Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[F:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:52][CH:50]([C:47]2[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=2)[CH3:51])=[O:41])=[C:18]([CH3:23])[CH:17]=1
Reactant: CC(N)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4ccc(F)cc4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (78 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4-fluorophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (79 mg, yield 66%).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][C:22]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])=[O:23]>C1(C)C=CC=CC=1>[Br-:20].[CH3:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][C:22]([CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:23]
Reactant: COCCOCCOC(=O)CBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COCCOCCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 12.8 g (49 mmol) of triphenylphosphine in 80 ml of toluene was treated within 10 minutes with a solution of 10.7 g (44.3 mmol) of 2-(2-methoxyethoxy)ethyl bromoacetate in 20 ml of toluene. The reaction mixture was stirred at room temperature for 4 hours. The precipitate was filtered off, washed with toluene and dried in a water-jet vacuum. There was obtained [[[2-(2-methoxyethoxy)-ethoxy]carbonyl]methyl]triphenylphosphonium bromide which is processed directly.
Reaction SMILES: N.[OH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[Na]>C(O)C>[CH3:14][O:13][C:10]1[CH2:11][CH:12]=[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][OH:2])[CH2:8][CH:9]=1
Reactant: COc1ccc(CCCCO)cc1
Agent: N
Agent: [Na]
Solvent: CCO
Product: COC1=CCC(CCCCO)=CC1
Reaction time: 0.17 h

Procedure:
Ammonia (75 ml) is liquified in a flask at -40° and a solution of 5 g (28 mmol) of p-(4-hydroxybutyl)-anisole in 25 ml ethanol is added 2.76 g (0.12 mmol) of sodium is added in small pieces over 1 h. The blue solution is then stirred at -40° for 10 min during which time the solution decolorizes with the formation of a white precipitate. The reaction is quenched using 5.88 g solid ammonium chloride followed by 25 ml water. The solvent is evaporated under a stream of nitrogen and then poured into brine and extracted with ether (4×100 ml). The organic extracts are combined, dried, filtered and subjected to evaporation to give 1-methoxy-4-(4-hydroxybutyl)-cyclohexa-1,4-diene as an oil.
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].CCO[C:13]([S-:15])=[S:14].[K+]>CN(C)C=O.O.Cl>[I:9][C:7]1[CH:6]=[CH:5][C:3]2[N:4]=[C:13]([SH:15])[S:14][C:2]=2[CH:8]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccc(I)cc1F
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Sc1nc2ccc(I)cc2s1
Temperature: 95 °C
Reaction time: 5 h

Procedure:
A mixture of 2-fluoro-4-iodoaniline (24.19 g, 0.100 mole) and potassium ethylxanthogenate (35.27 g, 0.220 mole) in N,N-dimethylformamide (80 mL) was stirred at 95° C. for 5 hours. The reaction mixture was cooled to room temperature then diluted with water (150 mL) and 1 N aqueous HCl (200 mL). The mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration and rinsed with water. The solid was dried overnight at 85° C. in a vacuum oven to provide 6-iodobenzo[d]thiazole-2-thiol. 1H NMR (300 MHz, CD3OD) δ ppm 7.09 (d, J=8 Hz, 1H), 7.70 (dd, J=2, 8 Hz, 1H), 8.10 (d, J=2 Hz, 1H), 13.82 (sbroad, 1H); MS (DCI/NH3) m/z 294 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH2:19]([C:21]1[O:22][CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1)[CH3:20]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:24]3[N:25]=[C:21]([CH2:19][CH3:20])[O:22][CH:23]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: CCc1nc(C(=O)O)co1
Product: CCc1nc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)co1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 2-ethyl-oxazole-4-carboxylic acid following procedure I yielded the title compound as a brown oil. MS (ISP): m/z=383.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][C:33]1[O:37][C:36]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:38]([C:36]1[O:37][C:33]([CH3:32])=[CH:34][CH:35]=1)(=[O:40])=[O:39]
Reactant: Cc1ccc(S(=O)(=O)Cl)o1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (50 mg, 0.120 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 5-methylfuran-2-sulfonyl chloride (24 mg, 0.130 mmol) and pyridine (11 uL, 0.130 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 58 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-5-methylfuran-2-sulfonamide (percentage yield: 85%), was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=O)[CH:6](Br)[CH2:7][CH2:8][CH3:9].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[S:20])=[CH:17][CH:16]=1>C(O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[N:21]=[C:19]([C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:24])([F:13])[F:25])=[CH:23][CH:22]=2)[S:20][C:6]=1[CH2:7][CH2:8][CH3:9]
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: CCCC(Br)C(=O)CC(=O)OC
Solvent: CCO
Product: CCCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CC(=O)OC
Temperature: 25 °C
Yield: 99.2 %

