Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][S:13][C:14]3[NH:15][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][NH:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:28]=O.[CH3:30][NH:31][CH3:32].O>C(O)(=O)C.O>[CH3:30][N:31]([CH2:28][C:21]1[NH:20][C:18]2[N:19]=[C:14]([S:13][CH2:12][C:11]3[CH:24]=[CH:25][C:8]([C:6](=[O:7])[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:27][CH:26]=4)=[CH:9][CH:10]=3)[NH:15][C:16](=[O:23])[C:17]=2[CH:22]=1)[CH3:32]
Reactant: O=C(c1ccc(F)cc1)c1ccc(CSc2nc3[nH]ccc3c(=O)[nH]2)cc1
Reactant: CNC
Reactant: C=O
Solvent: O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(=O)[nH]c(SCc3ccc(C(=O)c4ccc(F)cc4)cc3)nc2[nH]1
Temperature: 60 °C
Reaction time: 13 h
Yield: 5.5 %

Procedure:
In 80% acetic acid/water (15 ml) was dissolved 2-[4-(4-fluorobenzoyl)benzyl]thio-7H-pyrrolo[2,3-d]-pyrimidin-4(3H)-one (570 mg) followed by addition of 37% formalin (244 mg) and, then, 50% dimethylamine-water (270 mg). The mixture was stirred at 60° C. for 13 hours. The solvent was then distilled off under reduced pressure and the residue was dissolved in water (15 ml), made basic with concentrated aqueous ammonia, and extracted with chloroform. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography (silica gel; ethanol-chloroform: 1:49-ethanol (containing 7% ammonia)-chloroform=1:19-1:9) to provide the title compound (36 mg of compound A and 233 mg of compound B).
Reaction SMILES: C1(N[C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)CCCCC1.CC[N:25]([CH2:28][CH3:29])CC.[CH:30]1([CH2:36][C:37](Cl)=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)(Cl)Cl>[CH:30]1([CH:36]([C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[C:37]([NH:25][CH:28]2[CH2:29][CH2:13][CH2:12][CH2:11][CH2:16]2)=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: CCN(CC)CC
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCCCC1)C(c1c2ccccc2nn1-c1ccccc1)C1CCCCC1
Temperature: 80 °C
Yield: 63 %

Procedure:
To a solution of cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (30 mg, 103 μmol) in chloroform was added Et3N (16 μl, 113 μmol) and cyclohexylacetylchloride (16 μl, 108 μmol; CAS Reg. No. 23860-35-7) at ambient temperature under an argon atmosphere. The mixture was heated to 80° C. for 12 h, poured onto ice water/1 N HCl 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/1 N NaOH 1/1 and ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure and the crude product was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to give the title compound (27 mg, 65 μmol; 63%) as colorless foam. MS: m/e=416.5 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].I[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: COc1ccc(I)cc1
Product: COc1ccc(-c2ccc(Br)cc2[N+](=O)[O-])cc1

Procedure:
2,5-Dibromo-1-nitrobenzene and 4-iodoanisole were reacted under Ullmann conditions to give 4-bromo-4'-methoxy-2-nitrobiphenyl, m.p. 130°-131°C. This was reduced to give 2-amino-4-bromo-4'-methoxybiphenyl, m.p. 128°-130°C., which was subjected to the Schiemann reaction using hydrofluoroboric acid to give the product, b.p. 134°-138°C./0.15mm.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.[Cl:12][C:13]([Cl:17])([Cl:16])[S:14]Cl.[C:18](Cl)([Cl:20])=[O:19]>C(#N)C>[Cl:12][C:13]([Cl:17])([Cl:16])[S:14][N:4]([CH2:1][CH2:2][CH3:3])[C:18]([Cl:20])=[O:19]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: CCCN
Reactant: O=C(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCN(SC(Cl)(Cl)Cl)C(=O)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.1 %

