Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:42]=[CH:41][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[OH-].[Na+].O.Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:42]=[CH:41][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: CCOC(=O)CCCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCCC(=O)O)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ethyl 5-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanoate (150 mg, 0.26 mmol) in 10 ml of THF was added 2 ml of 1M NaOH solution. The mixture was heated at 55 C. for 3 hours, cooled to room temperature and poured into 100 ml of water. 2M HCl was added dropwise with vigorous stirring until pH=4. The precipitates were filtered, washed with water, and dried in vacuo to give 5-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanoic acid as white solid. Yield: 130 mg, 91%.
Reaction SMILES: [C:1]([Mg]Cl)#[CH:2].[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](=[O:13])[CH3:12].C(OCC)(=O)C>O1CCCC1>[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([OH:13])([C:1]#[CH:2])[CH3:12]
Reactant: CC(=O)c1cnccn1
Reactant: C#C[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CC(C)(O)c1cnccn1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A 0.5 M solution of ethynylmagnesium chloride in tetrahydrofuran (31.90 mmol, Aldrich) is diluted with 50 ml of tetrahydrofuran and then cooled to 0° C. 3 g of 1-pyrazin-2-ylethanone (24.56 mmol, Lancaster) are then added in several fractions, and the mixture is stirred at 0° C. for 4 hours. The mixture is cooled once again with an ice bath and a solution of NH4Claq is added slowly. The mixture is extracted twice with ethyl acetate and the organic phases are then combined, dried over sodium sulphate, filtered, and concentrated under vacuum. The oily residue obtained is purified by silica chromatography (elution with a cyclohexane:ethyl acetate gradient, 70:30 to 50:50) and 2.9 g of the expected product are obtained in the form of a yellow oil (yield=80%).
Reaction SMILES: C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:14][N:15]([C:23]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]=1[N+:40]([O-])=O)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>O.O1CCOCC1>[NH2:40][C:24]1[CH:25]=[CH:26][C:27]([O:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)=[CH:28][C:23]=1[N:15]([CH3:14])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1N

Procedure:
Sodium bicarbonate (4.2 g) and sodium dithionite (3.5 g) were added to a solution of t-butyl N-methyl-N-[5-(4-trifluoromethylphenoxy)-2-nitrophenyl]carbamate in water/dioxane=1/5 (60 ml). The mixture was heated at reflux for 1 hour. At the end of this time the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane/ethyl acetate=3/1-2/1 as the eluant to give the title compound (0.7 g).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([N:22]3[C:26]4=[N:27][CH:28]=[CH:29][CH:30]=[C:25]4[CH:24]=[CH:23]3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:31][CH2:32][N:33]([CH3:36])[C:34](=[O:35])[C:10]=12)C1C=CC=CC=1.[H][H].CO>C(O)C.ClCCl.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([N:22]3[C:26]4=[N:27][CH:28]=[CH:29][CH:30]=[C:25]4[CH:24]=[CH:23]3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:31][CH2:32][N:33]([CH3:36])[C:34](=[O:35])[C:10]=12
Reactant: [H][H]
Reactant: CN1CCn2c(CC3(n4ccc5cccnc54)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CN1CCn2c(CC3(n4ccc5cccnc54)CCCC3)nc(=O)c(O)c2C1=O
Reaction time: 0.67 h
Yield: 80.5 %

Procedure:
A solution of 9-benzyloxy-2-methyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (407) (60 mg, 0.12 mmol) in ethanol (10 mL) was degassed, Pd—C (10%) (6 mg) added and hydrogenated for 40 min (hydrogen bludder) (TLC, 5% methanol in dichloromethane, Rf=0.2). The catalyst was filtered of and washed with 10% dichloromethane in ethanol (3×20 mL). The combined solvents were concentrated and the resulting sticky solid was washed with pentane to get pure 9-hydroxy-2-methyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (408) (38 mg, 78%) as an off-white solid.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[O:37][CH:38]=[CH:39][CH:40]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[O:37][CH:38]=[CH:39][CH:40]=4)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccco1
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1ccco1
Reaction time: 2 h
Yield: 88 %

