Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[OH:6].[F:16][C:17]([F:23])([F:22])[S:18](Cl)(=[O:20])=[O:19]>CCOCC>[F:15][C:4]([F:3])([F:14])[C@H:5]([O:6][S:18]([C:17]([F:23])([F:22])[F:16])(=[O:20])=[O:19])[C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: O[C@H](c1ccc(F)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(O[C@H](c1ccc(F)cc1)C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
NaH (11.87 g, 296.7 mmol) was added to Et2O (700 mL) at 0° C. under N2 followed by addition of an Et2O solution of 2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethanol (44.3 g, 228.2 mmol). The reaction mixture was stirred for 10 min at 0° C. then 1 h at room temperature. Trifluoromethanesulfonyl chloride (50 g, 296.7 mmol) in Et2O was added at 0° C. under N2 and the reaction mixture was stirred 10 min at 0° C. then 3 h at room temperature. The solvent was removed under the reduced pressure and H2O (100 mL) was added slowly. The aqueous layer was extracted by hexane and the combined organic layer was dried over MgSO4. The solvent was removed under the reduced pressure to give trifluoromethanesulfonic acid 2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethyl ester (70 g) as colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[Br:18])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:39][C:40](O)([CH3:42])[CH3:41].C1CCN2C(=NCCC2)CC1.Cl>CN(C=O)C>[C:40]([O:13][C:12](=[O:14])[C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]([Br:18])=[C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)([CH3:42])([CH3:41])[CH3:39]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(Br)c(OCc2ccccc2)c1
Reactant: CC(C)(C)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(Br)c(OCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred solution of 3,5-bis-benzyloxy-4-bromo-benzoic acid (200b) (153 g, 0.37 mol) in DMF (1 L) was added CDI (90 g, 0.56 mol) in several portions. The solution was stirred at 40° C. for 1 hr. t-BuOH (55 g, 0.74 mol) was added to the mixture and then followed by the drop wise addition of DBU (56.3 g, 0.37 mol). The resulting solution was stirred at 40° C. for 2 days. TLC (EtOAc/petroleum ether=1/10) showed that the reaction was complete. The mixture was cooled to room temperature and poured into ice water (1 L). The mixture was acidified to pH 5 with conc. HCl and stirred for 1 hr. The formed solid was filtered and washed with water, then dried in vacuo to give the title compound (165 g, 86% yield) as a brown solid. 1H NMR (400 MHz, CDCl3): δ 7.57-7.25 (m, 12H), 5.21 (s, 4H), 1.58 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]2[S:19][C:18](=[O:20])[NH:17][C:16]=2[CH:21]=1.Cl[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]2[S:19][C:18](=[O:20])[N:17]([CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[C:16]=2[CH:21]=1
Reactant: ClCc1cccnc1
Reactant: Cc1ccn2c(C)c(-c3ccc4sc(=O)[nH]c4c3)nc2c1
Product: Cc1ccn2c(C)c(-c3ccc4sc(=O)n(Cc5cccnc5)c4c3)nc2c1
Yield: 47.5 %

Procedure:
5-(3,7-Dimethylimidazo[1,2-a]pyridin-2-yl)-3-(pyridin-3-ylmethyl)-2-benzothiazolinone (0.92 g) was prepared in substantially the same manner as that of Example 47 from 5-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)-2-benzothiazolinone (1.48 g) and 3-chloromethylpyridine (1.27 g). mp. 201°-202° C.
Reaction SMILES: CO[C:3]1([CH2:10][CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][C:17]([O:22]C)([O:20]C)OC)[CH:7]=[CH:6][CH:5]([O:8]C)O1.O.P([O-])(O)(O)=[O:26].[Na+].O1CCOCC1.S(=O)(=O)(O)O>P([O-])([O-])(O)=O.[Na+].[Na+].O>[OH:26][CH:7]1[CH2:6][C:5](=[O:8])[C:10]([CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][C:17]([OH:20])=[O:22])=[CH:3]1
Reactant: O=P([O-])(O)O
Reactant: COC1C=CC(CCC#CCCCC(OC)(OC)OC)(OC)O1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCC#CCC1=CC(O)CC1=O
Temperature: 50 °C
Yield: 112.5 %

