Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[C:5]#[N:6].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)cc(Cl)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2cc(Cl)cc(C#N)c2)CC1
Temperature: 140 °C
Yield: 65.8 %

Procedure:
A mixture of 3-chloro-5-fluoro-benzonitrile (1 g, 6.45 mmol), 1-methyl-piperazine (0.715 ml, 6.45 mmol), and K2CO3 (2.64 g, 19.3 mmol) in DMF (5 ml) was heated to 140° C. for 40 min in a microwave apparatus. The resulting slurry was filtered and the solvent was removed in vacuo to give 1 g of 3-chloro-5-(4-methyl-piperazin-1-yl)-benzonitrile. The crude reaction mixture was used in the next step without any further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[C@H:4]([CH3:12])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:15][C:16]([F:37])([F:36])[C:17]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:18]=1[CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22][CH2:21]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:37][C:16]([F:15])([F:36])[C:17]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:18]=1[CH2:19][N:20]1[CH2:25][CH2:24][CH:23](/[CH:26]=[C:10]2/[C:6]([NH:5][C@H:4]([C:3]([N:2]([CH3:1])[CH3:14])=[O:13])[CH3:12])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:22][CH2:21]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: C[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)alaninamide (646 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1018 mg) in 2-propanol (10 mL) was added piperidinium acetate (436 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (1.08 g).
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:11]=2)[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@H:25]([OH:27])[CH3:26])[C@H:4]([O:29]C2CCCCO2)[CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:11]=2)[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@H:25]([OH:27])[CH3:26])[C@H:4]([OH:29])[CH2:3]1
Reactant: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](O)C[C@H]2Cl)s1
Temperature: 17 °C
Reaction time: 17 h
Yield: 95.5 %

Procedure:
A 20 mL vial equipped with a magnetic stirbar was charged with 210 mg of THP-ether 10 (0.40 mmol) was dissolved in 6 mL of methanol. To this was then added 300 mg of pyridinium p-toluenesulfonate (1.20 mmol) and the mixture was stirred at 17° C. over 17 h. The reaction was sampled by TLC and worked up by concentration in vacuo to remove methanol. The residual products were taken up in ethyl acetate and filtered through a 10 g plug of silica gel, eluting the polar product away from the salts with ethyl acetate (300 mL). Concentration of the filtrate yielded 170 mg of products. Final preparative thin layer chromatographic purification yielded 161 mg (91%) of triol 11 as an oil; 1H NMR (CDCl3): 1.18 (d, J=6.3 Hz, 3H), 1.36-1.62 (m, 8H), 1.77 (m, 3H), 1.94 (m, 2H), 2.10-2.34 (m, 5H), 2.43 (Br s, 1H), 2.83 (m, 2H), 3.50 (br s, 1H), 3.71 (br s, 1H), 3.79 (m, 1H), 3.86 (s, 3H), 3.98 (m, 1H), 4.09 (m, 1H), 5.51 (m, 2H), 6.78 (dd, J=3.9 Hz, 1H), 7.62 (d, J=3.9 Hz, 1H).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:4]1=2.[N+:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21]>C(OCC)C>[CH3:19][O:18][C:14]1[C:5]2[O:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3/[C:3](=[CH:2]\[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:28]=3)/[C:4]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc2c1OCc1ccccc1C2=CBr
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Solvent: CCOCC
Product: COc1cccc2c1OCc1ccccc1/C2=C\c1cccc([N+](=O)[O-])c1
Yield: 33 %

Procedure:
Following procedures essentially as described in Example 230, 11-bromomethylene-4-methoxy-6,11-dihydro-dibenzo[b,e]oxepine is combined with m-nitrophenyl boronic acid. The pure E isomer is isolated by recrystallization with hexanes and diethyl ether to give 311 mg of product (33% yield). 1H NMR (400 MHz, CDCl3) δ 7.979-7.949 (d, 1H), 7.874 (s, 1H), 7.509-7.491 (d, 1H), 7.365-7.324 (t, 1H), 7.305-7.237 (m, 2H), 7.204-7.162 (t, 1H), 7.123-7.100 (d, 1H), 6.992-6.912 (m, 3H), 6.864-6.840 (d, 1H), 5.75 (broad s, 1H), 5.19 (broad s, 1H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:4]2[N:5]=[N:6][C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:2]([CH3:1])[N:3]=2)=[CH:19][CH:18]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Product: Cc1nc(Nc2ccc(Cl)cc2)nnc1-c1ccccc1
Yield: 75.2 %