Procedure:
4-Bromo-3-oxo-heptanoic acid methyl ester (6.0 g, 25.0 mmol) is dissolved into denatured ethanol (100 mL) and para-trifluoromethyl thiobenzamide (5.0 g, 24.4 mmol) is added in one portion. The reaction is purged of air and flushed with nitrogen then heated to reflux. The reaction is monitored by TLC and HPLC and when complete, the reaction is allowed to cool to room temperature. The solvent is removed and the reaction is diluted with ethyl acetate (200 mL), followed by ishes with saturated sodium bicarbonate solution, water, and brine. The ethyl acetate solution is dried over anhydrous sodium sulfate, then concentrated add further purified using flash column chromatography (10% EtOAc/Hexanes) to yield pure [[5-Propyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid methyl ester (8.66 g, 24.2 mmol) or 98% yield.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][O:4][CH:3]1[C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl>[CH3:1][CH:2]1[CH:3]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[O:4][CH2:5][C:6]2([CH3:8])[CH:7]1[O:26]2
Reactant: CC1=CC(C)C(c2c([N+](=O)[O-])cnn2C)OC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1C(c2c([N+](=O)[O-])cnn2C)OCC2(C)OC12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-(6-methoxy-3,5-dimethyl-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-pyrazole (100 mg, 0.38 mmol) in DCM (1 mL) cooled to −78° C. was added boron trifluoride diethyl etherate (0.14 mL, 1.13 mmol) and triethylsilane (0.36 mL), 2.68 mmol). After stirring at −78° C. for 1 hr, the reaction mixture was allowed to warm to room temperature and stirred for 18 hr. Saturated aqueous NaHCO3 (5 mL) and DCM (5 mL) were added and the organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave 5-(3,5-dimethyl-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-pyrazole as a yellow oil. The reaction was repeated to provide more material. To a solution of 5-(3,5-dimethyl-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-pyrazole (305 mg, 1.29 mmol) in DCM (6.5 mL) cooled to 0° C. was added m-CPBA (70-75%, 382 mg, 1.54 mmol) and the mixture was stirred at 0° C. for 90 min. More m-CPBA (70-75%, 191 mg, 0.774 mmol) was added and the mixture was slowly warmed to room temperature over 6 hr. The mixture was filtered through Celite® washing with DCM (15 mL) and the filtrate washed with saturated aqueous NaHCO3 (2×10 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave 5-(2,6-dimethyl-4,7-dioxabicyclo[4.1.0]heptan-3-yl)-1-methyl-4-nitro-pyrazole as a single diastereomer as an off-white solid (189 mg, 53% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 5.32-5.28 (m, 1H), 4.15-4.08 (m, 1H), 4.06 (s, 3H), 3.78 (d, J=12.9 Hz, 1H), 3.30 (d, J=5.6 Hz, 1H), 2.71-2.61 (m, 1H), 1.38 (s, 3H), 0.92 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:7][CH2:8][C:9]1[O:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:14]C1OC(CBr)=CC=1.C(Br)C1OC=CC=1>CCOCC>[CH2:8]([O:7][CH2:1][C:2]1[O:6][C:5]([CH3:14])=[CH:4][CH:3]=1)[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1coc(COCc2ccco2)c1
Reactant: Cc1ccc(CBr)o1
Agent: BrCc1ccco1
Solvent: CCOCC
Product: Cc1ccc(COCc2ccco2)o1

