Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:13][C:12]=3[N:23]([CH3:33])[S:24]([C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)(=[O:26])=[O:25])=[N:6][CH2:5]1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.O>[CH3:22][O:21][CH2:20][CH2:19][O:18][C:14]1[CH:15]=[C:16]2[C:11](=[C:12]([N:23]([CH3:33])[S:24]([C:27]3[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:26])[CH:13]=1)[NH:10][C:9]([C:7]1[S:8][CH:4]([CH2:3][N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)[CH2:5][N:6]=1)=[CH:17]2
Reactant: C1COCCN1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C3=NCC(C(OC)OC)S3)cc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C3=NCC(CN4CCOCC4)S3)cc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a mixture of N-[2-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-5-(2-methoxyethoxy)-1H-indol-7-yl]-N,1-dimethyl-1H-imidazole-2-sulfonamide (580 mg), trifluoroacetic acid (7 mL) and water (14 mL) was added concentrated sulfuric acid (7 mL), and the mixture was stirred at 60° C. for 3 hr. The excess trifluoroacetic acid was evaporated under reduced pressure, and the residue was neutralized with sodium hydrogencarbonate. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in tetrahydrofuran (15 mL), morpholine (0.1 mL) was added, and the mixture was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (466 mg) was added, and the mixture was stirred for 1 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (ethyl acetate:hexane=10:90-80:20) to give the title compound (183.5 mg, yield 30%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][O:30][C:31]([C@@H:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=2)[CH2:34]1)=[O:32].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:29][O:30][C:31]([C@@H:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42]([O:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:41][CH:40]=2)[CH2:34]1)=[O:32]
Reactant: COC(=O)[C@@H]1CC(=O)N(c2ccc(O)cc2)C1
Reactant: OCc1ccc(F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
A solution of 550 mg (4.3 mmol) of 4-fluoro-benzylalcohol and 1.27 g (4.7 mmol) of triphenylphosphine in 7 ml of tetrahydrofurane is added dropwise at 0° C. to a solution of 1.11 g (4.7 mmol) of (R)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester and 1.01 g (4.7 mmol) of diisopropyl azodicarboxylate in 11 ml of tetrahydrofurane. The mixture is left to warm to RT and stirring is continued for 18 hours. For the working-up, after addition of 2 g of silica gel the reaction mixture is evaporated under reduced pressure. For purification, the material obtained is chromatographed on silica gel using first a 2:1-mixture, then a 1:1-mixture of heptane and ethyl acetate as the eluent. There are obtained 1.39 g (95% of theory) of (R)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid; MS: m/e=344 (M+H)+.
Reaction SMILES: C([O:8]C([NH:11][C@H:12]([C:28]([NH:30][C@@H:31]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:35])[CH2:32][OH:33])=[O:29])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20]CC2C=CC=CC=2)=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.C(O)(=O)C>[Pd].CO>[OH2:8].[NH2:11][C@H:12]([C:28]([NH:30][C@@H:31]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:35])[CH2:32][OH:33])=[O:29])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@H](CO)C(=O)NCCCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](CO)C(=O)NCCCc1ccccc1
Product: O
Reaction time: 30 h
Yield: 29.6 %