Procedure:
A mixture of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (4.15 g) and p-chloroaniline (4.22 g) was heated at 150° to 160° C. for 18 hours. After cooling, the resulting solid was washed successively with ethyl acetate, chloroform and methanol, and then dried to give 3-(4-chloroanilino)-5-methyl-6-phenyl-1,2,4-triazine (4.26 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[C:7]1([C:12]([C:14]2[CH:24]=[CH:23][C:17]([CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:16][CH:15]=2)=[O:13])[S:11][CH:10]=[CH:9][CH:8]=1>O1CCOCC1>[S:3]1[CH2:4][CH2:5][N:6]=[C:2]1[NH:1][C:19](=[O:20])[CH:18]([C:17]1[CH:16]=[CH:15][C:14]([C:12](=[O:13])[C:7]2[S:11][CH:10]=[CH:9][CH:8]=2)=[CH:24][CH:23]=1)[CH3:22]
Reactant: NC1=NCCS1
Reactant: CC(C(=O)Cl)c1ccc(C(=O)c2cccs2)cc1
Solvent: C1COCCO1
Product: CC(C(=O)NC1=NCCS1)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred and refluxing solution of 3.06 parts of 2-amino-2-thiazoline in 60 parts of dioxane is added a solution of 4.2 parts of p-(2-thenoyl)hydratropoyl chloride in 45 parts of dioxane. Upon completion, stirring at reflux is continued for 30 minutes. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is purified by column-chromatography over silicagel, using a mixture of chloroform and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from ethanol, yielding N-(2-thiazolin-2-yl)-p-(2-thenoyl)hydratropamide; mp. 186.4° C.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[N:5]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1(P(=[CH:38][C:39]([O:41][CH3:42])=[O:40])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:42][O:41][C:39](=[O:40])[CH:38]=[CH:2][CH2:3][CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[N:5]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)CCCCC1CC=O
Solvent: Cc1ccccc1
Product: COC(=O)C=CCC1CCCCC(=O)N1C(=O)OC(C)(C)C

Procedure:
Example 209) The crude aldehyde of this Example, part B above, is dissolved in toluene and treated with 1.2 equivalents of methyl (triphenylphosphoranylidene)acetate. The mixture is refluxed for four hours. After cooling, the mixture is concentrated and the residue is triturated with several volumes of pentane to remove the phosphorous salts. The extracts are filtered and stripped of all solvent. The crude residue is then purified by column chromatography to give the title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]([C@@:17]1([C:37]2([OH:41])[CH2:40][CH2:39][CH2:38]2)[CH2:21][CH2:20][C@@H:19]([N:22](C(=O)C(F)(F)F)[C@@H:23]2[C@H:28]([O:29][CH3:30])[CH2:27][O:26][CH2:25][CH2:24]2)[CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]([C@@:17]1([C:37]2([OH:41])[CH2:40][CH2:39][CH2:38]2)[CH2:21][CH2:20][C@@H:19]([NH:22][C@@H:23]2[C@H:28]([O:29][CH3:30])[CH2:27][O:26][CH2:25][CH2:24]2)[CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1CC[C@@](C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)(C2(O)CCC2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@@](C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)(C2(O)CCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
A mixture of 1.31 g (2.23 mmol) of 1,5-anhydro-3-{[(1R,3S)-3-{[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-(1-hydroxycyclobutyl)cyclopentyl](trifluoroacetyl)amino}-2,3-dideoxy-4-O-methyl-D-erythro-pentitol and 860 mg (23 mmol) of sodium borohydride in 6.3 mL of ethanol was stirred at ambient temperature for 18 h, then partitioned between water and dichloromethane. The aqueous phase was extracted with additional dichloromethane, and the combined organic phase dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography on silica using 6-15% methanol in dichloromethane afforded 1.08 g (98%) of the title compound as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42-1.47 (m, 9H) 1.56-2.35 (m, 14H) 2.72 (br. s., 1H) 3.11-3.68 (m, 10H) 3.90-3.98 (m, 1H) 4.08 (dd, J=12.6, 2.7 Hz, 1H) 4.38-4.58 (m, 1H) 4.84-5.16 (m, 1H). LC-MS ES+ 494.3. HRMS calculated for C26H43N3O6: 494.3230; found: 494.3260.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2].I[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:1]([N:3]([CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH:24]([CH3:26])[CH3:25])[CH3:2]
Reactant: CCNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC(C)N1c2ccccc2Sc2ccc(C#N)cc21)C(C)C
Temperature: 150 °C