Procedure:
A stirred mixture of 7.1 g of 2,5-dihydro-2,5-di- methoxy-2-(8,8,8-trimethoxy-3-octynyl)furan, 2.76 g of sodium dihydrogen phosphate monohydrate, 140 mg of disodium hydrogen phosphate, 60 ml of dioxane and 40 ml of water was boiled under reflux for 19 hours, then cooled to 50° C. and treated dropwise with 4.1 ml of concentrated sulfuric acid. The resulting solution was boiled under reflux for 12 hours, cooled and partitioned with ether and brine. The ether layer was separated, washed with brine, dried and concentrated, giving 5.0 g of crude 7-(4-hydroxycyclopent-2-en-1-on-2-yl)-5-heptynoic acid. This crude product was dissolved in 40 ml of pyridine and the stirred solution treated at 0° to 10° C. with 10.5 ml of hexamethyldisilizane followed by 6.3 ml of chlorotrimethylsilane. The resulting mixture was stirred at 25° C. for 3 hours and then concentrated to dryness at 30° C. The residue was extracted with hexane, the extract filtered through diatomaceous earth and concentrated. The residue was distilled at 0.11 mm on a Kugelrohr at 155°-170° C., giving 1.66 g of the desired compound as an oil.
Reaction SMILES: [N:1]([O-])=O.[Na+].[N+:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([NH2:18])=[CH:10][CH:9]=1)([O-:7])=[O:6].[ClH:19]>O.CC(O)=O>[ClH:19].[NH:18]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=1)[NH2:1]
Reactant: Nc1ccc([N+](=O)[O-])c2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NNc1ccc([N+](=O)[O-])c2ccccc12
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.9 g of sodium nitrite in 10 ml of water is added to a suspension, cooled to -5° C., of 5.2 g of 4-nitro-1-naphthylamine in 150 ml of concentrated HCl, 100 ml of 1N HCl and 150 ml of AcOH. The mixture is left stirring for 1 hour 15 minutes at a temperature of between -5° C. and 0° C. It is cooled to -15° C., and a solution of 12.5 g of stannous chloride dihydrate in 30 ml of concentrated HCl is added very slowly. The temperature is allowed to rise to RT and the reaction mixture is kept stirring for 2 hours 30 minutes. It is filtered, the solid is then taken up with water and the mixture is filtered again. 5.9 g of the expected product are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>CN(C)C=O>[CH2:20]([O:19][C:17](=[O:18])[C:16](=[CH:15][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:21]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ncnc2ccccc12
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ncnc2ccccc12)C(=O)OCC
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
A mixture of 4-aminoquinazoline (11.6 g) and diethyl ethoxymethylenepropanedioate (19.0 g) in N,N-dimethylformamide (40 ml) was stirred for 1 hour and 20 minutes at 160° C. and then cooled to 0° C. to precipitate crystals. To the mixture was added small volume of water with stirring. The crystals were separated by filtration, washed with water, dried overnight under reduced pressure and dissolved in ethyl acetate. The resultant solution was dried over anhydrous magnesium sulfate and recrystallized from a mixture of ethyl acetate and hexane to give crystalline diethyl[(4-quinazolinylamino)methylene]propanedioate (22.7 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[N:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10](Cl)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[C:38]([Cl:51])[C:37]=1[OH:52]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:20]=[N:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]3)=[N:17][CH:16]=1)=[N:11][C:10]([C:40]1[CH:41]=[C:36]([Cl:35])[C:37]([OH:52])=[C:38]([Cl:51])[CH:39]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1cnc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1cnc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 78.6 %

Procedure:
Following general procedure II, tert-butyl 1-[5-(3-acetyl-6-chloro-1,5-naphthyridin-4-ylamino)pyrimidin-2-yl]pyrrolidin-3-ylcarbamate (120 mg, 0.25 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (110 mg, 0.38 mmol) to afford the product (120 mg, 80%) as an orange solid: 1H NMR (500 MHz, CDCl3) δ 12.02 (s, 1H), 9.12 (s, 1H), 8.28-8.20 (m, 3H), 7.93 (d, J=8.8 Hz, 1H), 7.39 (s, 2H), 4.72 (br s, 1H), 4.36 (br s, 1H), 3.86 (br s, 1H), 3.65 (br s, 2H), 3.40 (br s, 1H), 2.80 (s, 3H), 2.28 (br s, 1H), 2.03-1.93 (m, 1H), 1.48 (s, 9H); ESI MS m/z 610 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13]C(=O)OCC2C=CC=CC=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reaction time: 3 h

Procedure:
Under an N2 atmosphere, a solution of benzyl(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate (1.85 g, 5.75 mmol) in 10 mL MeOH was added to a flask containing Pd/C (185 mg, 10% weight Pd on carbon). After evacuating the flask under vacuum and purging it twice with N2, the reaction was stirred for 3 h under an H2 atmosphere at ambient pressure. The reaction was filtered through a bed of Celite, and the solvent was evaporated under reduced pressure to obtain (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate which was used without further purification. LC/MS: m/z 187.3 (M+H)+ at 1.07 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10](O)=[O:11].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH2:47]([NH2:56])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([NH:56][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[O:11]
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1C(=O)O
Reactant: CCCCCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1OC
Temperature: 25 °C
Yield: 85.2 %