Procedure:
A mixture of (N-benzyloxycarbonyl-O-benzyl-L-tyrosyl)-N-(3-phenylpropyl)-D-serinamide (1.25 g.), acetic acid (125 mg.) and palladium on carbon (10%, 100 mg.) in methanol (50 ml.) was hydrogenated under pressure for 30 hours, then filtered. The filtrate was stripped of volatiles. The residue was purified by reverse phase high pressure liquid chromatography on octadecylsilated silica gel (350 g.) using ammonium acetate (0.2%) in methanol-water (1:1) as the eluant, and an aqueous solution of the product was lyophilized, affording as an amorphous white solid L-tyrosyl-N-(3-phenylpropyl)-D-serinamide hydrate (3:2) (245 mg.; [α]D25 +16.9°, c=1, methanol), whose unsolvated form is the compound of Formula II wherein Q is Ser, R1, R2 and R5 are each hydrogen and R4 is (CH2)nY wherein n is 3 and Y is phenyl.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:32])([F:31])[O:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH:15][S:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][C:19]([F:18])([F:31])[F:32])[CH:22]=3)(=[O:29])=[O:28])[CH:12]=[CH:11][CH:10]=2)=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Product: O=S(=O)(Nc1cccc(COCc2ccc(F)cc2)n1)c1cccc(OC(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.07 g) and 3-(trifluoromethoxy)-benzenesulfonyl chloride (0.086 g) as a light yellow gum (0.097 g). MS (ESI−): 455.2 ([M−H]−).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1/[C:15](=[N:33]/[O:34][CH3:35])/[C:16]([NH:18][C@@H:19]1[C:31](=[O:32])[N:21]2[C:22]([C:28]([OH:30])=[O:29])=[C:23]([CH2:26][OH:27])[CH2:24][S:25][C@H:20]12)=[O:17].C(C(CCCC)C([O-])=O)C.[Na+:46]>CO.C1COCC1.ClCCl>[CH3:35][O:34]/[N:33]=[C:15](\[C:16]([NH:18][C@@H:19]1[C:31](=[O:32])[N:21]2[C:22]([C:28]([O-:30])=[O:29])=[C:23]([CH2:26][O:27][C:3]([NH2:5])=[O:4])[CH2:24][S:25][C@H:20]12)=[O:17])/[C:11]1[O:10][CH:14]=[CH:13][CH:12]=1.[Na+:46]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.17 h

Procedure:
A mixture of THF (130 ml), dichloromethane (45 ml), and trichloroacetyl isocyanate (9.3 ml) was protected from moisture and cooled to -10°.To the stirred mixture was added (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (20 g) in one charge followed by THF (40 ml). The mixture was stirred for 10 minutes at 0° to +5° and then warmed to 22° , There was then added, in one charge, a solution of sodium 2-ethylhexanoate (20 g) in methanol (40 ml) and, after stirring for1 minute, the mixture was left undisturbed at 25° for 2 hours to crystallise. The crystalline material was collected by filtration, washed with ethanol (2×100 ml), and dried in vacuo at 35° to give sodium cefuroxime (24.1 g). The isolated product was shown by G.L.C. to contain 5.3% w/w of ethanol, 0.6% w/w of THF, and 0.04% w/w of methanol.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.[C-]#[N:20].[K+].[C:22]([OH:25])(=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2([C:22]([NH2:20])=[O:25])[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:11])[O:12]2)=[CH:17][CH:18]=1
Reactant: [C-]#N
Reactant: CC(=O)O
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Agent: [K+]
Product: NC(=O)C1(c2ccc(F)cc2)OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-(4-fluorobenzoyl)benzoic acid (75 g), potassium cyanide (28 g), and glacial acetic acid (160 mL) was heated at 115-125 C. in a sealed pressure bottle for 48 h. After cooling to ambient temperature, the mixture was poured into ice water (1.5L). The solid was collected by filtration and crystallized from ethanol to give the title compound (42 g) as a white solid, m. p. 170-173° C. Mass spectrum (EI, M+) m/z 271.
Reaction SMILES: [OH:1][N:2]1[C:6]([O:7][CH3:8])=[N:5][NH:4][C:3]1=[O:9].[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[O:13]>C(#N)C>[OH:1][N:2]1[CH:6]([O:7][CH3:8])[N:5]([C:24]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:22])=[O:21])=[O:25])[NH:4][C:3]1=[O:9]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1n[nH]c(=O)n1O
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)N1NC(=O)N(O)C1OC
Temperature: 20 °C
Reaction time: 5 h
Yield: 32.6 %

