Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH2:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1>>[ClH:1].[CH3:28][N:8]([C:9]1[CH:27]=[CH:26][C:12]2[N:13]([CH3:25])[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][C:11]=2[CH:10]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH2:40])(=[O:38])=[O:39])=[CH:32][CH:31]=2)[N:7]=1
Reactant: CN(c1ccc2c(c1)nc(NCCc1ccccc1)n2C)c1ccnc(Cl)n1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Product: CN(c1ccc2c(c1)nc(NCCc1ccccc1)n2C)c1ccnc(Nc2ccc(CS(N)(=O)=O)cc2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example 1 with N5-(2-Chloro-pyrimidin-4-yl)-1,N5-dimethyl-N2-phenethyl-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and (4-amino-phenyl)-methanesulfonamide (46 mg, 0.25 mmol) as a white solid (37 mg, 26%). 1H NMR (300 MHz, d6-DMSO) δ 9.17 (s, 1H), 7.76-7.78 (m, 3H), 7.21-7.34 (m, 8H), 7.19 (s, 1H), 7.13 (d, J=1.8 Hz, 1H), 7.00 (br s, 1H), 6.84 (dd, J=8.1 and 1.5 Hz, 1H), 6.77 (s, 2H), 5.63 (d, J=6.0 Hz, 1H), 4.16 (s, 2H), 3.54-3.61 (m, 2H), 3.52 (s, 3H), 3.45 (s, 3H), 2.92-2.97 (m, 2H) ppm. MS (ESI) m/z=543 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:34]([NH2:37])(=[O:36])=[O:35])[C:30]([CH3:33])=[CH:31][CH:32]=1>>[CH3:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])=[CH:28][C:29]=1[S:34](=[O:36])(=[O:35])[NH2:37]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Product: Cc1ccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(N)(=O)=O

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-6-methyl-benzenesulfonamide [CAS-No. 6973-09-7] according to general procedure II. Yellow solid. MS (ISP) 526.2 [(M+H+]; mp 249° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[C:7]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)#[N:8].N1C=CC=CC=1>C(Cl)Cl>[C:7]([C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:4](=[O:5])[CH2:3][CH2:2][Cl:1])=[CH:11][CH:10]=1)#[N:8]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(Cl)CCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(NC(=O)CCCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
3-Chloropropionylchloride (1.08 g; 8.5 mmol) was added to a cooled (10° C.) solution of 4-cyanoaniline (1.0 g; 8.5 mmol) and pyridine (0.69 mL; 8.5 mnol) in DCM (40 mL), and the reaction mixture was stirred at rt. for 1 h. The reaction mixture was extracted with HCl (2N), washed with water, dried and concentrated to give the sub-title compound in a 81% yield.
Reaction SMILES: [C:1]([CH:5]1CCC(=O)CC1)(C)([CH3:3])[CH3:2].C(N(S(F)(F)[F:18])CC)C.[F:21][C:22]1[CH:27]=[CH:26][C:25](OC)=[CH:24][CH:23]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:21][C:22]1([F:18])[CH2:27][CH2:26][CH:25]([C:1]([CH3:5])([CH3:3])[CH3:2])[CH2:24][CH2:23]1
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc(F)cc1
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C1CCC(F)(F)CC1
Yield: 67 %

Procedure:
A reaction of 4-t-butylcyclohexanone (2 mmol) with diethylaminosulfur trifluoride (3.0 mmol) in CH2Cl2 (10 mL) containing TiCl4 (0.3 mmol) at room temperature gave a 99% conversion of starting material to products and a 67% yield of 1,1-difluoro-4-t-butylcyclohexane after 6 h. as determined by NMR (4-fluoroanisole as internal standard).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[Cl:21][C:22]1[CH:31]=[CH:30][C:25]([CH2:26][N:27]=[C:28]=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][NH:27][C:28]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])=[C:8]([C:14]3[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=3)[CH:9]=2)=[O:29])=[CH:30][CH:31]=1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=NCc1ccc(Cl)cc1
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)NCc2ccc(Cl)cc2)cc1-c1ccnn1C
Reaction time: 8 h

