-yl)phenoxy]phenyl}-N-methylcarbamate (1.25 g) and 4N hydrogen chloride/dioxane (25 ml) and the reaction mixture was purified to give the title compound (0.94 g).
Reaction SMILES: [F:1][CH:2]([F:19])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([CH3:17])[CH:8]=1)=O.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][CH:2]([F:19])[C:3]1[N:22]2[N:23]=[CH:24][C:25]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=3)=[C:21]2[N:20]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([CH3:17])[CH:8]=2)[CH:4]=1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Reactant: Cc1cc(C(=O)CC(=O)C(F)F)ccc1C(F)(F)F
Product: Cc1cc(-c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)c(C)c4)nc23)ccn1
Yield: 78.4 %

Procedure:
Reaction of 4,4-difluoro-1-(3-methyl-4-trifluoromethyl-phenyl)-butane-1,3-dione (140 mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2-methyl-pyridine, CAS No. 130138-46-4, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (164 mg, 78%). MS (ISP) 419.3 [(M+H)+]; mp 221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12]O.OS(O)(=O)=O>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Product: COC(=O)Cc1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 107.8 %

Procedure:
To a stirred solution of 3-chlorophenylacetic acid (21.76 g, 127.6 mmol) in dichloroethane (100 ml) was added MeOH (15.6 ml, 383 mmol) and H2SO4 (1 ml) at room temperature. After 20 minutes stirring, the mixture was heated at 80° C. for 2 h. The reaction mixture was poured into ice water and extracted with CHCl3. The combined extracts were washed with aq NaHCO3 and brine. After dried over Na2SO4, the extract was concentrated in vacuo to give methyl 3-chlorophenylacetate (25.4 g, 100%) as a colorless oil. 1H-NMR (CDCl3) δ3.60 (s, 2H), 3.70 (s, 3H), 7.15-7.26 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:31])=[CH:4][C:5]([C:27]([F:30])([F:29])[F:28])=[C:6]([CH:26]=1)[C:7]([N:9]([CH:23]([CH3:25])[CH3:24])[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)=[O:8].Br[CH:33]([CH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:34](Cl)=[O:35]>>[CH:23]([N:9]([C:7]([C:6]1[C:5]([C:27]([F:30])([F:28])[F:29])=[CH:4][C:3]2[O:31][CH:33]([CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[C:34](=[O:35])[NH:1][C:2]=2[CH:26]=1)=[O:8])[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11]1)([CH3:24])[CH3:25]
Reactant: O=C(Cl)C(Br)C1CCOCC1
Reactant: CC(C)N(C(=O)c1cc(N)c(O)cc1C(F)(F)F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C1CCOCC1)C(=O)N2)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1

Procedure:
Using tert-butyl (3R)-3-[[5-amino-4-hydroxy 2-(trifluoromethyl)benzoyl](isopropyl)amino]-piperidine-1-carboxylate and bromo (tetrahydro-2H-pyran-4-yl)acetyl chloride, the title compound was obtained in a similar manner to Reference Example 55.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](O)([CH:8]([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[C:4]([F:7])([F:6])[F:5].[F:20]C(F)(F)C(F)=C(F)F.CN(C)C.F>O1CCCC1>[F:1][C:2]([F:19])([F:18])[CH:3]([C:8]([F:20])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[C:4]([F:7])([F:6])[F:5]
Reactant: OC(C(F)C(F)(F)C(F)(F)F)(C(F)(F)F)C(F)(F)F
Reactant: FC(F)=C(F)C(F)(F)F
Agent: CN(C)C
Agent: F
Solvent: C1CCOC1
Product: FC(F)(F)C(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
To prepare 2-trifluoromethyl-1,1,1,3,4,4,5,5,5-nonafluoro-2-pentanol, commercially available hexafluoropropene may be oligomerized with commercially available trimethylamine in a dipolar aprotic solvent such as commercially available tetrahydrofuran to provide (CF3)2C:CFCF2CF3 which is then reacted with commercially available hydrogen fluoride to yield 2-trifluoromethyl-1,1,1,3,3,4,4,5,5,5-decafluoropentane as taught by W. Brunskill et al., "Anionic Oligomerisation of Hexafluoropropene: Fission of a Carbon-Carbon Bond by Fluoride Ion", Chemical Communications, 1444 (1970). The 2-trifluoromethyl-1,1,1,3,3,4,4,5,5,5-decafluoropentane may then be dehydrohalogenated and then reacted with sulfuric acid and then water to form 2-trifluoromethyl-1,1,1,3,4,4,5,5,5-nonafluoro-2-pentanol.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=O)[CH3:2].[ClH:15].[NH2:16][C:17]1[C:22]([NH2:23])=[CH:21][N:20]=[CH:19][N:18]=1>P(Cl)(Cl)(Cl)=O>[ClH:15].[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:5]=1[C:6]1[NH:23][C:22]2[C:17](=[N:18][CH:19]=[N:20][CH:21]=2)[N:16]=1)[CH3:2]
Reactant: Nc1cncnc1N
Reactant: CCOc1cc(SC)ccc1C(=O)O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc(SC)ccc1-c1nc2ncncc2[nH]1