Procedure:
A mixture of 1.31 g (10 mmol) of 4-hydroxy-5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one, 2.89 g (12 mmol) of 2-methoxycarbonyl-phenylsulphonyl isocyanate and 40 ml of acetonitrile is stirred for 5 hours at 20° C. and subsequently concentrated under a water pump vacuum. The residue is stirred with diethyl ether, and the product which has been obtained in crystalline form is isolated by filtration with suction and recrystallised from isopropanol. 1.22 g (33% of theory) of 4-hydroxy-5-methoxy-1-(2-methoxycarbonyl-phenylsulphonylaminocarbonyl)-2,4-dihydro-3H-1,2,4-triazol-3-one of melting point 180° C. are obtained.
Reaction SMILES: [CH:1]1([C:4]([OH:12])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])[CH2:3][CH2:2]1.N1C=CN=C1.Cl[Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[CH:1]1([C:4]([O:12][Si:19]([CH3:22])([CH3:21])[CH3:20])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)(CCCC)C1CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC(CCCC)(O[Si](C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of 27.8 g. of 4-cyclopropyl-4-hydroxy-1-octyne (Example 9) and 33.3 g. of imidazole in 130 ml of dimethylformamide at 5° C. is added 24 ml. of chlorotrimethylsilane during 5 minutes. The solution is stirred at ambient temperature for 17 hours and then partitioned with 600 ml of hexane and 250 ml of ice-water. The hexane phase is separated and washed successively with water and brine. The solution is dried over magnesium sulfate and evaporated to give a liquid, p.m.r. spectrum (CDCl3): δ0.12 (singlet, trimethylsiloxy group), 2.02 (triplet, HC≡C), and 2.45 (doublet, C≡CH2).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.C([Li])CCC.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH3:1][O:2][CH:3]([O:9][CH3:10])[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=1[F:16]
Reactant: O=C(Cl)c1ccccc1F
Reactant: COC(OC)c1ccsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(OC)c1ccsc1C(=O)c1ccccc1F
Temperature: 0 °C

Procedure:
To 3-thiophenecarboxaldehyde dimethylacetal (50.6 g) and ether (500 ml) was added n-butyllithium (132 ml, 2.5M in hexanes) at a rate so as to maintain gentle reflux of the mixture. The reaction mixture was heated at reflux an additional 30 mins, diluted with tetrahydrofuran (600 ml), and cooled to 0° C. A solution of 2-fluorobenzoyl chloride (44.0 ml, 368 mmol) and tetrahydrofuran (500 ml), precooled to -78° C., was added with stirring. The mixture was stirred at -78° C. for 1 hr and then allowed to warm to room temperature overnight. Dilute aqueous ammonium chloride solution and ether were added and the layers were separated. The organic layer was washed with dilute aqueous sodium bicarbonate solution, and the combined aqueous layers were back-extracted with ether. The combined organic layers were washed with brine, dried over anhydrous potassium carbonate, filtered, and concentrated to give 2-(2-fluorobenzoyl)-3-thiophenecarboxaldehyde dimethylacetal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[CH:7]=O.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:6]([CH2:7][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cc(Cl)ccc1N1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(Cl)ccc2N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 113.9 %

Procedure:
A round-bottom flask was charged with 5-chloro-2-(morpholin-4-yl)benzaldehyde (1.60 g, 7.09 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (1.20 g, 6.43 mmol, 0.910 equiv), 1,2-dichloromethane (20 mL). The mixture was stirred at room temperature for 0.5 hour. Sodium triacetoxyborohydride (4.09 g, 19.3 mmol, 2.72 equiv) was added. The resulting solution was stirred overnight at room temperature and diluted with H2O (50 mL). The resulting solution was extracted with dichloromethane (2×20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/4) to yield 2.90 g (crude) of tert-butyl 4-[[5-chloro-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 396 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:33][C:34]([F:37])([F:36])[F:35])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:33][C:34]([F:35])([F:36])[F:37])[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(C#N)cc(C(=O)Cl)cc1OC(F)(F)F
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(C#N)cc(C(=O)N2CSc3ccccc32)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (359 mg) and 37% formalin (0.24 mL) in the same manner as in Example 1 was dissolved in chloroform (10 mL), and triethylamine (0.80 mL) and 3-cyano-4-methoxy-5-trifluoromethoxybenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 17 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (j).
Reaction SMILES: [CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]2)[CH2:13][CH2:12]4)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[N+:31]([O-])([O:33]C(C)C)=[O:32]>CO>[CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14](=[C:15]([N+:31]([O-:33])=[O:32])[C:16](=[O:24])[CH2:17][CH2:18]2)[CH2:13][CH2:12]4)[CH2:2][CH2:3]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Reactant: CC(C)O[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C([N+](=O)[O-])C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1

