Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[CH:8][CH:9]=1.[Cl:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1F>C1COCC1.CN(C=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[O:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=1
Reactant: OCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
Sodium hydride (60% dispersion in oil, 1.4 g, 33.5 mmol) was suspended in anhydrous THF (50 ml) under nitrogen and the resulting mixture is cooled to 0° C. To above suspension was added dropwisely (3-Fluoro-phenyl)-methanol (2.90 ml, 27 mmol), followed by a solution of 2-chloro-1-fluoro-4-nitro-benzene (4.2 g, 24 mmol) in dry DMF (20 ml). The reaction mixture was then stirred at room temperature for another 4 hours. The reaction mixture concentrated under vacuum to about 40 mL, and was poured into 200 ml of ice:water. The resultant solid was isolated by filtration, washed with water (50 ml), and air dried to yield a yellow solid, 2-Chloro-1-(3-fluoro-benzyloxy)-4-nitro-benzene (5.8 g). The solid was suspended in MeOH (50 ml) and treated wet 5% Pt/C (Degussa type, Aldrich, 1.5 g). The flask is flushed with hydrogen gas from a balloon and the reaction mixture was stirred under hydrogen balloon for 2 hours. The reaction mixture was filtered through a Celite plug and the solvent is removed under reduced pressure to yield 5.2 g of the desired product.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#N.[OH-].[Na+].[C:11]([OH:19])(=[O:18])C1C=CN=CC=1.[C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)#[N:21].N>>[C:20]([NH2:21])(=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1.[CH:8]1[CH:7]=[N:6][CH:5]=[C:4]([C:11]([OH:19])=[O:18])[CH:3]=1
Reactant: N#Cc1ccncc1
Reactant: O=C(O)c1ccncc1
Reactant: N#Cc1cccnc1
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1cccnc1
Product: O=C(O)c1cccnc1

Procedure:
As to preparative methods for these compounds, cyanopyridines have frequently been hydrolyzed in batch and continuous processes with catalytic to stoichiometric excesses of a base. A majority of the methods reported have been batch processes. For example, 4-cyanopyridine in the presence of sodium hydroxide at a molar ratio of 1:(0.03-0.075) and at 120°-170° C. is reported to give isonicotinamide. See U.S.S.R. SU 1,553,531 (1990); CA:113:78174f (1990). Similarly, 2-cyanopyridine is reported to react with sodium hydroxide at a molar ratio of 1:(0.03-0.20) and at temperatures ranging from 100°-130° C. to give 2-picolinamide. See U.S.S.R. SU 1,553,530 (1990); CA:113:78173e (1990). With a molar ratio of 4-cyanopyridine:sodium hydroxide of 1:(1.5-1.75) and a hydrolysis temperature of 50°-80° C., the reported hydrolysis product was isonicotinic acid. See U.S.S.R. SU 1,288,183; CA:106:176187n (1987). The hydrolysis of 3-cyanopyridine with excess ammonia at 107°-109° C. for 12 hours was reported to give mixtures of nicotinamide and niacin. See J. Am Chem. Soc. 65, at pages 2256-7 (1943). In still another variation, the hydrolysis of 3-cyanopyridine has been reported with a polymeric base, Dowex 1X4 (in the hydroxide form), to yield nicotinamide. See Dutch Patent Application No. 7706612-A; CA:90:186814e. U.S. Pat. No. 4,314,064 describes the continuous hydrolysis of 3-cyanopyridine with 0.3 to 3.0 moles of an alkali metal hydroxide for each 100 moles of cyanopyridine at pressures of between 3 to 20 bars and with heating or cooling to maintain the prescribed reaction temperature. Similarly, 3-cyanopyridine is reported to react in a continuous process with aqueous ammonia at a molar ratio of 1:0.5 and a contact time of 40-50 minutes at 200°-260° C. to give nicotinamide. See Journal of Applied Chemistry of the USSR (English Translation: 45:2716-2718 (1972).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([I:9])[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1.[H-].[Na+].Br[CH2:15][C:16]([CH3:18])=[CH2:17]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([I:9])[C:7]=1[O:8][CH2:17][C:16]([CH3:18])=[CH2:15]
