Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:27][N:28]([CH3:33])[CH:29]1[CH2:32][NH:31][CH2:30]1>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:31]3[CH2:32][CH:29]([N:28]([CH3:33])[CH3:27])[CH2:30]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Reactant: CN(C)C1CNC1
Product: CN(C)C1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 38 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1) and N,N-dimethylazetidin-3-amine to afford a white solid. HPLC (Condition 7) tR=5.768 min, UPLC-MS (Condition 3) tR=0.78 min, m/z=463.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.01 (s, 6H) 2.90-3.06 (m, 1H) 3.51-3.62 (m, 2H) 3.71-3.86 (m, 2H) 6.37-6.48 (m, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.53-7.93 (m, J=9.4 Hz, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.74 (d, J=1.95 Hz, 1H) 10.19-10.29 (m, 1H) 12.91-13.22 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])[NH:5][C:6](=[O:9])[C:7]=1[NH2:8].[C:20](O)(=O)C.C(N)=N.C([O-])(=O)C.[Na+]>C(O)C>[CH2:17]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:4]1[N:3]=[C:2]2[C:7](=[N:8][CH:20]=[N:1]2)[C:6](=[O:9])[N:5]=1)[CH2:18][CH3:19]
Reactant: CC(=O)O
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: N=CN
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccccc1C1=NC(=O)C2=NC=NC2=N1

Procedure:
A mixture of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one (0.3 g), formamidine acetate (0.18 g) and anhydrous sodium acetate (0.1 g) was heated in an oil bath at 155°-165° C. for 21/2 hours. The mixture melted and then resolidified. Ethanol (1 ml) was added and the title compound was collected by filtration, 0.31 g, m.p. 256°-258° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[C:13](C(O)=O)[C:12](O)=[CH:11][CH:10]=1.FC1C=C(F)C=CC=1N>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Nc1ccc(F)cc1F
Solvent: c1ccccc1
Product: Fc1ccc(-c2ccccc2)c(F)c1

Procedure:
5-(2,4-difluorophenyl)salicylic acid, an anti-inflammatory, anti-pyretic, analgesic agent is prepared by: (1) diazotizing 2,4-difluoroaniline in the presence of benzene to yield 2,4-difluorobiphenyl; (2) Friedel-Crafts acylation to produce 2',4'-difluoro-4-alkanoylbiphenyl; (3) oxidation of the alkanoyl group to produce 2',4'-difluoro-4-alkanoyloxybiphenyl; (4) hydrolysis of the alkanoyl group to produce 4-(2,4-difluorophenyl)phenol; and (5) Kolbe-Schmitt carboxylation to produce the final product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](C(=O)C)=[C:4]([OH:11])[CH:3]=1.C(=O)([O-])[O-:13].[Cs+].[Cs+].[I-].[Na+].Br[CH2:21][CH3:22]>CN(C)C=O.O>[CH2:21]([O:11][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[OH:13])[CH3:22]
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: CCBr
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4′-fluoro-2′-hydroxyacetophenone (3.08 g), cesium carbonate (13.0 g) and sodium iodide (0.6 g) in N,N-dimethylformamide (20 mL) was added bromoethane (2.24 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To a solution of the residue and 4,4′-thiobis(6-tert-butyl -o-cresol) (39 mg) in methylene chloride (57.6 mL) was added 3-chloroperbenzoic acid (4.97 g) under ice-cooling, and the mixture was heated for reflux overnight. The reaction mixture was cooled in ice. To the mixture was added 10% aqueous sodium sulfite solution, and the resulting mixture was stirred for 20 minutes. The organic layer was separated and washed with water three times, a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (10 mL) -tetrahydrofuran (20 mL). To the solution was added sodium methoxide (28% methanol solution, 5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2-ethoxy-4-fluorophenol (3.0 g). The title compound was obtained in a similar manner to that described in Reference Example 142 using this material instead of 4-fluoro-2-methoxyphenol.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH:7]1[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1.O>C(O)(=O)C>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][CH:7]1[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: FC(F)(F)c1cccc(OC2CCC3(CC2)OCCO3)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC(Oc2cccc(C(F)(F)F)c2)CC1

