Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:12]([CH3:13])[N:11]=[N:10][C:9]=1[CH2:14][O:15][Si](C(C)(C)C)(C)C)(=O)=O.[NH:23]1[CH2:26][CH2:25][CH2:24]1>C1COCC1>[N:23]1([CH2:6][CH2:7][C:8]2[N:12]([CH3:13])[N:11]=[N:10][C:9]=2[CH2:14][OH:15])[CH2:26][CH2:25][CH2:24]1
Reactant: C1CNC1
Reactant: Cn1nnc(CO[Si](C)(C)C(C)(C)C)c1CCOS(C)(=O)=O
Solvent: C1CCOC1
Product: Cn1nnc(CO)c1CCN1CCC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 28.5 %

Procedure:
A solution of 2-[4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-methyl-1H-1,2,3-triazol-5-yl]ethyl methanesulphonate (642 mg, 1.84 mmol) and azetidine (2.48 ml, 18.4 mmol) in THF (10 ml) was heated at reflux for 4 h and then concentrated under reduced pressure while dry loading onto silica. The mixture was purified by column chromatography on silica using 2% MeOH/CH2Cl2 containing 1% NH3 solution as eluent. After concentrating under reduced pressure, THF (3 ml), H2O (3ml) and AcOH (9 ml) were added and the mixture stirred at RT for 60 h. The solvents were removed under reduced pressure while azeotroping with toluene (2×25 ml). The residue was dissolved in CH2Cl2, dry loaded onto silica and purified by column chromatography on silica using 15% MeOH/CH2Cl2 containing 1% NH3 solution as eluent to yield the desired hydroxymethyltriazole (103 mg, 29%). 1H NMR (360 MHz, CDCl3) δ 4.65 (2H, s), 3.94 (3H, s), 3.25 (4H, t, J=7.2 Hz), 2.76-2.62 (4H, m), 2.11 (2H, quintet, 7.2 Hz). m/z (ES+) 196 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Sn](CCCC)(CCCC)CCCC)[N:26]=1>CN(C=O)C.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>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[N:26]=3)=[CH:3][C:4]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(Br)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cccc(OC)n3)c2s1
Temperature: 120 °C
Yield: 11.2 %

Procedure:
To a solution of 1-(7-bromo-5-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea (0.50 g, 1.32 mmol) in DMF (5.0 mL) was added 2-methoxy-6-tributylstannanyl-pyridine (1.05 g, 2.65 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was then degassed for half an hour followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.20 mmol). The reaction mixture was then again degassed for half an hour and heated at 120° C. for 6 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), DMF was distilled off; water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified by prep HPLC to get the title compound as white solid (0.06 g, 11%). M.P. 300.10° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[O:7][C@H:6]1[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH:32][CH:33]1[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]1)(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.ClCCl>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[O:7][C@H:6]1[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(C(C)(C)C)no2)O[C@H]1n1cnc2c(NC3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(C(C)(C)C)no2)O[C@H]1n1cnc2c(NC3CCNCC3)ncnc21
Reaction time: 16 h
Yield: 96.8 %

