Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:8]2[N:9]=[C:10]([NH2:12])[N:11]=[C:7]2[CH:6]=[CH:5][N:4]=1.[CH2:13]([N:20]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.S1C=CC=C1C([O-])=O.[Cu+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([N:20]1[CH:24]=[C:23]([C:3]2[N:8]3[N:9]=[C:10]([NH2:12])[N:11]=[C:7]3[CH:6]=[CH:5][N:4]=2)[CH:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CSc1nccc2nc(N)nn12
Reactant: OB(O)c1cnn(Cc2ccccc2)c1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1CCOC1
Product: Nc1nc2ccnc(-c3cnn(Cc4ccccc4)c3)n2n1
Temperature: 130 °C

Procedure:
A microwave vial containing 5-methylsulfanyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-ylamine (0.05 g, 0.276 mmol), 1-benzyl-1H-pyrazole-4-boronic acid (123 mg, 0.607 mmol), copper(I)thiophene carboxylate (116 mg, 0.607 mmol) and tetrakis(triphenylphosphine)palladium (33 mg, 0.028 mmol) in THF (1.2 mL) was heated under microwave irradiation (130° C., 15 min). The reaction mixture was filtered through celite and the cake washed with dichloromethane. The filtrate was washed with water followed by brine, dried over magnesium sulfate and concentrated under vacuum. Trituration with diethyl ether provided a yellow solid that did not require further purification. Yield: 0.05 g, 63%; LCMS method: 2, RT: 3.18 min, MI: 292 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[C:15]([C:24]([NH2:26])=O)=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1.ClC1C=CC(N2C(=O)C3C(C(O)=O)=NN(C4C=CC=CC=4)C=3N=C2C2C=CC(C(C)C)=CC=2)=CC=1.O=P(Cl)(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[C:15]([C:24]#[N:26])=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:28]=[CH:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(-c2nc3c(c(C(N)=O)nn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Agent: CC(C)c1ccc(-c2nc3c(c(C(=O)O)nn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1ccc(-c2nc3c(c(C#N)nn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid amide (10 mg, 0.021 mmol; prepared from 5-(4-chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid following the procedure as in example 342) is treated with POCl3 at 80° C. for 30 min. The mixture is then cooled down to room temperature and concentrated under vacuum. The residue is treated with sat. aqueous NaHCO3 solution (1 mL) and extrated with EtOAc. The combined extracts is then concentrated and purified by preparative thin layer chromatography (silica gel, 30% EtOAc/hexane) to provide the title compound 5-(4-Chloro phenyl)-6-(4-isopropylphenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile as white solid. 1H NMR (CDCl3) δ (ppm) 8.13(d, 2H), 7.54(t, 2H), 7.44(t, 1H), 7.33(d,2H), 7.25(d, 2H), 7.10(m, 4H), 2.87(m, 1H), 1.20(d, 6H). HPLC-MS calculated C27H20ClN5O (M+1+): 466.1. Found: 466.1.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[C:12]([C:18]([O:20]C)=[O:19])=[N:13][CH:14]=[N:15][C:16]=1[OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO>[CH2:3]([O:10][C:11]1[C:12]([C:18]([OH:20])=[O:19])=[N:13][CH:14]=[N:15][C:16]=1[OH:17])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ncnc(O)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ncnc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
Methanol (6 ml) and 1N aqueous sodium hydroxide solution (2.5 ml) were added to methyl 5-benzyloxy-6-hydroxypyrimidine-4-carboxylate (530 mg) obtained in the previous step, and the mixture was stirred at room temperature for 1 hr. 2N Hydrochloric acid (2.5 ml) was added to the reaction mixture, and methanol was evaporated under reduced pressure. The precipitate was collected by filtration, washed with water and dried to give 5-benzyloxy-6-hydroxypyrimidine-4-carboxylic acid (253 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCc1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1

Procedure:
The title compound is prepared in analogy to Example 3a) from 4-fluorobenzyl alcohol and 4-fluoro-nitrobenzene. Yield: 86% of a yellowish solid. Mp=124–126° C.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[N+:15]([O-])=O.[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][CH:28]1[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]1
Reactant: O=[N+]([O-])c1cccc2cc(C3=NCCS3)[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cc(C4=NCCS4)[nH]c23)CC1

Procedure:
2-(4,5-Dihydro-thiazol-2-yl)-7-nitro-1H-indole prepared in Preparation 101 and 1-BOC-4-piperidone were reacted according to the same procedure as Example 1 to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[N:8]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH2:7][CH2:6][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4]1.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O>[Si:25]([O:1][CH2:2][CH:3]1[N:8]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH2:7][CH2:6][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C2COC2)C(CO)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C2COC2)C(CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.9 %

Procedure:
(+/−) Tert-butyl 3-(hydroxymethyl)-4-(oxetan-3-yl)piperazine-1-carboxylate (1 g, 3.67 mmol) was taken up in DMF (2 mL) and imidazole (0.500 g, 7.34 mmol) and TBS-Cl (0.609 g, 4.04 mmol) were added. The reaction was stirred at room temperature over the weekend. An additional 0.2 eq. of TBS-Cl and 0.5 eq. of imidazole were added, and the reaction mixture was heated at 40° C. overnight, then at 45° C. for 24 h. The reaction mixture was diluted with EtOAc and washed with water 4×. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-60% EtOAc/Hex). (+/−) Tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(oxetan-3-yl)piperazine-1-carboxylate (665 mg) was obtained as a colorless oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N+:6]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1O)=[N:16][CH:15]=[CH:14][CH:13]=2)([O-:8])=[O:7].CC(C)=O.[CH2:24]([NH2:28])[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[CH3:26][CH:25]([CH3:27])[CH2:24][NH:28][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[N:11]=[CH:10][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1O
Reactant: CC(C)CN
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: CC(C)CNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 25 °C