Procedure:
To a suspension of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-benzoic acid (150 mg, 0.42 mmol) in CH2Cl2 (2 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) and 1-hydroxybenzotriazole hydrate (77 mg, 0.50 mmol) with stirring at RT. To the resulting yellow solution was added nonylamine (154 μl, 0.84 mmol) at RT. The resulting mixture was stirred 2 h at RT then solvent removed under a dry nitrogen stream. The residue was purified by preparative TLC (5% Et2O, 45% hexanes, 50% CH2Cl2) to give the title compound of Step C (173 mg). MS (APCl+) Calc.: 482.1, Found: 483.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:12]([CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:11][C:10]2[C:9]([CH3:25])([CH3:24])[CH2:8][CH2:7][C:6]([CH3:27])([CH3:26])[C:5]=2[CH:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:40])C.O>ClCCl>[CH:1]([C:3]1[C:12]([CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:11][C:10]2[C:9]([CH3:25])([CH3:24])[CH2:8][CH2:7][C:6]([CH3:27])([CH3:26])[C:5]=2[CH:4]=1)=[O:40]
Reactant: CC(=O)O
Reactant: CC1(C)CCC(C)(C)c2cc(CCCO[Si](C)(C)C(C)(C)C)c(C#N)cc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(CCCO[Si](C)(C)C(C)(C)C)c(C=O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a solution of 4.6 g (11.9 mmol) of 2-cyano-3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene.in 40 mL of dichloromethane at −78° C. was added 17.9 mL (17.9 mmol) of diisobutylaluminum hydride (1.0 M in toluene). The reaction mixture was stirred and allowed to slowly warm to room temperature. After 16 hours, acetic acid was added dropwise, followed by addition of water and dichloromethane. The organic fraction was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient elution: 4-25% ethyl acetate/hexane) to afford 2.48 g (53%) of 2-formyl -3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene. M+=389).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]([NH:24][CH2:25][CH2:26][CH:27]=C)=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOC[CH2:30]1.CO>O>[CH2:25]([N:24]([CH3:30])[C:19]1[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:3])=[O:5])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])=[CH:23][CH:22]=[CH:21][N:20]=1)[CH:26]=[CH2:27]
Reactant: C=CCCNc1ncccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Reactant: C1COCCO1
Solvent: CO
Solvent: O
Product: C=CCN(C)c1ncccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 38 h
Yield: 100 %

Procedure:
A 100 mL round bottom flask which contains 2-{[2-(allyl-methyl-amino)-pyridine-3-carbonyl]-amino}-indan-2-carboxylic acid ethyl ester (339, 280 mg, 0.74 mmol) is charged with 1,4-dioxane (2 mL) and MeOH (2 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1 mL) is added followed by the LiOH monohydrate (78 mg, 1.86 mmol). After 38 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 15 days, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides white solid (0.26 g, 100%).
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][P:8]([CH2:28][NH2:29])([CH2:10][CH:11]([C:16](=[O:27])[NH:17][C@H:18]([C:23](=[O:26])[NH:24][CH3:25])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH3:6].[CH3:30][O:31][C:32]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:34]2[C:35]([O:37][C:38](=O)[C:33]=12)=[O:36]>>[CH2:5]([O:7][P:8]([CH2:28][N:29]1[C:35](=[O:36])[C:34]2=[C:40]([O:43][CH3:44])[CH:41]=[CH:42][C:32]([O:31][CH3:30])=[C:33]2[C:38]1=[O:37])([CH2:10][CH:11]([C:16](=[O:27])[NH:17][C@H:18]([C:23](=[O:26])[NH:24][CH3:25])[CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH3:6]
Reactant: COc1ccc(OC)c2c1C(=O)OC2=O
Reactant: CCOP(=O)(CN)CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC
Solvent: CC(=O)O
Product: CCOP(=O)(CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC)CN1C(=O)c2c(OC)ccc(OC)c2C1=O
Yield: 50.1 %