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (20.5 mg, 0.075 mmol) in CH2Cl2 (2 mL) was added 4-chlorobenzyl isocyanate (0.17 μL, 0.128 mmol) and stirred overnight. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 126 as a slightly yellow oil (29.8 mg, 90%). LCMS m/z (%)=442 (M+H35Cl, 100), 444 (M+H37Cl, 40) 1H NMR (400 MHz, DMSO-d6) δ: 8.53 (bs, 1H), 7.43 (d, J=1.81 Hz, 1H), 7.41-7.36 (m, 4H), 7.34-7.28 (m, 3H), 7.03 (d, J=8.94 Hz, 1H), 6.63 (d, J=6.00 Hz, 1H), 6.20 (d, J=1.83 Hz, 1H), 4.26 (d, J=5.96 Hz, 2H), 3.94 (t, J=6.36 Hz, 2H), 3.63 (s, 3H), 2.18 (t, J=7.05 Hz, 2H), 2.06 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[C:22]([O:27][CH3:28])(=[O:26])[C:23]([CH3:25])=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([C:22]([O:27][CH3:28])=[O:26])[CH3:25])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(F)cc2C(c2ccccc2Cl)=NC1
Reactant: COC(=O)C(C)=O
Product: COC(=O)C(C)=NNC1=Nc2ccc(F)cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 7-fluoro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be stirred with methyl pyruvate at room temperature to give 7-fluoro-2-[[1-(methoxycarbonyl)ethylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH:12]1([CH2:17][NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:2]([NH:18][CH2:17][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCC1)OCc1ccccc1
Reaction time: 8 h
Yield: 121.7 %

Procedure:
Benzyl chloroformate (0.919 g, 5.38 mmol) was added to a solution of cyclopentylmethylamine (0.445 g, 4.49 mmol) and DIEA (1.74 g, 13.5 mmol) in 50 mL of CH2Cl2 and the mixture was strried overnight at R.T. The mixture was concentrated in vacuo and the residue was taken up in EtOAc, washed with water, sat. aq. NaHCO3, brine, dried over MgSO4 and concentrated to give the crude N-Cbz-cyclopentylmethylamine (1.275 g) which was used without further purification. 1H NMR consistent with structure.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26]([CH3:34])[CH:27]=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>C(C(C)=O)C.C1(C)C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH:26]([CH3:34])[CH:27]=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CCOC(=O)C=CC(C)Br
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCC(C)=O
Product: CCOC(=O)C=CC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 40 °C

Procedure:
40 ml of dimethyl sulfoxide, 4.2 g of hydroquinone, 5.0 g of 2-chloro-5-trifluoromethylpyridine and 2.3 g of potassium hydroxide were reacted with stirring in a nitrogen gas stream at 150° C. for 2 hours to obtain 2.5 g of 4-(5-trifluoromethyl-2-pyridyloxy)phenol. The thus-obtained 4-(5-trifluoromethyl-2-pyridyloxy)phenol was dissolved in 20 ml of methyl ethyl ketone, and 1.7 g of anhydrous potassium carbonate was added thereto. The mixture was reacted with stirring under reflux for 1 hour, and the reaction product thusobtained was cooled to 40° C., and 2.5 g of ethyl 4-bromo-2-pentenoate was dropwise added thereto gradually. The mixture was allowed to stir for 30 minutes and then to react under reflux for 7 hours. After completion of the reaction, the reaction product was thrown into 100 ml of water, and an oily matter was extracted with methylene chloride. The extracted phase was washed with water several times, and dried over anhydrous sodium sulfate. The solvent was evaporated off to obtain a crude product which was subsequently subjected to silica gel column chromatography using toluene as an eluent to obtain 1.5 g of the object product having a refractive index, nD23, of 1.5145. This was found to have a boiling point of 148°-151° C./l mm Hg with some decomposition.
Reaction SMILES: CCC1C=CC(CC[O:11][C:12]2[CH:13]=CC(C[CH:19]3SC(=O)N[C:20]3=[O:21])=C[CH:17]=2)=NC=1.Cl.[OH2:27].CC(C)=[O:30]>CO>[CH3:17][CH:12]([OH:11])[C:13]([OH:30])=[O:27].[CH2:20]([OH:21])[C:19]([OH:30])=[O:27]
Reactant: O
Reactant: CC(C)=O
Reactant: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Agent: Cl
Solvent: CO
Product: CC(O)C(=O)O
Product: O=C(O)CO
Temperature: 40 °C

