Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([C:4]1[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1)=O.[F:13][C:14]([F:18])([F:17])[CH2:15][NH2:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:13][C:14]([F:18])([F:17])[CH2:15][NH:16][CH2:2][C:4]1[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: NCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: OB(O)c1cccc(CNCC(F)(F)F)c1
Reaction time: 72 h
Yield: 36.3 %

Procedure:
Dissolve 3-formylphenyl boronic acid hydrochloride (2.5 g, 16.67 mmol) and 2,2,2,-trifluoroethylamine (2.97 g, 30.01 mmol) in DCM (100 mL). Add sodium triacetoxyborohydride (10.6 g, 50.02 mmol) portionwise over 10 min and stir the resulting solution for 72 h. Then quench with water (50 mw). Dry the organic fraction over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with dichloromethane:methanol (1:0 to 19:1) to give the title compound as a colourless oil (1.41 g, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:38]#[C:39][CH2:40][OH:41])=[C:32]([CH:37]=3)[C:33]([O:35][CH3:36])=[O:34])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[H][H]>C(O)C.O=[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([S:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:38][CH2:39][CH2:40][OH:41])=[C:32]([CH:37]=3)[C:33]([O:35][CH3:36])=[O:34])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [H][H]
Reactant: COC(=O)c1cc(CSc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)c(OC)c2)ccc1C#CCO
Agent: O=[Pt]=O
Solvent: CCO
Product: COC(=O)c1cc(CSc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)c(OC)c2)ccc1CCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a Parr bottle charged with methyl 5-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-ylthio)methyl)-2-(3-hydroxyprop-1-ynyl)benzoate (140 mg, 0.23 mmol) in degassed ethanol (10 mL) was added PtO2 (100 mg). The reaction vessel was pressurized to 60 psi with hydrogen gas and agitated at room temperature for 16 h. After LCMS analysis showed complete conversion, the reaction mixture was filtered through Celite™ and concentrated in vacuo to give the title compound (120 mg, 85%). MS (EI) m/z 619 (MH+).
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:20]([OH:22])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C.Cl.[NH2:57][C@H:58]([C:74]([O:76][CH3:77])=[O:75])[CH2:59][C:60]1[CH:65]=[CH:64][C:63]([O:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[CH:62][CH:61]=1>CN(C=O)C>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C@H:2]([C:20]([NH:57][C@H:58]([C:74]([O:76][CH3:77])=[O:75])[CH2:59][C:60]1[CH:61]=[CH:62][C:63]([O:66][CH2:67][C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)=[CH:64][CH:65]=1)=[O:22])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 169.3 %

Procedure:
Dipeptide Boc-Arg(Tos)-Tyr(Bzl)-OCH3 : A solution of Boc-Arg(Tos)-OH (2.14 g, 5 mmol) and DPPA (1.37 g, 5 mmol) in DMF (100 mL) was cooled to -5° C. DIEA (2.6 mL, 15 mmol) and HCl.H-Tyr(Bzl)-OCH3 (1.44 g, 4.5 mmol) were added, each in one portion, to the cooled solution. The solution was stirred at -10° C. for 2h, allowed to stand at 4° C. for 18h, and then evaporated to dryness. The residue was dissolved in EtOAc (75 mL). The solution was washed sequentially with H2O, 1N HCl, 5% aqueous NaHCO3 and H2O, dried, and evaporated to dryness. The residue was dissolved in EtOAc. Addition of Et2O caused an oil to separate from the solution. The mixture was cooled (0° C.) and triturated. The solvent phase of the mixture was removed by decantation. Et2O was added to the residue. After warming the mixture, the preceding trituration and decantation treatment was repeated. Finally, the product was dried under reduced pressure to yield Boc-Arg(Tos)-Tyr(Bzl)-OCH3 (5.3 g).
