Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[CH2:10][OH:11])[C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[S:5]2.[H-].[Na+].[C:18]1(C(Cl)=O)[S:22][CH:21]=[CH:20][CH:19]=1.CN(C)[CH:28]=[O:29]>>[CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[CH2:10][O:11][C:28](=[O:29])[C:20]1[CH:19]=[CH:18][S:22][CH:21]=1)[C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[S:5]2
Reactant: CN(C)C=O
Reactant: Cc1nc2sc3ccccc3n2c1CO
Reactant: O=C(Cl)c1cccs1
Agent: [H-]
Agent: [Na+]
Product: Cc1nc2sc3ccccc3n2c1COC(=O)c1ccsc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 30 ml of dry dimethylformamide was suspended 2.18 g of 2-methylimidazo[2,1-b]benzothiazole-3-methanol. Then, 0.50 g of 60% sodium hydride was added to the suspension. After stirring for 30 minutes, 1.76 g of thenoyl chloride was added to the mixture followed by stirring at room temperature for 3 hours. Ice water was added to the reaction mixture and the system extracted with chloroform. After the chloroform was removed, 1.76 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23]([C:25]2[C:26](=[O:38])[N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]([CH3:31])[C:29]=2[CH3:30])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:45][C:46]1([O:49][CH2:48]1)[CH3:47]>CN(C=O)C.CC(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23]([C:25]2[C:26](=[O:38])[N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]([CH3:31])[C:29]=2[CH3:30])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:45][C:46]([OH:49])([CH3:48])[CH3:47])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: CC1(C)CO1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3F)ccnc2cc1OCC(C)(C)O
Temperature: 50 °C
Reaction time: 72 h
Yield: 39.9 %

Procedure:
To a mixture of N-(3-fluoro-4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carb oxamide (5.00 g, 9.73 mmol) and Cs2CO3 (1.35 g, 4.14 mmol) in DMF/t-BuOH (15.60 mL/3.90 mL) was added isobutylene oxide (8.60 mL, 97.30 mmol). The reaction was warmed to 50° C. and stirred for three days. The reaction mixture was concentrated in vacuo and purified by a silica gel column chromatography (1:25 (v/v)=methanol/dichloromethane) to give the title compound as a white solid (2.28 g, 40%).
Reaction SMILES: [CH:1]([C@H:4]1[N:9]([C:10]2[N:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]([F:21])([F:20])[F:19])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:22]3[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[C:26]([C:33](OC)=[O:34])=[CH:25][C:23]=3[N:24]=[C:5]12)([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.[NH4+].[Cl-]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH:1]([C@H:4]1[N:9]([C:10]2[N:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]([F:21])([F:19])[F:20])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:22]3[CH:28]=[C:27]([S:29]([CH3:32])(=[O:30])=[O:31])[C:26]([CH2:33][OH:34])=[CH:25][C:23]=3[N:24]=[C:5]12)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(F)(F)F)c(OC)n1)[C@@H]3C(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc(N2CCn3c(nc4cc(CO)c(S(C)(=O)=O)cc43)[C@H]2C(C)C)ncc1C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a solution of (R)-methyl 1-isopropyl-2-(4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (15 mg, 0.028 mmol) in CH2Cl2 (2 mL) was added DIBAL H (1M in toluene, 0.1 mL, 0.1 mmol) at −78° C. The mixture was stirred at −78° C. for 2 h and warmed to rt for 6 h. Sat. NH4Cl solution (1 mL) was added and the mixture was filtered. The filtrate was concentrated under vacuum. Water (5 mL) and EtOAc (5 mL) were added to the mixture. The aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-(1-isopropyl-2-(4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methanol (3.50 mg, 24.6% yield) as a white solid. Analytical chiral HPLC: tR=6.598 min in 15 min chromatography, 94.60% ee (Method: OD-H_3_5_40_2.35 ML). LC-MS MS (ESI) m/z 500.1 [M+H]+. 1H NMR (CDCl3 300 MHz): δ 8.31 (s, 1H), 8.12 (s, 1H), 7.86 (s, 1H), 6.02-5.98 (m, 1H), 5.43-5.38 (m, 1H), 5.04-4.98 (m, 2H), 4.32-4.28 (m, 1H), 4.16 (dt, J=5.1 and 12.0 Hz, 1H), 4.01 (s, 3H), 3.77-3.68 (m, 1H), 3.21 (s, 3H), 3.11-3.06 (m, 1H), 2.50-2.47 (m, 1H), 1.30 (d, J=6.6 Hz, 3H), 1.07 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:16][C:15]([CH3:18])([CH3:17])[C:14]3[N:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]([CH:22]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([O:25]C)=[O:24])=[C:10]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[C:9]=3[CH2:8]2)[CH:2]=1.O.[OH-].[Li+].[OH-].[Na+]>>[C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:16][C:15]([CH3:18])([CH3:17])[C:14]3[N:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]([CH:22]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])[C:23]([OH:25])=[O:24])=[C:10]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[C:9]=3[CH2:8]2)[CH:2]=1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CN(c1cccc(-c3ccccc3)c1)CC2(C)C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(c1cccc(-c3ccccc3)c1)CC2(C)C
Temperature: 70 °C
Reaction time: 16 h
Yield: 42.5 %