Procedure:
PLGA (PLGA7520, lactic acid/glycolic acid=75/25, weight average molecular weight 20,000, manufactured by Wako Pure Chemical Industries, Ltd.) (2 g) was dissolved in acetone (20 mL), and pioglitazone hydrochloride (100 mg) dissolved in methanol (10 mL) was added to give a polymer solution. The solution was added dropwise at a constant rate of 4 mL/min to an aqueous solution (50 mL) of 2 wt % polyvinyl alcohol (PVA, manufactured by KURARAY CO., LTD.) with stirring at 40° C. At this time, an emulsion droplet of a nanometer size is prepared due to a self-emulsion action caused by the turbulence in the emulsion droplet surface by mutual diffusion of acetone, methanol and water. Thereafter, acetone and methanol were evaporated and the obtained PLGA nanoparticle suspension was centrifuged (centrifuge acceleration 41000 G, −20° C., 20 min) to give PLGA nanoparticle precipitate, which was resuspended in purified water to remove excess PVA not adsorbed on the PLGA surface. Thereto was added an aqueous solution (50 mL) of 0.02 wt % chitosan (manufactured by Katakura Chikkarin Co., Ltd.), and the mixture was stirred for 1 hr and freeze-dried at −45° C. to powderize pioglitazone-containing chitosan-modified PLGA nanoparticles.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([CH2:25][C:26]#[N:27])(=[O:24])=[O:23].O>N1CCCCC1.C(O)C>[CH:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[C:25](/[S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)(=[O:24])=[O:23])\[C:26]#[N:27])[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:3])[CH3:2]
Reactant: N#CCS(=O)(=O)c1ccccn1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Solvent: C1CCNCC1
Solvent: O
Solvent: CCO
Product: CC(C)c1cc(/C=C(\C#N)S(=O)(=O)c2ccccn2)cc(C(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.3 %

Procedure:
The reaction mixture of 450.0 mg of 3,5-diisopropyl-4-hydroxylbenzaldehyde, 400.0 mg of 2-pyridinesulphonylacetonitrile and a few drops of piperidine in 10.0 mL of ethanol was refluxed for 3 h and then cooled to room temperature. To the above reaction mixture was added 5.0 mL of water until crystallization began. After standing at 0° C. for 2 h, the solid was filtered, washed with cold water and dried in oven at 40° C. overnight to provide 350.0 mg of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=O)[NH:14][C:13](=[S:17])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.Br[CH2:25][CH2:26][CH:27]1[CH2:29][CH2:28]1.[C:30]([O-:33])([O-])=O.[K+].[K+]>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:30](=[O:33])[N:14]([CH2:15][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:13]([S:17][CH2:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)=[N:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: BrCCC1CC1
Reactant: O=C1NC(=S)NC12CC(c1ccccc1)Oc1ccc(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1N(CCC2CC2)C(SCCC2CC2)=NC12CC(c1ccccc1)Oc1ccc(Br)cc12
Temperature: 60 °C
Reaction time: 4 h
Yield: 11.8 %

