Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]([N:30]3[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]3)=[O:19])[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cccc(C(=O)O)n2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cccc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1OC

Procedure:
Using 6-(3,4-dimethoxyphenyl)pyridine-2-carboxylic acid and t-butoxycarbonylpiperazine, 1-{[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(t-butoxycarbonyl) piperazine was obtained in a similar manner to Example 2 to be mentioned below. Further, a 4M hydrogen chloride/ethyl acetate solution was added thereto and the whole was reacted to obtain an objective compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([N:12]([OH:14])[CH3:13])=[NH:11].[C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])#[C:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[CH2:30]([O:29][C:27]([C:20]1([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:14][N:12]([CH3:13])[C:10]([C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=2[N:3]2[CH2:4][CH2:5][CH2:6][CH2:7][S:2]2(=[O:1])=[O:19])=[N:11]1)=[O:28])[CH3:31]
Reactant: CN(O)C(=N)c1ccccc1N1CCCCS1(=O)=O
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CC1(C(=O)OCC)N=C(c2ccccc2N2CCCCS2(=O)=O)N(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a stirred solution of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-N-hydroxy-N-methyl-benzamidine (3.5 g) in ethanol (100 mL, 200 proof) was added diethyl acetylene-dicarboxylate (3.2 mL, 20 mmol) and the resulting mixture stirred at room temperature for 30 min. The mixture was concentrated and purified on a silica gel column (10%–30% ethyl acetate/hexanes) to afford the title compound as a yellow oil (3.62 g, 40% yield). 1HNMR (300 MHz, CDCl3) δ: 7.57 (2H, td, J=7.14, 1.28 Hz,), 7.50 (1H, td, J=7.68, 1.83 Hz), 7.39 (1H, td, J=7.50, 1.46 Hz), 4.34–4.22 (2H, m), 4.18 (2H, q, J=7.08 Hz), 3.42 (1H, d, J=16.47 Hz), 3.22–3.18 (2H, m), 3.07 (3H, s), 3.05 (1H, d, J=16.46 Hz), 2.38–2.24 (2H, m), 2.00–1.42 (2H, m), 1.33 (3H, t, J=7.14 Hz), 1.26 (3H, t, J=7.14 Hz). HRMS calcd for C20H28SN3O7 (M+H): 454.1648; found: 454.1650.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([NH2:16])[CH:13]=[C:12](Cl)[N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2nc(N)cc(Cl)n2)CC1
Solvent: CCO
Product: CC(=O)N1CCN(c2nccc(N)n2)CC1
Reaction time: 2.5 h

Procedure:
2-(4-acetylpiperazin-1-yl)-6-chloropyrimidin-4-amine 4-3 (0.90 g, 3.52 mmol) was dissolved in 95% ethanol and then evacuated and back flushed with nitrogen before introducing 10% Pd/C (0.50 g). A hydrogen atmosphere was introduced and this suspension was stirred for 2.5 hours. The catalyst was then filtered off and the filtrate was evaporated to a solid. The solid was purified on a silica column (DCM:MeOH:NH4OH 95:5:0.5) and the product 4-4 was isolated upon evaporation. 1H-NMR(DMSO): 7.75 ppm (d, 1H); 6.44 ppm (s, 2H); 5.74 ppm (d, 1H); 3.66 ppm (m, 2H); 3.59 ppm (m, 2H); 3.45 ppm (m, 4H); 2.03 ppm (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2[N+](=O)[O-])C1
Yield: 98 %