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)furan-2-sulfonamide (20 mg, 0.036 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 15 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)furan-2-sulfonamide (percentage yield: 88%), was obtained.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10](Cl)=[N:9][C:8]=2[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:22][CH:23]=1.C(OCC)C>O>[C:1]1([C:7]2[S:11][C:10]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[N:9][C:8]=2[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1nc(Cl)sc1-c1ccccc1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1nc(Nc2cccc(C(F)(F)F)c2)sc1-c1ccccc1
Reaction time: 8 h

Procedure:
A reaction vessel was charged with 2.8 g of methyl 5-phenyl-2-chloro-4-thiazolecarboxylate and 9.7 g of meta-aminobenzotrifluoride. The reaction mixture was stirred overnight and then heated and stirred at 150° C. for about 6 hours during which time a crystalline solid appeared. The mixture was treated with ethyl ether and water. The ether extract was dried with magnesium sulfate and concentrated. The residue was crystallized from anhydrous ethyl ether to provide a white amorphous powder (m.p. 147°-149° C.) identified in Table I.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH2:18]1N2CN3CN(C2)CN1C3.C(OC(=O)C)(=O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:8](=[O:17])[CH:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:18]2
Reactant: O=C(CCC1CCCCC1)c1ccccc1Cl
Reactant: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1c2c(Cl)cccc2CC1CC1CCCCC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 57.9 %

