Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O)=[O:13].[CH2:25]=[CH:26]O>>[C:12]([OH:14])(=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:25][CH3:26]
Reactant: C=CO
Reactant: CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O
Product: CCCCCCCCCCCCCC(=O)O
Temperature: 46 °C

Procedure:
A 4% w/w dispersion was emulsified with 0.4% Span 20 and 1% w/w Mowiol 8-88 using a Silverson mixer. These 5 μm droplets also crystallised rapidly on cooling to 46° C. but it was noticeable under the microscope that in the presence of sonication the crystallisation rate within the droplets increased (crystallised within 10 sec).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Br)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[O:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.C([O-])(=O)C.[K+].O1CCOCC1>CO.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:29]3[CH2:30][CH2:31][O:26][CH2:27][CH:28]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ccccc2[nH]1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(Oc2ncccc2C2=CCOCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 100 °C

Procedure:
A clear 150 ml pressure tube was charged with (1H-benzo[d]imidazol-2-yl)(4-(3-bromopyridin-2-yloxy)phenyl)methanone (1.5 g, 3.80 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.959 g, 4.57 mmol), Bis-[4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine]Palladium dichloride (2.69 g, 3.80 mmol), potassium acetate (0.373 g, 3.80 mmol), Dioxane (9 mL) and Water (1.000 mL). The reaction flask was flushed with nitrogen and capped. The reaction was heated to 100° C. for 16 hours. The reaction was then cooled down to RT and partitioned with ethyl acetate (50 ml) and water (50 ml). The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and then filtered. The volatile were reduced to a smaller volume and the solid that precipitated out was filtered off. The cake obtained was suspended in hot MeOH, filtered and dried to give (1H-benzo[d]imidazol-2-yl)(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanone as a yellow solid. MS (ESI, pos. ion) m/z: 397.9 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](Cl)=[O:13])([CH3:4])([CH3:3])[CH3:2].C([NH:26][NH:27][CH:28]([CH3:30])[CH3:29])(OCC1C=CC=CC=1)=O.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:13])[N:27]([CH:28]([CH3:30])[CH3:29])[NH2:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)NNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 65.7 %

Procedure:
Carbamoyl chloride 1 (4 mmol, crude), prepared as described above, was combined with carbazide 4 (3.50 mmol; 0.728 g) and triethylamine (0.557 ml; 4.00 mmol) in dry THF (2 ml). The mixture was heated at reflux for 7 hours, then filtered and evaporated to a thick oil. This was dissolved in benzene (10 ml) and hydrogenated with 10% Pd(C) (0.35 g) at 1 atm. for 6 hours. Filtration of the catalyst and evaporation gave a light yellow oil which was purified by flash chromatography on silica gel (CH2Cl2 --CH3OH, 50:1). There was obtained pure carbazide 5 (0.622 g; 2.30 mmol; 66%) as a light yellow solid. Recrystallization from hexanes gave a sample, mp 87°-91° C. TLC (silica gel; CH2Cl2 --CH3OH; 20:1) Rf=0.4. MS m/e 271 (M+). Analysis: Calculated for C13H25N 3 O3 : C, 57.54; H, 9.29; N, 15.48. Found: C, 57.67; H, 9.46; N, 15.44. NMR (CDCl3): δ1.08 (3H,d, J=6); 1.13 (3H, d, J=6); 1.43 (9H,s); 1.7-2.2 (4H,m); 2.4-2.7 (2H,m); 3.3 (2H,bs); 4.07 (1H, septet, J=6); 4.3-4.5 (1H,m). lR(CHCl3): 3600-3300, 1730, 1630 cm-1. [α]D =15.9°±b 0.5°. [α]d =15.9°±0.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH2:13][CH2:14][CH3:15])[CH:7]=[CH:8][CH:9]=2)[C:4]=1[O:16]COC.Cl.O.[C:22](OCC)(=[O:24])C>CC(C)=O>[OH:16][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:13][CH2:14][CH3:15])[C:11]([CH:22]=[O:24])=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: CCOC(C)=O
Reactant: CCCc1cccc2ccc(OC)c(OCOC)c12