Procedure:
A mixture of methyl 2-(6-([1,1′-biphenyl]-3-yl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-(tert-butoxy)acetate (intermediate 8) (10 mg, 0.017 mmol), lithium hydroxide monohydrate (2.12 mg, 0.05 mmol) and 1N NaOH (0.17 mL) were stirred at 70° C. for 16 h. The mixture was then filtered and purified by preparative HPLC (10% CH3CN/90% H2O/0.1% CF3CO2H, Xterra 19×100 mm, C18, 5 μm column) to give 2-(6-([1,1′-biphenyl]-3-yl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-(tert-butoxy)acetic acid (4.2 mg, 41% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 7.62-7.47 (m, 3H), 7.46-7.38 (m, 3H), 7.38-7.29 (m, 3H), 7.26 (t, J=7.9 Hz, 1H), 7.02 (d, J=7.3 Hz, 1H), 6.96 (s, 1H), 6.77 (dd, J=8.2, 1.5Hz, 1H), 4.92 (d, br. s., 1H), 4.07 (d, J=15.6 Hz, 1H), 3.71 (d, J=15.6 Hz, 1H), 3.63 (dt, J=12.8, 6.4 Hz, 1H), 3.49 (d, J=12.5Hz, 1H), 3.37 (br. s., 1H), 1.48 (d, J=3.7 Hz, 6H), 1.32 (d, J=6.4 Hz, 3H), 1.20 (d, J=6.7 Hz, 3H), 1.01 (s, 9H). 19F NMR (500 MHz, CD3OD) δ ppm −115.74. LCMS (M+H) calcd for C37H42FN2O3: 581.3. found: 581.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[CH2:16])[CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.S(Cl)([Cl:20])=O>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([C:7]([Cl:20])=[O:8])[CH:10]=[C:11]([O:13][CH2:14][CH:15]=[CH2:16])[CH:12]=1
Reactant: C=CCOc1cc(C(=O)O)cc(C(=O)OC)c1
Reactant: O=S(Cl)Cl
Product: C=CCOc1cc(C(=O)Cl)cc(C(=O)OC)c1

Procedure:
A solution of 2.17 g (9.18 mmol) of 5-allyloxy-isophthalic acid monomethyl ester in 9.2 ml of thionyl chloride is heated to reflux for 1 h. Excess thionyl chloride is removed under reduced pressure to yield 3-allyloxy-5-chlorocarbonyl-benzoic acid methyl ester in the form of a color-less oil, which is used without further purification. To a solution of 2.36 g (9.18 mmol) of 3-allyloxy-5-chlorocarbonyl-benzoic acid methyl ester in 9 ml of DCM 27.6 ml of a 1 M solution of dimethylamine in THF (3 eq.) are added at 0° C. The mixture is stirred at rt for 2 h. 100 ml of a half-saturated aq ammonium chloride solution are added. The mixture is extracted with TBME (2×75 ml), and the combined organic layers are washed with 50 ml of water, dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel (EtOAc) to give the product as a colorless oil.
Reaction SMILES: CC1C(=O)CC(N2CC3C(=CC=CC=3)N(CCNC3N=CN=C4C=3N=CN4COCC[Si](C)(C)C)C2)=C(C=1)[C:7]#[N:8].O[C:42]1[CH:43]=[C:44]([N:48]2[C:57](=[O:58])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][C:55]=3[CH3:59])[N:50]=[C:49]2[CH:60]([NH:62][C:63]2[N:71]=[CH:70][N:69]=[C:68]3[C:64]=2[N:65]=[CH:66][NH:67]3)[CH3:61])[CH:45]=[CH:46][CH:47]=1>>[CH3:59][C:55]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:56]=1[C:57](=[O:58])[N:48]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:42][C:43]=1[C:7]#[N:8])[C:49]([CH:60]([NH:62][C:63]1[N:71]=[CH:70][N:69]=[C:68]3[C:64]=1[N:65]=[CH:66][NH:67]3)[CH3:61])=[N:50]2
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(O)c3)c(=O)c12
Reactant: CC1=CC(C#N)=C(N2Cc3ccccc3N(CCNc3ncnc4c3ncn4COCC[Si](C)(C)C)C2)CC1=O
Product: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3C#N)c(=O)c12