Procedure:
In a manner analogous to that described in Example 3(A), from 0.5 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester acetate and 0.27 g of 3,6-dimethyoxyphthalic anhydride, there was obtained 0.325 g of [(3,6-dimethoxyphthalimido)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester in the form of a pale yellow foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].S([O-])([O-])(=O)=O.CS[C:13]([NH2:25])=[NH+:14][CH2:15][CH2:16][S:17][CH2:18][C:19]1[N:20]=[CH:21][NH:22][C:23]=1[CH3:24].CS[C:28]([NH2:40])=[NH+:29][CH2:30][CH2:31][S:32][CH2:33][C:34]1[N:35]=[CH:36][NH:37][C:38]=1[CH3:39]>O>[CH3:39][C:38]1[NH:37][CH:36]=[N:35][C:34]=1[CH2:33][S:32][CH2:31][CH2:30][N:29]=[C:28]([NH2:40])[NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:13]([NH2:25])=[N:14][CH2:15][CH2:16][S:17][CH2:18][C:19]1[N:20]=[CH:21][NH:22][C:23]=1[CH3:24]
Reactant: CSC(N)=[NH+]CCSCc1nc[nH]c1C
Reactant: NCCCN
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Cc1[nH]cnc1CSCCN=C(N)NCCCNC(N)=NCCSCc1nc[nH]c1C

Procedure:
1,3-Diaminopropane (0.37 g) was added to a solution of S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiouronium sulphate (2.93g) in water (10 ml) and the mixture was heated under reflux for 2 hours. Following concentration the residue was converted into the picrate with an aqueous solution of sodium picrate. Recrystallisation from ethanol afforded the title compound as the dipicrate (1.1 g) m.p. 114°-6°.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][CH:10]1[C:26]2([CH3:27])[CH:13]([CH:14]3[CH:23]([CH2:24][CH2:25]2)[C:22]2[CH:21]=[C:20]([O:28][CH3:29])[C:19]([OH:30])=[CH:18][C:17]=2[CH2:16][CH2:15]3)[CH2:12][CH2:11]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][CH2:7][CH2:8][O:9][CH:10]1[C:26]2([CH3:27])[CH:13]([CH:14]3[CH:23]([CH2:24][CH2:25]2)[C:22]2[CH:21]=[C:20]([O:28][CH3:29])[C:19]([OH:30])=[CH:18][C:17]=2[CH2:16][CH2:15]3)[CH2:12][CH2:11]1
Reactant: COc1cc2c(cc1O)CCC1C2CCC2(C)C(OCCO[Si](C)(C)C(C)(C)C)CCC12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc2c(cc1O)CCC1C2CCC2(C)C(OCCO)CCC12
Reaction time: 8 h
Yield: 78.2 %

Procedure:
A solution of TBS protected alcohol 47 (110 mg, 0.24 mmol) in THF (5 mL) was treated with TBAF (250 mL, 0.25 mmol). After stirring overnight the reaction was extracted with ethyl acetate (25 mL), the organics washed with water and brine, dried and evaporated. The resultant pale yellow oil was purified by column chromatography (2% methanol in chloroform) to give the desired diol 48 as a clear colourless oil (65 mg) which showed δH 6.78 (1H, s, ArH), 6.64 (1H, s, ArH), 5.51 (1H, s, OH), 3.86 (3H, s, OMe), 3.40-3.68 (5H, m, 2×OCH2 and CHOR), 2.72-2.82 (2H, m, 6-CH2), 1.20-2.30 (14H, m) and 0.81 (3H, s, 18-Me); δC 144.6, 143.5, 131.7, 129.5, 114.6, 109.1, 89.4, 70.9, 62.1, 56.1, 50.2, 44.2, 38.6, 38.0, 28.9, 28.1, 27.2, 26.6, 23.0 and 11.7.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3]1.S(Cl)([Cl:21])=O.CCOC(C)=O>C1(C)C=CC=CC=1>[Cl:21][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3]1
Reactant: CCOC(=O)C1CCC(O)C=C1c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(Cl)C=C1c1ccccc1
Reaction time: 3 h
Yield: 102.1 %