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCCc1cccc2c(C=O)cc(OC)c(O)c12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
206 g of 2-methoxy-1-methoxymethoxy-8-propylnaphthalene was dissolved in 1160 ml of acetone and cooled to 0° C. Diluted hydrochloric acid (concentrated hydrochloric acid 84 ml/water 206 ml) was added to the solution in 15 minutes, which was returned to room temperature at which the reaction was effected at 20° C. for 5 hours, followed by addition of water and extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution to neutrality, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. 173 g of the resultant brown oily substance was dissolved in 1350 g of dichloromethane without purification and cooled down to 0° C. 176.3 ml of titanium tetrachloride was dropped in the solution at 5° C. or below, to which 114.3 ml of dichloromethyl methyl ether was added at 5° C. or below at which the reaction was carried out for 10 minutes. The reaction solution was slowly added to iced water and extracted with ethyl acetate. The resultant organic phase was washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated saline solution in this order and dried with anhydrous magnesium sulfate, and was concentrated under reduced pressure. The resultant crystals were washed with a 30% isopropyl ether/hexane solution to obtain 103 g of the captioned compound as yellowish brown crystals.
Reaction SMILES: S(Cl)(Cl)=O.C(O)(=O)CCCCCCCCCCCCC.C(Cl)(=O)CCCCCCCCCCCCC.[C:37]([N:52]=[C:53]=[S:54])(=[O:51])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50].[CH3:55][O:56][C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][C:66]=1[O:67][CH3:68])[N:63]=[CH:62][CH:61]=[C:60]2[O:69][C:70]1[CH:76]=[CH:75][C:73]([NH2:74])=[CH:72][CH:71]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:55][O:56][C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][C:66]=1[O:67][CH3:68])[N:63]=[CH:62][CH:61]=[C:60]2[O:69][C:70]1[CH:71]=[CH:72][C:73]([NH:74][C:53]([NH:52][C:37](=[O:51])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[S:54])=[CH:75][CH:76]=1
Reactant: CCCCCCCCCCCCCC(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCCCCCCCCCCCCC(=O)Cl
Agent: CCCCCCCCCCCCCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCCCCCCCCC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available tetradecanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and tetradecanoyl isothiocyanate was prepared using the resultant tetradecanoyl chloride as a starting compound according to the description of the literature. Tetradecanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (58 mg, yield 60%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:19])[C:10]=1[C:20]1[C:29]2[N:28]=[C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]3)[CH:26]=[N:25][C:24]=2[C:23]([C:39](O)=[O:40])=[CH:22][CH:21]=1>C(Cl)Cl.CO>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:39]([C:23]1[C:24]2[N:25]=[CH:26][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]3)=[N:28][C:29]=2[C:20]([C:10]2[C:9]([Cl:8])=[C:14]([O:15][CH3:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[Cl:19])=[CH:21][CH:22]=1)=[O:40]
Reactant: Nc1ccccn1
Reactant: CCN1CCN(Cc2cnc3c(C(=O)O)ccc(-c4c(Cl)c(OC)cc(OC)c4Cl)c3n2)CC1
Solvent: CO
Solvent: ClCCl
Product: CCN1CCN(Cc2cnc3c(C(=O)Nc4ccccn4)ccc(-c4c(Cl)c(OC)cc(OC)c4Cl)c3n2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 2-aminopyridine, 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-(4-ethyl-piperazin-1-ylmethyl)-quinoxaline-5-carboxylic acid (Step 83.1) and stirring the reaction mixture for 2 days at rt. Title compound: ESI-MS: 581.0/583.2 [M+H]+; tR=3.62 min (System 1); TLC: Rf=0.45 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].O>C1COCC1>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: Sc1ccccc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