Procedure:
A suspension of 10-[(2RS)-1-ethylamino-2-propyl]-2-phenothiazinecarbonitrile (4.5 g), 2-iodopropane (7.2 cc) and sodium carbonate (4.6 g) in dry dimethylformamide (60 cc) is heated for 34 hours at a temperature in the region of 150° C. After cooling, the mixture is concentrated to dryness under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. The residue is taken up with ethyl acetate (200 cc), washed with distilled water (3×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual brown oil is purified by chromatography on a column (height: 25 cm; diameter: 4 cm) of silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (75:25 by volume) (500 cc) of ethyl acetate and cyclohexane and collecting 60-cc fractions. The combined fractions 3 to 7 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-{(2RS)-1-[N-Ethyl-N-(1-methylethyl)amino]-2-propyl}-2-phenothiazinecarbonitrile (2.37 g) is thereby obtained in the form of an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1S(=O)(=O)N1CCOCC1
Yield: 80.9 %

Procedure:
Following the procedure for Intermediate 1 using 5-fluoro-2-methylbenzenesulfonyl chloride (10.0 g, 48 mmol), triethylamine (13.9 mL, 100 mmol) and morpholine (8.37 g, 96 mmol) gave the title compound as white solid (10.07 g, 81% yield). 1H NMR (300 MHz, CDCl3) δ: 7.58 (1H, dd, J=8.6, 2.7 Hz), 7.27 (1H, dd, J=8.4, 5.1 Hz), 7.15 (1H, td, J=8.1, 2.8 Hz), 3.72-3.68 (4H, m), 3.16-3.13 (4H, m), 2.57 (3H, s). LCMS (M+H) calcd for C11H15FNO3S: 260.07; found: 260.15.
Reaction SMILES: C([CH2:4][C:5]1[NH:9][N:8]=[C:7]([NH:10][C:11]([CH2:13][CH2:14][CH3:15])=[O:12])[CH:6]=1)(O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.C1C[O:26]CC1>>[OH:26][CH2:4][C:5]1[NH:9][N:8]=[C:7]([NH:10][C:11]([CH2:13][CH2:14][CH3:15])=[O:12])[CH:6]=1
Reactant: C1CCOC1
Reactant: CCCC(=O)Nc1cc(CC(=O)O)[nH]n1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Product: CCCC(=O)Nc1cc(CO)[nH]n1
Temperature: 0 °C
Reaction time: 6.5 h
Yield: 15 %

Procedure:
A solution of 787 mg of crude XII in 10 ml of dry THF was cooled to 0° C. in an ice bath. To this mixture was added 14 ml of 1 M LiAlH4 in THF while maintaining the temperature at 0° C. The reaction was allowed to stir at 0° C. for 6.5 hours at which point the solution was poured over 100 g of crushed ice. Once the ice had melted, the solution was brought to pH 7 by addition of HCl. The water layer was filtered to remove aluminum salts and the filtrate was extracted three times with 75 ml of ethyl acetate. The organic layer was collected, dried over MgSO4 and evaporated to an orange solid. The solid was purified on silica gel to give 79 mg of the alcohol (15%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:15][CH2:16][O:17][CH3:18])[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[OH-].[Li+]>CO.O>[CH3:18][O:17][CH2:16][CH2:15][N:9]1[C:10]([C:11]([F:14])([F:12])[F:13])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(CCOC)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCn1ncc(C(=O)O)c1C(F)(F)F
Yield: 70.5 %

Procedure:
To a solution of 1-(2-methoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.291 g, 1.09 mmol) in methanol (3 mL) and water (3 mL) was added lithium hydroxide (0.072 g, 1.73 mmol). The reaction mixture was stirred at reflux for 2 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was then acidified carefully with 6.0 N aqueous HCl. The resulting mixture was extracted with methylene chloride (3×25 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide 1-(2-methoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid as a orange oil (0.183 g, 71%), which was used without further purification. Mass spectrum: m/z: 239.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][S:12]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[O:10])=[CH:4][C:3]=1[CH3:21].[C:22]1([CH2:28]C(O)=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>>[Cl:20][C:17]1[S:16][C:15]([S:12]([NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:3]([CH3:21])[CH:4]=2)=[O:10])(=[O:14])=[O:13])=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Cc1cc(NC(=O)NS(=O)(=O)c2ccc(Cl)s2)ccc1N
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Product: Cc1cc(NC(=O)NS(=O)(=O)c2ccc(Cl)s2)ccc1NCc1ccccc1