Procedure:
This compound was prepared in a manner analogous to that of Step D of Example 2, using 7.6 grams (0.025 mole) of 8-(3-trifluoromethylphenoxy)-1,4-dioxaspiro[4.5]decane and 25 mL of water in 50 mL of acetic acid, yielding 4-(3-trifluoromethylphenoxy)cyclohexanone.
Reaction SMILES: [CH3:1][Li].[C:3]([CH2:6][N:7]1[C:11]([NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=[N:8]1)([OH:5])=O>C(OCC)C.O1CCCC1>[C:3]([CH2:6][N:7]1[C:11]([NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=[N:8]1)(=[O:5])[CH3:1]
Reactant: [Li]C
Reactant: O=C(O)Cn1nccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)Cn1nccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of methyllithium in diethyl ether (250 ml) was added to a solution of 1-carboxymethyl-5-triphenylmethylaminopyrazole (25.95 g) in tetrahydrofuran (400 ml) under ice-cooling and the mixture was stirred for 6 hours at ambient temperature. The reaction mixture was added to a mixture of ice-cold water (500 ml) and diethyl ether (500 ml). The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-acetylmethyl-5-triphenylmethylaminopyrazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:32])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C@@H:15]([CH3:33])[CH2:14]2)[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[BH4-].[Na+]>[Co](Cl)Cl>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([N:9]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:32])[C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[C@@H:15]([CH3:33])[CH2:14]2)[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3cccc(C#N)c3)C[C@@H]2C)cc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3cccc(CN)c3)C[C@@H]2C)cc1

Procedure:
N-(3-cyanophenyl)-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide was further treated with cobalt(II)chloride and sodium borohydride (1 eq, 3 eq) to afford N-[3-(aminomethyl)phenyl]-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:28]2[N:29]=[C:30]([CH2:37][CH2:38][CH2:39][CH3:40])[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[C:27]=2[C:26]2[N:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1>>[NH2:18][C:19]1[C:28]2[N:29]=[C:30]([CH2:37][CH2:38][CH2:39][CH3:40])[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:13](=[O:15])[C:12]3[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:17][CH:16]=3)[C:27]=2[C:26]2[N:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)c1ccc(C(=O)c2ccccc2)cc1
Yield: 18 %

Procedure:
Using the general method of Example 112 Part B, 4-benzoylbenzoic acid (72 mg, 0.32 mmole) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (100 mg, 0.32 mmol) to provide 30 mg of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-4-benzoylbenzamide as a white solid. Mass-spec (M+1=521.31).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH:15]=O.Cl.[NH:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1)N>C(O)C.C(O)(=O)C.O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[NH:18][CH:15]=1
Reactant: NNc1ccc(CC(=O)O)cc1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
A solution of 4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butanal, diethyl acetal (36 g) in absolute ethanol (125 ml) was added to a solution of 4-hydrazinobenzene acetic acid, hydrochloride (25 g) in 25% aqueous acetic acid (640 ml) heated to 80° under nitrogen. The mixture was heated at 70°-80° for 2.75 h and the solvent was removed under reduced pressure to give a red oil. This was diluted with water and extracted with ethyl acetate (5×250 ml). A gummy solid insoluble in either phase was collected and triturated with ethanol to give the title compound as a beige solid (7.4 g). The organic extracts were dried (MgSO4) and concentrated to an oil which was taken up in chloroform and treated with diethyl ether to give a second crop as a yellow solid (13.1 g). A sample (0.5 g) of this material was purified by column chromatography (Whatman MFC silica, 25 g) and elution with ethyl acetate--light petroleum (1:1) gave the title compound as a yellow solid (0.35 g) m.p. 189°-191.5°.
Reaction SMILES: [CH:1]([C:3]12[O:11][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH2:2].[CH2:12]([Li])[CH2:13][CH2:14][CH3:15].[CH3:17]CCCCC.BrCBr.C([Mg]Cl)CCC>>[CH2:2]([CH:1]1[C:3]2([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]2[OH:11])[CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC
Reactant: [Li]CCCC
Reactant: C=CC12CCCCCCC1O2
Agent: CCCC[Mg]Cl
Solvent: BrCBr
Product: CCCCCC1CC12CCCCCCC2O
Yield: 65 %

