Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[S:25][C:26]3[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:27]=3[N:28]=2)=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl.C([O-])(=O)C.[NH4+]>C1COCC1.CO.O>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:36])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][NH:23][C:24]2[S:25][C:26]3[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:27]=3[N:28]=2)=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CNc2nc3ccc([N+](=O)[O-])cc3s2)cc1
Agent: CC(=O)[O-]
Agent: Cl[Sn]Cl
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CNc2nc3ccc(N)cc3s2)cc1
Yield: 76.9 %

Procedure:
To a suspension of compound 141 (200 mg, 0.385 mmol) in a mixture of THF/MeOH/H2O (10 mL/10 mL/10 mL) were successively added tin(II) chloride dihydrate (1.35 g, 8.46 mmol) and ammonium acetate (1.09 g, 14.12 mmol). The mixture was refluxed for 2 days, the tin salts were filtered off and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and H2O (brine was added to break the emulsion). Organic phase was successively washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo to afford the title compound 143 (145 mg, 77% yield). 1H NMR: (DMSO-d6) δ (ppm): 12.89 (bs, 1H), 10.79 (s, 1H), 8.12 (d, J=2.0 Hz, 1H), 8.05 (d, J=8.8 Hz, 2H), 7.90-7.68 (m, 3H), 7.62 (d, J=8.4 Hz, 2H), 7.48 (bs, 1H), 7.21 (dd, J=4.9, 3.7 Hz, 1H), 4.65 (s, 2H). m/z: 490.5 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:2]2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2ccc(I)cc2c(N2CCOCC2)c1S(C)(=O)=O
Yield: 80.6 %

Procedure:
4-Chloro-6-iodo-3-methanesulfonyl-2-methyl-quinoline (compound of example D.2) (1 g, 2.62 mmol), morpholine (274 mg, 3.1 mmol) and N,N-diisopropyl ethyl amine (406 mg, 3.1 mmol) were heated at 100° C. in dry N,N-dimethylformamide (10 mL) for 30 min. The reaction mixture was evaporated to dryness, and the residue extracted with dichloromethane, 10% Na2CO3 and sat. NaCl. The crude product was purified by chromatography on silica gel in dichloromethane/ethyl acetate 5:1. One obtained 913 mg (80%) of a yellow foam. MS: m/z=433 (M+H).
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH:12]1[CH2:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[C:19]([F:29])[CH:18]=3)(O)[CH2:13]1)=[O:11])[CH2:2]2.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH:5]12[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:10]([CH:12]1[CH2:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)=[C:19]([F:29])[CH:18]=3)=[CH:13]1)=[O:11])[CH2:4]2
Reactant: O=C(C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1)N1CC2CCC(CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C(C1C=C(c2ccc(CN3CCCC3)c(F)c2)C1)N1CC2CCC(CC2)C1

Procedure:
A solution of example 26, 3-aza-bicyclo[3.2.2]nonan-3-yl(3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-3-hydroxycyclobutyl)methanone (0.59 g, 1.48 mmol) in trifluoroacetic acid (2.5 mL) and 1,2-dichloroethane (16 mL) was refluxed for 20 h and concentrated to give crude 3-aza-bicyclo[3.2.2]nonan-3-yl(3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)cyclobut-2-enyl)methanone trifluoroacetate salt as a dark purplish-brown oil, with residual TFA. This material was dissolved in EtOH (40 mL) and added to a hydrogenation bottle containing 10% palladium on carbon (93 mg) slurried in EtOH (˜3 mL). The mixture was shaken at room temperature under 48 psi of hydrogen for 2 h, filtered through diatomaceous earth with an EtOH rinse and concentrated to yield an orange oil. This was dissolved in EtOAc and washed with aqueous K2CO3 and brine, dried over MgSO4 and concentrated to afford 0.38 g of light orange oil. Flash chromatography on a 2″×3.5″ silica gel column flushing with 2% MeOH/EtOAc (500 mL) and then eluting with 500 ml each 5% and 10% MeOH/EtOAc afforded 0.256 g (45%) of the title compound as a light orange oil: Rf=0.21 (20% MeOH/EtOAc).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18]O)[CH2:7][CH2:6][CH2:5][CH2:4]1.C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:21][CH2:18][C:9]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=1[C:3]1([O:2][CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: COC1(c2ccc(C(F)(F)F)cc2CO)CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC1(c2ccc(C(F)(F)F)cc2CBr)CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.9 %