Procedure:
66 g (263 mmole) 1-(2-Chloro-phenyl)-3-cyclohexyl-propan-1-one, 77.5 g (2.1 eq.) urotropine and 72.6 g (2.7 eq.) of acetic anhydride were placed in a 500 ml roundbottom flask and the mixture was stirred at 80° C. for 4 h. Then 100 ml water and 100 ml 2M NaOH were added and the mixture was extracted two times with 200 ml dichloromethane each. The organic layer was washed two times with 100 ml saturated aqueous ammonium chloride and dried over magnesium sulphate. The solvent amount was reduced in vacuo to a total of 150 ml volume and the solution was added dropwise over a period of 2.5 h to 660 g of hot (70-75° C.) concentrated sulphuric acid. After stirring for an additional 30 min at 75° C. the mixture was allowed to stand overnight at room temperature. The mixture was poured onto approx. 500 g of ice and extracted three times with 150 ml dichloromethane each. The organic layer was washed twice with 150 ml of a saturated sodium bicarbonate solution and once with 100 ml of a saturated sodium chloride solution. After drying over magnesium sulphate the solvent was removed in vacuo. The product was purified by column chromatography on silica (heptane/dichloromethane 5:1) to yield 40.0 g (61%) of the desired product as a slightly off-white oil, which slowly crystallized. 1H-NMR (400 MHz, CDCl3): δ=7.42 (t, 1H, aromatic), 7.29 (d, 1H, aromatic), 7.24 (d, 1H, aromatic), 3.25 (dd, 1H, COCH), 2.71 (m, 2H, benzylic), 1.78-0.87 (m, 13H, aliphatic) ppm.
Reaction SMILES: [CH2:1]=O.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>ClCCCl>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:1])[CH2:13][CH2:12]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C=O
Solvent: ClCCCl
Product: COc1ccccc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Formaldehyde (1.84 ml in solution) is added to a solution of 1-(2-methoxyphenyl)-piperazine (4.77 g, 24.3 mmol) in 1,2-dichloroethane. NaHB(OAc)3 (7.59 g, 34 mmol) is then added portionwise. After stirring at RT overnight, the reaction is quenched by addition of a saturated solution of NaHCO3. The mixture is extracted several times with EtOAc and the combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo to afford the title compound as a colorless oil, Rt=0.615 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 207 (M+1)+.
Reaction SMILES: [C:1]([C:9]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([OH:23])[C:17]([O:24]C)=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].Cl>N1C=CC=CC=1>[C:1]([C:9]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([OH:23])[C:17]([OH:24])=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1C(=O)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1C(=O)c1ccccc1
Temperature: 77 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a mixture of ethyl 2-benzoyl-4-hydroxy-5-methoxy-3-nitrobenzoate (reference example 18-1) (806 mg) and ethyl acetate (10 mL) were added aluminum chloride (610 mg) and pyridine (0.889 mL). The mixture was stirred at 77° C. for 2 hours. After cooling to room temperature, 2 mol/L hydrochloric acid was added to the mixture. The separated organic layer was washed with brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane:diethyl ether=4:1 to give the title compound (430 mg).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:33]=[CH:32][N:13]([C@@H:14]2[O:31][C@H:21]([CH2:22][O:23][Si](C(C)(C)C)(C)C)[C@@H:16]([O:17][CH2:18]SC)[CH2:15]2)[C:12](=[O:34])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC1C=CN([C@@H]2O[C@H](CO[Si](C(C)(C)C)(C)C)[C@@H](O)C2)C(=O)N=1)(=O)C1C=CC=CC=1.[N-:66]=[N+:67]=[N-:68].[Na+].[NH4+].[F-]>C(Cl)Cl>[C:1]([NH:9][C:10]1[CH:33]=[CH:32][N:13]([C@@H:14]2[O:31][C@H:21]([CH2:22][OH:23])[C@@H:16]([O:17][CH2:18][N:66]=[N+:67]=[N-:68])[CH2:15]2)[C:12](=[O:34])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSCO[C@H]1C[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(NC(=O)c3ccccc3)nc2=O)C[C@@H]1O
Agent: [F-]
Agent: [NH4+]
Solvent: ClCCl
Product: [N-]=[N+]=NCO[C@H]1C[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To 0.5580 g N4-benzoyl-3′-O-(methylthiomethyl)-5′-O-(tert-butyldimethylsilyl)-2′-deoxycytidine (6c) (1.04 mmol) dissolved in 8 mL dry CH2Cl2 were added 0.56 mL cyclohaxene and 220 μL SO2Cl2 (2.7 mmol) at 0° C. and stirred at the ice-cold temperature for 1 h. During this time, the starting material converted to the chlorinated product as shown by the 3′-OH (5c) compound in the TLC. The volatiles were then removed under vacuum and resuspended in dry DMF (5 mL) and treated with NaN3 (400 mg, 6.6 mmol) and stirred for 2 h at room temperature. The sample was then partitioned between water and CH2Cl2 and the organic extracts were combined and dried over Na2SO4 and concentrated under vacuum. The crude sample was then dissolved in MeOH (5 mL) and treated with NH4F (600 mg, 16.2 mmol) for 20 h at room temperature. Then solvent was removed under vacuum and extracted with CH2Cl2 and the organic extract was then dried over Na2SO4 and concentrated under vacuum. The sample was then purified by silica gel column chromatography (Hex:EtOAc 1:4 to 1:10), and the product (9c) was obtained as white powdery substance (˜200 mg, 50% yield in three steps, Rf=0.5, EtOAc:Hex/5:0.5). HR-MS: Obs. m/z 387.1408, calcd for C17H19O5N6 387.1417 [M+H]+. 1H-NMR (CDC3): δH 8.30 (d, J=7.2 Hz, 1H), 7.93 (d, J=7.50 Hz, 1H), 7.66-7.51 (m, 5H), 6.18 (t, J=6.4 Hz, 1H), 4.81-4.68 (m, 2H), 4.52 (m, 1H), 4.25 (m, 1H), 4.08-3.88 (m, 2H), 2.69 (m, 1H), and 2.50 (m, 2H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:10]=[C:9]([CH:8]=[CH:7][C:5]=1[NH2:6])[C:11]#[N:12]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(N)c(N)c1
Yield: 26.3 %