Procedure:
d. 5-Methyl-furfuryl furfuryl ether is prepared by the procedure described by J. E. Zanetti in J.Am.Chem.Soc. 49, 1066 (1927) for the difurfuryl ether, starting with 5-methyl-furfuryl bromide (Compt, Rend. 222, 1441 (1946) instead of furfuryl bromide of Zanetti. The product was isolated by ether extraction of the crude mixture after having diluted with water. For purification the ether extract was distilled twice -- b.p. 68°-70°C. at 0.01 mm./Hg vacuum. The product was a viscous colourless liquid, darkening rapidly on contact with air.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:29])=[C:5]([N:16]2[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18][CH2:17]2)[S:6][C:7]=1[NH:8][C:9](=[O:15])[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])#[N:2].FC(F)(F)C(O)=O.C(=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.ClC(Cl)C>[CH2:22]([N:19]1[CH2:18][CH2:17][N:16]([C:5]2[S:6][C:7]([NH:8][C:9](=[O:15])[CH:10]([CH2:11][CH3:12])[CH2:13][CH3:14])=[C:3]([C:1]#[N:2])[C:4]=2[CH3:29])[CH2:21][CH2:20]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=Cc1ccccc1
Reactant: CCC(CC)C(=O)Nc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1C#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)C(=O)Nc1sc(N2CCN(Cc3ccccc3)CC2)c(C)c1C#N

Procedure:
To a solution of 1.06 g (2.52 mmol) of the title compound from Example 30 in 10 mL of CH2Cl2 was added 10 mL of trifluoroacetic acid. After 2 h at ambient temperature the reaction was concentrated in vacuo. To 0.040 g (0.092 mmol) of this intermediate in 1 mL of dichloroethane was added 0.032 mL (0.20 mmol) of benzaldehyde, followed by 0.066 g (0.31 mmol) of sodium triacetoxyborohydride. After 16 h at ambient temperature the reaction was quenched by the addition of 10 mL of saturated aqueous NaHCO3. The reaction was extracted with CH2Cl2 and the organic layer was dried (Na2SO4) and concentrated in vacuo. Purification by preparative thin layer chromatography (15% EtOAc in hexane) afforded the title compound as a white solid. 1H NMR (500 MHz, CDCl3) 8.69 (s, 1H), 7.35 (m, 5H), 3.72 (s, 1H), 3.57 (s, 1H), 2.94 (t, J=5.0 Hz, 4H), 2.58 (s, 4H), 2.26 (m, 1H), 2.16 (s, 3H), 1.73 (m, 2H), 1.61 (m, 2H), 0.95 (t, J=7.5 Hz, 6H); mass spectrum (ES) m/e=411.2 (M+H).
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(N(CC)CC)C.[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]=[O:22])[CH:16]=[C:17]([Cl:19])[CH:18]=1>C(Cl)(Cl)Cl>[CH3:2][N:3]([OH:4])[C:21]([NH:20][C:15]1[CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]([Cl:12])[CH:14]=1)=[O:22]
Reactant: CNO
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(O)C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
A mixture of 10 g of N-methyl-hydroxylamine hydrochloride in 100 ml of chloroform was stirred while 18 ml of triethylamine were added at 0° C. Then, 20 g of 3,5-dichlorophenyl isocyanate in 30 ml of chloroform were added to the mixture at 10° to 15° C and the mixture was stirred for 5 hours at 20° C and was then distilled to dryness under reduced pressure. The residue was taken up in water and dried to obtain 22 g of N-methyl-N-hydroxy-N'-(3,5-dichlorophenyl)-urea melting at 131°-132° C.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]([C:15]([NH2:17])=O)=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]([C:15]#[N:17])=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:3]=1
Reactant: NC(=O)c1sc2ccc(Br)cc2c1-c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1sc2ccc(Br)cc2c1-c1ccccc1