Procedure:
To a solution of (2-(1-methoxycyclopentyl)-5-(trifluoromethyl)phenyl)methanol (10 mg, 0.036 mmol) in anhydrous dichloromethane (5 mL) was added carbon tetrabromide (14.5 mg, 0.043 mmol) followed by triphenylphosphine (11.47 mg, 0.043 mmol). The mixture was stirred at room temperature for 72 hours then the solvent was removed under reduced pressure. The residue was diluted with dichloromethane and hexanes, placed on 1 g of silica gel (Bakerbond spe disposable extraction columns, Mallinkrodt Baker Inc. Phillipsburg, N.J.) and eluted with hexanes to give the title compound (12 mg, 97.6%). 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H) 7.46 (d, J=9.1 Hz, 1H) 7.40 (d, J=8.3 Hz, 1H) 4.97 (s, 2H) 2.94 (s, 3H) 2.30 (m, 2H) 2.0 (m, 2H) 1.85 (m, 2H) 1.74 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[OH:15]O>CC(O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:15])=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[CH:3]=1
Reactant: Cc1ccnc(NC(=O)C(C)(C)C)c1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cc[n+]([O-])c(NC(=O)C(C)(C)C)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a solution of N-(4-methylpyridin-2-yl)pivalamide (10 g, 52 mmol) in AcOH (300 ml) was added H2O2 (7.0 ml, 68 mmol) dropwise at 0° C. The mixture was stirred overnight at 70° C. The reaction mixture was quenched with water, extracted with ethyl acetate (200 mL×3) and washed with saturated Na2SO3 solution. The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by chromatography on silica gel (5% ethyl acetate in petroleum ether) to afford 4-methyl-2-pivalamidopyridine 1-oxide (8.4 g, 77%). 1H NMR (CDCl3, 300 MHz) δ 10.38 (br s, 1H), 10.21 (br s, 1H), 8.34 (s, 1H), 8.26 (d, J=6.9 Hz, 1H), 6.83 (d, J=6.9 Hz, 1H), 2.37 (s, 3H), 1.33 (s, 9 H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=O)[C:5]=1[OH:12].C1(C)C=CC(C2C(C([NH:28][NH2:29])=O)=CC=CC=2)=CC=1.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34](S(O)(=O)=O)=[CH:33][CH:32]=1>CO>[CH3:1][NH:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[N:28][NH:29][C:34]2[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=2)[C:5]=1[OH:12]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CNC(=O)c1cccc(C=O)c1O
Reactant: Cc1ccc(-c2ccccc2C(=O)NN)cc1
Solvent: CO
Product: CNC(=O)c1cccc(C=NNc2ccc(C)cc2)c1O
Temperature: 22.5 °C
Reaction time: 14 h

Procedure:
A soluton of 200 mg (1 mmol) of the aldehyde of Example 4 in 30 ml of anhydrous methanol was reacted with 140 mg (1 mmol) of p-toluenebenzohydrazide with acid catalysis (para-toluenesulfonic acid). After the reaction mixture had been stirred for approximately 14 hours at 20 to 25° C., it was freed from the solvent. 340 mg of the title compound, which corresponded to 99% of theory, were obtained from the residue. (m.p. 108-125° C.)
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([CH:25](O)[CH2:26][CH2:27][CH:28]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[OH:29])[CH:10]=[C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:25]2[CH2:26][CH2:27][C@H:28]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[O:29]2)[CH:10]=[C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(OCc2ccccc2)cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCO
Reaction time: 1 h