Reaction SMILES: [SH:1][CH:2]([CH:14]([C:19]([NH:21][C@H:22]([C:32]([NH:34][CH3:35])=[O:33])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:36](OC(=O)C)(=[O:38])[CH3:37].CN1CCOCC1>C(Cl)(Cl)Cl>[C:36]([S:1][CH:2]([CH:14]([C:19]([NH:21][C@H:22]([C:32]([NH:34][CH3:35])=[O:33])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])(=[O:38])[CH3:37]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(S)CC(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)OCc1ccccc1)SC(C)=O
Temperature: 0 °C
Reaction time: 72 h

Procedure:
The benzyl ester (D8) (41 g, 0.088 mole) was dissolved in thiolacetic acid (170 ml) and left to stand at room temperature under nitrogen for 19 days. Volatile material was removed in vacuo and the residue chromatographed on silica gel with initially ether, rising slowly to ethyl acetate. After removal of high Rf impurities the title compound was obtained as a mixture of diastereomers as a pale yellow foam (29.76 g, 62.4%). (Found: C, 64.29; H, 7.16; N, 4.86. C29H38N2SO6 requires C, 64.18; H, 7.06; N, 5.16%). Later fractions contained olefinic material (D8). However, more complete reaction can be obtained by addition of a suitable base, for example triethylamine. An aliquot (2 ml) was removed from the above reaction mixture after 14 days, treated with triethylamine (3 drops) and left to stand for a further 5 days at room temperature under nitrogen. The same work-up procedure as for the bulk of the reaction mixture described above gave only the diastereomer mixture (E3) with no olefinic material remaining. 3-Mercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid, benzyl ester (E4, Isomer A, 2.0 g 0.004 mol) was dissolved in chloroform (100 ml) under an atmosphere of nitrogen. The reaction mixture was cooled to 0° C. and acetic anhydride (2.04 g, 0.02 mol) was added followed by N-methylmorpholine (2.02 g, 0.02 mol). The reaction mixture was allowed to warm to room temperature, then stirred under nitrogen for 3 days.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[C:9]2[N:10]([CH3:17])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[C:25]([O:29][C:30](ON=C(C1C=CC=CC=1)C#N)=[O:31])([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[CH3:1][N:2]([CH2:3][CH:4]1[C:9]2[N:10]([CH3:17])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7][CH2:6][CH2:5]1)[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31]
Reactant: CNCC1CCSc2c1n(C)c1ccccc21
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CC1CCSc2c1n(C)c1ccccc21)C(=O)OC(C)(C)C
Yield: 87 %

Procedure:
A solution of 4-methylaminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (3.2 g) in dry tetrahydrofuran (30 ml) is allowed to react with triethylamine and 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile in the same manner as in Example 6(a) to give 4-(N-methyl-N-t-butoxycarbonylaminomethyl)-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole: Yield 87.0%. Mp. 111.5°-114° C. (decomp.) (b) The above product is treated in the same procedure as in Example 12 to give 4-(N-methyl-N-t-butoxycarbonylaminomethyl)-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole 1-oxide. Mp. 218°-220.5° C. (decomp.). The product is dissolved in methylene chloride (20 ml) and trifluoroacetic acid (4 ml) is added thereto. The mixture is kept at room temperature for 2 hours and then treated in the usual manner to give the title compound (1.13 g): Yield 89.7%.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CN1CCOCC1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25]>C(Cl)Cl>[C:24](=[O:25])([O:26][C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=1)[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (36.1 g, 168 mmol) and NMM (20 mL, 182 mmol) in DCM (500 mL) at 0° C. was added p-nitrophenyl chloroformate (33.9 g, 168 mmol). The reaction mixture was stirred at room temperature overnight and then washed sequentially with 1M aq HCl (500 mL), sat aq NaHCO3 solution (3×500 mL), dried (MgSO4) and concentrated in vacuo to give (1-(tert-butoxy-carbonyl)piperidin-4-yl)methyl 4-nitrophenyl carbonate (61.2 g, 96%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=S)[CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=[N:19][NH2:20])[C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[CH:3]=1
Reactant: Cc1cc(C)nc(NC(=S)c2cnccn2)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(C)nc(NC(=NN)c2cnccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1 g of compound of Example 24 dissolved in 30 ml of ethanol is added 0.6 ml of hydrazine monohydrate and the mixture is left stirring for 30 minutes at room temperature. The reaction medium is then poured into ice-water. It is stirred vigorously for 20 minutes. The mixture is filtered and dried and the residue is recrystallized from isopropyl ether.