Procedure:
Compound 141 was treated with 4N HCL in NeOH for 1 hour using the procedure described for compound 121 (step B) to provide compound 140. m/z=423 (M+H). The structure of compound 140 is shown below.
Reaction SMILES: C([Mg:4][Br:5])(C)C.Br[C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17].[CH2:18]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>>[F:13][C:12]1[C:7]([Mg:4][Br:5])=[C:8]([F:17])[C:9]([F:16])=[C:10]([F:15])[C:11]=1[F:14].[CH2:18]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]
Reactant: CC(C)[Mg]Br
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Solvent: CCCCOCCCC
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Temperature: 35 °C
Reaction time: 2 h

Procedure:
Air inside a reaction vessel of the same type as the one used in Example 1 was replaced with a nitrogen gas in a satisfactory manner, after which 90 ml of a dibutyl ether (chain ether solvent) solution containing 0.188 mol of isopropyl magnesium bromide as the hydrocarbon magnesium halide (2) was charged to the reaction vessel. Meanwhile, 0.182 mol of bromopentafluorobenzene and 50 ml of dibutyl ether (chain ether solvent) were charged to the dropping funnel. Then, the dibutyl ether solution of bromopentafluorobenzene in the dropping funnel was dropped to the reaction vessel over 2 hours at room temperature, and the reaction solution was stirred for 2 hours at 35° C. Consequently, pentafluorophenyl magnesium bromide was obtained in the form of a light-yellow dibutyl ether solution. The yield of pentafluorophenyl magnesium bromide measured in the same manner as Example 1 was 97.5 mol % based on bromopentafluorobenzene.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH3:10].[C:17]([CH2:19][C@@H:20]([OH:27])[CH2:21][C:22](OCC)=[O:23])#[N:18].Cl>O1CCCC1>[C:17]([CH2:19][C@@H:20]([OH:27])[CH2:21][C:22](=[O:23])[CH2:10][C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C[C@H](O)CC#N
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CC#N
Reaction time: 0.83 h

Procedure:
To a stirred -50° C. solution of lithium diisopropylamide (100 kg of 2 M) in tetrahydrofuranheptane is added tertiary-butyl acetate (30 kg, 255 mol) followed by a rinse of 3 kg of tetrahydrofuran and the mixture is stirred at -45° C. to -5° C. for 50 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (10 kg, 64 mol) as a solution in 30 kg of tetrahydrofuran is then added to the previous mixture. The reaction mixture is stirred for 30 minutes at -5° C. to -30° C., and transferred to 240 L of 0° C. 2.8 N aqueous hydrochloric acid solution. The aqueous layer is extracted with 50 kg of ethyl acetate, the aqueous layer is separated and reextracted with 36 kg of ethyl acetate, the extracts are combined and concentrated in vacuo to afford crude (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo -hexanoate which is not isolated. A small sample is purified by column chromatography on flash silica gel eluting with 1:1 hexane:ethyl acetate. 1H--NMR: (CDCl3) 1.48 (9H, s), 2.61 (2H, m), 2.88 (2H, d), 3.43 (2H, s), 3.58 (1H, bs), 4.40 (1H, m). MS:(EI) m/e, (%): 229 (3), 228(26),173(10), 172(100), 154(62), 112(30), 59(50), 57(77).
Reaction SMILES: O=[C:2]1[CH:20]=[C:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[C:13]=3[CH2:14][CH2:15][N:6]2[C:5](=[O:21])[CH2:4][NH:3]1.O=P(Cl)(Cl)Cl.[CH:27]1([C:30]2[N:31]=[CH:32][NH:33][CH:34]=2)[CH2:29][CH2:28]1>ClCCCl.C(Cl)Cl>[CH:27]1([C:30]2[N:31]=[CH:32][N:33]([C:2]3[CH:20]=[C:7]4[C:8]5[CH:9]=[CH:10][CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[C:13]=5[CH2:14][CH2:15][N:6]4[C:5](=[O:21])[CH2:4][N:3]=3)[CH:34]=2)[CH2:29][CH2:28]1
Reactant: c1nc(C2CC2)c[nH]1
Reactant: COC(=O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2c1CCN1C(=O)CN=C(n3cnc(C4CC4)c3)C=C21
Temperature: 100 °C
Yield: 39 %

