Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([C@H:16]([N:20]2[CH:24]=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=[N:21]2)[CH2:17][C:18]#[N:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.O1CCOCC1.O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]1([C@H:16]([N:20]2[CH:24]=[C:23]([C:2]3[C:3]4[CH:10]=[CH:9][NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH:22]=[N:21]2)[CH2:17][C:18]#[N:19])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC1(C)OB(c2cnn([C@H](CC#N)C3CCCC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#CC[C@H](C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 95 °C
Reaction time: 17 h
Yield: 64.3 %

Procedure:
Method C. To a 25 mL round bottom flask equipped with a stir bar, condenser, and three-way valve connected to nitrogen and vacuum was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 154 mg, 1.00 mmol), (3R)-3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile ((R)-24, 445 mg, 1.41 mmol, 1.41 equiv), 1,4-dioxane(2.78 mL, 35.6 mmol), water (1.39 mL, 77.2 mmol), and potassium carbonate (K2CO3, 693 mg, 5.02 mmol, 5.0 equiv) at room temperature. The resulting mixture was degassed three times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (207 mg, 0.180 mmol, 0.18 equiv). The resulting reaction mixture was degassed four times back filling with nitrogen each time and then warmed to 95° C. The reaction mixture was stirred at 95° C. for 17 hours. When the reaction was deemed complete, the reaction mixture was cooled to room temperature before being diluted with ethyl acetate (20 mL) and 20% aqueous brine (11 mL). The mixture was stirred vigorously at room temperature until the majority of solids had gone into solution. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic extracts were washed with saturated brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was then purified by flash chromatography (SiO2, 0-100% ethyl acetate/hexanes gradient elution) to afford (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile ((R)-12, 197 mg, 306.4 mg theoretical, 64.3% yield) as colorless oil, which was solidified upon standing at room temperature. For (R)-12: 1H NMR (DMSO-d6, 400 MHz) δ ppm 12.1 (bs, 1H), 8.80 (d, 1H, J=0.42 Hz), 8.67 (s, 1H), 8.37 (s, 1H), 7.59 (dd, 1H, J=2.34, 3.51 Hz), 6.98 (dd, 1H, J=1.40, 3.44 Hz), 4.53 (td, 1H, J=19.5, 4.63 Hz), 3.26 (dd, 1H, J=9.77, 17.2 Hz), 3.18 (dd, 1H, J=4.32, 17.3 Hz), 2.40 (m, 1H), 1.79 (m, 1H), 1.65 to 1.13 (m, 7H); C17H18N6(MW, 306.37) LCMS (EI) m/e 307 [M++H].
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH3:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].C(=O)C1C=CC=CC=1>[OH-].[Na+]>[CH3:6][C:7]1[CH:14]=[C:13]([O:15][CH2:1][CH:3]2[O:5][CH2:4]2)[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: ClCC1CO1
Reactant: Cc1cc(O)ccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=Cc1ccccc1
Product: Cc1cc(OCC2CO2)ccc1C=O
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To epichlorohydrin (20 g., 0.216 mole) heated at 55° C. is added dropwise a solution of 2-methyl-4-hydroxybenzaldehyde (9.0 g., 0.066 mole) in 2.5 N sodium hydroxide solution (40 ml.). After the addition, the solution is allowed to stir an additional 3 hours at 55° C. and then at room temperature overnight. The oil is distilled to give 8.3 g. of 2-methyl-4-82,3-epoxypropyl)benzaldehyde, m.p. 160°-170° C. at 1 mm. Hg.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([Br:1])=[CH:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Brc1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cn(Cc2ccccc2)c2ncccc12
Reaction time: 0.83 h

Procedure:
To a solution of 3-bromo-1H-pyrrolo[2,3-b]pyridine (500 mg) in N,N-dimethylformamide (10 mL) was added NaH (70 mg). The mixture was stirred for 50 minutes, and (bromomethyl)benzene (0.290 mL) was added dropwise. The reaction was stirred for 48 hours and quenched by the addition of water and ethyl acetate. The layers were separated, and the organic layer was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography, eluting with 2:1 hexane to ethyl acetate, to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].[C:18](OC)(OC)(OC)[CH2:19][CH2:20][CH3:21]>C(O)(=O)C>[CH3:11][N:10]1[CH:9]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:18]1[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(OC)(OC)OC
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Solvent: CC(=O)O
Product: CCCC1=Nc2ccccc2CC(c2sccc2C)N1C