Procedure:
To a 20 mL microwave vial containing 4-chloro-3-nitropyridine (Aldrich, 1.350 g, 8.515 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 1.922 g, 9.597 mmol), 1-butanol (13.0 mL) was added, followed by DIPEA (2.213 g, 17.12 mmol). The reaction mixture was irradiated with microwaves at 130° C. for 1 h. The reaction mixture was then allowed to cool and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a yellow solid (2.69 g, 98%). LCMS calc. for C15H23N4O4 (M+H)+: m/z=323.2. found 323.2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][CH:4]=1.Cl.[CH3:10][O:11][C:12](=N)[NH:13][N+:14]([O-:16])=[O:15].[OH-].[Na+]>O.C(Cl)(Cl)Cl>[CH3:10][O:11][C:12](=[N:13][N+:14]([O-:16])=[O:15])[NH:1][CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][CH:4]=1
Reactant: COC(=N)N[N+](=O)[O-]
Reactant: NCc1cnc(Cl)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
5-(Aminomethyl)-2-chlorothiazole (7.43 g, 50.0 mmol) was dissolved in water (96 ml), and concentrated hydrochloric acid (4.22 ml, 50.0 mmol) was added. To this reaction mixture was added O-methyl-N-nitroisourea (6.25 g, 52.5 mmol) and chloroform (30 ml), and adjusted to pH 6.7 with aqueous sodium hydroxide solution (0.5 N) using pH meter. After 24 hours of stirring at room temperature, maintaining pH 6.7, the organic phase was separated from the water phase. The water phase was extracted with chloroform (100 ml), and the combined organic phase was concentrated under reduced. Water (50 ml) was added to the residue to stir for a while. The resulting crystals were collected by filtration under reduced pressure, and washed with water. The washed crystals were dried under reduced pressure (80° C., 2 hours) to provide 7.80 g (62.2% yield) of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([Si:27]([CH3:39])([CH3:38])[O:28][C@H:29]1[C@H:33]2[O:34][CH2:35][C@@H:36]([OH:37])[C@H:32]2[O:31][CH2:30]1)([CH3:26])([CH3:25])[CH3:24]>ClCCl>[Si:27]([O:28][C@H:29]1[C@H:33]2[O:34][CH2:35][C:36](=[O:37])[C@H:32]2[O:31][CH2:30]1)([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2C(=O)CO[C@@H]21
Temperature: 32.5 °C
Reaction time: 20 h
Yield: 90.7 %

Procedure:
Dess-Martin periodinane (31.18 g, 73.5 mmol) was added to a stirred solution of alcohol (86) (9.56 g, 36.8 mmol) in dichloromethane (110 mL) under an atmosphere of argon. The mixture was stirred at 30-35° C. for 5 hours, at ambient temperature for 16 hours, at 30-35° C. for 8 hours and at ambient temperature for 20 hours before adding Isolute® HM-N then removing the solvents in vacuo. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 5:95 to 40:60 gave ketone (87) as a pale yellow oil (8.62 g, 91%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]([S:15][C:16]1[CH:17]=[C:18]([CH2:22][OH:23])[CH:19]=[CH:20][CH:21]=1)([F:14])[F:13].C(N(CC)CC)C>ClCCl.O>[F:11][C:12]([S:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH:22]=[O:23])([F:14])[F:13]
Reactant: OCc1cccc(SC(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cccc(SC(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 90.5 %

Procedure:
Add a solution of dimethyl sulfoxide (0.82 mL, 11.5 mmol) in dichloromethane (2 mL) over a period of 5 minutes to a solution of oxalyl chloride (0.46 mL, 5.28 mmol) in dichloromethane (10 mL) cooled to −78° C. Stir 10 minutes then add a solution of (3-trifluoromethylsulfanyl-phenyl)-methanol (1.00 g, 4.80 mmol) in dichloromethane (4 mL). Stir 15 minutes then add triethylamine (3.35 mL, 24.0 mmol). Slowly warm to ambient temperature, add water and separate the organic layer. Extract the aqueous layer with dichloromethane. Dry (sodium sulfate) the combined organic layers, filter, and concentrate in vacuo. Purify by silica gel chromatography (10% ethyl acetate/hexane) to afford the titled compound as a yellow liquid (896 mg, 91%). 1H NMR (400 MHz, DMSO) δ 7.74 (dd, J=7.6, 7.6, 1H), 8.01 (d, J=7.9, 1H), 8.09 (d, J=7.5, 1H), 8.12 (s, 1H), 10.03 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[CH3:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[S:28])[NH2:27])[N:25]=1>C(#N)C.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:27]=[C:26]([C:24]3[N:25]=[C:21]([CH3:20])[S:22][CH:23]=3)[S:28][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: Cc1nc(C(N)=S)cs1
Solvent: CC#N
Solvent: CCO
Product: CSc1ccc(-c2sc(-c3csc(C)n3)nc2-c2ccc(F)cc2)cc1
Yield: 48.7 %