Procedure:
A mixture of 6-bromo-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (250 mg, 0.644 mmol), excess (2-bromoethyl)cyclopropane (381 mg, 2.58 mmol), and solid K2CO3 (356 mg, 2.58 mmol) in CH3CN (10 mL) was stirred for 4 hours at 60° C. The mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC to give 6-bromo-1′-(2-cyclopropylethyl)-2′-(2-cyclopropylethylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (40 mg, 11%).
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17](=O)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:14]=3)[C:9]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:8]2[CH2:32][C:33]([CH3:39])([CH3:38])[C:34]([O:36]C)=[O:35])=[CH:4][CH:3]=1.ClC1C=C[C:46]([CH2:47][N:48]2C3C(=CC(OC(=O)C4C=CC=CC=4)=CC=3)C(C(=O)C3C=CC=CC=3)=C2CC(C)(C)C(OC)=O)=[CH:45]C=1>>[Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]5[C:47](=[CH:46][CH:45]=[CH:19][CH:20]=5)[N:48]=4)=[CH:13][CH:14]=3)[C:9]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:8]2[CH2:32][C:33]([CH3:39])([CH3:38])[C:34]([OH:36])=[O:35])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)c2ccccc2)c2cc(OC(=O)c3ccccc3)ccc2n1Cc1ccc(Cl)cc1
Reactant: COC(=O)C(C)(C)Cc1c(Cc2ccccc2)c2cc(OC(=O)c3ccccc3)ccc2n1Cc1ccc(Cl)cc1
Product: CC(C)(Cc1c(Cc2ccccc2)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared under the conditions described in Step B and Step C of Example 9 but substituting the ester from Example 10 (Step A) for the ester of Example 9 (Step A), m.p. 178° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[O:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[CH:26][C:23]=1[CH:24]=O.C[O-].[Li+].Cl>CN(C)C=O.CO.O>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[CH:26][C:23]=1/[CH:24]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[O:16][N:15]=2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2cc(C)on2)cc1
Reactant: COc1cc(OC)c(-c2cccs2)cc1C=O
Agent: C[O-]
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)Nc2cc(C)on2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
4-Acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide (Ex-1B, 2.50 g, 8.9 mmol) and 2,4-dimethoxy-5-thien-2-ylbenzaldehyde (Ex-1A, 2.20 g, 8.9 mmol) were dissolved in a dimethylformamide-methanol solution (55 mL, 7:3). After complete dissolution, lithium methoxide (1.35 g, 35.6 mmol) was added and the resulting orange slurry was stirred in the dark at room temperature for 1 h. Upon completion, as determined by HPLC, the mixture was diluted with water (80 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3×40 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethanol (20 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 3.78 g (83%) of the title compound as an orange solid, mp 202–203° C. 1H-NMR (300 MHz, DMSO-d6) 8.31 (d, 2H, J=8.1 Hz), 8.27 (s, 1H), 8.08 (d, 1H, J=15.9 Hz), 8.01 (d, 2H, J=8.1 Hz), 7.88 (d, 1H, J=15.9 Hz), 7.66 (d, 1H, J=3.3 Hz), 7.53 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.3 Hz), 6.84 (s, 1H), 6.18 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 2.31 (s, 3H). Anal. Calcd. for C25H22N2O6S2: C, 58.81; H, 4.34; N, 5.49; S, 12.56; Found: C, 58.68; H, 4.40; N, 5.61; S, 12.62. HRMS (EI) Calcd. for C25H22N2O6S2: 511.0997 (M+); Found: 511.0983.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][Si:5]1([CH3:19])[O:12][Si:11]([CH3:14])([CH3:13])[O:10][Si:9]([CH3:16])([CH3:15])[O:8][Si:7]([CH3:18])([CH3:17])[O:6]1.N1C=CC=CC=1.[F:26][C:27]([F:50])([C:31]([F:49])([F:48])[C:32]([F:47])([F:46])[C:33]([F:45])([F:44])[C:34]([F:43])([F:42])[C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37])[C:28](Cl)=[O:29]>>[F:26][C:27]([F:50])([C:31]([F:48])([F:49])[C:32]([F:46])([F:47])[C:33]([F:44])([F:45])[C:34]([F:42])([F:43])[C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37])[C:28]([O:1][CH2:2][CH2:3][CH2:4][Si:5]1([CH3:19])[O:12][Si:11]([CH3:14])([CH3:13])[O:10][Si:9]([CH3:16])([CH3:15])[O:8][Si:7]([CH3:18])([CH3:17])[O:6]1)=[O:29]
Reactant: C[Si]1(C)O[Si](C)(C)O[Si](C)(CCCO)O[Si](C)(C)O1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: c1ccncc1
Product: C[Si]1(C)O[Si](C)(C)O[Si](C)(CCCOC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)O[Si](C)(C)O1

Procedure:
A 25 mL round bottom flask equipped with a magnetic stirring bar and an addition funnel was charged with 4.0 g of (3-hydroxypropyl)heptamethylcyclotetrasiloxane (12 mmoles) and 1.0 g of pyridine (13 mmoles). The mixture was stirred and 5.0 g of perfluorooctanoyl chloride (12 mmoles) was added dropwise. After complete addition of the acid fluoride a gas chromatographic analysis indicated that essentially all of the acid chloride and most of the cyclosiloxane were consumed with one product as 96.5% of the mixture. The contents of the flask were filtered using a 0.45 micron syringe filter into a 50 mL 1-necked round bottom flask. The solids in the flask were washed with 2.5 mL of pentane and this suspension added to the syringe and filtered into the 50 mL flask. The solids in the syringe were washed with an additional 2.5 mL of pentane and filtered into the 50 mL flask. The contents of the flask were distilled at 82° C. and 0.04 mmHg to yield a fraction of [3-(perfluorooctanoyl)oxypropyl]-heptamethylcyclotetrasiloxane which corresponds to formula (I) wherein m is 1, n is 3, X is OC(O), and RF is a perfluorinated straight chain monovalent alkyl radical of 7 carbons atoms, or more specifically as shown in formula (VIII) below. ##STR9##
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])C=C.B(Cl)(Cl)Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:15]([C:13]1[CH:12]=[C:7]([CH:6]=[C:5]([OH:4])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:16]
Reactant: C=CCOc1cc(C#N)cc(C(=O)OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: COC(=O)c1cc(O)cc(C#N)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.3 %