Procedure:
1.0 equivalent of N-(4-amino-3-methylphenyl){[(5-chloro(2-thienyl))sulfonyl]amino}-carboxamide was treated with 1.0 equivalent of PhCH2COOH/PyBOP to give X═CH2, {[(5-chloro(2-thienyl))sulfonyl]amino}-N-{3-methyl-4-[benzylamino]phenyl}carboxamide. ES-MS (M+H)+=464, 466 (Cl).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[CH2:13]([S:15](Cl)(=[O:17])=[O:16])[CH3:14]>C(N(CC)CC)C>[CH2:13]([S:15]([O:11][C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH2:3][C:2]([CH3:12])([CH3:1])[C:6]=2[CH:7]=1)(=[O:17])=[O:16])[CH3:14]
Reactant: CC1(C)COc2ccc(O)cc21
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Oc1ccc2c(c1)C(C)(C)CO2

Procedure:
The same compound was also prepared by reacting 2,3-dihydro-3,3dimethyl-5-benzofuranol with ethanesulphonyl chloride in the presence of triethylamine in an analogous way to that described in Example 37(a).
Reaction SMILES: [OH:1][OH:2].[C:3](O)([CH3:6])([CH3:5])[CH3:4]>>[CH3:4][C:3]([O:1][O:2][C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:6])[CH3:5]
Reactant: CC(C)(C)O
Reactant: OO
Product: CC(C)(C)OOC(C)(C)C

Procedure:
Hydrogen peroxide is reacted with tertiary butyl alcohol in accordance with the invention to form DTBP. About 4.5 grams of 30% aqueous hydrogen peroxide are combined with 0.5 grams of 12-tungstophosphoric acid catalyst (H3PW12O40) and 5.92 grams of tertiary butyl alcohol, and the mixture is heated to 80° C. under a nitrogen blanket. After 4 hours reaction time, 3.50 grams of an organic layer was separated. Analysis of the organic layer showed 20 wt% tertiary butyl alcohol, 34 wt% tertiary butyl hydroperoxide, 35 wt% ditertiary butyl peroxide, 4 wt% acetone and 2.4 wt% methanol.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([O:11][C:12]2[CH:17]=[C:16](I)[C:15]([O:19][CH3:20])=[CH:14][C:13]=2[CH:21]([CH3:23])[CH3:22])=[CH:6][N:5]=1)[CH3:2].[C:24]([Cu])#[N:25].O>CN(C=O)C>[NH2:10][C:8]1[C:7]([O:11][C:12]2[C:13]([CH:21]([CH3:23])[CH3:22])=[CH:14][C:15]([O:19][CH3:20])=[C:16]([CH:17]=2)[C:24]#[N:25])=[CH:6][N:5]=[C:4]([NH:3][CH2:1][CH3:2])[N:9]=1
Reactant: CCNc1ncc(Oc2cc(I)c(OC)cc2C(C)C)c(N)n1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1ncc(Oc2cc(C#N)c(OC)cc2C(C)C)c(N)n1
Temperature: 120 °C
Yield: 71 %