Procedure:
Prepared as described in Example 24 from 1-vinyl-9-oxabicyclo[6.1.0]nonane (J P Kokai S49-047345, Takasago Perfumery Co., Ltd.) (3 g, 18 mmol), n-butyl lithium 1.6 M in hexane (11 ml, 18 mmol), dibromomethane (12.5 g, 72 mmol) and tent-butyl magnesium chloride (36 ml, 72 mmol). Work-up and bulb-to-bulb distillation at 98° C./0.05 mbar gave 2.6 g (65%) of a colorless oil (dr=93:7). 1H NMR (CDCl3): δ 0.3 (m, 1H), 0.5 (m, 1H), 0.8 (m, 1H), 0.8-1.1 and 1.2-2.4 (22H), 3.25 (1H) ppm. 13C-NMR (CDCl3): δ 14.1 (q), 20.7 (t), 22.7 (t), 23.3 (t), 23.5 (t), 24.3 (d), 26.5 (t), 26.8 (t), 28.9 (t), 29.4 (s), 29.7 (t), 30.4 (t), 31.2 (t), 31.7 (t), 73.7 (d). cis-configuration assigned by COSY, HMBC, HSQC, NOESY in DMSO-D6. MS (EI): m/z (%) 224 (M+, 1), 206 ([M-18]+, 10), 178 (4), 163 (5), 149 (12), 135 (22), 126 (24), 109 (22), 107 (24), 98 (58), 97 (33), 96 (80), 95 (46), 93 (54), 69 (41), 68 (42), 67 (84), 55 (100), 41 (80). IR (film): 3362 (br, OH), 2919 (s), 2852 (m), 1456 (m), 1364 (w), 1106 (w), 1029 (m), 989 (m), 811 (w), 741 (w), 726 (w).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[CH3:24].[C:25](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:25])[C:10]2=[O:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[CH3:24]
Reactant: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-(4-Chloro-6-fluoro-3-methyl-2-nitrophenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (10.1 g) was dissolved in dimethylformamide (100 ml) and potassium carbonate (5.7 g, 41.3 mmol) and dimethylsulfate (11.9 g, 55.1 mmol) were added. Solution was stirred at ambient temperature for 14 hr, water was added and product extracted with ethyl acetate. The title compound was separated by column chromatography on silica gel (eluent, hexane-ethyl aceatate, 9:1; 8.5 g).
Reaction SMILES: [CH2:1]([N:4]1[CH2:12][CH:11]2[C:6]([C:22]3[S:23][CH:24]=[C:25]([Br:27])[CH:26]=3)([N:7]=[C:8]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:9][CH2:10]2)[CH2:5]1)[CH:2]=[CH2:3].CN(C)CC>C(O)C>[CH2:1]([N:4]1[CH2:12][C@@H:11]2[C@@:6]([C:22]3[S:23][CH:24]=[C:25]([Br:27])[CH:26]=3)([N:7]=[C:8]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:9][CH2:10]2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CC2CSC(NC(=O)c3ccccc3)=NC2(c2cc(Br)cs2)C1
Agent: CCN(C)C
Solvent: CCO
Product: C=CCN1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(Br)cs2)C1
Yield: 48.3 %