Reactant: C=C(C)CBr
Reactant: OCc1cc(I)c(O)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)COc1c(I)cc(CO)nc1Cl
Reaction time: 0.5 h
Yield: 86 %

Procedure:
C2 (6.3 g, 22 mmol) is dissolved in 30 mL DMF in a dry flask under N2. The flask is placed in an ice bath, and 60% sodium hydride in mineral oil (880 mg, 22 mmol) is added. The reaction is stirred 30 min while the flask is kept in an ice bath. The ice bath is removed for 30 min and then the flask is placed back into the ice bath to cool the reaction. 3-Bromo-2-methylpropene (23.1 mmol) is added, and the reaction is stirred overnight at rt. The reaction is diluted with 150 mL EtOAc and is washed with 4×50 mL 50% saturated 1:1 NaCl/NaHCO3. The organic layer is dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo to a pale oil which is crystallized from hexanes to afford (6-chloro-4-iodo-5-[(2-methyl-2-propenyl)oxy]-2-pyridinyl)methanol (C19) (86% yield). HRMS (FAB) calculated for C10H11ClINO2+H: 339.9603, found 339.9604 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([NH:21][C:6]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:8])[CH2:18][CH2:19][CH3:20]
Reactant: COc1ccc(C(OC(C)=O)C(=O)O)cc1
Reactant: CCCCN
Product: CCCCNC(=O)C(OC(C)=O)c1ccc(OC)cc1

Procedure:
was prepared from intermediate 79a and butylamine following Method A. 1H NMR (300 MHz, CDCl3) δ 7.34 (d, 2H, J=8.85 Hz), 6.87 (d, 2H, J=8.67 Hz), 6.01 (s, 1H), 3.79 (s, 3H), 3.31–3.23 (m, 2H), 2.15 (s, 3H), 1.54–1.43 (m, 2H), 1.37–1.22 (m, 2H), 0.94–0.87 (m, 3H). LCMS (ESI+) [2M+Na]/z Calc'd 581, found 581.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[CH3:14].C([O-])=O.[NH4+]>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[CH3:14]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1ccc(N)cc1C
Reaction time: 3 h

Procedure:
To a solution of 2-methyl-4-nitro phenylacetic acid methyl ester (10 mmol) in dry THF (20 mL) and methyl alcohol (20 mL), ammonium formate (0.1 mol) and 10% Pd/C (0.5 g) have been added and the resulting mixture has been left stirring for 3 h, until complete disappearance of the starting reagent. The catalyst has been filtered off and the filtrate evaporated under vacuum to give 2-methyl-4-amino phenylacetic acid methyl ester as a waxy solid (9.22 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]([C@@H:9]([NH2:11])[CH3:10])=[N:8][C:4]=2[CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:7]([C@@H:9]([NH:11][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)nc([C@H](C)N)n2-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc2c(c1)nc([C@H](C)Nc1ncnc3[nH]cnc13)n2-c1ccccc1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-1-(5-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 14 (100 mg, 0.398 mmol), 6-chloro-9H-purine (74 mg, 0.478 mmol) and DIPEA (0.347 mL, 1.99 mmol) in n-butanol (2 mL) was stirred in a sealed vial for 20 h at 120° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% MeOH in EtOAc) and then triturated with acetonitrile affording 117 as an off-white solid (54 mg, 37%). LCMS: RT 3.11 min [M+H]+ 370.1. 1H NMR (DMSO, 400 MHz): δ 12.90 (1H, bs), 8.20-8.00 (2H, m), 7.84 (1H, s), 7.69-7.39 (6H, m), 7.07-6.89 (2H, m), 5.49 (1H, bs), 2.39 (3H, s), 1.53 (3H, d, J=6.79 Hz)
Reaction SMILES: [Cl:1][C:2]1[N:3]=NC(Cl)=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.O.NN.C1N=C[N:27]([C:30]([N:32]2[CH:36]=[N:35]C=C2)=[O:31])C=1.C(OCC)(=O)C>C(O)C>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[C:36]2[N:32]([C:30](=[O:31])[NH:27][N:35]=2)[N:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Clc1ccc(-c2c(Cl)nnc(Cl)c2-c2ccncc2)cc1