Procedure:
2-Nitro-4-cyanoaniline (2.21 g) was hydrogenated using 7.5% palladium carbon (320 mg) in ethanol (44 ml) at atmospheric pressure over 2 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was evaporated. To the obtained residue was added chloroform and the resultant solid was collected by filtration and dried under reduced pressure to give the title compound (474 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]2[C:21]([O:22]C=O)=[C:20]([O:25][CH2:26][C@@H:27]3[O:29][CH2:28]3)[CH:19]=[CH:18][C:10]=2[S:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].O>O1CCCC1>[Cl:7][C:8]1[C:9]2[C:21]3[O:22][C@@H:27]([CH2:28][OH:29])[CH2:26][O:25][C:20]=3[CH:19]=[CH:18][C:10]=2[S:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1sc2ccc(OC[C@H]3CO3)c(OC=O)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1sc2ccc3c(c2c1Cl)O[C@@H](CO)CO3
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
Saturated aqueous potassium carbonate solution (20 ml) was added to a stirred solution of ethyl (R)-3-chloro-5-(2,3-epoxypropoxy)-4-formyloxy-benzo[b]thiophene-2-carboxylate (1.85 g, prepared as described above) in tetrahydrofuran (20 ml) and the mixture stirred for 24 hours at room temperature. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (2×100 ml). The combined extracts were dried over sodium sulphate and evaporated under reduced pressure to give a yellow solid. Purification by flash chromatography on silica using a 1:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant gave ethyl (S)-9-chloro-2,3-dihydro-2-(hydroxymethyl)thieno[3,2-f]-1,4-benzodioxin-8-carboxylate (1.44 g) as a pale-yellow solid; m.p. 165-166° C.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][S:7]([O-])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Na+].S(Cl)([Cl:16])=O>CN(C)C=O>[CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][S:7]([Cl:16])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CS(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CS(=O)(=O)Cl)cc1
Temperature: -10 °C

Procedure:
In dimethylformamide (90 ml) is dispersed sodium p-methylbenzylsulfonate (30 g, 0.145 mol) which is sufficientry dry. The dispersion is cooled to -10° C. and under stirring, thionyl chloride (19.2 ml, 0.29 mol) is added dropwise. The mixture is stirred at room temperature for 3 hours and poured in ice-water (500 g) and extracted with ether (3 times, 150 ml each). The ethereal layers are combined, washed twice with cold water and dried over sodium sulfate. The ether is distilled off and petroleum ether is added to the crystalline residue, followed by cooling. The crystals are collected by filtration.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][C:5](O)([C:12]([F:15])([F:14])[F:13])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:12]([F:14])([F:15])[F:13])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C1=C(C)OCC1(O)C(F)(F)F
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(F)(F)F)coc1C
Yield: 75.1 %

Procedure:
10 g of the product of Stage A were heated for 7 hours at reflux in 50 ml of toluene in the presence of 0.5 g of toluenesulfonic acid and the mixture was allowed to return to room temperature. The solvent was evaporated and the residue was chromatographed on silica (eluent: 95/5 n-hexane/ethyl acetate) to obtain 6.95 g of the expected product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH3:10])[C:3]=1[O:11][CH3:12].[Cl-].[Al+3].[Cl-].[Cl-].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].O>C(Cl)Cl>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([C:7]1[CH:6]=[C:5]([CH3:8])[C:4]([O:9][CH3:10])=[C:3]([O:11][CH3:12])[C:2]=1[CH3:1])=[O:24]
Reactant: COc1c(C)ccc(C)c1OC
Reactant: O=C(Cl)CCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1c(C)cc(C(=O)CCCCCBr)c(C)c1OC
Temperature: 0 °C
Reaction time: 19 h
Yield: 45.6 %

Procedure:
A solution of 0.227 g (1.5 mmol) of 3,6-dimethylveratrole in 1 mL of methylene chloride was added to an ice cooled mixture of 0.245 g (1.8 mmol) of aluminum chloride and 0.416 g (1.9 mmol) of 6-bromohexanoyl chloride in 3 mL of methylene chloride. The reaction mixture was kept at 0° for 19 hours. Water was added and the organic layer was separated and washed with sodium bicarbonate solution. The dried extract was concentrated to an oil which was chromatographed on 60 g of silica gel using 10% ethyl acetate-hexane to give 0.235 g of 6-bromo-1-(3,4-dimethoxy-2,5-dimethylphenyl)-1-hexanone as an oil. The nmr spectrum was consistent with the structure and the mass spectrum gave the molecular ion at m/z 342 (C16H23BrO3)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([N:12]=[CH:13][NH:14][NH:15][C:16](C2NC=CN=2)=[O:17])=[O:11])=[N:4][C:5]([F:9])=[C:6]([NH2:8])[N:7]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[NH2:1][C:2]1[C:3]([C:10]([N:12]=[CH:13][NH:14][NH:15][C:16]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:17])=[O:11])=[N:4][C:5]([F:9])=[C:6]([NH2:8])[N:7]=1
Reactant: Nc1nc(N)c(C(=O)N=CNNC(=O)c2ncc[nH]2)nc1F
Reactant: CC(C)N
Product: CC(C)NC(=O)NNC=NC(=O)c1nc(F)c(N)nc1N

