Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:10]2[C:5]([C:6](SC)=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[N:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH2:21][NH:22][CH:23]2[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[N:10]2[C:5]([C:6]([N:22]([CH:23]3[CH2:25][CH2:24]3)[CH2:21][C:20]3[CH:26]=[CH:27][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[N:4][CH:3]=1
Reactant: COc1ccc(CNC2CC2)cc1
Reactant: CSc1nc(SC)c2ncc(Br)n2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nc(SC)nn3c(Br)cnc23)C2CC2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a 25 mL flask was added a mixture of 7-bromo-2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine (2.0 g, 6.87 mmol), N-(4-methoxybenzyl)cyclopropanamine (1.34 g, 7.56 mmol) in anhydrous THF (20 mL). The reaction solution was cooled to −78° C. and treated drop wise with 1.0 M lithium bis(trimethylsilyl)amide in THF solution (20.61 mL, 20.61 mmol, 3 eq, 1M solution in THF). The reaction was stirred at −78° C. for 1 hour, then allowed to come to room temperature and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride. The product was extracted with ethyl acetate; the organic layer was dried with sodium sulfate and concentrated in vacuo. The crude product mixture was purified via ISCO (0-100% of ethyl acetate/heptane in 10 minutes, 24 g silica column) to give the pure product 7-bromo-N-cyclopropyl-N-(4-methoxybenzyl)-2-(methylthio)imidazo[2,1-f][1,2,4]triazin-4-amine (2.1 g)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:21]([NH:20][CH2:19][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:26])[F:25])=[CH:24][CH:23]=3)=[O:22])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc2c(Cl)nccc12
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c(Cl)nccc12

Procedure:
Prepared from 1-chloroisoquinolin-5-amine (1Description 48) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 380, 382 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([NH:25][C:26]1[C:29]2([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:28](=[O:35])[C:27]=1[Cl:36])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15](=[O:24])[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])[CH2:10][CH2:9]2.ClC1C=NC=C(Cl)C=1C(N1C2C(=CC(CC(NC3C4(CCCCC4)C(=O)C=3)C(O)=O)=CC=2)CC1)=O>>[Cl:36][C:27]1[C:28](=[O:35])[C:29]2([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:26]=1[NH:25][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15](=[O:24])[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])[CH2:10][CH2:9]2)[C:3]([OH:37])=[O:2]
Reactant: COC(=O)C(Cc1ccc2c(c1)CCN2C(=O)c1c(Cl)cccc1Cl)NC1=C(Cl)C(=O)C12CCCCC2
Agent: O=C(O)C(Cc1ccc2c(c1)CCN2C(=O)c1c(Cl)cncc1Cl)NC1=CC(=O)C12CCCCC2
Product: O=C(O)C(Cc1ccc2c(c1)CCN2C(=O)c1c(Cl)cccc1Cl)NC1=C(Cl)C(=O)C12CCCCC2

Procedure:
The title compound was prepared from the compound of Example 12 in a similar manner to the compound of Example 2 as a white lyophilised powder (82%). δH NMR (d6 DMSO), 8.71 (0.8H, J 9.2 Hz), 8.61 (0.2H, d, J 9.5 Hz), 8.05 (0.8H, d, J 8.2 Hz), 7.56 (3H, br m), 7.14 (2H, m), 6.71 (0.2H, d, J 6.9 Hz), 5.51 (0.2H, d, J 8.4 Hz), 4.60 (0.8H, m), 4.49 (0.2H, m), 4.20 (0.4H, m), 3.71 (1.6H, t, J 8.5 Hz), 3.21 (0.8H, m), 3.11 (2H, m), 2.99 (0.8H, dd, J 13.8 and 9.5 Hz), 2.82 (0.2H, dd, J 13.7 and 10.3 Hz) 1.44 (10H, br m); m/z (ES+, 70 eV) 549 (M+H)+.