Procedure:
A solution of 1-[3-(2-hydroxyethylsulfonyl)-4-propoxy-5-benzyloxyphenyl]-4-(3,4,5-trimethoxyphenyl)butan-1,4-diol (from previous experiment) in chloroform (20 mL) was treated with 10% trifluroacetic acid (20 mL). The reaction was monitored by TLC. After 1 h, anhydrous sodium carbonate was added, and the solid was filtered off and washed with chloroform. The solvent was evaporated and the residue was passed through a flash column of silica gel (hexane-ethyl acetate; 2:1, v/v). The cis- and trans-isomers were then separated by HPLC (hexane-ethyl acetate; 1:1, v/v): mp 112°-113° C.; Rf 0.33 (hexane-ethyl acetate; 1:1, v/v); NMR (CDCl3) δ 0.98 (t, J=7.5 Hz, CH2CH2CH3), 1.83 (m, CH2CH2CH3), 2.85 (t, J=6.5 Hz, OH), 3.67 (q, SO2CH2), 3.98 (q, SO2CH2CH2), 4.17 (t, CH2CH2CH3), 5.18 (s, CH2C6H5), 6.63 (s, 2 H, C5ArH).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[CH:9][C:8]=1[C:18]1[C:19]2[CH:28]=[C:27]([C:29](O)=[O:30])[NH:26][C:20]=2[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=1.C(Cl)(=O)C(Cl)=O.[F:39][C:40]([F:44])([F:43])[CH2:41][NH2:42]>ClCCl.CN(C)C=O>[F:1][C:2]1([F:32])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][CH3:17])(=[O:14])=[O:15])=[CH:9][C:8]=1[C:18]1[C:19]2[CH:28]=[C:27]([C:29]([NH:42][CH2:41][C:40]([F:44])([F:43])[F:39])=[O:30])[NH:26][C:20]=2[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=1
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2(F)F)c(-c2cn(C)c(=O)c3[nH]c(C(=O)O)cc23)c1
Reactant: NCC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(OCC2CC2(F)F)c(-c2cn(C)c(=O)c3[nH]c(C(=O)NCC(F)(F)F)cc23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a solution of Example 327d (0.070 g, 0.15 mmol) in anhydrous dichloromethane (5 mL) were added oxalyl chloride (0.026 mL, 0.300 mmol) and dimethylformamide (0.581 μl, 7.50 μmol). The reaction mixture was stirred at ambient temperature for 2 hours and then evaporated. The residue was dissolved in dichloromethane (5 mL) and treated with 2,2,2-trifluoroethylamine (0.048 mL, 0.600 mmol) and the mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between water (15 mL) and ethyl acetate (25 mL). The aqueous layer was extracted with additional ethyl acetate (15 mL) twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (C18, mobile phase A:water (10 mM NH4HCO3); B: acetonitrile, Gradient 25-60% B in A) to give the title compound (70 mg, 85%). 1H NMR (400 MHz, CD3OD) δ ppm 7.96-7.90 (m, 2H), 7.66-7.25 (m, 2H), 6.92 (s, 1H), 4.29 (t, J=7.5 Hz, 1H), 4.16 (t, J=9.2 Hz, 1H), 4.05 (tt, J=9.2, 4.5 Hz, 2H), 3.72 (s, 3H), 3.22 (q, J=7.4 Hz, 2H), 2.00 (td, J=12.0, 7.3 Hz, 1H), 1.58-1.46 (m, 1H), 1.32-1.25 (m, 4H). MS (ESI+) m/z 548.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[S:13])=[CH:10][N:9]=1.[CH3:17][O:18][C:19](=[O:27])[CH:20]([CH3:26])[C:21](=O)[CH:22](Br)[CH3:23].[CH2:28](O)C>>[CH2:17]([O:18][C:19](=[O:27])[CH:20]([C:21]1[N:14]=[C:12]([C:11]2[CH:10]=[N:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:16][CH:15]=2)[S:13][C:22]=1[CH3:23])[CH3:26])[CH3:28]
Reactant: CCO
Reactant: COC(=O)C(C)C(=O)C(C)Br
Reactant: NC(=S)c1ccc(-c2ccccc2F)nc1
Product: CCOC(=O)C(C)c1nc(-c2ccc(-c3ccccc3F)nc2)sc1C

Procedure:
A mixture of 6-(2-Fluoro-phenyl)-thionicotinamide (3.0 g, 12 mmol) and 4-bromo-3-oxo-2-methyl-pentanoic acid methyl ester (3.2 g, 14.4 mmol) in ethanol (100 mL) is heated to reflux for 24 h, and concentrated. The residue is purified by column chromatography on silica gel yielding 2.6 g of the product.
Reaction SMILES: C(OC(Cl)=O)C(C)C.[NH:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:10]([C:14]([OH:16])=O)[C@@H:11]([CH3:13])[OH:12].CN1CCOCC1.[NH2:31][C@H:32]([C:43]([NH:45][C@H:46]([CH2:50][OH:51])[C@@H:47]([CH3:49])[OH:48])=[O:44])[CH2:33][S:34][CH2:35][C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1.FC(C(O)=O)(F)F>C1COCC1>[NH:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:10]([C:14]([NH:31][C@H:32]([C:43]([NH:45][C@H:46]([CH2:50][OH:51])[C@@H:47]([CH3:49])[OH:48])=[O:44])[CH2:33][S:34][CH2:35][C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)=[O:16])[C@@H:11]([CH3:13])[OH:12]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(CSC[C@H](N)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(CSC[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Temperature: -25 °C
Reaction time: 0.08 h