Procedure:
A solution of 5.0 g of 2-amino-N-methyl-α-(3-methyl-2thienyl)benzeneethanamine, 18.02 ml trimethyl orthobutyrate and 6.8 ml of glacial acetic acid was refluxed for 8 hours under a nitrogen atmosphere. The solution was concentrated at 40° C. on a rotary evaporator and the residual oil was acidified with 10% hydrochloric acid solution (60 ml) and extracted with diethyl ether (3×70 ml). The acidic aqueous phase was basified with 10% sodium hydroxide solution (100 ml) and extracted with diethyl ether (3×100 ml). The ethereal phase was dried over sodium sulfate/magnesium sulfate, filtered and concentrated to an oil. Purification was accomplished by HPLC (Water's Associates Prep LC/System 500A, silica gel, utilizing methanol followed by 2% triethylamine in methanol as successive eluents). Concentration of the appropriate fractions yielded 4,5-dihydro-3-methyl-4-(3-methyl-2-thienyl)-2-(1-propyl)-3H-1,3-benzodiazepine as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[CH3:7][C:8]([CH3:10])=O.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>N1C=CC=CC=1>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([N:5]1[C:8]([CH3:10])([CH3:7])[S:6][C:3]([NH:2][CH3:1])=[N:4]1)=[O:15]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CC(C)=O
Reactant: CNC(=S)NN
Solvent: c1ccncc1
Product: CNC1=NN(C(=O)c2ccccc2F)C(C)(C)S1

Procedure:
A 42 g. portion of 4-methylthiosemicarbazide was reacted with 400 ml. of acetone, and then with 32 ml. of pyridine and 63.6 g. of 2-fluorobenzoyl chloride to prepare 66.5 g. of the desired product, m.p. 136°-140°.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[Br:10]N1C(=O)CCC1=O.O>CN(C)C=O.[Cl-].[Na+].O>[Br:10][C:7]1[CH:6]=[C:5]([CH3:9])[C:3]([NH2:4])=[C:2]([F:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(F)c1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc(F)c1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of crude 2-fluoro-6-methylaniline from step 3 (about 32 mmol) in anhydrous N,N-dimethylformamide (100 mL) was cooled in an ice bath, placed under a nitrogen atmosphere, treated with N-bromosuccinimide (5.7 g, 32 mmol), and then stirred at room temperature for 10 minutes. The reaction mixture was poured into a water solution of diluted brine and extracted with EtOAc. The organic extracts were washed with diluted brine three times, dried over MgSO4, filtered through a pad of silica, and concentrated under vacuum to afford 4-bromo-2-fluoro-6-methylaniline as a yellow foam.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH3:23])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)CCl>[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[C:15]1[CH3:23])[CH3:13]
Reactant: CCn1c(C)cc2ccccc21
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a stirred suspension of 22.5 g (0.15 mole) of phthalic anhydride and 61.0 g (0.30 mole) of 77.5 percent active 1-ethyl-2-methylindole in 120 ml of ethylene dichloride chilled to 0° to 5° C. by means of an ice bath, there was added in small portions 32.0 g (0.24 mole) of aluminum chloride. The mixture was maintained at 0°-5° C. for an additional 15 minutes, allowed to warm to room temperature and stirred overnight. Then, 240 ml of water was added to the reaction mixture and the ethylene dichloride layer was separated from the acidic aqueous layer. The organic layer was extracted with 600 ml of 3.5 percent aqueous sodium hydroxide. The alkaline extract was acidified with dilute hydrochloric acid and the separated solid collected, washed with water and dried to obtain 24.0 g of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]benzoic acid (formula VIII: R°=R1 =R2 = R3 =Y1 =H; R5 =CH3 ; R6 =CH2CH3), a slightly pink solid having a melting point of 184°-185° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH:8]=[CH:7]2)(=O)[CH3:2].[C:27](#[N:31])[CH2:28][C:29]#[N:30]>N1C=CC=CC=1>[C:23]([O:22][C:20]([N:17]1[CH2:16][CH2:15][N:14]([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:1]([CH3:2])=[C:28]([C:27]#[N:31])[C:29]#[N:30])[CH:5]=3)[CH:10]=2)[CH2:19][CH2:18]1)=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(=O)c1ccc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1
Reactant: N#CCC#N
Solvent: c1ccncc1
Product: CC(=C(C#N)C#N)c1ccc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1
Reaction time: 5.5 h
Yield: 77 %