Benzenethiol (13.2 g) was dissolved in THF (100 ml), and to this solution was added triethylamine (17.1 ml) and then 4-nitrobenzyl bromide (21.6 g). The reaction solution was stirred for 30 minutes at room temperature, added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane/ethyl acetate (=10/1), to give 1-nitro-4-[(phenylsulfanyl)methyl]benzene (20.7 g).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([S:21][CH3:22])=[N:12][N:13]3[C:18](O)=[CH:17][C:16]([CH3:20])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:25]>>[C:1]1([S:7]([C:10]2[C:11]([S:21][CH3:22])=[N:12][N:13]3[C:18]([Cl:25])=[CH:17][C:16]([CH3:20])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1nn2c(O)cc(C)nc2c1S(=O)(=O)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A suspension of 3.0 g (8.94 mmol) of 3-benzenesulphonyl-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol in 20 ml of POCl3 was heated at reflux for 45 min. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was treated with 100 ml of ice-water and the pH value of the solution was adjusted to 8 with sat. NaHCO3 solution. The aqueous phase was extracted three times with 100 ml of CH2Cl2, and the organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/AcOEt 19:1) of the residue yielded 3.0 g (94%) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as pale yellow crystals, m.p. 163-165° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](Cl)=[O:9])[C:3]=1[N+:11]([O-:13])=[O:12].C(Cl)Cl.[CH3:17][OH:18].C(N(CC)CC)C>C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:18][CH3:17])=[O:9])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CO
Reactant: Cc1cccc(C(=O)Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 93.7 %

Procedure:
In this example a solution containing 1.002 mole of 2-methyl-6-chlorocarbonyl-nitrobenzene in 200 ml of ethyl ether and a small amount of methylene chloride was added to mixture containing 1.5 mole (60.8 ml) of methanol 1.002 mole (139.7 ml) of triethylamine and 200 ml of ethyl ether at about 0° C. The resulting mixture was stirred for one hour and then allowed to stand overnight. The mixture was then filtered and the filtrate washed with dilute aqueous acid and then washed with an aqueous sodium bicarbonate solution. The washed filtrate was dried and evaporated affording 183.3 g of the title product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[CH:9][N:10]=1)=[O:5])[CH3:2].C1C(=O)N([Br:26])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])[CH:8]=[C:9]([Br:26])[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nccn1COCC[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)cn1COCC[Si](C)(C)C
Temperature: 60 °C
Yield: 38.7 %

Procedure:
To a solution of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid ethyl ester (0.20 g, 0.74 mmol) (prepared in the previous step) in 2 mL of CH3CN was added NBS (0.13 g, 0.74 mmol) and the mixture heated to 60° C. for 2 h. The mixture was concentrated and the title compound purified by elution from a 20-g SPE column with 20% EtOAc/hexanes to give 0.10 g (39%) of a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C12H21BrN2O3Si, 349.0 (M+H). found 348.7.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:6]1=2.I.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](SC)=[NH:24]>CCO.C([O-])(O)=O.[Na+]>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[C:12]([NH:15][C:23]([C:19]3[S:18][CH:22]=[CH:21][CH:20]=3)=[NH:24])[CH:13]=[CH:14][C:6]1=2
Reactant: CN(C)CCN1CCOc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCN1CCOc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