Procedure:
Racemic N-[6-Allyl-7a-(4-bromo-2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (2.24 g, 4.84 mmol) is purified by chiral HPLC: (Chiralpak AD 8×40.5 cm; eluent: 100% ethanol with 0.2% dimethylethyl amine); flow: 400 mL/min at UV 270 nm). Analysis conditions: Chiralpak AD-H 0.46×15 cm; eluent: 100% ethanol (0.2% isopropyl amine); flow: 0.6 mL/min at UV 320 nm; Rt=3.03 minutes. The second eluting isomer is isolated to give the title compound (1.08 g, 48%, >99% ee). ES/MS (m/e) (79Br/81Br) 462/464 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]=[O:14])=[CH:7][CH:6]=1)=[O:4].[CH3:15][Si:16]([CH3:19])([CH3:18])Cl.C(N(CC)CC)C>CN(C)C=O.C(=O)(O)[O-]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]=[CH:13][O:14][Si:16]([CH3:19])([CH3:18])[CH3:15])=[CH:7][CH:6]=1)=[O:4]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(CCC=O)cc1
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CC=CO[Si](C)(C)C)cc1

Procedure:
9.61 g (50 mmol) 3-(4-Methoxycarbonylphenyl)propanal are dissolved, together with 8.3 ml (68 mmol) of trimethylchlorosilane and 18.1 ml (0.13 mol) of triethylamine, in 15 ml of absolute dimethyl formamide and the solution is heated under reflux for 2 hours under nitrogen. After cooling, the reaction mixture is diluted with a saturated bicarbonate solution and extracted with petroleum ether. The organic phase is washed 3 times with a saturated bicarbonate solution, dried with sodium sulphate and concentrated by evaporation. The residue is distilled under a high vacuum (distillation apparatus silylated). 11.06 g of a pale yellow, oily product are thus obtained in the form of a mixture of the cis- and trans-isomers.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=3[CH3:21])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=4)[CH:17]=[CH:16][C:15]=3[CH3:21])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1NC(=O)c1csc2c(N)ncnc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(N)ncnc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.2 %

Procedure:
4-Amino-N-(5-amino-2-methylphenyl)thieno[3,2-d]pyrimidine-7-carboxamide (30 mg, 0.1 mmol) was dissolved in THF (1 mL) and TEA (42 μL, 0.30 mmol) was added thereto. 3-(trifluoromethyl)benzoyl chloride (19 μL, 0.13 mmol) was added to reaction mixture at 0° C. and stirred at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with brine. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by silica gel chromatography (3/97 MeOH/DCM) to obtain the title compound (35 mg, 74% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11].[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:17]1([S:23][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Sc1ccccc1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC=C(C(=O)OC)c1ccccc1CSc1ccccc1
Yield: 97 %

Procedure:
2 g of methyl α-(2-bromomethylphenyl)-β-methoxyacrylate, 0.65 g of thiophenol and 1.1 g of potassium carbonate are reacted similarly to Example 1. 1.8 g of white crystals of melting point 71° C. are obtained (compound No. 2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][OH:9].C([O-])(O)=O.[Na+].Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].O>C(Cl)Cl>[OH:9][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:16](=[O:17])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccccc1NO
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1N(O)C(=O)Oc1ccccc1
Temperature: -10 °C
Yield: 72 %