Procedure:
Following the procedure of Example 54, Step B but substituting 3,5-diamino-6-fluoro-N-{[(imidazolcarbonyl)amino]aminomethylene}-2-pyrazinecarboxamide (1.3 g.) and isopropylamine (0.45 ml) in place of the corresponding reactants in Example 54, Step B there is obtained 3,5-diamino-6-fluoro-N-{[(isopropylaminocarbonyl)amino]aminomethylene}-2-pyrazinecarboxamide. Yield: 600 Mg. M.P. 221° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:48][C@H:49]([C:57]([CH:59]1[CH:66]2[CH2:67][CH:62]3[CH2:63][CH:64]([CH2:68][C:60]1([NH2:69])[CH2:61]3)[CH2:65]2)=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>O1CCCC1>[C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:48][C@H:49]([C:57]([CH:59]1[CH:66]2[CH2:67][CH:62]3[CH2:63][CH:64]([CH2:68][C:60]1([NH2:69])[CH2:61]3)[CH2:65]2)=[O:58])[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2CC3CC(C2)CC1(N)C3
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of 1.88 g of Boc-L-tyrosyl-D-methionyl-glycine and 0.45 ml of N-methylmorpholine in 25 ml of dry tetrahydrofuran under nitrogen is cooled to -45° C. with stirring. To the cooled solution is added 0.52 ml of isobutylchloroformate. The reaction mixture is allowed to warm to -20° C. over a 10 minute period and is then cooled to -35° C. Following the addition of 1.9 g of L-phenylalanyl-1-aminoadamantane the reaction mixture is warmed to room temperature and allowed to stand overnight. The reaction mixture is filtered and the tetrahydrofuran is removed under reduced pressure. The residue is dissolved in methylene chloride and washed with cold 1 M potassium bisulfate solution and saturated sodium chloride solution. Removal of the solvent and purification by chromatography on silica gel gives Boc-tyrosyl-D-methionyl-glycyl-phenylalanyl-1-aminoadamantane which is represented by the following formula ##STR39##
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[CH:13][C:14]#[N:15])=[CH:5][CH:4]=1.[BH4-].[Na+].[ClH:18]>CO.[Co](Cl)Cl>[ClH:18].[CH3:1][S:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:13][CH2:14][NH2:15])=[CH:5][CH:4]=1
Reactant: CSc1ccc2c(c1)C(=CC#N)CCC2
Agent: Cl[Co]Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: CSc1ccc2c(c1)C(CCN)CCC2
Reaction time: 3 h

Procedure:
0.0046 mol of the compound obtained in Step D is dissolved in 70 ml of methanol. 0.0092 mol of cobalt chloride is added, with magnetic stirring, and then, in small portions, 0.0325 ml of sodium borohydride. Stirring is carried out for 3 hours at ambient temperature and the mixture is then acidified with 6M hydrochloric acid solution until the black precipitate dissolves. The methanol is evaporated off under reduced pressure and then extraction with ethyl ether is carried out. The two phases are separated, and the aqueous phase is then rendered alkaline with 20% ammonium hydroxide solution. Extraction with ethyl ether is carried out twice; the organic phase is dried over magnesium sulphate and evaporated under reduced pressure. The oil obtained is dissolved in alcohol at 95° C. and then an ethanolic solution saturated with HCl is added. The solvent is evaporated off under reduced pressure and the residue obtained is recrystallised.