Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([SH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[CH2:14]([O:13][C:11](=[O:12])[C:10]([S:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:17])[CH3:16])[CH3:15]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: SC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC1CCCC1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
To a solution of 5 g (48.7 mmol) of cyclopentyl thiol in ethanol (50 mL) are added 2.7 g (48.75 mmol) of KOH pellets, followed by 9.5 g (48.7 mmol) of ethyl α-bromoisobutyrate. The reaction is heated to reflux for 2 h and then cooled to room temperature. The solid (KBr) is separated by filtration and rinsed with ethanol (20 mL). The filtrate is concentrated under reduced pressure and the residue dissolved in DCM (50 mL). The organic layer is washed with saturated aqueous NaHCO3 solution (50 mL). The aqueous washes are back-extracted with DCM (10 mL). The combined organics are washed with brine, dried over Na2SO4. Filtration and concentration under reduced pressure affords 8.1 g of 2-cyclopentylsulfanyl-2-methyl-propionic acid ethyl ester. Yield: 77%, ES-MS: m/z 217 [M+H]
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][P:5]([CH2:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])(=[O:8])[O:6][CH3:7].[CH2:15]([Li])[CH2:16][CH2:17][CH3:18].Br[CH2:21]C#CCC.Cl>O1CCCC1.CCCCCC>[CH3:3][O:4][P:5]([CH2:9][C:10](=[O:14])[C:11]([CH3:21])([CH3:12])[CH2:13][C:15]#[C:16][CH2:17][CH3:18])(=[O:8])[O:6][CH3:7]
Reactant: CCC#CCBr
Reactant: COP(=O)(CC(=O)C(C)C)OC
Reactant: [Li]CCCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC#CCC(C)(C)C(=O)CP(=O)(OC)OC
Reaction time: 1.5 h

Procedure:
To a suspension of 7.1 g of sodium hydride (50% suspension in oil) in 220 ml of absolute tetrahydrofuran a solution of 31.5 g of 3-methyl-2-oxo-butylphosphonic acid dimethyl ester in 74 ml of absolute tetrahydrofuran is added in drops at 24° C.; the product is stirred for 1.5 hours and then, at 0° C., 111 ml of a 1.6 molar butyl lithium solution in hexane is added drop by drop and stirred for 20 minutes. A solution of 29 g of 1-bromo-2-pentine in 44 ml of absolute tetrahydrofuran is then added to the above solution drop by drop, stirred for 3 hours at 0° C., neutralized with 3N of hydrochloric acid and concentrated in a vacuum. 50 ml of brine is added; extraction is performed three times, each time with 200 ml of methylene chloride; the organic extract is shaken twice, each time with 50 ml of brine; the product is dried with magnesium sulfate and concentrated by evaporation in a vacuum. After distillation of the residue at 0.6 Torr and 125° C., 23 g of the title compound is obtained in the form of a colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:10][C:11]1[C:12](Cl)=[N:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:25][C:26](=[O:45])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH2:23]([O:25][C:26](=[O:45])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([C:12]2[C:11]([CH2:10][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])[CH2:8][CH3:9])=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:29]=1)[CH3:24]
Reactant: CCN(Cc1cc2ccccc2nc1Cl)C(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
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: O
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(-c2nc3ccccc3cc2CN(CC)C(=O)OC(C)(C)C)c1

Procedure:
(2-Chloro-quinolin-3-ylmethyl)-ethyl-carbamic acid tert-butyl ester (1.0 g, 3.11 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (1.07 g, 3.34 mmol), potassium carbonate (1.08 g, 7.8 mmol), and catalytic tetrakis(triphenylphosphine)palladium(0) were combined in 2:1 DME:H2O (18 mL), and stirred at 80° C. for 6 hours. After standard work-up, the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25]CC3C=CC=CC=3)=[C:21]([CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])[C:20]=2[OH:38])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[OH:38][C:20]1[C:21]([CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=1[C:17](=[O:18])[CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: CC(C)=CCc1c(OCc2ccccc2)ccc(C(=O)C=Cc2ccc(OCc3ccccc3)cc2)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CCc1c(O)ccc(C(=O)CCc2ccc(O)cc2)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.6 %