Procedure:
To a solution of N2-Ethyl-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (1.65 g, 4.12 mmol) in anhydrous DMF (10 ml) was added CuCN, and the reaction mixture was heated to 120° C. for 3 hrs. The reaction mixture was poured into water (200 ml) and the insoluble portion was collected by filtration. The solid was triturated with 10% MeOH/methylene chloride/0.1% NH4OH solution (100 ml) and filtered again. The filtrate was concentrated and flash chromatographed on silica (3% MeOH in methylene chloride with 0.1% NH4OH) to give 5-(4-Amino-2-ethylamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (0.87 g, 71%) as a white solid.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:10](=[O:12])[CH3:11].C(O)(=O)C>CCOCC>[OH:4][CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:3])=[O:20])[C:10](=[O:12])[CH3:11]
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(C)=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCC(O)CCCN(CCCCCCC(=O)OC)C(C)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approx. 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 7-[N-(4-hydroxynonyl)acetamido]heptanoic acid (9.8 g., 0.03 mole) (Example 1, Step C) in ether (50 ml.). The resulting solution is allowed to stand 4 hours at room temperature. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 7-[N-(4-hydroxynonyl)acetamido]-heptanoate as a viscous oil.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([CH2:14][N:15]([CH3:17])[CH3:16])[CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1.[NH3:19]>CO>[CH3:16][N:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]2[O:7][CH:6]=[C:5]([CH2:4][C:3]([NH2:19])=[O:2])[C:9]=2[CH:10]=1)[CH3:17]
Reactant: COC(=O)Cc1coc2ccc(CN(C)C)cc12
Reactant: N
Solvent: CO
Product: CN(C)Cc1ccc2occ(CC(N)=O)c2c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
A solution of (5-dimethylaminomethyl-benzofuran-3-yl)-acetic acid methyl ester (170 mg, 0.69 mmol) in a mixture of methanol (15 mL) and liquid ammonia (15 mL) is stirred for 2 days in an autoclave at 60° C. After careful evaporation of the ammonia, the remaining solvent is evaporated in vacuo to afford the title compound as a yellow oil (160 mg, 0.69 mmol, 100%). MS (ES+): 233 (M(C13H16N2O2)+H)+.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH3:15])([CH3:14])[CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:3][CH:2]=1.[CH2:22]([Li])CCC.CI>O1CCCC1.CCCCCC.O>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:2]=[CH:3][C:4]([Si:7]([CH3:15])([CH3:14])[CH2:8][N:9]2[C:13]([CH3:22])=[N:12][CH:11]=[N:10]2)=[CH:5][CH:6]=1
Reactant: C[Si](C)(Cn1cncn1)c1ccc(-c2ccccc2)cc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncnn1C[Si](C)(C)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
A solution of 5.9 g (0.020 mol) of (1,1'-biphenyl-4-yl)dimethyl(1H-1,2,4-triazol-1-ylmethyl)silane in 40 ml of dry tetrahydrofuran was chilled to -40° under N2 and stirred while 12.5 ml (0.020 mol) of 1.6 molar n-butyllithium in hexane was added dropwise. The resulting yellow solution was stirred another 15 minutes at -40°, treated with 1.9 ml (4.2 g, 0.030 mol) of methyl iodide, and allowed to warm to room temperature. The resulting solution was diluted with water and extracted with hexanes. Washing the organic extracts with water and brine, drying over magnesium sulfate, and evaporation give 5.7 g of solid, which was purified by dry-column chromatography over silica gel (ethyl acetate elution) to give 1.1 g of crude product. Recrystallization from 12 ml of 3:1 hexanesethyl acetate then gave 0.97 g (16%) of the title compound as an off white solid: m.p. 95°-98°; ir (Nujol® ) 1590, 1270, 1250, 1180, 1120, 830, 765, 700 cm-1 ; nmr (CDCl3) 0.5 (6H, s), 2.2 (3H, s), 3.7 (2H, s), 7.2-7.7 (9H, m), 7.8 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH:13]1[CH2:16][CH2:15][CH2:14]1)[C:7]2=[O:17].P(Cl)(Cl)([Cl:20])=O.CCN(C(C)C)C(C)C.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:20])[N:8]([CH:13]1[CH2:16][CH2:15][CH2:14]1)[C:7]2=[O:17]
Reactant: O=c1[nH]c2c(Br)cccc2c(=O)n1C1CCC1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=c1c2cccc(Br)c2nc(Cl)n1C1CCC1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A solution of 8-bromo-3-cyclobutylquinazoline-2,4(1H,3H)-dione (2.33 g, 7.89 mmol), phosphorous oxychloride (Acros Organics, Geel, Belgium; 3.68 ml, 39.5 mmol), and DIPEA (5.50 ml, 31.6 mmol) was heated over a 130° C. oil bath for 5 h. The reaction mixture was then cooled to RT and poured onto ice, and the resulting mixture was diluted with water (250 mL) to provide a brown suspension. 10N aqueous NaOH was added to the vigorously stirred suspension (maintaining the reaction mixture at 0° C.) until a pH of 10 was achieved. The precipitated solid was collected by vacuum filtration, washed with water (3×20 mL), and dried in vacuo to provide 8-bromo-2-chloro-3-cyclobutylquinazolin-4(3H)-one (1.888 g, 6.02 mmol, 76% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (1H, dd, J=8.0, 1.4 Hz), 7.99 (1H, dd, J=7.8, 1.4 Hz), 7.32 (1H, t, J=7.8 Hz), 5.22 (1H, quin, J=8.8 Hz), 2.89-3.05 (2H, m), 2.43-2.56 (2H, m), 1.98 (1H, q, J=10.7 Hz), 1.74-1.90 (1H, m). m/z (ESI, +ve) 313.0/314.9/316.9 (M+H)+.