Reaction SMILES: Br[C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3]1.[N-:33]=[N+]=[N-].[Na+].O>CN(C=O)C.CCO.[Pd]>[NH2:33][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Br)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Pd]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](N)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 72 h
Yield: 94.6 %

Procedure:
To a stirred solution of cis-4-bromo-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy) methylpyrrolidine (480 mg, 0.93 mmol) in DMF (5 ml) was added NaN3 (241 mg, 3.70 mmol) at room temperature. The reaction mixture was stirred at 70 for 3 days. Water was added thereto, and extracted with EtOAc. The extract was washed with water, then dried over Na2SO4, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. The solution of the crude residue in EtOH (10 ml) was hydrogenated over 10% Pd—C under an atmospheric pressure at room temperature for 4 hr. The catalyst was filtered off, and the filtrate was concentrated in vacuo to give trans-4-amino-1tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methylpyrrolidine (400 mg, 95%) as a colorless oil. 1H-NMR (CDCl3) δ 1.06 (s, 9H), 1.32 and 1.45 (each s, total 9H), 2.20–2.35 (m, 1H), 3.05–3.18 (m, 1H), 3.55–4.05 (m, 6H), 7.35–7.41 (m, 6H), 7.61–7.69 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[C:24]([F:34])=[CH:25][C:26]([F:33])=[C:27]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[C:24]([F:34])=[CH:25][C:26]([F:33])=[C:27]([S:29]([NH2:32])(=[O:30])=[O:31])[CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 5-bromo-2,4-difluoro-benzenesulfonamide (68 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (91 mg, 75%). MS (ISP) 485.1 [(M+H)+]; mp 272-275° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[Br-:10].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:10][C:6]1[C:5]([CH3:8])=[CH:4][C:3]([OH:9])=[C:2]([F:1])[CH:7]=1
Reactant: [Br-]
Reactant: Cc1ccc(F)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
2-Fluoro-5-methylphenol (5.0 g, 40 mmol) was dissolved in chloroform (200 mL). Tetrabutylammonium tribromide (19 g, 40 mmol) was added and the reaction stirred at ambient temperature for 30 minutes. The reaction was concentrated and purified over silica gel (20% EtOAc in hexanes) to afford 4-bromo-2-fluoro-5-methylphenol (7.8 g, 38 mmol, 96% yield) as an amber oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[S:34])[CH:29]=[CH:30][CH:31]=1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:33](=[S:34])[NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=2)[CH2:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Reactant: O=C1c2ccccc2CCCC1(CO)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2CCCC1(CO)COC(=S)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 6,6-bis(hydroxymethyl)-6,7,8,9-tetrahydrobenzocyclohepten-5-one (500 mg, 2.27 mmol) in 28 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.35 ml, 2.5 mmol) and 3-(trifluoromethyl)phenyl isothiocyanate (862 μl, 5.68 mmol). The mixture was heated to reflux for 72 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 ethyl acetate/hexane). The product was obtained in a yield of 284 mg (30%).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[NH:9][N:10]=[C:11]([C:12]([OH:14])=O)[C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:36]([C:38]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH3:46])[C:39]=1[NH2:40])[CH3:37].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:36]([C:38]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH3:46])[C:39]=1[NH:40][C:12]([C:11]1[C:7]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:8]=2[NH:9][N:10]=1)=[O:14])[CH3:37]
Reactant: O=C(O)c1n[nH]c2c1CCCCC2=O
Reactant: CCc1cccc(CC)c1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1cccc(CC)c1NC(=O)c1n[nH]c2c1CCCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