Procedure:
A solution of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-bromoethanone (9.69 g, 28.6 mmol) (Example 1, Step 3) and 2-methylthiazole-4-thiocarboxamide (3.90 g, 24.7 mmol) in 35 mL of acetonitrile and 20 mL of ethanol was heated to reflux for 1 hour. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a yellow solid. The crude solid was purified by flash chromatography over silica gel eluting with 1:1 hexane:ethyl acetate. The appropriate fractions were combined and the solvent removed in vacuo to provide pure 4-(4-fluorophenyl)-5-(4-methylthiophenyl)-2-[2-(methyl)-4-thiazolyl]thiazole (4.79 g; 49%): mp 132.5°-135° C. 1H NMR (CDCl3) 300 MHz 7.89 (s, 1H), 7.55 (m, 2H), 7.25 (d, J=8.5Hz, 2H), 7.17 (d, J=8.5Hz, 2H), 7.01 (t, J=8.8Hz, 2H), 2.78 (s, 3H), 2.49 (s, 3H). 19F NMR (CDCl3) -113.80 (m). Mass spectrum M+H+ =399.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.IC1C=C(O)C=CC=1>>[OH:33][C:29]1[CH:28]=[C:27]([C:24]2[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:26][CH:25]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2cccc(O)c2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: Oc1cccc(I)c1
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2cccc(O)c2)o1
Yield: 41 %

Procedure:
3-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)phenol. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (99 mg, 0.149 mmol) and 3-iodophenol following General Procedure A. Flash chromatography (10-30% EtOAc/hexanes) yielded the title compound as a clear oil (29 mg, 41%): 1H NMR (CDCl3, 500 MHz) δ 7.79-7.77 (m, 1H), 7.62 (s, 1H), 7.56 (br s, 1H), 7.39-7.35 (m, 2H), 7.29-7.24 (m, 4 H), 7.09-7.04 (m, 2H), 4.95 (t, 1H, J=6.0 Hz), 2.65 (t, 2H, J=7.5 Hz), 2.05-1.95 (m, 2H), 1.67-1.64 (m, 2H), 1.47-1.34 (m, 6H), 0.97 (s, 9H), 0.17 (s, 3H), 0.07 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 164.3, 153.1, 148.8, 143.2, 129.7, 128.8, 128.6, 126.5, 126.0, 124.8, 121.0, 116.8, 115.6, 69.0, 37.0, 36.3, 31.8, 30.1, 26.2, 26.2, 25.5, 18.6, −4.5, −4.7.
Reaction SMILES: C1COCC1.C([O:13][C:14]1[CH:47]=[CH:46][C:17]([C:18]([O:20][CH2:21][N:22]2[C:31]3[C:26](=[C:27]([F:36])[CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][CH3:35])[C:25](=[O:37])[C:24]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)=[CH:23]2)=[O:19])=[CH:16][CH:15]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][N:22]2[C:31]3[C:26](=[C:27]([F:36])[CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][CH3:35])[C:25](=[O:37])[C:24]([C:38]3[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=3)=[CH:23]2)=[O:19])=[CH:46][CH:47]=1
Reactant: [H][H]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(COC(=O)c3ccc(OCc4ccccc4)cc3)c12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(COC(=O)c3ccc(O)cc3)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
10% palladium/carbon (260 mg) was added to a THF (30 ml) and ethanol (15 ml) solution of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-benzyloxybenzoate (2.6 g, 4.6 mmol). The mixture was subjected to hydrogen substitution and stirred at room temperature for 3 hours. After completion of the reaction, the catalyst was removed by conducting filtration using Celite, and the mixture was concentrated to dryness under reduced pressure, giving a pale yellow powder of 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl 4-hydroxybenzoate (2.22 g, yield: quantitative).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:19]([O-])=O)=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:12]=2)[CH:6]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:8]=[CH:9][C:10]([NH2:19])=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:12]=2)[CH:6]=1
Reactant: Cc1cnn(-c2ccc([N+](=O)[O-])c(N3CCCCC3)c2)c1
Solvent: C1CCOC1
Product: Cc1cnn(-c2ccc(N)c(N3CCCCC3)c2)c1
Yield: 95 %