Procedure:
A solution of 59.1 g (1 mol) N-propylamine and 101.2 g (1 mol) triethylamine in 200 ml acetonitrile was added dropwise to a solution of 185.9 g (1 mol) of trichloromethylsulfenyl chloride in 1 liter of acetonitrile at about 0°-5° C over a 1-hour period. Into the reaction mixture was then added 98.9 g (1 mol) phosgene over a 1-hour period. The reaction was stirred at about 25° C for about 16 hours. The solvent was evaporated under reduced pressure, and the residue was extracted with hexane. The hexane extracts were evaporated under reduced pressure to give a dark oil. The oil was distilled through a short column to give 22 g of the carbamoyl chloride product, b.p. 71°-81° C at 0.75 mm Hg.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](N)[CH:18]=1)[CH3:3].N([O-])=O.[Na+].[I:29]I>CCOCC.C(O)(=O)C>[CH2:2]([O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([I:29])[CH:18]=1)[CH3:3]
Reactant: CCOC(=O)CCCCCCCCCCCc1cccc(N)c1
Reactant: II
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCCCCCCCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
Glacial acetic acid (4 ml) and concentrated HCl (2.5 ml) were added to a 50 ml Erlenmeyer flask containing ethyl-12-(m-aminophenyl)-dodecanoate (3.92 g, 12.28 mmol). The mixture was cooled in a NaCl/ice bath. A cold aqueous solution of NaNO2 (4 ml, 3.1 M) was added to the mixture. The reaction was stirred for 40 minutes before a cold aqueous solution of KI/I2 2.31/1.78 g, 7 ml) was added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. Ether was added to the reaction mixture. The ether layer was separated and extracted with H2O, 10% Na2S2O3, H2O, sat. NaHCO3, and brine. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give a reddish oil. The crude product was purified by column chromatography (120 g silica gel, hexanes:ethyl acetate 20:1) to yield a clear oil, compound 6, ethyl-12-(m-iodophenyl)-dodecanoate (5.28 g, 56.8% yield).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)OC)[C:5]1=[O:28])(=[O:3])[CH3:2].[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>CN(C)C=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)[C:5]1=[O:28])(=[O:3])[CH3:2]
Reactant: CN1CCC(N)CC1
Reactant: COC(=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21)c1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)C(=C(NC1CCN(C)CC1)c1ccc([N+](=O)[O-])cc1)C(=O)N2C(C)=O

Procedure:
2.7 g (7 mmol) 1,5-diacetyl-3-[4-nitrophenyl-methoxy-methylidene]-2-indolinone (Ex. VI.2) are suspended in 20 ml of dimethylformamide and stirred with 0.9 g (7.7 mmol) 4-amino-N-methylpiperidine for 6 h at 80° C. Then the mixture is evaporated down and the acetyl-protected intermediate product is washed with a little water and suction filtered.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)=[O:5].[CH2:26]1COCC1.C[Li]>CCOCC>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:10]=[C:6]2[C:4](=[O:5])[CH3:26])=[CH:23][CH:22]=1
Reactant: CON(C)C(=O)c1ccc(-c2ccccc2)n1Cc1ccc(F)cc1
Reactant: C1CCOC1
Agent: [Li]C
Solvent: CCOCC
Product: CC(=O)c1ccc(-c2ccccc2)n1Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 1-(4-fluorobenzyl)-5-phenyl-1H-pyrrole-2-carboxylic acid methoxy-methylamide AV-7-1 (0.726 g, 2.16 mmol) and dry THF (20 mL). This solution was cooled to −78° C. and methyllithium (3.39 mL of a 1.4 M solution in Et2O, 4.75 mmol). The mixture was stirred 30 min at −78° C. then the reaction was quenched with saturated aqueous NH4Cl solution. The mixture was warmed to room temperature and stirred 2 h. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. The crude product was chromatographed on silica gel using 15% EtOAc in hexanes as eluant to give 1-[1-(4-fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]ethanone AV-8-1 as an oil. 1H NMR (CDCl3) δ 2.42 (3H, s), 5.59 (2H, s), 6.29 (1H, d, j=4.2 Hz), 6.78 to 6.91 (4H, m), 7.12 (1H, d, j=4.2 Hz), 7.29 (2H, m), 7.38 (3H, m).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]=1[N+:16]([O-:18])=[O:17])[O:8][CH2:9][C:10](Cl)=[O:11])([O:3][CH3:4])=[O:2].[CH2:23]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]=1[N+:16]([O-:18])=[O:17])[O:8][CH2:9][C:10]([N:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:11])([O:3][CH3:4])=[O:2]
Reactant: CCCCCCNCCCCCC
Reactant: COC(=O)c1cc(OCC(=O)Cl)cc(C(=O)OC)c1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCN(CCCCCC)C(=O)COc1cc(C(=O)OC)c([N+](=O)[O-])c(C(=O)OC)c1