A suspension of 8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxylic acid (0.045 g, 0.232 mmol) in anhydrous DMF (2 mL) was treated with HOBt (0.047 g, 0.347 mmol), EDCI (0.065 g, 0.347 mmol), 2,6-diethylaniline (0.253 mL, 0.925 mmol) and DIPEA (0.188 mL, 1.390 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water, extracted with AcOEt (2×20 mL). The organic fractions were combined, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (eluant: AcOEt/hexane 2/8) provided 0.027 g (35% yield) of the title compound.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[F:30][C:31]([F:36])([F:35])[C@H:32]1[CH2:34][O:33]1.C(N(CC)CC)C>C(O)C.CO>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([CH2:34][C@@H:32]([OH:33])[C:31]([F:36])([F:35])[F:30])[CH2:6]4)[C:12]([CH3:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: FC(F)(F)[C@H]1CO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C[C@@H](O)C(F)(F)F)C1
Temperature: 120 °C
Yield: 28.2 %

Procedure:
A mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (20 mg, 0.044 mmol, chiral intermediate from peak 1 of Example 1, Step 7), (2R)-2-(trifluoromethyl)oxirane (9.4 μL, 0.11 mmol), and triethylamine (18 μL, 0.13 mmol) in ethanol (0.3 mL) was heated in a microwave at 120° C. for 25 min. The mixture was diluted with MeOH and purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 6.2 mg (28%) of the desired product. The product was isolated as a single enantiomer. LCMS calculated for C22H27ClF3N6O2(M+H)+: m/z=499.2; Found: 499.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][CH:9]([C:11]1[C:20]2[O:19][CH2:18][CH2:17][O:16][C:15]=2[C:14]([O:21][CH3:22])=[CH:13][CH:12]=1)[OH:10].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][C:9]([C:11]1[C:20]2[O:19][CH2:18][CH2:17][O:16][C:15]=2[C:14]([O:21][CH3:22])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)c2c1OCCO2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
Compound 178a (3.0 g) obtained in Step A was dissolved in acetone (30 ml), mixed with Jones reagent (2.6 M) (4.9 ml), and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was mixed with water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate anhydride, and evaporated under reduced pressure for removing the solvent. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give Compound 178 (3.0 g, 75%) as colorless crystals.
Reaction SMILES: [C:1](#[N:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:4]#[N:5]>ClC1C2C(=CC=CC=2)C=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH:7]1[CH:8]=[CH:9][C:2]2[C:3](=[C:4]3[N:5]=[C:4]4[N:10]=[C:1]([C:2]5[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=54)[N:10]=[C:1]4[NH:5][C:4]([C:3]5[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=54)=[N:10][C:1]4=[N:5][C:4]([C:3]5[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=54)=[N:10][C:1]=2[NH:5]3)[CH:6]=1
Reactant: N#Cc1ccccc1C#N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Clc1cccc2ccccc12
Product: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Temperature: 140 °C

Procedure:
Phthalonitrile (1100 grams) and titanium tetrachloride (813 grams) were suspended in 6800 ml of 1-chloronaphthalene and heated to 215°-220° C. and maintained for 2.5 hours at this temperature. The reaction mixture was cooled to 140° C. and the dark solid was collected, and washed with acetone, and methanol. After drying, the dark blue solid (1090 grams) was refluxed five times for two hours in 10 liters of distilled water, filtered, to yield crude titanyl phthalocyanine. The x-ray diffraction spectrum (FIG. 1) exhibited major peaks of the Bragg angle at 7.5°, 8.3°, 10.5°, 12.7°, 14.2°, 14.6°, 18.9°, 22.1°, 24.3°, 26.1°, 29.9° (all +/-0.2°).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cu](C#N)[C:13]#[N:14].C(OCC)(=O)C.O>CN1CCCC1=O>[F:11][C:4]1[CH:3]=[C:2]([CH:9]=[C:6]([CH:7]=[O:8])[C:5]=1[F:10])[C:13]#[N:14]
Reactant: N#C[Cu]C#N
Reactant: O=Cc1cc(Br)cc(F)c1F
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(F)c(F)c(C=O)c1