Procedure:
Reflux 2.1 g. 5-bromo-3-phenylbenzo[b]thiophene-2-carboxamide (0.0063 mole) together with 10 ml. of phosphorus oxychloride for 11/2 hours and then carefully pour onto ice water. Filter off the white precipitate. Dry. Recrystallize the title compound from methanol; m.p. 145°-146°.
Reaction SMILES: [Cl:1][C:2]1[C:7]2OCO[C:6]=2[CH:5]=[C:4]([C:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:12]=2[NH2:26])[CH:3]=1.[H-].[Na+].[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30].[OH2:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([C:16]([F:18])([F:17])[F:19])=[N:14][N:13]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:12]=2[N:26]([C:32](=[O:33])[NH:31][CH2:29][CH3:30])[C:20]([NH:13][CH2:12][CH3:11])=[O:34])[CH:5]=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:7]=1
Reactant: CCN=C=O
Reactant: Nc1c(-c2cc(Cl)c3c(c2)OCO3)c(C(F)(F)F)nn1-c1ncccn1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)N(C(=O)NCC)c1c(-c2cc(Cl)cc(C(F)(F)F)c2)c(C(F)(F)F)nn1-c1ncccn1
Temperature: 22.5 °C
Yield: 16 %

Procedure:
To a mixture of 4-(7-chloro-1,3-benzodioxol-5-yl)-2-pyrimidin-2-yl-5-(trifluoromethyl)pyrazol-3-amine (0.200 g, 0.50 mmol) and NaH (0.015 g, 0.64 mmol) in tetrahydrofurane is added ethylisocyanate (0.078 g, 1.10 mmol). The mixture is refluxed for 4 hours. The reaction was cooled to room temperature (20-25° C.), diluted with water and extracted with ethyl acetate; the organic layer separated and further washed with water and then dried and concentrated. The residue was re-crystallized with a mixture of ethyl acetate and petrole ether to give the title compound (46 mg; 16%).
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH:16]=O.C([O-])(=O)C.[Na+].Cl.[NH2:24][OH:25]>O>[CH3:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH:16]=[N:24][OH:25]
Reactant: NO
Reactant: COc1ccc2ccccc2c1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2ccccc2c1C=NO
Yield: 97.7 %

Procedure:
To 400 ml of ethanol and 180 ml of water were added 80 g (0.43 mole) of 2-methoxy-1-naphthaldehyde, 66 g (0.81 mole) of sodium acetate and 35.5 g (0.51 mole) of hydroxylamine hydrochloride, and the mixture was heated at reflux for 2 hours. After the reaction, the reaction mixture was added to 1 liter of water. The precipitated crystals were collected by filtration to give 85 g (0.42 mole) of 2-methoxy-1-naphthaldoxime.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[N:26]1([CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][NH:34]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH:33]1[CH2:32][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: C1CCN(CC2CCCCN2)CC1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2CN2CCCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(piperidin-1-ylmethyl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.09 minutes; C28H33Cl2N5O2 (542.51); mass spectrum: (M−H)−=542/544/546 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].[CH3:10][C:11]1([CH3:27])[C:20]2[CH:21]=[C:22]([C:24](Cl)=[O:25])[S:23][C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12]1>N1C=CC=CC=1.C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[N:4]([CH3:5])[C:24]([C:22]1[S:23][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([CH3:27])([CH3:10])[C:20]=2[CH:21]=1)=[O:25]
Reactant: CC1(C)Oc2ccccc2-c2sc(C(=O)Cl)cc21
Reactant: CNc1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OC2(C)C)c1ccccc1Cl
Temperature: 25 °C
Yield: 31 %