Procedure:
Then, 21.03 g of the so-obtained 4,4'-dibenzyloxy-2'-hydroxy-3'-(3-methyl-2-butenyl)chalcone was added to 200 ml of an ethyl acetate suspension of 7.01 g of 5% palladium/carbon, in which hydrogen had been adsorbed in advance, and the mixture was stirred at room temperature for 6 hours and hydrogen was absorbed. After the reaction, the suspension was filtered to remove the palladium/carbon, and the solvent was removed from the filtrate by distillation and the obtained residue was recrystallized from benzene to obtain 11.85 g (yield=86.6%) of 1-(2,4-dihydroxy-3-isopentylphenyl)-3-(4-hydroxyphenyl)-1-propanone in the form of a colorless needle.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([O-:10])=[O:9])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[CH2:11]([OH:17])[CH2:12]CCCC.[C:18]1(C)[CH:23]=[CH:22][C:21](S(O)(=O)=[O:25])=[CH:20][CH:19]=1>CO>[CH3:12][C:11]([O:17][CH2:4][CH2:3][C@H:2]([NH2:1])[C:8]([OH:10])=[O:9])=[O:25].[NH2:1][C@H:2]([C:8]([O:10][CH:18]([CH2:19][CH2:20][CH3:21])[CH2:23][CH3:22])=[O:9])[CH2:3][CH2:4][C:5]([O-:7])=[O:6]
Reactant: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCCO
Solvent: CO
Product: CC(=O)OCC[C@H](N)C(=O)O
Product: CCCC(CC)OC(=O)[C@@H](N)CCC(=O)[O-]
Reaction time: 20 h

Procedure:
20 g of poly(γmethyl L-glutamate)(molecular weight: 150000; average degree of polymerization: 1050) was dissolved in 300 ml of a 1,2-dichloroethane/tetrachloroethylene(8/2) mixed solvent. To the resulting solution were added 100 ml of n-hexanol and 5 g of p-toluenesulfonic acid. The reaction was allowed to proceed at 60° C. for 20 hr. The reaction mixture was poured into a large amount of methanol to precipitate the formed polymer. The polymer was collected and dried. Subsequently, the polymer was dissolved in 1,2-dichloroethane again, reprecipitated with methanol, filtered and dried to obtain a purified γ-methyl L-glutamate/γ-hexyl L-glutamate copolymer. The ratio of the methyl ester to the hexyl ester in the copolymer was determined by NMR and was found to be 51:49.
Reaction SMILES: [CH3:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:18][C:19]([O:21]CC)=[O:20].[OH-].[Na+]>CN(C=O)C.C1COCC1.O>[CH3:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][C:5]2[N:6]([CH2:18][C:19]([OH:21])=[O:20])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cc2c(cc1C)OCC(=O)N2
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C)OCC(=O)N2CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of 7-methyl-6-(methyloxy)-2H-1,4-benzoxazin-3(4H)-one (2.13 g, 11 mmol) in DMF (20 mL) was added NaH (528 mg, 13.2 mmol) in two portions. The reaction mixture was stirred for 30 minutes at room temperature, and ethyl bromoacetate (1.22 mL, 11 mmol) was added. The reaction mixture was stirred for 3 hour until all starting material was consumed, then poured into cold water (200 mL). The precipitate was collected by filtration, washed with water, and dried in the air to afford a pale solid. This solid was dissolved in THF (22 mL) and NaOH (2.0 M, 5.5 mL) was added, and the reaction mixture was stirred at room temperature for 2 h, poured into cold water (100 mL), and extracted with EtOAc (2×100 mL). The aqueous layer was acidified with HCl (6 N) to pH˜1, extracted with EtOAc (3×100 mL). The organic extracts were combined, washed with brine, and dried (Na2SO4). The solvent was removed via rotovap to give the title compound (2.35 g, 85%) as a pale solid. MS (ES) m/e 252 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:12][O:13]2)=[CH:18][CH:17]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(-c2coc3cc(OC(C)=O)ccc3c2=O)cc1OC
Yield: 74 %

Procedure:
In a similar manner to Example 3.1 above, 3-(3,4-dimethoxyphenyl)-7-hydroxychromen-4-one (1.7 g) was reacted with acetic anhydride (10 ml) and pyridine (1.9 ml) to give 7-acetoxy-3-(3,4-dimethoxyphenyl)chromen-4-one as colourless prisms (1.44 g, 74%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:12]=2[OH:18])[CH:10]=1)=[O:5])[CH3:2].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)(C)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[C:16]([O:17][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1cn(-c2c(O)cccc2O)cn1
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2c(OCc3ccccc3)cccc2OCc2ccccc2)cn1

Procedure:
by reaction of the compound produced in Example 2 with benzyl chloride; mp: 125°-126° C. (isopropanol).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl>[C:1]([S:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Sc1ccccc1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)Sc1ccccc1
Reaction time: 18 h
Yield: 91.2 %