Temperature: 170 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of 10.0 g of 5-bromo-2,3-difluorobenzaldehyde in 40.0 mL of 1-methyl-2-pyrrolidone was added 4.26 g of copper cyanide (I) at room temperature and stirred at 170° C. for 8 hours. Adding ethyl acetate and water, the solution was stirred, and insoluble substances were filtered out through celite. The organic layer of filtrate was washed successively with saturated aqueous ammonium chloride, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:20), to afford 2.64 g of the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:21])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][CH:10]=1)[CH3:7])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.CS(O)(=O)=O.[CH3:38][O:39][C:40]1[CH:41]=[C:42]([CH2:46][N:47]([C:49]([NH2:51])=[O:50])[NH2:48])[CH:43]=[CH:44][CH:45]=1>C(OCC)(=O)C.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:48][N:47]([CH2:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([O:39][CH3:38])[CH:41]=2)[C:49]([NH2:51])=[O:50])=[O:20])=[CH:13][CH:14]=1)[CH3:21])=[O:5])[CH3:2]
Reactant: COc1cccc(CN(N)C(N)=O)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)NN(Cc2cccc(OC)c2)C(N)=O)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 64.9 %

Procedure:
4-[4-(1-Ethoxycarbonyl-1-methyl-ethoxy)-phenyl] butyric acid (4.86 g, 16.5 mmol) was dissolved in ethyl acetate (40 mL). Oxalyl chloride (2.43 g, 19.14 mmol) was added to this solution dropwise in the presence of a catalytic amount of N,N-dimethylformamide (100 mg, 1.37 mmol). Completion of acid chloride formation was verified by HPLC. This solution was then added dropwise to a suspension of 1-(3-methoxyphenylmethyl)hydrazine carboxamide methanesulfonate (4.80 g, 16.5 mmol) and pyridine (1.30 g, 16.5 mmol) in ethyl acetate (55 mL) at 0° C. After stirring at 0° C. for 6 h, an additional charge of pyridine was added (1.30 g, 16.5 mmol) and the solution was stirred at 0° C. for 1 h. The solution was warmed to rt and washed with 1N HCl (2×80 mL) and 5% aq. NaHCO3 (2×80 mL). The organic layer was dried (MgSO4), filtered and concentrated to a waxy solid. The solids were recrystallized from a mixture of toluene (17 mL) and heptane (7 mL) at 60° C., cooled to 0° C. and filtered. The solids were dried in vacuo at 40° C. to afford the title compound as a white solid (5.05 g, 65%): mp 91.9-93.4° C.; 1H NMR (DMSO-d6, 60° C.) δ 9.60 (s, 1 H), 7.19 (t, 1 H, J=8 Hz), 7.00 (d, 2 H), 6.80 (m, 3 H), 6.71 (d, 2 H, J=8 Hz), 5.92 (s, 2 H), 4.52 (s, 2 H), 4.15 (q, J=7 Hz), 3.71 (s, 3 H), 2.45 (t, 2 H, J=7 Hz ), 2.07 (t, 2 H, J=7 Hz ), 1.73 (quint, 2 H, J=7 Hz), 1.48 (s, 6 H), 1.17 (t, 3 H,. J=7 Hz); 13C NMR (DMSO-d6) δ 174.0, 171.9, 159.9, 159.3, 153.7, 140.5, 135.9, 129.9, 129.7, 120.9, 119.4, 114.1, 113.1, 79.2, 61.6, 55.5, 50.9, 34.3, 33.4, 27.2, 25.7, 14.6; IR (KBr mull) 3450, 3320, 3275, 3202, 2997, 2940, 1730, 1646, 1511 cm−1; Anal. Calcd. for C25H33N3O6: C, 63.68; H, 7.05; N, 8.91. Found: C, 63.49; H, 7.02; N, 8.99.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH2:19]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[CH2:19]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]2[C:10]3[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:17])[CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC1CCNCC1
Reactant: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCC1CCN(C[C@@H](C)CN2C(=O)COc3ccc(OC)cc32)CC1
Yield: 40.9 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF36) (0.636 g, 1.77 mmol) and 4-butylpiperidine (0.226 g, 1.6 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) and prep HPLC gave the title compound (111MF38) (0.245 g, 27%). 1H NMR (CDCl3) δ 6.89 (d, J=8.8 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.50 (dd, J=2.8, J=8.8 Hz, 1H), 4.54 (q, J=32.4, J=14.8, 2H), 3.94-3.90 (m, 2H), 3.77 (s, 3H), 2.90 (d, J=11.2 Hz, 1H), 2.72 (d, J=10.8 Hz, 1H), 2.25-2.10 (m, 3H), 1.93 (t, J=11.2 Hz, 1H), 1.80 (t, J=11.2 Hz, 1H), 1.61 (d, J=10.8 Hz, 2H), 1.31-1.19 (m, 9H), 0.90-0.86 (m, 6H); 13C NMR (CDCl3) δ 165.3, 155.5, 139.7, 129.8, 117.2, 107.1, 103.3, 68.0, 64.2, 55.9, 55.7, 54.5, 45.5, 36.5, 36.0, 32.9, 32.5, 29.2, 29.2, 23.1, 16.9, 14.3.