Procedure:
Three grams of 2-ethoxy-4-methylmercapto-benzoic acid and 2.2 g of 4,5-diamino-pyrimidine hydrochloride were refluxed in 30 ml of phosphorus oxychloride for three hours. The reaction mixture was poured on ice and then made ammoniacal, and the supernatant solution was decanted from the semicrystalline residue. After dissolution in methanol and filtering off from the insoluble products, the residue was purified over a silicagel column (eluate: methylene chloride/ethanol in volume ratio of from 100:0 to 98:2). The hydrochloride was precipitated from acetone with ethereal hydrochloric acid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(F)cc1)OCC
Temperature: 150 °C
Reaction time: 22 h

Procedure:
4-fluorobenzyl bromide (100 g) and triethyl phosphite (120 ml) were mixed, and the mixture was stirred at 150° C., for 22 hours. The obtained reaction mixture was distilled under reduced pressure (bp 115-120° C./1.5 mmHg) to give diethyl 4-fluorobenzylphosphonate (125 g). To a solution of 4-fluorobenzylphosphonate (60.8 g), 15-Crown-5 (4 ml) in THF (400 ml) was added 60% sodium hydride in mineral oil (9.75 g) under ice cooling with stirring, and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of 1-tert-butoxycarbonyl-4-piperidone (42.0 g) in THF (150 ml) under ice cooling, and the mixture was stirred at room temperature for 22 hours. After the addition of water under ice cooling, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate, saturated aqueous solution of sodium chloride, successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 650 g, hexane/ethyl acetate=30/1 to 10/1), and the desired fraction was concentrated under reduced pressure to give 1-tert-butoxycarbonyl-4-(4-fluorobenzylidene)piperidine (47.0 g).
Reaction SMILES: [CH:1]([C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:18]SC1C(C2C=NC=CC=2)=NNC=1>C(OCC)C>[CH:1]([C:7]1[C:8]([C:12]2[CH2:13][N:14]([CH3:18])[CH2:15][CH2:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CSc1c[nH]nc1-c1cccnc1
Reactant: CCCCC=Cc1c[nH]nc1-c1cccnc1
Solvent: CCOCC
Product: CCCCC=Cc1c[nH]nc1C1=CCCN(C)C1

Procedure:
Compound 46A (0.34 g, 0.97 mmol), 0.7 g of KOH and 1 ml of NH2NH2.H2O were combined in diethylene glycol (10 ml) and warmed to reflux for 1 hour under N2. The mixture was cooled, concentrated and redissolved in MeOH. Filtration over 25 g of SCX-2 (MeOH followed by 1 N NH3/MeOH) and subsequent purification by flash chromatography (ethyl acetate) afforded 3-(4-hex-1-enyl-1H-pyrazol-3-yl)-pyridine (the deprotected analog of 46A). Yield 0.18 g (86%). (TLC diethyl ether Rf 0.18). 3-(4-Hex-1-enyl-1H-pyrazol-3-yl)-pyridine was converted to the title compound 47A, using the methodology described for the conversion of 21A to 22A (see Scheme 3).
Reaction SMILES: BrC1C=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=C(F)C=1.C(C1NC(=O)N(CC2C=CC(OC)=CC=2)C1=O)(C)C.[CH3:44][C:45]1[C:46]([N:52]2[CH2:57][CH2:56][N:55]([C:58]([C:60]3[CH:65]=[CH:64][C:63]([N:66]4[CH:70]([CH:71]([CH3:73])[CH3:72])[C:69](=[O:74])[N:68](CC5C=CC(OC)=CC=5)[C:67]4=[O:84])=[CH:62][C:61]=3[F:85])=[O:59])[CH2:54][CH2:53]2)=[N:47][CH:48]=[C:49]([CH3:51])[CH:50]=1>>[CH3:44][C:45]1[C:46]([N:52]2[CH2:53][CH2:54][N:55]([C:58]([C:60]3[CH:65]=[CH:64][C:63]([N:66]4[CH:70]([CH:71]([CH3:72])[CH3:73])[C:69](=[O:74])[NH:68][C:67]4=[O:84])=[CH:62][C:61]=3[F:85])=[O:59])[CH2:56][CH2:57]2)=[N:47][CH:48]=[C:49]([CH3:51])[CH:50]=1
Reactant: COc1ccc(CN2C(=O)C(C(C)C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(F)c3)C2=O)cc1
Agent: COc1ccc(CN2C(=O)NC(C(C)C)C2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C(C)C)cc3F)CC2)c(C)c1

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (235 mg) described in Preparation Example 114 and 5-isopropyl-3-(4-methoxybenzyl)imidazolidine-2,4-dione (157 mg) described in Preparation Example 209 and by the reaction and treatment in the same manner as in Example 508, the title compound (144 mg) was obtained via 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-isopropyl-3-(4-methoxybenzyl)imidazolidine-2,4-dione.