Procedure:
tert-Butyl 4-(6-acetyl-2-naphthyl)-1-piperazinecarboxylate (177 mg, 0.5 mmol), prepared as described in Example 1(d), was heated with 40 mg (0.6 mmol) of malononitrile in 4 mL pyridine at 105-110° C. After 5.5 hours, an additional 24 mg of malononitrile was added, and heating was continued for a total of 12 hours and 40 minutes. The mixture was cooled and evaporated in vacuo. Polar components of the mixture were removed by column chromatography (70-230 mesh silica, Φ20×120 mm, chloroform), and the product, tert-butyl-4-[6-(2,2-dicyano-1-methylvinyl)-2-naphthyl]-1-piperazinecarboxylate, was finally purified by radial chromatography (silica, 2 mm, chloroform). 155 mg (77%) of tert-butyl-4-[6-(2,2-dicyano-1-methylvinyl)-2-naphthyl]-1-piperazinecarboxylate were obtained, which, after recrystallzation from dichloromethane—petroleum ether mixture, melted at 169-171° C. Anal. Calculated for C24H26N4O2: C, 71.62; H, 6.51; N, 13.92. Found: C, 71.62; H, 6.66; N, 13.87. 1H NMR: δ 1.50 (s, 9H, —C(CH3)3), 2.72 (s, 3H, CH3), 3.34 and 3.64 (t, J=5.1 Hz, 8H, piperazine), 7.09 (d, 1H, 5-H), 7.33 (dd, 1H, 7-H), 7.58 (dd, 1H, 3-H), 7.74 (d, 1H, 4-H), 7.81 (d, 1H, 8-H), 8.02 (d, 1H, 1-H); J5,7=2 Hz, J7,8=9.1 Hz, J1,3=2 Hz, J3,4=9.1 Hz.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:10](=[O:11])[C:9]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:8][N:7]=[C:6]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>O1CCCC1>[CH2:16]([O:15][C:13]([NH:12][C:9]1[C:10](=[O:11])[N:5]([CH2:4][CH:3]=[O:2])[C:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:7][CH:8]=1)=[O:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)OC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O
Temperature: 25 °C
Yield: 102.9 %

Procedure:
(EX-1D) A solution of [5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetaldehyde dimethyl acetal (17.24 g, 42.11 mmol) in 103.0 mL tetrahydrofuran was added 35.0 mL 1 N HCl. The resulting biphasic mixture was allowed to heated to reflux for 12 hours. The reaction mixture was allowed to cool to room temperature and the volatiles were removed under vacuum. The resulting residue was diluted with water (200 mL) and the pH was adjusted to 7 by addition of solid NaHCO3. The resulting emulsion was extracted with dichloromethane (4×150 mL). The combined organic solutions were washed with water (1×200 mL), dried (MgSO4), filtered, and concentrated to give 15.74 g crude [5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=1)=[O:13])[CH2:5]2.CS(O[CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][O:28]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][O:28]3)=[CH:16][N:15]=1)=[O:13])[CH2:5]2
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Reactant: O=C(N[C@@H]1Cc2ccc(Br)cc2C1)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1Cc2ccc(Br)cc2C1)c1ccc(OC[C@@H]2CCCO2)cn1
Temperature: 60 °C