Reaction SMILES: [CH2:1]([C:8]([N:20]([CH3:22])[CH3:21])([CH2:18][CH3:19])[C:9]([C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([CH2:25][NH2:26])[OH:24].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.O>[CH2:1]([C:8]([N:20]([CH3:22])[CH3:21])([CH2:18][CH3:19])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:26][CH2:25][CH2:23][OH:24])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(F)cc1)N(C)C
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(NCCO)cc1)N(C)C
Temperature: 140 °C
Reaction time: 16 h

Procedure:
44.9 g (0.15 mol) 2-Benzyl-1-(4-fluorophenyl)-2-dimethylamino-1-butanone and 61.08 g (1.05 mol) ethanolamine are dissolved in 400 ml dimethylacetamide. 41.5 (0.3 mol) Potassium carbonate are added and the suspension is heated to 140° C. while stirring. The reaction mixture is kept at this temperature during 16 hours, cooled to room temperature and diluted with water. The aqueous phase is several times extracted with ethyl acetate, the combined organic extracts washed with water and dried over magnesium sulfate. Evaporation of the solvent gives the crude product as a yellowish-brown oil. The product is purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate 2:1→1:1). The fractions containing the product are collected to give a slightly yellowish solid product. Recrystallisation from ethyl acetate/hexane gave 2-benzyl-1-[4-(2-hydroxyethylamino)phenyl]-2-dimethylamino-1-butanone as slightly yellowish crystals melting at 109-111° C. Yield: 34.7 g (68%). 1H-NMR data are in agreement with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.[Li+].[CH3:17][CH:18]([N-]C(C)C)C.C(I)C>C1COCC1>[CH2:17]([CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=1)[C:11]([OH:13])=[O:12])[CH3:18]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(Cc1cccc(C(F)(F)F)c1)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1 eq. of 3-(3-trifluoromethylphenyl)propionic acid was converted, in THF and at -78° C., into the dianion using 2 eq. of LDA (stirring for 30 min. at -78° C., then 30 min. at RT). 2 eq. of ethyl iodide were then added at -78° C. and the mixture was subsequently stirred at RT. Acidic working-up using 2N HCl and purification by chromatography yielded 2-ethyl-3-(3-trifluoromethylphenyl)-propionic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][N:3]=1.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>C(OCC)(=O)C.O>[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=3)=[CH:4][N:3]=2)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(-c2ccc(OCc3ccccc3)cc2)nc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
Palladium chloride (dppf) methylene chloride complex (0.193 g) was added to a mixture of 2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (1.0 g), (4-benzyloxyphenyl)boronic acid (1.08 g), 2M aqueous sodium carbonate solution (4.74 mL) and N,N-dimethylformamide (18.9 mL) under nitrogen atmosphere, and the mixture was stirred at 65° C. under nitrogen atmosphere overnight. To the mixture were added water and ethyl acetate, and then, insoluble material was removed by filtration using Celite. The organic layer was separated, washed with saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=88:12 to 80:20) to obtain 2-[4-(benzyloxy)phenyl]-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (1.038 g).