Procedure:
A stirred solution of (3,5-dicarbomethoxy-4-nitrophenoxy)acetyl chloride in tetrahydrofuran, cooled in an ice bath, is treated dropwise with a tetrahydrofuran solution containing 1 equivalent each of dihexylamine and triethylamine. After the addition, the precipitated amino hydrochloride is removed by filtration and the tetrahydrofuran filtrate is concentrated under reduced pressure to an oil which is used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:23])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.N1C=CN=C1.[C:29]([Si:33]([CH3:36])([CH3:35])Cl)([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C.CCOC(C)=O>[Si:33]([O:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:23])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@@H]3c4cc([N+](=O)[O-])c(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cc2c(cc1[N+](=O)[O-])[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 3-hydroxy-2-nitroestra-1,3,5(10)-trien-17-one (76b, 1.10 g, 3.5 mmol) in DMF (10 mL) were added imidazole (0.476 g, 7.0 mmol) and tert-butyldimethylchlorosilane (0.690 g, 4.6 mmol) at room temperature. The reaction mixture was stirred for 1 h, and diluted with EtOAc, and washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:EtOAc (5:1→2:1, v/v) to afford 1.45 g of 89 (97% yield) mp: 184-185° C.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[OH-].[Na+].O.[C:12]1([CH3:24])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20](Cl)(=[O:22])=[O:21]>C1(C)C=CC=CC=1>[C:12]1([CH3:24])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)(=[O:21])=[O:22]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(OS(=O)(=O)c2c(C)cc(C)cc2C)cc1
Reaction time: 1 h

Procedure:
10.8 g of p-cresol is added to a mixture containing 9.17 g of 48% NaOH, 50 ml of water and 50 ml of toluene. To the resulting mixture is added 22.9 g of mesitylenesulfonyl chloride, and reaction is carried out at 60° to 65° C. for 1 hour. After separating the aqueous layer, toluene is removed from the toluene layer by distillation. The resulting desired compound is purified with methanol.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].CI.[CH2:9]([C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]=1[C:22]([OH:24])=O)[CH3:10].CN([CH:28]=[O:29])C>>[CH2:9]([C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:13]([C:14]([O:16][CH3:1])=[O:15])[C:12]=1[C:22]([O:29][CH3:28])=[O:24])[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: CCc1cc(OC)cc(C(=O)O)c1C(=O)O
Agent: [K+]
Solvent: CI
Product: CCc1cc(OC)cc(C(=O)OC)c1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
K2CO3 (63.9 g, 462 mmol) and MeI (28.8 mL, 462 mmol) were added to a solution of compound H (34.6 g, 154 mmol) in DMF (500 mL) at 0° C. The mixture was warmed to room temperature and stirred for 2 h, and at 40° C. for 1 h. MeI (28.8 mL, 462 mmol) was added and the mixture was stirred for 14 h. Additional MeI (28.8 mL, 462 mmol) was then added to the reaction mixture. After being stirred for 8 h, the mixture was concentrated in vacuo and water was added to the residue. The aqueous phase was extracted 3 times with ethyl acetate and the combined organic phases were washed with H2O, then brine, and dried over Na2SO4. The organic phase was then concentrated in vacuo and purified by silica gel column chromatography (ethyl acetate:hexane=1:6), yielding the desired compound I (36.0 g, 143 mmol) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C=O.[C:34](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH:26]5[CH2:27][CH2:28][N:29]([CH3:34])[CH2:30][CH2:31]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OC4CCNCC4)cc32)nc1-c1cccc(Cl)c1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(Oc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a mixture of 0.041 g (0.09 mmole) 4-(3-chloro-phenyl)-2-[6-(piperidin-4-yloxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.21), 0.0135 mL of 37% aqueous formaldehyde solution, 0.0062 mL (0.11 mmole) of acetic acid and 2.1 mL of methanol-dichloromethane (2:5) was added 0.029 g (0.14 mmole) of sodium triacetoxy-borohydride. The mixture was stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure. The residue was diluted with dichloromethane-ethyl acetate and washed with aqueous 1M sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 10:90-20:80) to give 0.034 g of 4-(3-chloro-phenyl)-2-[6-(1-methyl-piperidin-4-yloxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (1.22). MH+/Z=468
Reaction SMILES: [C:1](Cl)(=[O:19])[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][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[OH2:27].Cl.[C:29]([O:32][CH2:33][CH3:34])(=[O:31])[CH3:30]>>[C:1]([OH:19])(=[O:31])[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][CH2:16][CH2:17][CH3:18].[C:29]([OH:32])(=[O:31])[CH2:30][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1].[OH:19][CH2:1][CH:34]([CH2:33][OH:32])[OH:27].[OH:19][CH2:1][CH:34]([CH2:33][OH:32])[OH:27]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: O
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)O
Product: OCC(O)CO
Temperature: 25 °C
Reaction time: 27 h