Procedure:
A mixture of N-((R)-5-bromoindan-2-yl)-5-hydroxypyridine-2-carboxamide (1.50 g), (S)-1-(tetrahydrofuran-2-yl)methyl methanesulfonate (0.81 g), cesium carbonate (1.46 g) and DMF (20 ml) was heated to 60° C. for 4 hours. The cooled reaction mixture was admixed with water and extracted with ethyl acetate. The organic phase was washed three times with water, dried over magnesium sulfate and concentrated. This afforded the product with the molecular weight of 417.31 (C20H21BrN2O3); MS (ESI): 417 (M+H+).
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:15][CH:14]2[CH2:16][CH:11]1[CH2:12][NH:13]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1.C(=O)(O)[O-]>CS(C)=O>[CH2:3]([N:10]1[CH2:15][C@H:14]2[CH2:16][C@@H:11]1[CH2:12][N:13]2[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2C[C@H]3C[C@@H]2CN3Cc2ccccc2)cc1
Yield: 51.2 %

Procedure:
A stirring solution of title compound 206 (0.5 g, 1.914 mmol) and ethyl 4-fluorobenzoate (0.421 ml, 2.87 mmol) in DMSO (19.14 mL) was stirred at 140° C. overnight. The mixture was cooled down and poured over a diluted aqueous solution of bicarbonate and extracted with ethyl acetate (twice). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography: 0% to 60% ethyl acetate in hexanes over 20 min on 20 g SiO2 to afford title compound 207 (0.33 g, 51%) as beige oil. LRMS: (calc) 336.18. (found) 337.4 (MH)+.
Reaction SMILES: [OH:1][C@H:2]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:3](OC)=[O:4].S(C)C.[BH4-].[Na+].CO>C1COCC1>[OH:1][C@@H:2]([CH2:3][OH:4])[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C[C@@H](O)C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: COC(=O)C[C@@H](O)CO
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 112.7 %

Procedure:
To a solution of (R)-dimethyl 2-hydroxysuccinate (140 g, 0.86 mol) in THF (1400 mL) was added dropwise Me2S.BH3 (86 mL, 10 M) at 20° C. over 30 min. The mixture was stilted at 20° C. for 30 min. NaBH4 (1.63 g, 42.9 mmol) was added at 10° C. and stirred at 10° C. for 30 min. The mixture was warmed to room temperature and stirred for 1 h. CH3OH (200 mL) was slowly added to the mixture while cooling in an ice-water bath. The resulting mixture was evaporated to give (R)-methyl 3,4-dihydroxybutanoate (130 g, crude).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][C:10]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=4)[NH:15][CH:14]=3)=[CH:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH3:24]I>CN(C)C=O>[O:6]1[C:7]2([CH2:12][CH2:11][C:10]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=4)[N:15]([CH3:24])[CH:14]=3)=[CH:9][CH2:8]2)[O:3][CH2:4][CH2:5]1
Reactant: N#Cc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C2=CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
To a suspension of sodium hydride (60%, 1.74 g, 0.073 mol) in anhydrous N,N-dimethylformamide (100 ml) was added 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-cyano-1H-indole (9.9 g, 0.035 mol) at room temperature. The mixture was stirred for 30 minutes at room temperature, then methyl iodide (9 ml, 0.14 mol) was added at room temperature. The reaction was allowed to stir for 1 hour, then quenched with water (50 ml). The mixture was extracted with methylene chloride (3×150 ml) and water (3×150 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under vacuum. Chromatography (5% methanol-methylene chloride) afforded 2.54 g (24%) of product as a light yellow solid: mp 65-67° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18][OH:19].[CH3:22][C:23]([C:25]([O:27]C)=O)=C>O.C(OCC)(=O)C>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:3][CH2:2][CH2:7][CH2:6][CH2:22][CH2:23][C:25]([O:19][CH2:18]/[CH:17]=[C:16](/[CH:15]=[CH:14]/[CH:13]=[C:12](/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])\[CH3:21])\[CH3:20])=[O:27]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Reactant: C=C(C)C(=O)OC
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C