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)c(Cl)nn12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 3,6-dichloro-4-(4-chlorophenyl)-5-(pyridin-4-yl)pyridazine (0.69 g, 2.1 mmol) in ethanol (10 ml) was added hydrazine monohydrate (1.2 ml, 24.7 mmol). The reaction was stirred at 80° C. for 1 h. After this time, the reaction mixture was concentrated under reduced pressure. The crude product was then suspended in THF and CDI (1.36 g, 8.4 mmol) was added. The reaction turned to brownish clear solution, then to a suspension again. After stirring for 20 min, ethyl acetate was added. The resulting solution was washed with water and saturated NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with a gradient of 5%-10% methanol-dichloromethane to give 6-chloro-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one as a brown sold (0.52 g) and 6-chloro-8-(4-chlorophenyl)-7-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one as light brown solid (0.27 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:34][N:35]([CH3:41])[CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[CH3:34][N:35]([CH3:41])[CH:36]1[CH2:40][CH2:39][N:38]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:37]1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CN(C)C1CCNC1
Product: CN(C)C1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)C1
Yield: 9 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of N,N-dimethylpyrrolidin-3-amine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [NH3:1].CO.Cl[S:5]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)(=[O:7])=[O:6]>C1COCC1>[S:5]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)(=[O:7])(=[O:6])[NH2:1]
Reactant: N
Reactant: O=S(=O)(Cl)c1ncn2ccsc12
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 2 M ammonia/methanol solution (4 ml) was added to a solution of 0.44 g of 7-chlorosulfonylimidazo[5,1-b]thiazole in 10 ml of THF. The mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=10:1) to give 0.34 g of 7-sulfamoylimidazo[5,1-b]thiazole.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:23][CH:22]=[CH:21][N:9]2[C:10](=[O:20])[C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:23][CH:22]=[CH:21][N:9]2[C:10](=[O:20])[C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)[CH3:5]
Reactant: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(N)c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a stirred solution of 7-(1-azidoethyl)-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.295 g, 0.885 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (1.06 mL, 1.06 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate, and the mixture was extracted with aqueous 1N HCl solution (three times). The combined extract was neutralized with solid NaHCO3 and extracted with dichloromethane (two times). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the desired compound (0.241 g, 88.6%), which was used directly in next step. LCMS calculated for C14H12F2N3OS (M+H)+: m/z=308.1. Found: 308.0.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[CH:13](N(C(C)C)CC)(C)C.[Si](C=[N+]=[N-])(C)(C)C>C(#N)C.CO.CCOCC>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH3:13]
Reactant: Nc1cccc2c(O)cccc12
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Solvent: CC#N
Product: COc1cccc2c(N)cccc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 63 %

Procedure:
To a mixture of 10 g of 5-amino-1-hydroxynaphthalene in 250 ml of acetonitrile and 25 ml of methanol was added 15 ml of diisopropylethylamine followed by 44 ml of 2M TMSCHN2 in ether. The mixture was stirred at room temperature for 3.5 h after which it was concentrated to a dark oil. The material was purified by flash chromatography on silica gel, eluting with ethyl acetate/dichloromethane/heptane to provide 6.9 g (63%) of 5-amino-1-methoxynaphthalene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[CH2:5]CN.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:19][CH:20]=[CH:21][C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25].[CH3:28][N:29](C)C=O>>[CH3:25][C:24]([CH3:27])([CH3:26])[C:23]#[C:22]/[CH:21]=[CH:20]/[CH2:19][N:29]([CH2:5][C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([Br:1])[CH:3]=1)[CH3:28]