Procedure:
17β-cyclopropyloxy-androst-4-en-3-one (9.70 g, 29.5 mM), potassium tert-butoxide (7.0 g, 62.4 mM), and isopropyl nitrate (2.99 ml) are reacted by the method of Example 1 to yield 17β-cyclopropyloxy-4-nitroandrost-4-en-3-one, m.p. 137-38° C. (methanol)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:18])[S:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43](Cl)=[O:44]>C1COCC1>[N:23]1([CH2:22][CH2:21][CH2:20][NH:19][C:17]([NH:16][C:11]2[S:10][N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:43](=[O:44])[C:42]4[CH:46]=[CH:47][CH:48]=[C:40]([C:39]([F:38])([F:49])[F:50])[CH:41]=4)=[CH:7][CH:6]=3)[C:12]=2[C:13]([NH2:15])=[O:14])=[O:18])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCN1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c(-c2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2)nsc1NC(=O)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a mixture of 3-(4-aminophenyl)-5-(3-(3-morpholinopropyl)ureido)isothiazole-4-carboxamide (6 mg, 0.015 mmol) and N,N-diisopropylethylamine (0.0078 mL, 0.045 mmol) in 0.8 mL THF at rt was added 3-(trifluoromethyl)benzoyl chloride (0.0024 mL, 0.017 mmol). The reaction was stirred at rt for 2 hours, then quenched with aqueous Na2CO3 solution, stirred 5 min at rt, and then partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The solid was chromatographed eluting with CHCl3, then gradient 2.5% to 10% MeOH in CHCl3. The resulting solid was subjected to an EtOAc/NaHCO3 work-up to remove the presence of any silica gel impurity. Upon evaporation of the EtOAc layer the title compound was obtained as a white solid (7 mg, 76%).
Reaction SMILES: C1C=CC=CC=1.[C:7]([Cl:10])(Cl)=[O:8].C([N:18]1[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH2:19]1)C1C=CC=CC=1>O1CCCC1>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[O:23][CH:20]1[CH2:21][CH2:22][N:18]([C:7]([Cl:10])=[O:8])[CH2:19]1
Reactant: O=C(Cl)Cl
Reactant: Clc1cccc(OC2CCN(Cc3ccccc3)C2)c1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: O=C(Cl)N1CCC(Oc2cccc(Cl)c2)C1
Yield: 8.1 %

Procedure:
A benzene solution of 450 ml of 2M phosgene (0.9 mole) was cooled to 10° C. and while stirring, 210 g (0.81 mole) of 1-benzyl-3-(3-chlorophenoxy)pyrrolidine in 210 ml of tetrahydrofuran was added over a 31/2 hr period. The reaction mixture was allowed to stir overnight and then filtered to remove the hydrochloric acid salt of unreacted starting material. The filtrate was evaporated to give a dark colored oil which was triturated with three 500 ml portions of 30/60 petroleum ether decanting off the petroleum ether each time from the oil residue. The petroleum ether layers were cooled and the oils which separated were combined to give 17 g of pure title product as an oil. After washing with more petroleum ether, the oil (203 g) residue contained about 17% benzyl chloride by NMR analysis. Yield of contained product in both portions was 88%.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13]/[CH:14]=[CH:15]/[CH:16]=[CH:17][CH2:18][CH2:19][CH3:20])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:21]([C:23]#[C:24][C:25]#[N:26])#[N:22]>O1CCCC1.C1(C=CC(O)=CC=1)O>[C:21]([C:23]1[CH:17]([CH2:18][CH2:19][CH3:20])[CH:16]=[CH:15][CH:14]([CH2:13][CH2:12][C@H:9]2[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)[C:24]=1[C:25]#[N:26])#[N:22]
Reactant: CCCC=C/C=C/CC[C@H]1CC[C@H](CCCCC)CC1
Reactant: N#CC#CC#N
Agent: Oc1ccc(O)cc1
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CCC2C=CC(CCC)C(C#N)=C2C#N)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61.1 %