Procedure:
A solution of cinnamoyl chloride (14.6 g, 87.68 mmol) in dichloromethane (100 mL) was added to a solution of thiophenol (9.55 g, 86.68 mmol) and pyridine (7 mL) in dichloromethane (150 mL) in an ice-water bath. After 18 hours at room temperature, the reaction mixture was washed with dilute hydrochloric acid (100 mL, 1N), brine (100 mL), dried (MgSO4) and was concentrated to afford 19.0 g (91%) of the desired thioester as a crystalline solid.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[C:24]([O:20][C@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[O:21])[C@H:11]2[C@@:2]1([F:1])[C@:3]1([CH3:23])[C:8]([CH2:9][CH2:10]2)=[CH:7][C:6](=[O:22])[CH:5]=[CH:4]1)(=[O:26])[CH3:25]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F

Procedure:
A solution of 20 g of 9-fluoro-11β-hydroxyandrosta-1,4-dien-3,17-dione, 120 ml of glacial acetic acid, 120 ml of acetic anhydride and 5 g of p-toluenesulfonic acid was stirred at room temperature under nitrogen for 20 hours. The resulting solution was quenched with 5 g of sodium acetate. The solvent was partially removed in vacuo at 35°-40° C. and the resultant slurry was diluted with chloroform. The chloroform solution was washed with water, saturated sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound. This was crystallized from ethyl acetate-hexane to give 20 g of the title compound melting point 177°-178° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH-:20].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[CH:9]=[C:8]([C:10]2[C:15]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]([NH2:5])=[O:20]
Reactant: [OH-]
Reactant: N#Cc1ccc(-c2ncccc2C(F)(F)F)cc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1N
Temperature: 25 °C

Procedure:
Stir a mixture of 2-amino-4(3-trifluoromethyl-pyridin-2-yl)-benzo-nitrile (0.50 mmol) in 70% H2SO4 (10 ml) at 110° C. for 1 hour. Cool to room temperature, neutralize with NaOH, extract with EtOAc, dry over Na2SO4, and concentrate under vacuum. Purify the residue by flash chromatography (3:2 hexanes/EtOAc) to give 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12]C(=O)OC(C)(C)C)=[CH:4][N:3]=[CH:2]1.[ClH:20]>O1CCOCC1>[Cl-:20].[NH3+:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[N:1]=[CH:2][NH2+:3][CH:4]=1.[Cl-:20]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1-c1cnc[nH]1
Reactant: Cl
Solvent: C1COCCO1
Product: [Cl-]
Product: [NH3+]c1ccccc1C1=C[NH2+]C=N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
To a stirred solution of tert-butyl 2-(1H-imidazol-5-yl)phenylcarbamate (64.7 mg, 0.25 mmol) in 1,4-dioxane (2 mL) was added HCl (2 mL, 2.0 M in 1,4-dioxane). The mixture was allowed to stir at room temperature for 12 h and concentrated under reduced pressure. The residue was diluted with ethyl ether and the desired hydrochloride salt was precipitated. The colorless solid was collected by filtration, which afforded the desired product in 46% yield. 1H NMR: 6.66-6.82 (m, 2H), 7.11-7.20 (m, 2H), 7.21-7.38 (m, 4H), 7.40-7.68 (m, 3H).
Reaction SMILES: CCCCO[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13](NO)=O)=[CH:10][CH:11]=1.[C:17]([O-])(=O)C(C)=C.COCC(O)C.NC(OCC)=O>>[CH3:17][CH:13]=[CH:12][C:9]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCOc1ccc(CC(=O)NO)cc1
Reactant: C=C(C)C(=O)[O-]
Agent: CCOC(N)=O
Solvent: COCC(C)O
Product: CC=Cc1ccccc1
Reaction time: 2 h