Procedure:
5.9 ml chloroformic acid isobutyl-ester are added drop-wise to a solution of 9.7 g Boc-Thr-OH and 9.4 ml N-methyl-morpholine in 50 ml THF pre-cooled to -25° C. The solution is stirred for 5 min. at -15° C. and a solution of 20 g H-Cys(MBzl)-Thr-ol trifluoroacetate and 9.8 ml N-methylmorpholine in 50 ml THF, pre-cooled to -10° C. are added. The reaction mixture is stirred for 2 hrs. at 0° C., and for 2 hrs. at room temperature. 20 ml 10% KHCO3 are added and the mixture concentrated under vacuum. The product is diluted with AcOEt and washed with 2 N citric acid, 10% KHCO3 solution and then 30% NaCl solution. The AcOEt phase is dried over Na2SO4 and evaporated under vacuum, and the residue re-crystallised from MeOH/AcOEt/hexane. The title compound is obtained after further filtration, washing with ether and drying:
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([OH:24])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>[Pd]>[CH2:22]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7].[CH3:2][CH2:3][O:24][CH2:7][CH3:8]
Reactant: OCC(O)CO
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: [Pd]
Product: CCCCCCCCCCCCCCCCOCC(O)CO
Product: CCOCC
Temperature: 120 °C
Yield: 22 %

Procedure:
A stirred autoclave was charged, at room temperature, with 68.13 g (740 mmol) of glycerol, 4.40 g (17.2 mmol) of palmitic acid, 0.45 g (10 wt %) of AMBERLYST® (a polymer based catalyst) 35 resin and 0.39 g (1.0 mol %) of Pd/C at 5%. The autoclave was then pressurized at 50 bar of dihydrogen gas H2, and then it was heated at 120° C. for 16 h, stirring vigorously. After 16 h of reaction, the reaction mixture was brought back to room temperature. The catalyst was filtered on a MILLIPORE® filter (a membrane filter (0.1 μm) and was rinsed with absolute ethanol. The solvents were evaporated and the organic products were extracted from the glycerol phase by extraction with CH2Cl2 (3×50 ml). The organic phase was washed with water (2×30 ml) and the CH2Cl2 was then evaporated at reduced pressure. The crude reaction product was purified on a flash silica column (eluent: cyclohexane/ethyl acetate=6:1˜1:1). 1-O-hexadecanyl-glycerol ether was obtained at an isolated yield of 22%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[CH2:35][CH2:36][S:37]([N:40]1[CH2:45][CH2:44][C:43](=[O:46])[CH2:42][CH2:41]1)(=[O:39])=[O:38])[C:29]([OH:31])=O.[CH2:47]([O:50][CH2:51][CH2:52][NH:53][CH3:54])[CH:48]=[CH2:49].C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C.O>[CH2:47]([O:50][CH2:51][CH2:52][N:53]([CH3:54])[C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:34]([CH2:35][CH2:36][S:37]([N:40]2[CH2:45][CH2:44][C:43](=[O:46])[CH2:42][CH2:41]2)(=[O:39])=[O:38])=[C:26]([CH3:25])[CH:27]=1)[CH:48]=[CH2:49]
Reactant: C=CCOCCNC
Reactant: Cc1cc(C(=O)O)ccc1CCS(=O)(=O)N1CCC(=O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOCCN(C)C(=O)c1ccc(CCS(=O)(=O)N2CCC(=O)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.8 %

Procedure:
HATU (91 mg, 0.239 mmol) was added to a solution of 3-methyl-4-[2-(4-oxo-piperidine-1-sulfonyl)-ethyl]-benzoic acid (50 mg, 0.154 mmol), (2-allyloxy-ethyl)-methyl-amine (36 mg, 0.312 mmol) and diisopropylethylamine (0.065 ml, 0.384 mmol) in DMF (0.5 ml), and the mixture was stirred at room temperature overnight. Water (12 ml) and 1 N hydrochloric acid (1.5 ml) were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 0.1 N hydrochloric acid, water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give N-(2-allyloxy-ethyl)-3,N-dimethyl-4-[2-(4-oxo-piperidine-1-sulfonyl)-ethyl]-benzamide (76 mg, 100%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:22][C:23]2[CH:24]=[C:25]([CH:44]=[CH:45][CH:46]=2)[C:26]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])[CH:29]=2)=[O:27])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>O1CCOCC1.CO>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:11]([NH:22][C:23]2[CH:24]=[C:25]([CH:44]=[CH:45][CH:46]=2)[C:26]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])[CH:29]=2)=[O:27])[C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=2)=[CH:13][CH:14]=1)[CH:19]([CH3:20])[CH3:21]
Reactant: CCOC(=O)CCn1cc(C(=O)c2cccc(NC(c3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)c2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)Cc1ccc(C(Nc2cccc(C(=O)c3cn(CCC(=O)O)c4ccccc34)c2)c2ccc(CC(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.5 %