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[N:31]=[C:32]=[S:33]>ClCCl>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:32](=[S:33])[NH:31][C:25]5[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=5[CH3:23])[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)c(N=C=S)c1
Reactant: c1ccc(C2CC(c3csc(C4CCNCC4)n3)=NO2)cc1
Solvent: ClCCl
Product: Cc1ccc(C)c(NC(=S)N2CCC(c3nc(C4=NOC(c5ccccc5)C4)cs3)CC2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]piperidine (i.e. the product of Step B) (1.0 g, 3.2 mmol) in dichloromethane (10 mL) was added a solution of 2,5-dimethylphenyl isothiocyanate (0.52 g, 3.2 mmol) and dichloromethane (5 mL) over 1 minute. The reaction mixture was stirred at room temperature for 20 minutes, concentrated, dissolved in methyl acetate (4 mL), held at 0° C. overnight and filtered to give the title compound as a white powder (1.35 g) melting at 120-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[N:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][NH:7][C:8](=O)[C:9]([CH3:22])([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH3:10])=[O:5].N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:27]=[N:26][CH:25]=[CH:24][C:3]=1[C:4]1[O:5][C:8]([C:9]([CH3:22])([O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=2)[CH3:10])=[N:7][N:6]=1
Reactant: CC(C)(Oc1ccc(C(F)(F)F)cc1)C(=O)NNC(=O)c1ccncc1Cl
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(Oc1ccc(C(F)(F)F)cc1)c1nnc(-c2ccncc2Cl)o1
Temperature: -10 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
3-chloro-N′-{2-methyl-2-[4-(trifluoromethyl)phenoxy]propanoyl}isonicotinohydrazide (282 mg) was dissolved in dichloromethane (5 ml) and pyridine (130 μl) was added thereto. The reaction solution was cooled to −10° C., trifluoromethanesulfonic anhydride (230 μl) was added thereto, followed by standing to warm to room temperature and then stirring overnight. The reaction solution was diluted with saturated aqueous sodium bicarbonate, the organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain 3-chloro-4-(5-{1-methyl-1-[4-(trifluoromethyl)phenoxy]ethyl}-1,3,4-oxadiazol-2-yl)pyridine (231 mg) as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:26][C:27]([F:34])([F:33])[C:28]1([OH:32])[CH2:31][NH:30][CH2:29]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:30]3[CH2:31][C:28]([OH:32])([C:27]([F:34])([F:33])[F:26])[CH2:29]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: OC1(C(F)(F)F)CNC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CC(O)(C(F)(F)F)C1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.10 g, 1.0 eq.) and 3-(trifluoromethyl)azetidin-3-ol hydrochloride (0.055 g, 1.1 eq.) were dissolved in DCM (3.0 mL) The reaction mixture was cooled to −30° C. where T3P (0.3 mL, 1.5 eq.) and DIPEA (0.12 mL, 2.5 eq.) were added. The reaction mixture was stirred at −30° C. for 30 min. and diluted by DCM, washed with water. The combined organic layers were dried over sodium sulfate and distilled under reduce pressure (250° C., 20 mmHg) to obtain crude product. The crude product was purified by preparative TLC (70% ethyl acetate-Hexane) to yield to 0.020 g of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)prop-2-en-1-one. (Yield: 14.8%). 1H NMR (400 MHz, MeOD) δ 9.20 (s, 1H), 8.65 (s, 2H), 8.09 (s, 1H), 7.40-7.43 (d, J=10 Hz, 1H), 5.95-5.93 (d, J=10.6 Hz, 1H), 4.42-4.43 (m, 2H), 4.33-4.05 (m, 2H); LCMS calcd for C17H11F9N4O2 [M+H]+474.3. Found: 475.14 Retention time: 2.872 min,