Procedure:
Functionalized zirconia nanoparticles in which 50%, 25%, and 25% of the surface sites reacted with bufexamac, 2a (Preparatory Example 1), and 2b (Preparatory Example 2), respectively, were prepared as follows. A clean vial was charged with 10 grams of ZrO2 sol (47.3% weight) followed by 20 grams of 1-methoxy-2-propanol. Then 0.739 grams (0.70 mmol/g ZrO2) of bufexamac, 0.383 grams (0.35 mmol/g ZrO2) of 2a and 0.243 grams (0.35 mmol/g ZrO2) 2b were added to the vial. The content of the vial was stirred for 2 hours. The solution was then dried down to a powder, under vacuum, at 70° C. A total of 4.93 grams of zirconia nanoparticle powder was recovered. The powder was placed in a clean vial and redispersed in 4.93 grams of ultra-pure THF to yield a clear, slightly yellow solution. To this solution 0.48 grams of 3-isopropenyl-α,α-dimethylbenzyl isocyanine was added. The vial was sealed and stirred for 12 hours at room temperature. An FT-IR was taken of the sample, and an IR peak was observed at 1751 cm−1 and attributed to the ν(C═O) stretch in the urethane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C([Li])CCC.C[O:17][B:18](OC)[O:19]C>C1(C)C=CC=CC=1.C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:18]([OH:19])[OH:17])=[CH:3][C:4]=1[O:9][CH3:10]
Reactant: COB(OC)OC
Reactant: COc1cc(Br)ccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(B(O)O)ccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To 4-bromo-1-chloro-2-methoxybenzene (2.2 g, 9.9 mmol) in toluene/THF (16/6 mL) at −78° C. was added n-butyl lithium (8.7 mL, 1.6 M in hexane, 14 mmol) dropwise. The reaction was stirred at −78° C. for 30 min, then trimethylborate (2.2 mL, 19.8 mmol) was added. The reaction was allowed to warm to rt and stirred overnight and then quenched with 1 M HCl (15 mL). The organic layer was separated and dried over sodium sulfate. The solvent was removed and the crude product was purified by flash column chromatography to give 50A (1.2 g, 65% yield) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.87 (m, 3H) 7.11 (d, J=7.83 Hz, 1H) 7.20 (s, 1H) 7.29 (d, J=7.83 Hz, 1H).
Reaction SMILES: [C:1](#[N:4])[CH2:2]C.C(N(C(C)C)CC)(C)C.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=1)([O-:16])=[O:15].[I-].C(C[P+](C)(C)C)#N.Cl>C(OCC)(=O)C.O>[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][CH2:2][C:1]#[N:4])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CCC#N
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: N#CCCc1ccc([N+](=O)[O-])cc1
Temperature: 97 °C

Procedure:
Propionitrile (32 mL), diisopropylethylamine (2.5 g, 19.58 mmol) were added to a mixture of 4-nitrobenzyl alcohol (1 g, 6.53 mmol) and (cyanomethyl)trimethylphosphonium iodide (4 g, 16.32 mmol). The mixture was heated at 97° C. for 24 h. Water (1 mL) was added to the mixture and followed by conc. HCl (5 mL). Ethyl acetate (3×100 mL) was used to extract the product. Organic layer was washed with brine, dried with sodium sulfate, concentrated to give dark brown solid. The crude product was purified by flash column chromatography (Ethyl acetate:Hexanes 1:1) to give 740 mg of 3-(4-nitrophenyl)propionitrile as a light orange solid. 1H NMR (DMSO-d6): δ 8.20-8.17 (dd, J=8.7 Hz, 2H), 7.59-7.56 (d, J=9.0 Hz, 2H), 3.06-3.01 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1OCCCN1CCOCC1.Br[CH:28]([CH3:30])[CH3:29]>CN(C)C=O>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[CH:28]([CH3:30])[CH3:29]
Reactant: COc1ccc(C#N)cc1OCCCN1CCOCC1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1C(C)C
Temperature: 85 °C
Reaction time: 3 h

Procedure:
8 g Potassium carbonate and 2.7 g 3-hydroxy-4-methoxybenzonitrile (for synthesis see Example 47) was dissolved in 25 mL dimethylformamide. 2.15 mL 2-Bromopropane was added and the mixture stirred at 85° C. for 3 h. The mixture was concentrated, diluted in ethyl acetate and washed with water (×2) and saturated sodium chloride solution, dried over magnesium sulfate and concentrated.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:22]([OH:24])=O)[N:13]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH-:34])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH:34][C:22](=[O:24])[C@H:12]([CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[N:13]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:14])=[CH:28][CH:27]=1
Reactant: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O
Reactant: [NH-]CCc1ccc(F)cc1
Product: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(F)cc1