Procedure:
9.5 g of 1-(trans-4-pentylcyclohexyl)-3,5-trans-nonadiene were dissolved in 62 ml of tetrahydrofuran in a round flask and treated with 14 mg of hydroquinone. A solution of 3.2 g of dicyanoacetylene in 18 ml of tetrahydrofuran was subsequently added by means of a pipette and the pipette was rinsed twice with 9 ml of tetrahydrofuran each time. The mixture was stirred at room temperature for 2.5 hours and then overnight at 40°-45° C. (bath temperature) under nitrogen. The dark brown solution was thereafter concentrated in vacuo. The resulting dark brown oil (10.9 g) was chromatographed on silica gel using hexane, hexane/toluene (volume ratio 1:1) and toluene, there being obtained 4.2 g of unreacted 3-cis, 5-trans-diene as a colourless oil and 7.4 g of 1,2-dicyano-3-[2-(trans-4-pentylcyclohexyl)ethyl]-6-propyl-1,4-cyclohexadiene as a slightly yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:4]2[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:5]2[N:9]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nc(-c3cccs3)cc2n1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: Clc1cc(N2CCOCC2)n2nc(-c3cccs3)cc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
There was dissolved, in 1,4-dioxane (4 mL), 5,7-dichloro-2-thiophen-2-yl-pyrazolo[1,5-a]pyrimidine (184 mg, 0.679 mM), then morpholine (118 μL, 1.36 mM) was added to the solution and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off from the reaction mixture, the residue was diluted with water and then extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was then distilled off and the resulting solid was washed with methanol to thus give the title compound (114 mg, yield: 52%).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:9]=[C:8]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:24]([C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:35]=1[OH:36])[CH:31]=O)([CH3:27])([CH3:26])[CH3:25].C([BH3-])#N.[Na+]>CO>[CH3:40][C:37]([C:34]1[CH:33]=[C:30]([CH2:31][N:15]2[CH2:16][CH2:17][N:12]([C:10]3[CH:9]=[C:8]([N:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)[N:7]=[C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:11]=3)[CH2:13][CH2:14]2)[CH:29]=[C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:35]=1[OH:36])([CH3:38])[CH3:39]
Reactant: c1c(N2CCCC2)nc(N2CCCC2)nc1N1CCNCC1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc(CN2CCN(c3cc(N4CCCC4)nc(N4CCCC4)n3)CC2)cc(C(C)(C)C)c1O
Reaction time: 18 h

Procedure:
2,6-bis(1-pyrrolidinyl)-4-(1-piperazinyl)pyrimidine (PREPARATION A-22) is stirred in methanol (10 ml). To the above solution is added saturated ethereal hydrochloric acid until the solution clarifies. To this mixture is added 3,5-di-t-butyl-4-hydroxybenzaldehyde and the mixture stirred for 30 min at which time sodium cyanoborohydride is added in two batches. The mixture is stirred at 20°-25° for 18 hr and quenched with hydrochoric acid (10%, 25 ml) added dropwise at 0°. The methanol is removed under a stream of nitrogen and the acidic mixture is extracted with ethyl acetate (25 ml). The aqueous phase is then made basic with hydroxide (45%) at 0°. The aqueous basic phase is then extracted with methylene chloride (2×). The organic phases are combined and dried over sodium sulfate, following which the mixture is concentrated under at reduced pressure. The concentrate is flashed chromatographed on silica gel eluting with hexane/ethyl acetate (1/1) or ethyl acetate. The appropriate fractions are pooled and concentrated to give the title compound.