Procedure:
To a stirred solution of ethyl 4-hydroxy-2-phenylcyclohex-2-enecarboxylate (10 mg, 0.407 mmol) in toluene(2 ml) was added thionyl chloride(0.074 ml, 1.02 mmol) at 5° C. After stirring for 3 hr. at room temperature. AcOEt was added to the reaction mixture and it was washed with water, sat.NaHCO3 aq. and brine, dried over MgSO4. Concentration of the organic layer afford 110 mg of ethyl 4-chloro-2-phenylcyclohex-2-enecarboxylate(y=100%) as a pale yellow oil. 1H-NMR(ppm, 300 MHz, CDCl3) δ 7.25-7.37(5H, m), 6.27 and 6.18(1H, d and t, J=4.6 and 1.7 Hz), 4.87-4.91 and 4.74-4.79(1H, m), 4.03 and 3.96(2H, q, J=6.9 and 7.1 Hz), 3.68-3.76(1H, m), 2.05-2.37(4H, m), 1.09 and 0.97(3H, t, J=6.9 and 7.1 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[Br:30][CH2:31]/[CH:32]=[CH:33]/[C:34](Cl)=[O:35]>O1CCCC1>[Br:30][CH2:31]/[CH:32]=[CH:33]/[C:34]([NH:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:21][CH3:22])[N:13]=[CH:12][N:11]=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)=[O:35]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Reactant: O=C(Cl)/C=C/CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)/C=C/CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a stirred solution of N4-(3-chloro-4-fluorophenyl)-7-methoxy-4,6-quinazolinediamine (8) (4.0 g, 12.5 mmol) in dry tetrahydrofuran (150 mL) under nitrogen was added triethylamine (19 mmol), followed by freshly prepared (2E)-4-bromo-2-butenoyl chloride (15 mmol) in dry tetrahydrofuran (50 mL). The resulting solution was then stirred at room temperature for 2 hours and concentrated under reduced pressure. Trituration from dichloromethane gave crude (2E)-4-bromo-N-[4-(3-chloro-4-fluoroanilino)-7-methoxy-6-quinazolinyl]-2-butenamide (4.6 g) that was used directly.
Reaction SMILES: [CH3:1][C:2]12[CH:12]=[CH:11][CH:5]([CH:6]=[C:7]1[CH2:8][CH2:9][OH:10])[C:4]([CH3:14])([CH3:13])[C:3]2=[O:15].[H][H]>[Pd].C(O)(C)C>[CH3:1][C:2]12[CH2:12][CH2:11][CH:5]([CH2:6][CH:7]1[CH2:8][CH2:9][OH:10])[C:4]([CH3:14])([CH3:13])[C:3]2=[O:15]
Reactant: CC12C=CC(C=C1CCO)C(C)(C)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: CC1(C)C(=O)C2(C)CCC1CC2CCO
Temperature: 150 °C
Reaction time: 48 h

Procedure:
An autoclave is charged with 26.8 grams of 1,3,3-trimethyl-6-(2-hydroxyethyl)bicyclo(2.2.2)-octa-5,7-dien-2-one prepared according to the process of Example XVI, 2 grams 5% palladium/carbon catalyst, and 300 ml isopropyl alcohol. The autoclave is then sealed and pressurized with hydrogen to 400 psig, heated to 150° C. and maintained at that temperature, with stirring, for a period of 48 hours. At the end of this period of time, the autoclave is opened and the reaction mass is removed. The reaction mass is filtered, and the excess isopropyl alcohol is stripped therefrom. The reaction product (the title product) is distilled at 64°-65° C. at a pressure of 0.2 mm Hg (yield: 12.3 g). Its structure, confirmed by NMR and mass spectral analyses is as follows: ##STR36##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:11][CH:10]1[C:12](N(OC)C)=[O:13].[OH-:18].[K+].Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:11][CH:10]1[C:12]([OH:13])=[O:18]
Reactant: CON(C)C(=O)C1CC1c1cc(F)ccc1Br
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)C1CC1c1cc(F)ccc1Br
Temperature: 25 °C

Procedure:
A solution of 2-(2-bromo-5-fluorophenyl)-N-methoxy-N -methylcyclopropane-carboxamide (304 mg, 1.0 mmol), 10 M potassium hydroxide (3.5 mL, 35 mmol), and dioxane (2.5 mL) was heated at 130° C. in a sealed tube for 19 h. Upon cooling to room temperature, the reaction mixture was acidified with 3 M HCl (20 mL), and the product was extracted with 5% methanol/dichloromethane (3×30 mL). The organic fractions were combined, dried over sodium sulfate, and concentrated to afford the title compound as a white solid. MS m/z: 259 & 261 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](O)=O)=[CH:2]1.[NH2:9][C:10]1[C:11](=[O:24])[N:12]([CH2:21][CH2:22][CH3:23])[C:13](=[O:20])[N:14]([CH2:17][CH2:18][CH3:19])[C:15]=1[NH2:16]>>[CH2:21]([N:12]1[C:11](=[O:24])[C:10]2[NH:9][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[N:16][C:15]=2[N:14]([CH2:17][CH2:18][CH3:19])[C:13]1=[O:20])[CH2:22][CH3:23]
Reactant: O=C(O)c1ccsc1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(-c3ccsc3)nc2n(CCC)c1=O

Procedure:
The starting 1,3-dipropyl-8-(3-thienyl)xanthine is prepared in a manner analogous to that described in Example 2 hereinafter using 3-thiophenecarboxylic acid and 5,6-diamino-1,3-dipropyluracil, mp>250° C.