Reactant: NCCc1ccc(F)c(Br)c1
Reactant: CC(C)(C)C#CC=CCBr
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(C/C=C/C#CC(C)(C)C)Cc1ccc(F)c(Br)c1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
N-(3-bromo-4-fluorobenzyl)methylamine (4.00 g; 18.3 mmol) and sodium carbonate (2.78 g; 26.3 mmol) were added to N,N-dimethylformamide (35 ml). While the mixture was stirred at room temperature, 1-bromo-6,6-dimethyl-2-hepten-4-yne (3.51 g; 17.5 mmol) in N,N-dimethylformamide (15 ml) was added dropwise. The mixture was stirred for 4 hours at room temperature, and the mixture was poured into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 2.54 g of the target compound as orange oily matter (yield: 42.9%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[C:21]([CH2:22]Br)=[CH:20][S:19][C:18]=2[CH:24]=1)=[O:13].O>CN(C)C=O>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[C:21]([CH2:22][O:3][C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)=[CH:20][S:19][C:18]=2[CH:24]=1)=[O:13]
Reactant: Oc1cccnc1
Reactant: COC(=O)c1ccc2c(CBr)csc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(COc3cccnc3)csc2c1
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
Sodium hydride (0.12 g of 50% dispersion in mineral oil) was added to a solution of 3-hydroxypyridine (0.24 g) in dry N,N-dimethylformamide (5 ml) and the mixture was stirred for 30 minutes. 3-Bromomethylbenzo[b]thiophene-6-carboxylic acid methyl ester (0.71 g) in a small volume of N,N-dimethylformamide was added and the mixture was stirred at room temperature for 2 hours and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave a gummy solid which was chromatographed on silica gel. Elution with chloroform first gave some impurity followed by pure product. Evaporation of the product containing fractions gave 3-(3-pyridyloxymethyl)benzo[b]thiophene-6-carboxylic acid methyl ester (0.27 g) which was used directly in the next stage.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:17]([CH3:18])=[CH:16][S:15][C:10]=2[NH:11][C:12](=[O:14])[N:13]=1.[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[CH3:21][O:14][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:9]2[C:17]([CH3:18])=[CH:16][S:15][C:10]=2[N:11]=1
Reactant: CI
Reactant: Cc1csc2[nH]c(=O)nc(-c3ccccc3F)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(-c2ccccc2F)c2c(C)csc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 13.57 g of 4-(o-fluorophenyl)-5-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 271 ml of dimethylformamide is added 2.8 g of 63% sodium hydride. The mixture is stirred at room temperature for 1 hour. Then, 22.15 g of methyl iodide in 66 ml of dimethylformamide is added dropwise thereto. The mixture is stirred for 2 hours at room temperature. The reaction mixture is poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel, using chloroform as an eluent. From the first fraction, 2-methoxy-4-(o-fluorophenyl)-5-methyl-thieno[2,3-d]pyrimidine is obtained as crystals having a melting point of 177° - 179°C. From the second fraction, 1-methyl-4-(o-fluorophenyl)-5-methyl-1,2-dihydrotheino[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 275° - 277°C. From the the third fraction, 3-methyl-4-(o-fluorophenyl)-5-methyl-3H-thieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 176° - 178°C.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[I-].ClC1C=CC=C[N+]=1C.[OH:27][C:28]1[C:29]([CH3:44])=[C:30]2[C:35](=[C:36]([CH3:39])[C:37]=1[CH3:38])[O:34][C:33]([CH3:43])([C:40](O)=[O:41])[CH2:32][CH2:31]2.CCCCCC>CN(C)C1C=CN=CC=1.O1CCOCC1.C(OCC)(=O)C>[CH2:1]([O:17][C:40]([C:33]1([CH3:43])[CH2:32][CH2:31][C:30]2[C:35](=[C:36]([CH3:39])[C:37]([CH3:38])=[C:28]([OH:27])[C:29]=2[CH3:44])[O:34]1)=[O:41])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: CN(C)c1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCOC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reaction time: 2 h