Procedure:
1-[5-(4-Methyl-pyrazol-1-yl)-2-nitro-phenyl]-piperidine (110 mg, 0.38 mmol, as prepared in the previous step) was allowed to react with TiCl3 (2.3 mL, 3.8 mmol) in 3 mL of THF. The reaction was quenched with satd aq NaHCO3 (15 mL) and poured into 25 mL of EtOAc. The organic layer was separated, washed with water (2×25 mL), dried (Na2SO4), and concentrated in vacuo to afford 94 mg (95%) of 4-(4-methyl-pyrazol-1-yl)-2-piperidin-1-yl-phenylamine, which was allowed to react in a similar manner to Example 4, step (c), with 5-cyano-furan-2-carbonyl chloride (84 mg, 0.54 mmol) in the presence of DIEA (137 μL, 0.79 mmol) to afford 52.7 mg (47%) of the title compound as a light yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 9.65 (s, 1H), 8.50 (d, 1H, J=8.8 Hz), 7.92 (s, 1H), 7.71 (s, 1H), 7.37 (dd, 1H, J=2.5, 8.8 Hz), 7.29 (d, 1H, J=3.8 Hz), 7.23 (d, 1H, J=3.7 Hz), 6.46-6.45 (m, 1H), 2.94-2.89 (m, 4H), 2.14 (s, 3H), 1.85-1.80 (m, 4H), 1.66 (br s, 2H); Mass spectrum (ESI, m/z): Calcd. for C21H21N5O2, 376.1 (M+H), found 376.1.
Reaction SMILES: [O:1]=[C:2]([CH3:35])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[O:19]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].Cl.BrCCCN(C)C.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[O:1]=[C:2]([CH3:35])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([CH:18]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)[O:19]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Agent: CN(C)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CCCOc1c(O)cc(C2CCC(c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O

Procedure:
A mixture of 300 mg of trans 2-[3-(2-oxo-propylsulfonyl)-4-n-propoxy-5- hydroxyphenyl]5-(3,4,5-trimethoxyphenyl)tetrahydrofuran, 6 mL acetone, 150 mg 3-bromopropyl- N,N-dimethylamine hydrochloride, and 150 mg K2CO3 was heated at 50° for 16 hrs and filtered. Evaporation of the filtrate and purification by prep. TLC on silica plates (ethyl acetate) gave the title compound as a colorless gum: NMR (200 MHz, CDCl3) δ 1.06 (t, CH2CH2CH3), 1.88 (m, CH2CH2CH3), 2.39 (s, CH3C(O)CH2), 2.30 (s, N(CH3)2), 2.40-2.58 (m, CH2N(CH)2)2, 3.85 (s, OCH3), 3.88 (s, 2 OCH3), 4.12 & 4.15 (t, 2 ArOCH2), 4.46 (s, CH3C(O)CH2), 5.10-5.30 (m, 2-CH & 5 -CH), 6.62 (s, 5-ArH), 7.30 & 7.44 (2 d, 2-ArH).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[N:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=[C:15]2[CH2:14]1)=[O:12])=O)(C)(C)C.[ClH:36]>CO>[ClH:36].[NH2:8][C@H:9]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[N:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=[C:15]2[CH2:14]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2nc(C(F)(F)F)nc2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2nc(C(F)(F)F)nc2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 7-[(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl) butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine (63.1 mg, 0.12 mmol, from Step E) was added 3 mL of methanol saturated with hydrogen chloride at 0° C. The reaction was stirred at ambient temperature for 45 min. Concentration gave the title compound as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2)(=O)=O.[CH:19]([O:21]CCCC)=[CH2:20].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2)(=[O:21])[CH3:20]
Reactant: O=S(=O)(Oc1cccc2ncccc12)C(F)(F)F
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cccc2ncccc12
Reaction time: 0.5 h