Procedure:
tert-Butyl 4-[(9-{(2R,3R,4R,5S)-3,4-bis(acetyloxy)-5-[3-(tert-butyl)isoxazol-5-yl]tetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate (500 mg) was dissolved in trifluoroacetic acid:dichloromethane (1:9, 20 ml) and the mixture kept at 3° C. for 16 h. The mixture was then quenched with saturated sodium bicarbonate solution (100 ml) and extracted with dichloromethane (100 ml). The organic layer was washed with saturated sodium bicarbonate solution (100 ml) and evaporated to dryness in vacuo to afford the title compound (407 mg) as a yellow glassy solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17].[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1.CNC1C=CC=C(NC)N=1.C(N(CC)CC)C>ClCCl>[Si:19]([O:18][CH:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCCCCC(O)c1ccc2ccccc2c1
Agent: CNc1cccc(NC)n1
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc2ccccc2c1
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of alcohol 181 (1.0 g, 4.16 mmol) in dichloromethane (40 mL) at room temperature under nitrogen atmosphere were successively added solid t-butyldimethylsilyl chloride (815 mg, 5.41 mmol), imidazole (340 mg, 4.99 mmol), and a catalytic amount of 2,6-dimethylaminopyridine. The mixture was stirred over 1 hour and triethylamine (696 μL, 4.99 mmol) was added. The mixture was stirred for 2 days. The reaction was quenched with water and the layers separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed successively with a 1N HCl (2×10 mL), a saturated solution of sodium bicarbonate and brine, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash chromatography using hexane as the eluent, and affording the title compound 182 in 84% yield (1.24 g). 1H NMR: (300 MHz, CDCl3) δ: 7.83-7.79 (m, 3H), 7.70 (s, 1H), 7.47-7.40 (m, 3H), 5.78 (ddt, J=17.0, 10.4, 6.6 Hz, 1H), 5.85-5.71 (m, 2H), 4.79 (dd, J=6.9, 4.9 Hz, 1H), 2.04-1.98 (m, 2H), 1.80-1.54 (m, 2H), 0.90 (s, 9H), 0.04 (s, 3H), −0.14 (s, 3H). MS (ESI)=223 (MH+-TBSO).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:31])C(=O)C1>FC(F)(F)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][Br:31])[C:5]([OH:7])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: O=C(O)c1ccc(CBr)c(Br)c1
Temperature: 90 °C
Yield: 60 %

Procedure:
To a solution of 3-bromo-4-methylbenzoic acid (1.0 equiv.) and AIBN (0.05 equiv.) in trifluorotoluene (0.28 M) was added NBS (1.1 equiv.). The mixture was heated at 90° C. overnight. The reaction mixture was partitioned between EtOAc and H2O. The organic layer was washed with NaCl(sat.), dried over MgSO4, filtered, concentrated to yield 3-bromo-4-(bromomethyl)benzoic acid in 60% yield. LC/MS (m/z)=294.8 (MH+), Rt=0.80 min.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH:17]([C:25]2[CH:36]=[CH:35][C:28]([CH:29]=[C:30]([CH3:34])[C:31]([OH:33])=[O:32])=[CH:27][CH:26]=2)[CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[CH2:37](O)[CH3:38].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH:17]([C:25]2[CH:26]=[CH:27][C:28]([CH:29]=[C:30]([CH3:34])[C:31]([O:33][CH2:37][CH3:38])=[O:32])=[CH:35][CH:36]=2)[CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CCO
Reactant: CC(=Cc1ccc(C(CNS(=O)(=O)c2ccc(Cl)cc2)Cc2cccnc2)cc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)=Cc1ccc(C(CNS(=O)(=O)c2ccc(Cl)cc2)Cc2cccnc2)cc1
Reaction time: 3 h

Procedure:
To 0.60 g of 4-[1-(4-chlorobenzenesulfonamido)-3-(3-pyridyl)-2-propyl]-α-methylcinnamic acid thionyl chloride and stirred for one hour. To the mixture was added 5 ml of ethanol at 0° C., and stirred for three hours, followed by dropwise addition of saturated aqueous sodium hydrogencarbonate and extraction with ethyl acetate and then further washing in saturated aqueous sodium chloride solution, and dried over magnesium sulfate to distill off the solvent. The residue obtained was subjected to chromatography on a silica gel column, and from a fraction eluted with methanol-methylene chloride (5:95 v/v) was obtained 0.49 g of ethyl 4-[1-(4-chlorobenzenesulfonamido)-3-(3-pyridyl)-2-propyl]-α-methylcinnamate.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]1[CH3:23])(=[O:16])=[O:15].N1C=CC=CC=1>C(Cl)Cl>[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]([Cl:1])=[O:4])[CH2:19][C@@H:18]1[CH3:23])(=[O:15])=[O:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H]1CNCCN1S(C)(=O)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CN(C(=O)Cl)CCN1S(C)(=O)=O
Temperature: 25 °C
Yield: 154.7 %