Yield: 65.4 %

Procedure:
Under electromagnetic stirring, to a 100 mL reaction flask hexadecanol (970 mg, 4 mmol), 4-dimethylaminopyridine (1466 mg, 12 mmo), 2-chloro-1-methylpyridinium iodide (1533 mg, 6 mmol) and dioxane (20 mL) were added, and then to the reaction solution a solution of (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (1001 mg, 4 mmol) in dioxane (20 mL) was slowly dropwise added. The reaction mixture was reacted for 12 h at room temperature under the protection of nitrogen gas and electromagnetic stirring. The solvent (dioxane) was removed by a rotary evaporator, and thereto diethyl ether (50 mL) was added. The resulting mixture was stirred for 2 h, and the precipitate was removed by filtration. The filtrate was concentrated to 10 mL, and isolated by column chromatography (the stationary phase was 230-400 mesh silica gel, the eluent was hexane:ethyl acetate=10:1), to obtain (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid hexadecyl ester (1242 mg, yield 65.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:15])=[C:11]([CH3:14])[N+:12]=2[O-])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O.N>C(Cl)(Cl)Cl>[Cl:18][CH2:14][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:9][C:10]=1[CH3:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(-c2ccc(Cl)cc2)[n+]([O-])c1C
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc(Cl)cc2)nc1CCl
Temperature: 0 °C

Procedure:
1.00 g (4.47 mmol) of the compound from Example 45A are initially charged in 15 ml of chloroform, and 1.5 ml (16.10 mmol) of phosphoryl chloride are added carefully. With stirring, the reaction mixture is heated at reflux for 30 min. The mixture is then cooled to 0° C. and made slightly basic by addition of ammonia. The mixture is extracted three times with in each case 20 ml of ethyl acetate. The combined organic phases are washed twice with in each case 5 ml of water and then dried over magnesium sulfate. The solvent is removed on a rotary evaporator. The residue is used in the next steps without further purification.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C@@H:5]1[CH2:10][C@H:9]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:7]2([CH3:8])[C@H:6]1[OH:25])[C:19]1[CH:18]=[CH:17][C:16]([O:23]C)=[CH:15][C:14]=1[CH2:13][CH2:12]3)[CH3:4].C1C=C[NH+]=CC=1.Br[Br-]Br.C(OCC)(=O)C.C(OC(C)C)(C)C>CO>[CH2:3]([C@@H:5]1[CH2:10][C@H:9]2[C@H:11]3[C:20]([CH2:21][CH2:22][C@:7]2([CH3:8])[C@H:6]1[OH:25])=[C:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)[CH3:4]
Reactant: CC[C@@H]1C[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]2(C)[C@H]1O
Agent: [BH4-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CC(C)OC(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3CC[C@]2(C)[C@H]1O
Yield: 51 %

Procedure:
According to 1(b), 20.2 g of 16α-ethyl-3-methoxy-1,3,5(10)-estratrien-17-one, N,N-dimethylhydrazone, m.p. 101°-103° C. (from acetonitrile) is obtained from 20.4 g of 3-methoxy-1,3,5(10)-estratrien-17-one N,N-dimethylhydrazone after metallization and alkylation with 9.2 ml of bromoethane. By reaction with CuCl2.2H2O according to 1(c), the 17-ketone is obtained from the hydroazone and then, by reduction of the 17-ketone with sodium borohydride according to 1(d), 16.0 g of 16α-ethyl-3-methoxy-1,3,5(10)-estratrien-17β-ol, m.p. 75°-76° C. (from methanol) is prepared. 10.0 g of 16α-ethyl-3-methoxy-1,3,5(10)-estratrien-17β-ol is subjected analogously to 1(e) in succession to Birch reduction, acid hydrolysis, and reaction with pyridine hydrobromide perbromide, thus obtaining 7.8 g of 16α-ethyl-17β-hydroxy-4,9(10)-estradien-3-one, m.p. 132°-135° C. (from ethyl acetate/diisopropyl ether). This product is converted analogously to 1(f) with acetic anhydride/pyridine into the 17-acetate, m.p. 124°-126° C. (from ether) and analogously to 1(g) by ketalization and subsequent ketal cleavage into the 17β-acetoxy-16α-ethyl-5(10),9(11)-estradien-3-one.