Procedure:
To 42 parts by weight of the diglycerol monoisopropylidene obtained above were added 134 parts by weight of stearic acid chloride and 35 parts by weight of pyridine and the resulting mixture was stirred at room temperature for 27 hours. Then water and ethyl acetate were added to this mixture, followed by extraction. The ethyl acetate phase was separated therefrom and the ethyl acetate was distilled off under reduced pressure. 200 parts by weight of diethyl ether was added to the residue, which was dissolved therein. To the solution thus obtained was added 300 parts by weight of conc. hydrochloric acid and the resulting mixture was stirred at room temperature for 1 hour. Then the mixture was separated into two phases and the aqueous phase was eliminated. The diethyl ether phase was repeatedly washed with water until the aqueous phase became neutral. The diethyl ether phase was separated therefrom and the diethyl ether was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give diglycerol 1,2-distearate (containing about 90% by weight). (Preparation of oil-in-water type emulsion (modifier composition) b)
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([F:12])[CH:6]=1.[C:13]1(=O)[CH2:16][CH2:15][CH2:14]1.[OH-].[Na+]>C(O)(=O)C.O>[F:12][C:7]1[CH:6]=[C:5]([NH:4][C:13]2([C:1]#[N:2])[CH2:16][CH2:15][CH2:14]2)[CH:10]=[CH:9][C:8]=1[OH:11]
Reactant: [C-]#N
Reactant: Nc1ccc(O)c(F)c1
Reactant: O=C1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: N#CC1(Nc2ccc(O)c(F)c2)CCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.7 %

Procedure:
Sodium cyanide (2.5 g, 50.8 mmol) was added to a mixture of 4-amino-2-fluorophenol (4.3 g, 33.9 mmol) and cyclobutanone (3.8 mL, 50.8 mmol) in acetic acid (99%, 30 mL) hooked up to a NaOH scrubber and the resulting mixture was stirred at room temperature for 6 h. The mixture was poured in water and the aqueous layer was extracted with EtOAc (3×). The organics were combined, washed with a saturated solution of sodium bicarbonate (4×), dried over sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0 to 50% EtOAc/hexanes to afford 4.8 g of 1-((3-fluoro-4-hydroxyphenyl)amino)cyclobutanecarbonitrile as a beige solid. 1H NMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H), 6.80 (t, 1H), 6.36 (dd, 1H), 6.28 (m, 2H), 2.71-2.62 (m, 2H), 2.35-2.25 (m, 2H), 2.12-2.00 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]#[N:15])=[C:12]([C:16]([O:18]CC)=[O:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-:21].[K+].O>C(O)C.C(O)(=O)C>[C:16]([C:12]1[CH:11]=[N:10][N:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=2)[C:13]=1[C:14]([NH2:15])=[O:21])([OH:18])=[O:17]
Reactant: CCOC(=O)c1cnn(-c2ccc(C)c(Cl)c2)c1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-n2ncc(C(=O)O)c2C(N)=O)cc1Cl