Procedure:
To a solution of ethyl 3-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indol-1-yl]propionate (507 mg) in a mixture of 1,4-dioxane (8 ml) and methanol (2 ml) was added 1N aqueous sodium hydroxide (2 ml), and the mixture was stirred at 25° C. for 5 hours. After evaporation of the organic solvent, the residue was acidified (pH 2) with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (20 g) eluting with chloroform to give 3-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indol-1-yl]propionic acid 375 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[CH3:24][N:25]1[C:29]([C:30](O)=[O:31])=[CH:28][N:27]=[CH:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[S:12][C:10]3[C:9]([N:14]=2)=[CH:8][CH:7]=[C:6]([O:5][C:4]2[CH:3]=[C:2]([NH:1][C:30]([C:29]4[N:25]([CH3:24])[CH:26]=[N:27][CH:28]=4)=[O:31])[CH:23]=[CH:22][CH:21]=2)[N:11]=3)=[O:17])[CH2:20][CH2:19]1
Reactant: Cn1cncc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cncc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Yield: 88 %

Procedure:
In the same manner as in Example 101-4 and using N-[5-(3-aminophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (124 mg, 0.280 mmol), 1-methyl-1H-imidazole-5-carboxylic acid (71.9 mg, 0.570 mmol), HATU (260 mg, 0.684 mmol), N,N-diisopropylethylamine (298 μL, 1.71 mmol) and N,N-dimethylformamide (4 mL) as starting materials, the title compound (107 mg, 65%) was obtained as a white solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].O[CH2:14][CH:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O.C(O)CCC>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=2[Cl:12])[O:22][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: OCC(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: O
Solvent: c1ccccc1
Product: Clc1ccc(C2(CBr)OCC(c3ccccc3)O2)c(Cl)c1

Procedure:
A mixture of 13.4 parts of 2-bromo-2',4'-dichloroacetophenone, 8.4 parts of α-(hydroxymethyl)benzyl alcohol, 1.15 parts of p-toluenesulfonic acid, 160 parts of benzene and 140 parts of n-butanol is stirred and refluxed for 48 hours with a water-separator. The solvent is removed in vacuo. The residue is purified by column-chromatography over silica gel, using chloroform as eluent. The pure fractions are collected and the eluent is evaporated, yielding 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-phenyl-1,3-dioxolane as residue.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([C:14]2[N:15]=[CH:16][N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=2)(O)[CH3:12])[CH:4]=[CH:3][CH:2]=1.O.[OH-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.C(O)(=O)C>[NH:17]1[CH:18]=[C:14]([C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[CH2:12])[N:15]=[CH:16]1
Reactant: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2cccnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=C(c1c[nH]cn1)c1cccc2cccnc12
Temperature: 25 °C

Procedure:
1-Quinolin-8-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol (Intermediate C1) and p-toluenesulfonic acid catalyst in toluene was heated to reflux in a Dean-Stark apparatus for 18 h. The mixture was cooled to rt and freed of solvent. The residue was dissolved in 70% acetic acid:water and heated to 100° C. for 1 h. The reaction mixture was cooled to rt and basified with 2 M NaOH and extracted with chloroform:isopropyl alcohol (3:1). The organic layers were pooled, dried over MgSO4, filtered and concentrated onto silica gel. The product was eluted from a column of silica gel with 4% NH3-MeOH:CH2Cl2 to give 8-[1-(1H-imidazol-4-yl)-vinyl]-quinoline.
Reaction SMILES: FC1C=C(C(C)C(=O)C[OH:11])C=CC=1C1C=CC=CC=1.[C:20]1([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)(Cl)Cl>[C:33]1([P:26](=[O:11])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C(=O)CO)c1ccc(-c2ccccc2)c(F)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To 3-(2-fluoro-4-biphenylyl)-2-oxo-1-butanol (2.00 g, 7.74 mmol) in carbon tetrachloride (5 ml) was added triphenylphosphine (2.15 g, 8.20 mmol) at room temperature. After the addition, the mixture was stirred over night at room temperature, then concentrated to give triphenylphosphine oxide as precipitates. After filtration of the precipitates, the filtrates were evaporated under reduced pressure to a residue, which was chromatographed to afford 1-chloro-3-(2-fluoro-4-biphenylyl)-2-butanone (1.01 g, 47% yield) as crystalline materials: mp 57°-59° C.; NMR(CDCl3)δ 1.48(d, 3H), 4.07(m, 3H), 6.93-7.63(m, 8H); IR(neat) 1740, 1620, 1480, 1420, 1270 cm-1.