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:43])[CH2:4][C:5]1[CH:42]=[CH:41][CH:40]=[CH:39][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:10]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][NH:2][C:3](=[O:43])[CH2:4][C:5]1[CH:42]=[CH:41][CH:40]=[CH:39][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:16])[F:17])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[N:10]=1
Reactant: CNC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.9 %

Procedure:
tert-Butyl 4-(4-((4-(2-(2-(methylamino)-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I56) (0.087 g, 0.15 mmol) was dissolved in DCM (5 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (0.222 mL, 2.906 mmol) was added to the solution and the reaction was stirred at room temperature for 6 hours. Volatiles were removed in vacuo, EtOAc (70 mL) and 2 M aq. NaOH (70 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with EtOAc (2×70 mL), the combined organics were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give a solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice after which the sample was further dried on high-vacuum to give the title compound (14) (0.068 g, 94% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 7.93-7.85 (m, 1H), 7.60-7.53 (m, 2H), 7.23-7.12 (m, 4H), 6.91-6.86 (m, 2H), 3.50 (s, 2H), 3.14-3.06 (m, 2H), 3.02-2.93 (m, 6H), 2.87-2.80 (m, 4H), 2.56 (d, J=4.6 Hz, 3H). LCMS Method A: rt 4.37 min; m/z 499.6 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18](=[O:19])[N:17]([CH2:20][CH2:21][CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:16]=[N:15]2)=[CH:10][CH:9]=1.[C:28]([CH:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([S:41](Cl)(=[O:43])=[O:42])[CH:37]=2)[O:32]1)(=[O:30])[NH2:29]>O1CCCC1>[CH:23]1([CH2:22][CH2:21][CH2:20][N:17]2[C:18](=[O:19])[N:14]([C:11]3[CH:10]=[CH:9][C:8]([NH:7][S:41]([C:36]4[CH:37]=[C:38]5[C:33](=[CH:34][CH:35]=4)[O:32][CH:31]([C:28]([NH2:29])=[O:30])[CH2:40][CH2:39]5)(=[O:42])=[O:43])=[CH:13][CH:12]=3)[N:15]=[N:16]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Nc1ccc(-n2nnn(CCCC3CCCC3)c2=O)cc1
Reactant: NC(=O)C1CCc2cc(S(=O)(=O)Cl)ccc2O1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: NC(=O)C1CCc2cc(S(=O)(=O)Nc3ccc(-n4nnn(CCCC5CCCC5)c4=O)cc3)ccc2O1
Temperature: 50 °C
Yield: 55.5 %

Procedure:
Pyridine (650 mL, 8.03 mmol) followed by a solution of 1-(4-aminophenyl)-4-(3-cyclopentylpropyl)-5-tetrazolone (2.1 g, 7.32 mmol; prepared as described in WO 97/16189) in tetrahydrofuran (50 mL) were added to a cooled (0° C.) solution of the compound from Example 22 (2.02 g, 7.33 mmol) in tetrahydrofuran (50 mL). The mixture was heated to 50° C. overnight. Pyridine (650 mL) was added and the mixture re-heated to 50° C. After 72 hours the mixture was partitioned between ethyl acetate and water. The organic layer was washed with 5% aqueous hydrochloric acid (2×), saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried (MgSO4), and concentrated to a solid (3.7 g). The crude was recrystallized from ethyl acetate (260 mL). The recrystallization mixture was cooled to 0° C. before filtering to give colorless crystals (2.14 g). A second crop afforded 1.09 g. The combined yield was 3.22 g (83%). Mp 202-205° C.; H NMR (DMSO-d6, 300 MHz) δ 10.43 (s, 1 H), 7.69 (d, J=8.8 Hz, 2 H), 7.53 (m, 3 H), 7.37 (br s, 1 H), 7.26 (d, J=8.8 Hz, 2 H), 6.95 (d, J=8.5 Hz, 1 H), 4.57 (dd, J=8.5 Hz, 3.3 Hz, 1 H), 3.92 (t, J=7.0 Hz, 2 H), 2.71 (m, 2 H), 2.13 (m, 1 H), 1.89 (m, 1 H), 1.72 (m, 5 H), 1.49 (m, 4 H), 1.30 (m, 2 H), 1.03 (m, 2 H); MS (FAB) m/z 527 (MH+).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[F-].[K+]>C1(C)C=CC=CC=1.O.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>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: COc1cc(Br)ccc1C#N