Procedure:
A 9.5 g. portion of ethyl 1-(3-chloro-4-methylphenyl)-5-cyano-4-pyrazolecarboxylate was dissolved in250 ml. of ethanol, and 2 g. of potassium hydroxide was added. The mixture was then stirred under reflux for 30 minutes. One hundred ml. of water wasadded, and the mixture was stirred under reflux for an additional 4 hours. Isolation of the product was attempted, but it was found to be a difficultly separable mixture, and the entire reaction mixture was returned to the flask, redissolved in aqueous ethanol and refluxed for 1 hour on the steam bath with 6 g. of additional potassium hydroxide. The mixture was then diluted with aqueous acetic acid and filtered, and the solids were dried and identified as 5.2 g. of the desired product, m.p. 228°-232° dec. It was identified by elemental analysis.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC([O:24][CH:25]([CH3:27])C)=O.[C:34]1(=[O:63])[N:38]([CH:39]([CH2:55][CH2:56]O)[C:40]([NH:42][CH:43]([CH2:48][CH2:49][CH:50]([O:53][CH3:54])[O:51][CH3:52])[C:44]([O:46][CH3:47])=[O:45])=[O:41])[C:37](=[O:58])[C:36]2=[CH:59][CH:60]=[CH:61][CH:62]=[C:35]12.[S:64]1C=CC=C1CC(O)=O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[C:37]1(=[O:58])[N:38]([CH:39]([CH2:55][CH2:56][S:64][C:25](=[O:24])[CH3:27])[C:40]([NH:42][CH:43]([CH2:48][CH2:49][CH:50]([O:53][CH3:54])[O:51][CH3:52])[C:44]([O:46][CH3:47])=[O:45])=[O:41])[C:34](=[O:63])[C:35]2=[CH:62][CH:61]=[CH:60][CH:59]=[C:36]12
Reactant: COC(=O)C(CCC(OC)OC)NC(=O)C(CCO)N1C(=O)c2ccccc2C1=O
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: O=C(O)Cc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(CCC(OC)OC)NC(=O)C(CCSC(C)=O)N1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
A 0° C. solution of triphenylphosphine (1.26 g., 4.79 mmol., 1.5 eq.) in dry tetrahydrofuran (15 ml.) was treated with diisopropyl azodicarboxylate (943 μl., 4.79 mmol.). The resultant white slurry was stirred for 30 minutes and then treated with a solution of [S-(R*,R*)]-2-[(2-phthalimido-4-hydroxy-1-oxobutyl)amino]-5,5-dimethoxypentanoic acid, methyl ester [prepared as described in Example 4(i), 1,35 g., 3.20 mmol.]in dry tetrahydrofuran (15 ml.) followed by neat thiolacetic acid (343 μl., 4.79 mmol.). The mixture was stirred at 0° C. for 1.5 hours and then partitioned between ethyl acetate (150 ml.) and 50% sodium bicarbonate (100 ml.). The ethyl acetate layer was washed with brine, dried over magnesium sulfate, filtered, concentrated, adsorbed onto Celite® and dried in vacuo. The crude material was purified by chromatography on a 2.5×15 cm silica gel column eluting with 1:1 ethyl acetate:hexane (11.) and 6:4 ethyl acetate:hexane (11.). The desired fractions were combined, concentrated and dried in vacuo affording 1.35 g. of title produce as an oil. TLC (8:2, ethyl acetate:hexane) Rf =0.42.