A suspension of N,N-dimethyl-2-(7-nitro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanamine (210 mg, 0.836 mmol) and Pd—C (10% wt, 89 mg, 0.084 mmol) in dry EtOH (15 mL) was purged with hydrogen gas. The reaction was stirred at room temperature for 3 hours under hydrogen atmosphere (balloon pressure). The reaction mixture was then filtered through a Celite pad and washed with EtOH (15 mL). The light purple filtrate was concentrated to give crude 4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine. A solution of this crude 4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine (185 mg, 0.836 mmol) in dry EtOH (10 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (477 mg, 1.672 mmol) and stirred overnight at room temperature. The reaction was diluted with saturated NaHCO3 solution (50 mL) and the product was extracted into CH2Cl2 (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was subjected to flash chromatography on silica gel using 2:98 MeOH:CH2Cl2, followed by 5:95 (2M NH3 in MeOH):CH2Cl2, to give a yellow solid (150 mg, 54%). 1H-NMR (DMSO-d6) δ 7.69 (dd, J=3.6, 0.9 Hz, 1H), 7.56 (dd, J=5.1, 0.9 Hz, 1′-1), 7.07 (dd, J=5.1, 3.9 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.35-6.26 (m, 4H), 4.14 (t, J=3.9 Hz, 2H), 3.33-3.29 (m, 4H), 2.42 (t, J=6.9 Hz, 2H), 2.19 (s, 6H); ESI-MS (m/z, %): 331 (MH+, 100), 260 (25); ESI-HRMS calculated for C17H23N4OS (MH+): 331.1587, Observed: 331.1594; HPLC purity: 99.0% by area.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[N:18]([CH3:24])[N:17]=2)=[CH:12][CH:11]=1>CCOCC.CO.C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:20]=[C:19]([C:21]([O:23][CH3:1])=[O:22])[N:18]([CH3:24])[N:17]=2)=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1ccc(-c2cc(C(=O)O)n(C)n2)cc1
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nn1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylsilyldiazomethane (1.75 mL of a 2 M soln in Et2O, 3.49 mmol) was added to a stirred solution of 3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylic acid (0.507 g, 2.182 mmol) in dry MeOH (2.2 mL) and dry CH2Cl2 (19.6 mL) at 25° C. under N2. The reaction was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo to afford methyl 3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylate, as a colorless solid. LCMS calc.=247.11. found=247.03 (M+H)+. 1H NMR (600 MHz, CDCl3): δ 7.71 (d, J=8.5 Hz, 2H); 7.04 (s, 1H); 6.93 (d, J=8.5 Hz, 2H); 4.21 (s, 3H); 3.90 (s, 3H); 3.83 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C@H:12]2[O:16]C(C)(C)[O:14][C:13]2=O)[CH:5]=[C:6]([F:8])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>CO>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][C@@H:12]([OH:16])[C:13]2=[O:14])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(C)OC(=O)[C@@H](CCNc2cc(F)cc(F)c2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: O=C1[C@H](O)CCN1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
A stirred solution of (R)-5-(2-(3,5-difluorophenylamino)ethyl)-2,2-dimethyl-1,3-dioxolan-4-one (8.0 g, 29.5 mmol) and p-toluensulfonic acid monohydrate (508 mg, 2.95 mmol) in MeOH (75 mL) under nitrogen was heated to 70° C. for 75 minutes. The reaction mixture was slowly cooled to RT and then continued to stir at RT overnight. The reaction mixture was concentrated under reduced pressure to provide 9.5 g of a brown waxy solid. The solid was dissolved in MeOH (10 mL) and diethyl ether (100 mL) was added. The solution was allowed to stand at RT overnight. The solid was collected, washed with diethyl ether (2×25 mL) and dried under vacuum to provide (R)-1-(3,5-difluorophenyl)-3-hydroxypyrrolidin-2-one as a tan solid (4.09 g, 19.2 mmol, 65%). 1H-NMR (400 MHz, CDCl3) δ 7.35-7.27 (m, 2H), 6.68-6.63 (m, 1H), 4.51 (dd, J=8.3, 9.8 Hz, 1H), 3.85-3.71 (m, 2H), 3.08 (s, 1H), 2.69-2.62 (m, 1H) and 2.19-2.07 (m, 1H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=214.1; tR=0.97 min.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH2:14][CH2:15][S:16][CH3:17])[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>CN(C=O)C>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[C:3](=[O:18])[N:4]([CH2:14][CH2:15][S:16][CH3:17])[C:5](=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:23][CH:22]=1