Procedure:
A degassed solution of 5-trifluoromethanesulphonyloxyquinoline (0.41 g, 1.47 mmol), butyl vinyl ether (0.38 mL, 2.94 mmol), palladium acetate (10 mg, 0.043 mmol), potassium carbonate (0.24 g, 1.76 mmol), 1,3-bis(diphenylphosphino)propane (40 mg, 0.097 mmol) in DMF (3.67 mL) and water (0.88 mL) was heated in a sealed tube at 100° C. for 16 hours. The reaction mixture was then cooled and treated with 1M HCl and the mixture stirred for 30 minutes, then basified and extracted with dichloromethane. The organic layer was then evaporated under reduced pressure to afford the title compound.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)(=O)=O.C([Li])CCC.[CH:40]1([CH2:43][OH:44])[CH2:42][CH2:41]1>>[CH:40]1([CH2:43][O:44][C:5]2[N:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)[C:8]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:7]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[N:6]=2)[CH2:42][CH2:41]1
Reactant: OCC1CC1
Reactant: CS(=O)(=O)c1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Li]CCCC
Product: Fc1ccc(Oc2nc(OCC3CC3)nc(-c3ccc(Cl)cc3Cl)c2-c2ccc(Cl)cc2)cc1F

Procedure:
2-Methylsulfonyl-4-(3,4-difluorophenoxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 20 (65 mg, 0.12 mmol) was reacted with 2 equivalents each of n-butyl lithium and cyclopropylmethanol by the procedure described in Reference Example 6 and 7 to afford the title compound: HPLC/MS: m/e=533 (M++1); Rt=5.12 min. 1H-NMR 400 MHz (CDCl3): 0.56-0.61 (m, 2H), 1.23-1.30 (m, 2H), 1.57 (s, 1H), 4.01 (d, J=7 Hz, 2H), 6.90-6.94 (m, 1H), 7.04-7.10 (m, 1H), 7.12-7.28 (m, 7H), 7.35 (d, J=2 Hz, 1H).
Reaction SMILES: [N+](=C[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:5])=[N-].C.C[OH:20]>C([O-])(=O)C1C=CC=CC=1.[Ag+]>[C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[C:4]([OH:5])=[O:20])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C=[N+]=[N-]
Agent: [Ag+]
Agent: O=C([O-])c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O

Procedure:
tert-Butyl (2S)-2-(diazoacetyl)-1-pyrrolidinecarboxylate (16 g, 46 mmol) was dissolved in 50 mL anhydrous methanol. Silver benzoate (0.1 mL of a 1 g solution in 12 mL TEA) was added. After 14 at room temperature, Norit was added and the mixture was concentrated in vacuo. Purifcation on SiO2 (hexanes:EtOAc 6:1 then 4:1) provided the methyl ester as a clear oil (8.35 g, 34.3 mmol, 69% from Boc-proline): 1H NMR (400 MHz, CDCl3) δ 4.12 (bs, 1H), 3.65 (s, 3H), 3.34 (m, 2H), 2.85 (m, 1H), 2.29 (dd, J=9.6, 15.2 Hz, 1H), 2.1 (m, 1H), 1.8–1.6 (m, 3H), 1.44 (s, 9H) ppm. ESMS m/z 244 (MH)+, 144 (MH−C5H8O2)+.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].[Li]CCCC.[CH3:13][O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.ICC#N.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:13][O:14][C:15](=[O:24])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH2:2][C:1]#[N:4]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)Cc1ccc(Cl)cc1
Agent: N#CCI
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C(CC#N)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a stirred solution of diisopropylamine (8.65 ml, 61.8 mmol) in dry THF (100 ml) at −20° C. under nitrogen was added a 2.5M solution of nBuLi in hexanes (23.7 ml, 59.2 mmol) dropwise. The solution was allowed to warm to 0° C. over 20 min, and then cooled to −70° C. A solution of methyl-2-(4-chlorophenyl)acetate (9.5 g, 51.5 mmol) in THF (5 ml) was added dropwise over 5 min, and the whole then stirred for 30 min. Iodoacetonitrile (5.03 ml, 69.5 mmol) was then added slowly, and the combined solution allowed to warm to room temperature over 72 h. Saturated aq. NaHCO3 solution (20 ml) was added, the mixture was concentrated to about 50 ml under vacuum, and then treated with 1N HCl (100 ml). The mixture was extracted with EtOAc (120 ml) which was dried (MgSO4) and evaporated to give a dark brown oil, which was purified by column chromatography using 2:1 DCM:pentane as eluant to give the title product (8.6 g, 75%); 1HNMR (400 MHz, CDCl3) δ: 2.80 (dd, 1H), 3.00 (d, 1H), 3.73 (s, 3H), 3.92 (dd, 1H), 7.22 (d, 2H), 7.37 (d, 2H).