Procedure:
Second step: To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (560 mg, 1.88 mmol) in CH2Cl2 (10 mL) at −78° C., was added a solution of (S)-1-methanesulfonyl-2-methyl-piperazine (838 mg, 4.70 mmol) and pyridine (0.74 mL, 9.4 mmol) in CH2Cl2 (10 mL) over 1 hour. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo and flash chromatography (SiO2) EtOAc/H, 1:1) yielded 0.70 g (62%) of (S)-4-methanesulfonyl-3-methyl-piperazine-1-carbonyl chloride as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][CH2:11][CH2:12][O:13][Si](C(C)(C)C)(C)C)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC1OCCC1.C1COCC1>[C:1]([O:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc(OCCO)cc1
Temperature: 60 °C
Yield: 92.6 %

Procedure:
[2-(4-Tert-butoxyphenoxy)ethoxy](tert-butyl)dimethylsilane (1.7 g, 5.24 mmole) was taken up in 2-MeTHF (10 mL). To this was added 1M TBAF (16 mL, 16.00 mmole) in THF then the mixture was heated to 60° C. After 4 hr the mixture was cooled to RT and concentrated. The residue was taken up in H2O and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (Biotage-SNAP-50 g SiO2, 30% EtOAc/hexanes) gave the title compound (1.02 g, 93%) as a clear oil. 1H NMR (400 MHz, CDCl3): δ 6.94-6.90 (m, 2 H); 6.83-6.79 (m, 2 H); 4.07-4.02 (m, 2 H); 3.97-3.91 (m, 2 H); 1.30 (s, 9 H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:23]([SiH2:27][O:28][C:29]([CH3:41])([CH3:40])[C:30]1[CH:31]=[C:32]([CH2:37][CH2:38][NH2:39])[CH:33]=[CH:34][C:35]=1[Cl:36])([CH3:26])([CH3:25])[CH3:24].[F:42][C:43]([F:49])([F:48])[CH2:44][C:45](O)=[O:46].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:23]([SiH2:27][O:28][C:29]([CH3:41])([CH3:40])[C:30]1[CH:31]=[C:32]([CH2:37][CH2:38][NH:39][C:45](=[O:46])[CH2:44][C:43]([F:49])([F:48])[F:42])[CH:33]=[CH:34][C:35]=1[Cl:36])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)CC(F)(F)F
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCN)ccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCNC(=O)CC(F)(F)F)ccc1Cl
Reaction time: 1 h
Yield: 28.2 %

Procedure:
TBTU (2.09 g, 6.50 mmol) was added to a sol. of 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethylamine (1.30 g, 4.33 mmol), 3,3,3-trifluoropropionic acid (0.574 mL, 6.50 mmol) and DIPEA (2.97 mL, 17.3 mmol) in CH2Cl2 (43 mL). The mixture was stirred for 1 h, and CH2Cl2 was added. The mixture was washed with aq. sat. NH4Cl, aq. 10% Na2CO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 60:40) yielded the title compound (500 mg, 28%). LC-MS: tR=1.12 min; ES+: 410.14.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH2:29])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([NH:29][CH2:28][C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][C:24]=3[C:30]([F:31])([F:32])[F:33])=[O:19])[CH2:12]2)[N:3]=1
Reactant: COc1ccc(CN)c(C(F)(F)F)c1
Reactant: CNc1nc(C)nc(NC2CCCC(C(=O)O)C2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNc1nc(C)nc(N[C@@H]2CCC[C@H](C(=O)NCc3ccc(OC)cc3C(F)(F)F)C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.9 %