Procedure:
Example 132. A solution of methyl 2,5-dioxo-2,3,4,5,7,8-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylate (225 mg, 0.79 mmol) in DCE (20 mL) was treated with POCl3 (0.37 mL, 3.93 mmol) and the mixture was heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, and then concentrated in vacuo, and dried azeotropically with toluene. The residue obtained was taken up in DCE (40 mL) and 4-cyclopropyl-1H-imidazole (261 mg, 2.41 mmol) were added. The mixture was heated to to 100° C. for 1 h and then allowed to cool to RT, diluted with DCM and washed with a saturated aq, solution of NaHCO3. The org. layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, AcOEt/MeOH 100:0 to 90:10) and crystallization in Et2O/petroleum ether gave the title compound (116 mg). UPLC-MS: MS 377.2 (M+H+); UPLC rt 0.88 min. 1H NMR (600 MHz, DMSO-d6): δ ppm 0.54-0.73 (m, 2H); 0.73-0.88 (m, 2H); 1.74-1.89 (m, 1H); 3.25 (br s, 2H); 3.67-3.82 (m, 2H); 3.88 (s, 3H); 4.25 (br s, 2H); 7.13 (s, 1H); 7.44 (s, 1H); 7.48-7.57 (m, 1H); 7.96 (d, J=7.65 Hz, 1H); 8.09 (s, 1H); 8.19 (d, J=7.91, 1H).
Reaction SMILES: C([O:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:14]=1)C1C=CC=CC=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:14]=[C:10]([CH2:9][OH:8])[S:11][CH:12]=2)=[CH:20][CH:19]=1
Reactant: Clc1ccc(-c2csc(COCc3ccccc3)n2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OCc1nc(-c2ccc(Cl)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
A solution of 2-Benzyloxymethyl-4-(4-chloro-phenyl)-thiazole (2.0 g, 6.34 mmol) in 25 ml of DCM was cooled to −78° C. followed by addition of BBr3 (2.38 ml, 25.3 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), solution of NaHCO3 (20 mL) was added at 0° C. and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 40% EtOAc-Hexane) to get the desired product (0.8 g, 57%). The corresponding cyano derivative was also prepared by the same general method.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CCCCCC>[C:1]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCCCO
Solvent: CCCCCC
Product: CCC/C=C\CCCCCCCCC(=O)OCCCCCCCCCCCCCCCC
Reaction time: 8 h
Yield: 80 %

Procedure:
cis-10-Myristoleate, 7 (3.35 g, 0.014 mol) was enzymatically transesterified with cetyl alcohol (4.07 g, 0.0168 mol) in the presence of Novozyme 435 (0.745 g, 10 wt % of the total substrate), at 65 degree. C for 8 hr. The reaction was monitored by TLC and after completion of reaction, hexane (50 ml) was added and the lipase was separated by filtration and the solvent was evaporated to get the crude product and was purified by column chromatography to obtain hexadecyl cis-10-tetradecenoate, 8 (5.55 g, 0.0123) in 80% yield with 90% purity by GC. The structure of hexadecyl cis-10-tetradecenoate, 8 was confirmed by 1H NMR, IR, and GC-MS.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]#[C:12][Si](C)(C)C)=[CH:5][N:4]=1.[OH-].[Na+]>CO>[C:11]([C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[N:4][CH:5]=1)#[CH:12]
Reactant: COc1cc(C#C[Si](C)(C)C)cnc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1cnc(OC)c(OC)c1
Reaction time: 16 h
Yield: 81.7 %