Procedure:
A mixture of 350 g (purity about 80%; 2.3 mol; prepared by a similar method to Bamberger et al., Ann. Chem. 316 (1901), 278) of N-(2-methylphenyl)hydroxylamine and 286.8 g (3.4 mol) of NaHCO3 in 700 ml of CH2Cl2 is treated with 447 g (2.85 mol) of phenyl chloroformate with vigorous stirring at about -10° C. The mixture is stirred for about 1 hour at -10° C. and 600 ml of water are then added dropwise, the temperature of the reaction mixture increasing to 5°-10° C. and a vigorous evolution of gas occurring. The aqueous phase is then separated off and extracted once more with CH2Cl2. The combined organic phases are extracted with water, dried over MgSO4 and concentrated. The residue crystallizes and is stirred with cyclohexane. 407 g (72%) of the title compound are obtained as a colorless solid.
Reaction SMILES: [O:1]1[C@@H:3]2[CH2:4][C@H:5]([C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)[C@:6]3([CH2:8][CH2:9][C@H:10]4[C@H:19]([C@@:2]123)[CH2:18][CH2:17][C@H:16]1[C@:11]4([CH3:21])[CH2:12][CH2:13][C:14](=[O:20])[CH2:15]1)[CH3:7].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[H-].O>O1CCCC1C([O-])=O.O1CCCC1>[O:24]1[CH:25]=[CH:26][C:22]([C@H:5]2[CH2:4][C@H:3]3[O:1][C@@:2]43[C@H:19]3[C@H:10]([CH2:9][CH2:8][C@:6]24[CH3:7])[C@:11]2([CH3:21])[C@@H:16]([CH2:15][C@H:14]([OH:20])[CH2:13][CH2:12]2)[CH2:17][CH2:18]3)=[CH:23]1
Reactant: C[C@]12CCC(=O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)C[C@H]3O[C@]132
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=C([O-])C1CCCO1
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)C[C@H]3O[C@]132
Temperature: 25 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
To a solution of 4.5 g of 14β,15β-epoxy-17β-(3-furyl)-5β-androstan-3-one in 30 ml of dry tetrahydrofuran at-78° C, a solution of 9.8 g of tri-tert-butoxyaluminum-hydride in tetrahydrofuran was added dropwise. The mixture was stirred for 20 hrs, then 40 ml of water were added and the temperature raised to 25° C. The aluminum salts were filtered on a celite cake and washed with methanol. The solution was concentrated under reduced pressure and extracted with methylene chloride. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 4.3 g of the title compound (II-b) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH-].[Na+].[CH2:14]1[CH2:18][O:17][CH2:16][CH2:15]1.C(Cl)(=O)CCC>C(OCC)(=O)C>[C:16]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])(=[O:17])[CH2:15][CH2:14][CH3:18]
Reactant: C1CCOC1
Reactant: NC(=O)c1cc(Cl)ccc1N
Agent: CCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1ccc(Cl)cc1C(N)=O
Temperature: 0 °C
Reaction time: 96 h

Procedure:
2-Amino-5-chlorobenzamide (1.10 g, 6.5 mmol, 1 eq.), 1.000 N NaOH (6.50 mL, 6.5 mmol, 1 eq.) and THF (20 mL) were mixed and stirred at 0° C. To this mixture was added butyryl chloride dropwise (0.68 mL, 6.50 mmol, 1 eq.). More acid chloride and base were added to drive reaction to completion. The reaction was allowed to warm to rt. After 4 days the reaction was worked up by adding ethyl acetate, washing with 1 N HCl (3×), saturated sodium bicarbonate (1×), and brine (1×). The organic layer was dried and stripped to yield 1.44 g of a white powder as product. LCMS detects (M+H)+=241.0.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=O)[NH:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16])[CH3:2].P(Cl)(Cl)([Cl:20])=O.C(=O)([O-])O.[Na+]>>[Cl:20][C:8]1[C:7]2[C:12](=[CH:13][C:4]([NH:3][CH2:1][CH3:2])=[C:5]([N+:15]([O-:17])=[O:16])[CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: CCNc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCNc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 103.3 %

Procedure:
7-Ethylamino-6-nitro-4(3H)-quinazolinone (30.0 g, 128 mmol) was suspended in phosphorus oxychloride (270 ml, 2.90 mol) and the mixture was heated at 110° C. for 2 hours under an argon gas atmosphere (to form a clear solution). After it was confirmed that the starting material disappeared, unreacted phosphorus oxychloride was removed under reduced pressure. After the residue was subjected to azeotrope with toluene, the resulting oily substances were dissolved in the necessary minimum amount of tetrahydrofuran. The tetrahydrofuran solution obtained was poured onto ice-cold water by adding a sufficient amount of sodium hydrogen carbonate, followed by extraction with ethyl acetate. The organic layer was dried (over anhydrous magnesium sulfate), and the drying agent was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (33.4 g).