Procedure:
An aqueous phase was prepared by dissolving 0.5 g of poly(vinyl alcohol) in 50 ml water saturated by 6 ml of ethyl acetate. An organic phase was prepared by dissolving 0.075 g retinol palmitate, 0.1 g mineral oil, 0.01 g of an antioxidant (chosen from BHA, BHT, tocopherol or their mixture) and 0.815 g PMMA in 5 ml of ethyl acetate. The organic phase was poured into the aqueous phase while stirring and then 100 ml of fresh water were added. The microcapsules formed were filtered, washed by water and dried at the temperature no higher 20° C. An average diameter of the microcapsules was 40 μm.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]([CH:13]([CH2:23][CH2:24][CH2:25][CH:26]([O:32]CC1C=CC=CC=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:12])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][C:11]([CH:13]([CH2:23][CH2:24][CH2:25][CH:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:12]
Reactant: [H][H]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)O)C(=O)CCOCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(=O)CCO
Yield: 97 %

Procedure:
A magnetically stirred solution of 8-(3-benzyloxypropionyl)-12-benzyloxyheptadecanoic acid (2.37 g., 4.4 millimole) in ethanol (50 ml.) is subjected to hydrogenation at atmospheric pressure at 23° C. in the presence of a 10% palladium on charcoal catalyst (0.3 g.) for one hour. The hydrogen uptake is 2.4 ml. (100% theory). The catalyst is removed by filtration and the solvent is removed by evaporation in vacuo to give 8-(3-hydroxypropionyl)-12-hydroxyheptadecanoic acid . 1/3 chloroformate as a viscous, colorless liquid (1.55 g., 97% yield); pmr (CDCl3) δ 0.88 (3H, t), 2.03 (H,m), 2.32 (2H,t), 2.68 (2H,t, J=5.5 cps.), 3.65 (H, b.s.), 3.86 (2H,t, J=5.5 cps.), 5.50 (3H, exchangeable s) and 7.32 (1/3H,s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19]O)[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][S:30]([CH3:29])(=[O:32])=[O:31])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncn(-c2ccc(N3C[C@H](CS(C)(=O)=O)OC3=O)cc2F)n1
Temperature: 25 °C
Yield: 44.9 %

Procedure:
(5R)-3-[3-Fluoro-4-(3-methyl-1,2,4-triazol-1-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one (Intermediate 25) (10.08 g, 34.5 mmol) in dichloromethane (100 ml) and triethylamine (6.0 ml, 43 mmol) was cooled to 0° C. and methanesulfonyl chloride (3.2 ml, 41 mmol) was added by syringe. The reaction mixture was allowed to warm to room temperature overnight. More pyridine (50 ml) was added and the reaction mixture was cooled to 0° C. before adding additional methanesulfonyl chloride (3.2 ml, 41 mmol). The reaction was allowed to warm to room temperature and the solid was collected by filtration and washed with ethyl acetate to afford the crude title compound (5.49 g).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:16][C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][C:20]=2[CH:21]=1>>[CH:26]([C:23]1[CH:24]=[CH:25][C:19]2[O:18][C:17]([CH2:16][N:13]3[C:14]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:6][C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:21][C:20]=2[CH:22]=1)=[O:27]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: O=Cc1ccc2oc(CBr)cc2c1
Product: O=Cc1ccc2oc(CN3c4ccccc4Sc4ccccc43)cc2c1
Yield: 33.2 %

Procedure:
The title compound (1.14 g, 33%) was prepared as a syrupy liquid from phenothiazine (2.87 g, 14.0 mmol) and 2-bromomethyl-5-formyl benzofuran (2.3 g, 9.6 mmol) by a similar procedure to that described in preparation 5.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]([OH:14])=O)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:12](=[O:14])[CH2:11][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)Cc1ccc(O)c2[nH]ncc12
Product: O=C(Cc1ccc(O)c2[nH]ncc12)NCc1ccccc1

Procedure:
2.3 g of 2-(7-hydroxy-1H-indazol-4-yl)acetic acid is reacted analogously to Example 19(c) with benzylamine in place of dipropylamine. The product is recrystallized from methanol/diisopropyl ether, thus obtaining 2.6 g of 2-(7-hydroxy-1H-indazol-4-yl)acetic acid benzylamide, mp 188°-190° C.