Procedure:
Nδ-Boc-Nα-benzyl-Nα-methylornithine and 2-(4-fluorophenyl)ethylamide were coupled, as per Procedure C, to afford titled compound as a glassy solid: 1H NMR (400 MHz, CDCl3) δ1.52 (s, 9H), 1.73 (m, 1H), 1.65 (m, 2H), 1.79 (m, 1H), 2.78 (t, J=7.9 Hz, 2H), 3.02 (m, 1H), 3.14 (m, 2H), 3.52 (m, 4H), 6.96 (m, 2H), 7.11 (m, 5H), and 7.28 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:14])[C:8]=2Cl)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH:20]=O.[H][H]>[Ni].C(OCCO)C>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[CH2:8][C:7](=[N:14][CH2:20][C:19]3[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:17]([O:16][CH3:15])[CH:18]=3)[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: [H][H]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: Nc1nc(N)c2c(Cl)c(N)ccc2n1
Agent: [Ni]
Solvent: CCOCCO
Product: COc1cc(CN=C2C=Cc3nc(N)nc(N)c3C2)cc(OC)c1OC

Procedure:
In a similar manner, 2,4,6-triamino-5-chloroquinazoline can be reacted with 3,4,5-trimethoxybenzaldehyde and hydrogen in the presence of Raney nickel in 2-ethoxyethanol, affording the corresponding 2,4-diamino-6-[(3,4,5-trimethoxyphenylmethyl)imino]quinazoline. Step C of Example 15 describes in detail the preparation of this compound. In a similar manner there may also be prepared 2,4-diamino-6-(substituted-aminomethyl)quinazolines.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13](Br)([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].CN1CCCC1=O>O>[N:18]([C:13]([CH3:15])([CH3:14])[C:12]([NH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:17])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(Br)C(=O)NCCOCc1ccccc1
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(N=[N+]=[N-])C(=O)NCCOCc1ccccc1
Temperature: 50 °C

Procedure:
A mixture of the crude amide (104 g), sodium azide (23.6 g) and N-methyl-2-pyrrolidone (500 ml) was heated at 50° C. for 22 h. After cooling to room temperatur water was added and the resulting mixture was extracted with diethyl ether (2×400 ml). The combined organic phases were washed with brine (3×500 ml) and dried (Na2 SO4). Evaporation of the solvents in vacuo gave 2-azido-N-(2-benzyloxyethyl)-2-methylpropionamide as an oil:78 g.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][Br:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc(Br)cc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ccc(Br)cc2n1

Procedure:
A mixture of 220 g 7-bromoquinaldine, 180 g N-bromosuccinimide and 1 g dibenzoylperoxide in CCl4 (1 L) was illuminated with a 275 W sun lamp at reflux for 12 hours. The reaction mixture was cooled and directly chromatographed on 2 kg silica gel. Elution with toluene afforded the title compound which was used as is for the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([C:27]1[CH:37]=[C:31]3[C:32]([O:34][C:35](=[O:36])[C:30]3=[CH:29][CH:28]=1)=[O:33])(=[O:26])=[O:25])[CH:18]=[CH:17]2.C(OCC)C>CN(C=O)C>[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([C:27]1[CH:28]=[CH:29][C:30]([C:35]([N:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:12][CH2:11]3)=[O:36])=[C:31]([CH:37]=1)[C:32]([OH:34])=[O:33])(=[O:26])=[O:25])[CH:18]=[CH:17]2.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([C:27]1[CH:28]=[CH:29][C:30]([C:35]([OH:36])=[O:34])=[C:31]([C:32]([N:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:12][CH2:11]3)=[O:33])[CH:37]=1)(=[O:26])=[O:25])[CH:18]=[CH:17]2
Reactant: O=C1OC(=O)c2cc(S(=O)(=O)c3ccc4cc(Br)ccc4c3)ccc21
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(O)c1cc(S(=O)(=O)c2ccc3cc(Br)ccc3c2)ccc1C(=O)N1CCN(c2ccncc2)CC1
Product: O=C(O)c1ccc(S(=O)(=O)c2ccc3cc(Br)ccc3c2)cc1C(=O)N1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(4-Pyridyl)piperazine (0.163 g) was added, in one portion, to a stirred solution of 5-(6-bromonaphth-2-ylsulphonyl)phthalic anhydride (0.417 g.) in DMF (10 ml.) and the mixture was stirred at ambient temperature for 1 hour. Diethyl ether (40 ml.) was added and the mixture was stirred rapidly. The resultant white, amorphous precipitate was recovered by filtration. There was thus obtained a 1:1 mixture (0.474 g., 81%) of: 5-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoic acid and 4-(6-bromonaphth-2-ylsulphonyl)-2-[4-(4-pyridyl)piperazin-1-ylcarbonyl]benzoic acid; the mixture giving the following characterising data;