Reactant: CSCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Reactant: COc1ccc(N)cc1
Solvent: CN(C)C=O
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(CCSC)C2=O)cc1
Temperature: 150 °C

Procedure:
3-Chloro-1-[2-(methylthio)ethyl]-4-phenyl-1H-pyrrole-2,5-dione (0.40 mmol, 113 mg) and 4-methoxyaniline (0.88 mmol, 109 mg) were dissolved in DMF (1 mL). The mixture was heated in a microwave reactor at 150° C. for 10 min. After cooling, the solvent was evaporated under reduced pressure. The residue was partitioned between water and CH2Cl2. The organic phase was evaporated and purified by flash chromatography using a pre-packed silica column. The desired product was eluted with heptane/EtOAc 2:1. Yield 118 mg (80%).1H NMR (400MHz, CDCl3) δ 7.26 (bs, 1H), 7.15-7.06 (m, 3H), 7.01-6.96 (m, 2H), 6.63-6.52 (m, 4H), 3.83 (t, J=7.0 Hz, 2H), 3.69 (s, 3H), 2.79 (t, J=7.0 Hz, 2H), 2.18 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([NH:25][NH:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:24])[CH3:23].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=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([N:25]([CH:22]([CH3:24])[CH3:23])[NH:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:20])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)/C=C/c1cn(Cc2ccccc2)c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To solution containing (E)-3-(1-benzyl-1H-indol-3-yl)acrylic acid (30 mg, 0.14 mmol, 1.0 equivalent), N′-isopropylbenzohydrazide (28.92 mg, 0.16 mmol, 1.5 equivalent) and HATU (61.6 mg, 0.16 mmol, 1.5 equivalent) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.03 ml, 0.16 mmol, 1.5 equivalent) was slowly drop-wise added and stirred at room temperature for 24 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=1:1) and dried so that white solid form of (E)-N′-(3-(1-benzyl-1H-indol-3-yl)acryloyl)-N-isopropylbenzohydrazide was obtained (40.6 mg, 86%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH:11]1([N:17]2C(=O)O[C:20](=[O:21])[C:19]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:18]23)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([NH:17][C:18]2[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=2[C:20]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([OH:10])=[N:2]2)=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Oc1n[nH]c2ccccc12
Reactant: O=c1oc(=O)n(C2CCCCC2)c2ccccc12
Product: O=C(c1ccccc1NC1CCCCC1)n1nc(O)c2ccccc21
Yield: 20.1 %

Procedure:
1H-Indazol-3-ol was reacted with N-cyclohexylisatoic anhydride according to the general procedure A above and afforded the desired amine as yellow solid in 20.1% yield; m.p. 150°-152° C.
Reaction SMILES: [CH2:1]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:14][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:23](O)(=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH2:1]([C:11]1[S:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:21]=2)=[CH:14][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ncc(-c2ccc(O)cc2)s1
Reactant: CCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCCCCCc1ncc(-c2ccc(OC(=O)CCCCCC)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
In a 50 ml-round-bottomed flask, 0.60 g (1.89 mM) of 2-decyl-5-(4-hydroxyphenyl)thiazole, 0.28 ml (1.97 mM) of heptanoic acid and 15 ml of dichloromethane were placed and mixed. To the solution, 0.39 g (1.89 mM) of N,N'-dicyclohexylcarbodiimide and 0.03 g of 4-pyrrolidinopyridine were successively added under stirring at room temperature, followed by further stirring for 2 hours at room temperature. After stirring, the mixture was left standing overnight at room temperature to precipitate N,N'-dicyclohexylurea. The resultant N,N'-dicyclohexylurea was filtered off and the solvent of the filtrate was distilled-off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from acetone to obtain 0.62 g of 2-decyl-5-(4-heptanoyloxyphenyl)thiazole (Yield: 76.4%). ##STR92##