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-c2ccc(C(F)(F)F)cc2)ccc1C#N
Temperature: 110 °C
Reaction time: 12 h
Yield: 97.8 %

Procedure:
To a solution of 4-bromo-2-methoxybenzonitrile (2.08 g, 9.81 mmol) and 4-(trifluoromethyl)phenylboronic acid (2.80 g, 14.7 mmol), potassium fluoride (1.71 g, 29.4 mmol) and Pd(PPh3)4 (1.13 g, 0.98 mmol) in toluene (40 mL) added water (10 mL). The mixture was stirred at 110° C. for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography gave 3-methoxy-4′-(trifluoromethyl)biphenyl-4-carbonitrile (2.66 g) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J=8.4 Hz, 2H), 7.63-7.56 (m, 3H), 7.15 (dd, J=8.0, 1.2 Hz, 1H), 7.06 (s, 1H), 3.95 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:26]=[C:27]([CH2:31][C:32](=O)[CH3:33])[CH:28]=[CH:29][CH:30]=1>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:32]([CH3:33])[CH2:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:35])[F:36])[CH:26]=2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: CC(=O)Cc1cccc(C(F)(F)F)c1
Product: CCCC(NC(C)Cc1cccc(C(F)(F)F)c1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 1-(3-trifluoromethyl-phenyl)-propan-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 14.2, 19.1, 19.5, 20.0, 21.1, 24.3, 26.6, 26.6, 36.1, 36.5, 43.5, 44.1, 54.6, 55.2, 56.0, 59.1, 60.8, 61.1, 67.3, 104.6, 104.7, 123.4, 126.2, 129.0, 129.2, 131.1, 133.0, 137.2, 140.1, 172.3; MS m/z 494.3 (M+1).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:8]=[C:9]([C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([N:30]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:24]=2)[C:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]([O:21][CH3:22])=[C:18]([F:20])[CH:19]=2)=[N:11][CH:12]=1)[C:3]([F:6])([F:5])[F:4].[C:49]([N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1)([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C(N(CC)CC)C>CC#N>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:30]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[C:25]2[N:26]=[C:27]([CH3:29])[N:28]=[C:23]([C:9]3[CH:8]=[C:7]([CH:2]([N:59]4[CH2:58][CH2:57][N:56]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:61][CH2:60]4)[C:3]([F:4])([F:6])[F:5])[CH:12]=[N:11][C:10]=3[NH:13][C:14]3[CH:15]=[N:16][C:17]([O:21][CH3:22])=[C:18]([F:20])[CH:19]=3)[N:24]=2)=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(Cl)C(F)(F)F)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(N4CCN(C(=O)OC(C)(C)C)CC4)C(F)(F)F)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 100 °C
Yield: 96.1 %

Procedure:
A solution of 4-(5-(1-chloro-2,2,2-trifluoroethyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.059 g, 1.548 mmol) in CH3CN (10.00 mL) was treated with 1-N-Boc-piperazine (Aldrich, 0.577 g, 3.10 mmol) and triethylamine (1.079 mL, 7.74 mmol) and the mixture was heated at 100° C. for 3 h. The reaction mixture was concentrated and the crude product was adsorbed onto a plug of silica gel and chromatographed through a silica gel column (100% DCM to 5% MeOH (w/NH3 in DCM) to give tert-butyl 4-(1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-2,2,2-trifluoroethyl)piperazine-1-carboxylate (1.24 g, 1.487 mmol, 96% yield) as a brown foam. m/z (ESI, +ve ion) 834 (M+H)+.