Procedure:
To a solution of 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (0.100 g, 0.377 mmol) in N,N-Dimethylformamide (DMF) (5 ml) was added ({[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl} amine (0.132 g, 0.415 mmol), followed by diisopropylethylamine (0.197 ml, 1.131 mmol) and 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.183 g, 0.415 mmol). The reaction was stirred at room temperature for 4 hours and then purified by preparative HPLC to provide (cis)-3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}-N-{[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}cyclohexanecarboxamide (31 mg, 0.06 mmol, 16%). MS (ES+): m/e 453 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[C:9]1([CH:7]([CH3:8])[CH2:6][C:5]([C:15]([F:16])([F:17])[F:18])([OH:19])[CH2:4][OH:3])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(O)(CC(C)c1ccccc1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(CC(O)(CO)C(F)(F)F)c1ccccc1
Reaction time: 1 h
Yield: 110.2 %

Procedure:
4.35 g of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester is dissolved in 100 ml of diethyl ether and stirred at 0° C. with 1.3 g of lithium aluminum hydride for one hour at 0° C. and for 16 hours at room temperature. A little water is added while being cooled, and it is stirred for one hour. The diethyl ether phase is separated, dried (Na2SO4) and concentrated by evaporation and distilled on a bulb tube. 4.1 g of 4-phenyl-2-trifluoromethyl-1,2-pentanediol, boiling point 120° C./0.04 hPa, is obtained.
Reaction SMILES: CON(C)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][CH:6]=1.[CH3:13][C:14]([CH3:18])=[CH:15][Mg]Br.[Cl-].[NH4+].O>C1COCC1>[CH3:15][C:14]([CH3:18])=[CH:13][C:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:11]
Reactant: CC(C)=C[Mg]Br
Reactant: CON(C)C(=O)c1cccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CC(=O)c1cccnc1
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of N-methoxy-N-methylnicotinamide (500 mg, 3.0 mmol) in anhydrous THF (3.5 mL) under nitrogen at −78° C. add 2-methyl propenyl magnesium bromide (12 mL, 6.0 mmol, 0.5 M in THF) dropwise. After one hour at −78° C., allow to reach room temperature. After 2 h, add saturated aqueous ammonium chloride. (10 mL) and water (2 mL). Extract with ethyl acetate three times, dry the combined organic phases with anhydrous sodium sulfate and concentrate to obtain 442 mg (91%) of the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[C:13]([C:16]1[S:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])[CH3:14].C(=O)([O-])[O-].O>CN(C=O)C>[CH2:9]([O:8][C:6]1[N:5]=[C:4]([S:11][CH3:12])[N:3]=[C:2]([C:19]2[S:20][C:16]([C:13](=[O:15])[CH3:14])=[CH:17][CH:18]=2)[CH:7]=1)[CH3:10]
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: CCOc1cc(Cl)nc(SC)n1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-c2ccc(C(C)=O)s2)nc(SC)n1
Temperature: 80 °C
Yield: 27.9 %