Procedure:
To a solution of 2-chloro-N-methylaniline (32.10 uL, 0.2750 mmol) in 1.2 M of Pyridine in methylene chloride (0.8333 mL) was added a pinch of DMAP, followed by the addition of 4,4-dimethyl-4H-thieno[3,2-c]chromene-2-carbonyl chloride (70.2 mg, 0.250 mmol). The reaction was stirred at room temperature under N2 with LC/MS monitor. The crude product was purified on silica to give 30 mg 141bp. Yield=31% of theoretical. MS: (ESI+)=385
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:26]([NH:28][CH:29](NC=O)[NH:30]C=O)=O.C(N)=O.[OH-].[Na+]>O>[N:28]1[CH:26]=[CH:2][C:1]([C:4]2[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])=[CH:6][CH:5]=2)=[N:30][CH:29]=1
Reactant: O=CNC(NC=O)NC=O
Reactant: CC(=O)c1ccc(OCCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: NC=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccc(-c2ccncn2)cc1

Procedure:
A mixture of 10.0 g of 2-[4-(4-acetylphenoxy]-butyl]-1H-isoindole-1,3(2H)-dione (Example 42) 10.0 g of tris(formamido)methane, and 20 ml of formamide are combined and the mixture stirred and heated at 160°-165° C. for 8 hours. After dilution with 100 ml of water, the mixture is rendered basic with 10N NaOH, the precipitate collected, washed with water, and air dried. Recrystallization from ethanol gives the pure compound, m.p. 100°-102° C.; yield, 5.0 g.
Reaction SMILES: CS(C)=O.[OH-:5].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15]([F:18])([F:17])[F:16]>C(O)(C)(C)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([OH:5])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: FC(F)(F)c1cc(Cl)ccc1Cl
Reactant: [OH-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: Oc1ccc(Cl)cc1C(F)(F)F
Reaction time: 24 h

Procedure:
To a 300 ml, 3-necked flask fitted with a stirrer, condenser, thermometer and drying tube is added dimethylsulfoxide (100 ml), tert-butanol (20 ml), powdered potassium hydroxide (KOH) pellets (85%, 30 g) and 2,5-dichlorobenzotrifluoride (21.5 g, 0.10 mole). The reaction mixture is warmed to 71°-73° C. for 60 hours, then additional KOH (10 g) is added and heating is continued at 73°-75° C. for 24 hours. The reaction mixture is cooled and the solvent partially removed by distillation at 0.9 mm, bp 55° C.). The cooled pot residue is then poured into ice water (1000 g) which had been preacidified to pH 1 with conc. HCl (50 ml). The aqueous mixture is extracted with carbon tetrachloride (CCl4), the CCl4 layer decanted and dried and the solvent removed under vacuum to afford 10.8 g of 4-chloro-2-trifluoromethylphenol, which is sublimed to afford pure product, mp 81° -81.5° C. Elemental Anal. Calcd for C7H4ClF3O: C, 42.75; H, 2.06; Cl, 18.04: Found: C, 42.54; H, 2.36; Cl, 18.16. ##STR10##
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][C:15]2=[CH2:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH2:23].[OH-].[Na+].OO>O1CCCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][CH:15]2[CH2:22][OH:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: O
Reactant: C=C1CCN(CC)c2c(CO[Si](C)(C)C(C)(C)C)cccc21
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN1CCC(CO)c2cccc(CO[Si](C)(C)C(C)(C)C)c21

Procedure:
To a solution of 8-(t-butyldimethylsilyloxymethyl)-4-methylene-1-ethyl-1,2,3,4-tetrahydroquinoline (2.04 g) in tetrahydrofuran (50 ml), 10M solution (3.2 m) of borane-dimethylsulfide complex in tetrahydrofuran was added dropwise with stirring under ice-cooling. After stirring the mixture for 2 hours at room temperature, water was added to the reaction mixture, and furthermore 3N aqueous solution of sodium hydroxide (10 ml) and 30% hydrogen peroxide (10 ml) were added thereto. After stirring for 2 hours at room temperature, the reaction mixture was subjected to salting-out and extracted with dichloromethane. After the extract was dried, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (3:1)]to give 8-(t-butyldimethylsilyloxymethyl)-4-hydroxymethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (1.98 g).