Procedure:
A mixture of methyl 3-allyloxy-5-cyanobenzoate (1.5 g, 6.9 mmol) and tetrabutylammonium iodide (2.8 g, 7.6 mmol) in dichloromethane (38 mL) at −78° C., under argon, was treated with a solution of 1M boron trichloride in dichloromethane (24 mL, 24 mmol). After 5 minutes at −78° C., the reaction mixture was stirred at ambient temperature for 1 hour. The reaction was then quenched with ice water and stirred for an additional 30 minutes. The organic layer was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography using a gradient of 20-30% ethyl acetate/hexanes afforded 811 mg (67%) of methyl 3-cyano-5-hydroxybenzoate as a light yellow solid.
Reaction SMILES: S(=O)(=O)(O)O.CC1(C)C[O:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=N1.[OH-:27].[Na+]>O>[OH:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:9]([OH:10])=[O:27])=[CH:19][CH:20]=1
Reactant: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1-c1ccc(CO)cc1
Yield: 65 %

Procedure:
Water (6 ml) and sulfuric acid (3.6 g) were added to 2.0 g (7.11 mmol) of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)oxazoline, followed by heating under reflux for 30 hours. After the reaction liquid was cooled, it was neutralized with a 10% aqueous solution of sodium hydroxide and extracted with chloroform. After the organic phase was washed with water and dried, it was subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a chloroform/methanol system) to give 1.05 g of the title compound (yield 65%).
Reaction SMILES: [C:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[H][H]>[Ni].N>[CH2:17]([N:14]([CH2:15][CH3:16])[C:11]1[CH:12]=[CH:13][C:8]([C:3]2([CH2:1][NH2:2])[CH2:4][CH2:5][CH2:6][CH2:7]2)=[CH:9][CH:10]=1)[CH3:18]
Reactant: CCN(CC)c1ccc(C2(C#N)CCCC2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: CCN(CC)c1ccc(C2(CN)CCCC2)cc1
Yield: 93.4 %

Procedure:
In a pressure reactor was placed 10.4 g (0.043 mole) of 1-cyano-1-(4-diethylaminophenyl)cyclopentane, 100 mL of methanolic ammonia, and 10 g of Ra-Ni catalyst. The reactor was charged with hydrogen and shaken at room temperature until the theoretical amount of hydrogen was taken up. The reaction mixture was filtered and the filtrate concentrated in vacuo to yield 9.9 g of the desired amine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:19]=[N+:20]=[N-:21])=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CN=[N+]=[N-])cc1-c1ccccc1
Temperature: 75 °C
Yield: 77.1 %

Procedure:
A mixture of 4-bromomethyl-2-phenylbenzoic acid methyl ester (1.5 g, 4.9 mmol), sodium azide (1.28 g, 19.7 mmol) and tetrabutylammonium iodide (1.3 g, 4.9 mmol) in DMF (16 mL) was heated at 75° C. for 18 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (15% ethyl acetate-hexanes) to give the desired azide as a colorless oil (1.01 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.C(OC(=O)[C@@H](OC)CC1C=CC(O[CH2:29][CH2:30][Br:31])=CC=1)C>>[CH3:1][O:2][C:3](=[O:15])[CH:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:29][CH2:30][Br:31])[CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: COC(=O)C(Cc1cccc(O)c1)OC
Product: COC(=O)C(Cc1cccc(OCCBr)c1)OC

Procedure:
The title compound was prepared from 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (Example 291, Step 4) (4.76 mol, 1000 mg) via the same procedure used for the preparation of (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2). MS (ES) for C13H17BrO4 [M+NH4]+: 334:2.