Procedure:
2,3-Dimethoxy-5-[(trimethylsilyl)ethynyl]pyridine (Intermediate 31) (9.8 g, 42 mmol) was dissolved in a mixture of aqueous sodium hydroxide (21 ml, 2 M, 42 mmol) and methanol (50 ml) to give a colourless solution which was stirred for 16 hours. The reaction was evaporated and the residue was partitioned between ethyl acetate and water before the organic layer was dried and concentrated in vacuo. The crude material was purified by (SiO2; 0-10% ethyl acetate in petrol) to afford 5-ethynyl-2,3-dimethoxypyridine (5.6 g, 82%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:2]1.[CH3:32][C:33]1([CH3:41])[CH2:38][CH2:37][C:36](=[O:39])[O:35][C:34]1=[O:40].C(N(CC)CC)C>CS(C)=O>[CH3:32][C:33]([CH3:41])([CH2:38][CH2:37][C:36](=[O:39])[N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:23])[F:24])=[O:16])=[CH:10][CH:9]=2)[CH2:2]1)[C:34]([OH:40])=[O:35]
Reactant: O=C(Nc1ccc(OC2CCCNC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC1(C)CCC(=O)OC1=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(CCC(=O)N1CCCC(Oc2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)C1)C(=O)O
Yield: 56.4 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(piperidin-3-yloxy)-phenyl]-amide (44.1 mg, 0.102 mmol), 3,3-dimethyl-dihydro-pyran-2,6-dione (17.5 mg, 0.122 mmol) and triethylamine (28.5 uL, 0.204 mmol) in 1 mL DMSO were treated as above. The crude product was purified by flash chromatography to yield 2,2-dimethyl-5-oxo-5-(3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-piperidin-1-yl)-pentanoic acid as a white solid (33 mg, 56%). ES-MS calcd for C29H30F3N3O6 (m/e) 573.57, obsd 574 (M+H).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[SH:57][C:58]1[CH:67]=[CH:66][C:61]([C:62]([O:64][CH3:65])=[O:63])=[CH:60][CH:59]=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:65][O:64][C:62](=[O:63])[C:61]1[CH:66]=[CH:67][C:58]([S:57][CH:8]([C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:59][CH:60]=1
Reactant: OC(CC1CCCCC1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: COC(=O)c1ccc(S)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(SC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (300 mg, 0.88 mmol) in THF (2 mL) and toluene (4 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 325.0 mg, 1.29 mmol) at 0° C., followed by the addition of tributylphosphine (0.32 mL, 1.29 mmol) and methyl 4-mercaptobenzoate (173.3 mg, 1.03 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-benzoic acid methyl ester. The ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-benzoic acid (190 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]3[CH2:12][C:13]4[C:19]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=5)=[N:18][N:17](COCC[Si](C)(C)C)[C:14]=4[C:15]=3[CH:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]3[CH2:12][C:13]4[C:19]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=5)=[N:18][NH:17][C:14]=4[C:15]=3[CH:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(F)c(F)c4)cc2-3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4ccc(F)c(F)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 100 %

Procedure:
2-(3,4-Difluoro-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.11 g, 0.2 mmol) was dissolved in MeOH and treated with concentrated HCl (0.07 mL, 0.2 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 2-(3,4-Difluoro-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.08 g, 0.2 mmol) as brown solid in 95% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14](S(C)=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:20]([O:30][CH3:31])(=[O:29])[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:31][O:30][C:20](=[O:29])[C@H:21]([O:22][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][N:15]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: COC(=O)[C@H](O)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)[C@H](Oc1ncc(C(=O)Nc2ccc(F)cc2)cn1)c1ccccc1
Yield: 34.2 %

Procedure:
A suspension of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (100 mg, 0.36 mmol) and (R)-(−)-methyl mandelate (86 mg, 0.52 mmol) in 3.6 mL of THF was treated dropwise with DBU (80 μL, 0.54 mmol) at ambient temperature. The reaction mixture clarified and turned yellow over the course of 5 min. The reaction was quenched after 24 hours by the addition of 5 mL of 1 M HCl. The mixture was extracted with 2×25 mL portions of ethyl acetate. The organic extracts were combined, dried using Na2SO4 and concentrated in vacuo. The crude material was dissolved in 30% (v/v) ethyl acetate/hexanes and filtered though a 10 g plug of silica gel. The eluent was concentrated to dryness and triturated with 3×5 mL portions of hexane followed by 3×10 mL portions of 10% (v/v) portions of ethyl acetate/hexanes. The residue was dried to yield 47 mg (34%) of the titled compound as a white solid. ESI-MS m/z 382 (MH+), 380 (M−H−).