Procedure:
The crude product of Preparation 27, 4-chloro-6-ethoxy-2-methylsulfanylpyrimidine, (525 mg, 2.56 mmol) was dissolved in DMF (4 mL). To this solution was added 5-acetyl-2-thiopheneboronic acid (523 mg, 3.08 mmol), PdCl2dppf (209 mg, 0.26 mmol), potassim carbonate (1.06 g, 7.69 mmol) and water (0.4 mL). The reaction mixture was heated at 80° C. under nitrogen atmosphere for overnight. The reaction mixture was cooled and poured into 30 mL of water and was then extracted with diethyl ether (20 mL×3) three times. The ether layer was separated and dried with anhydrous MgSO4 and concentrated in vacuo. The resulting crude product was purified by flash silica column chromatography (20% ethyl acetate in hexane) to give product 1-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-ethanone (210 mg, 28% yield over two steps). 1H-NMR (CDCl3): δ 7.67 (m, 2 H), 6.68 (s, 1 H), 4.46 (q, J=7.1 Hz, 2 H), 2.60 (s, 3 H), 2.59 (s, 3 H), 1.40 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])[CH3:10].C(N(C(C)C)CC)(C)C.Cl>C(Cl)Cl>[Br:1][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:9][CH3:10])[C:12]=1[OH:17]
Reactant: CCc1ccccc1O
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
N-Bromosuccinimide (29.1 g, 163.7 mmol) was added as a suspension in CH2Cl2 (200 mL) over 2 h to a solution of 2-ethylphenol (20.0 gm, 163.7 mmol), diisopropylethylamine (2.3 mL, 16.4 mmol), and CH2Cl2 (300 mL). The resulting solution was maintained at room temperature for 2 h. One normal HCl (100 mL) was added and the mixture was stirred vigorously for 0.5 h. The layers were separated, and the organic phase was washed with 1 N HCl (2×100 mL). The combined aqueous layers were extracted with CH2Cl2 (1×100 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (SiO2, gradient elution 5 to 10% CH2Cl2/hexanes) to yield 26.5 g (80%) of 2-bromo-6-ethylphenol 1 as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH2:38])=[N:5][CH:6]=[N:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:16]([CH2:31][CH2:32][N:33]3[CH2:36][CH:35](F)[CH2:34]3)[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)[CH3:2].F[C:40]1C=CC(C2N=C(C3CCNCC3)N(CCN3CC(C)C3)C=2)=CC=1C(F)(F)F>>[CH2:1]([C:3]1[C:4]([NH2:38])=[N:5][CH:6]=[N:7][C:8]=1[N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[N:16]([CH2:31][CH2:32][N:33]3[CH2:34][CH:35]([CH3:40])[CH2:36]3)[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:28])([F:29])[F:30])[CH:21]=3)[N:19]=2)[CH2:13][CH2:14]1)[CH3:2]
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CC(F)C2)CC1
Reactant: CC1CN(CCn2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCNCC2)C1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CC(C)C2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine using 4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-methylazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine instead of 4-[1-[2-(3-Fluoro-azetidin-1-yl)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine. LC-MS: (M+1=532, obsd.=532).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].ClCCl.[OH:9][CH2:10][C@@H:11]1[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][N:13]([C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)=[O:23])[CH2:12]1>C(N(CC)CC)C>[CH3:1][S:2]([O:9][CH2:10][C@@H:11]1[C@@H:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][N:13]([C:22]([O:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:30]=2)=[O:23])[CH2:12]1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(OC(=O)N2C[C@H](CO)[C@@H](c3ccccc3)C2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](COS(C)(=O)=O)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
A 0.84 ml portion of methanesulfonyl chloride was added dropwise to a 30 ml dichloromethane solution of 3.5 g of 4-(methoxycarbonyl)phenyl (3R,4S)-3-(hydroxymethyl)-4-phenylpyrrolidine-1-carboxylate and 2.75 ml of triethylamine, and stirred at room temperature for 2Hours. Thereafter, its work-up was carried out in the standard method to obtain 4.3 g of 4-(methoxycarbonyl)phenyl (3R,4S)-3-{[(methylsulfonyl)oxy]methyl}-4-phenylpyrrolidine-1-carboxylate as a colorless amorphous substance. EP: 434.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:33])=[C:26]([CH2:28][S:29]([NH2:32])(=[O:31])=[O:30])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:33][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:26]([CH2:28][S:29]([NH2:32])(=[O:31])=[O:30])[CH:27]=1
Reactant: NS(=O)(=O)Cc1cc(Cl)ccc1O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CS(N)(=O)=O
Temperature: 60 °C
Yield: 30.8 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.028 g, 0.094 mmol) in dimethylformamide (1 mL) was added (5-chloro-2-hydroxy-phenyl)-methanesulfonamide (0.023 g, 0.10 mmol), potassium carbonate (0.026 g, 0.19 mmol) and potassium iodide (0.016 g, 0.094 mmol). The reaction was heated at 60° C. for 17 hours, cooled, diluted with water and extracted with ethyl acetate (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.014 g).