Procedure:
Phosphorous oxychloride (0.6 mL, 6.44 mmol) was reacted with N,N-dimethylformamide then added to a solution of 3-nitro[1,5]naphthyridin-4-ol (1.0 g, 5.23 mmol) in N,N-dimethylformamide (20 mL). The reaction mixture was warmed using a jacketed flask with refluxing acetone as a heat source. After 3 hours the reaction mixture was poured into ice water, isobutylamine (2.0 mL, 20.1 mmol) was added and the mixture was heated on a steam bath. After several hours the reaction mixture was cooled to ambient temperature, filtered and washed with water. The aqueous layer was extracted with dichloromethane. The dichloromethane extract was washed with aqueous sodium bicarbonate, washed with water, dried over magnesium filtrate then loaded onto a layer of silica gel. The silica gel was eluted initially with dichloromethane to remove an impurity then with 5% methanol in dichloromethane to recover the product. The eluant was concentrated to dryness to provide N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine as a solid, m.p. 97-99° C.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:25]=[C:24]4[C:19]([CH2:20][CH2:21][CH2:22][NH:23]4)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[NH2:26][CH2:27][C@@H:28]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].[F-].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:46][C:43]([O:42][C:40](=[O:41])[C@H:28]([CH2:27][NH:26][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:25]=[C:24]4[C:19]([CH2:20][CH2:21][CH2:22][NH:23]4)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1)[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])([CH3:44])[CH3:45]
Reactant: CCc1c(Br)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCc1c(NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Yield: 82.2 %

Procedure:
A mixture of 317 mg (0.79 mmoles) of 4-bromo-5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-pyrimidine, 279 mg (0.95 mmoles) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176), 168 mg (1.11 mmoles) of caesium fluoride, 36 mg (0.04 mmoles) of tris(dibenzylideneacetone)dipalladium(0), 49 mg (0.08 mmoles) of S(−)2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl in 11 ml of dioxane is heated under reflux for 21 hours. After cooling down another 140 mg (0.48 mmoles) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate, 168 mg (1.11 mmoles) of caesium fluoride, 36 mg (0.04 mmoles) of tris(dibenzylideneacetone)dipalladium(0), and 49 mg (0.08 mmoles) of S(−)2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl in 2 ml of dioxane are added and the reaction medium is heated under reflux for 3.5 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silicagel eluting with a gradient of heptane-ethyl acetate-methanol 50-50-0, 25-75-0, 0-100-0, and finally 0-100-3. 400 mg (Yield=83%) of expected product is obtained in the form of an oil.
Reaction SMILES: [CH:1]#[C:2][CH2:3][NH:4][C:5]([NH2:7])=[O:6].[F:8][C:9]1[C:10](I)=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])/[C:12]/2=[CH:19]\[C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH3:25]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:8][C:9]1[C:10]([C:1]#[C:2][CH2:3][NH:4][C:5]([NH2:7])=[O:6])=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])/[C:12]/2=[CH:19]\[C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH3:25]
Reactant: C#CCNC(N)=O
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCNC(N)=O)c21

Procedure:
Using Method C above, 2-propynylurea (50 mg, 0.51 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P)4Pd (23.5 mg) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-[3-[5-fluoro-2,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]urea. (Yield 11 mg, 16%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH:28]([F:30])[F:29])=[CH:22][C:21]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH3:36][O:37][CH2:38][C:39]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH:28]([F:30])[F:29])=[CH:22][C:21]=4[O:31][CH2:32][CH:33]4[CH2:34][CH2:35]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:40]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)c(OC(F)F)cc3OCC3CC3)ncnc12
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)c(OC(F)F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-cyclopropylmethoxy-4-(1,1-difluoro-methoxy)-5-fluoro-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A189) and methoxy-acetyl chloride the title compound is obtained as colorless solid
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][C:11]2([CH3:21])[CH3:20])[CH:8]=[N:7][CH:6]=1)=[O:4].[Br:22]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([Br:22])=[CH:12][C:11]2([CH3:21])[CH3:20])[CH:8]=[N:7][CH:6]=1)=[O:4]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COC(=O)c1cncn1C1c2ccccc2CCC1(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cncn1C1c2ccccc2C(Br)=CC1(C)C
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A solution of 8.5 g of 1-(2,2-dimethyltetralin-1-yl)-5-imidazolecarboxylic acid methyl ester in 100 ml of carbon tetrachloride is treated with 8.6 g of 1,3-dibromo-5,5-dimethylhydantoin and heated to reflux for 1 hour, while the reaction vessel is exposed to a 100W-irradiation lamp. The mixture is cooled to room temperature and concentrated to dryness. Chromatography of the residue at a silica gel column with methylene chloride affords 5.6 g of 1-(2,2-dimethyl-4-bromo-1,2-dihydronaphthalin-1-yl)-5-imidazolecarboxylic acid methyl ester in form of colourless crystals; mp. 101°-103° C.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([O:22][CH3:23])=[CH:20]C=[CH:18][N:17]=3)[CH2:12][CH:11]2[CH3:24])[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2.S(C1C=CC(C)=CC=1)([O-])(=O)=O.COC1C(N2CCNC(C)C2)=[N:44]C=NC=1>>[ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([O:22][CH3:23])=[CH:20][N:44]=[CH:18][N:17]=3)[CH2:12][CH:11]2[CH3:24])[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2
Reactant: COc1cccnc1N1CCN(CCCc2csc3ccccc23)C(C)C1
Reactant: COc1cncnc1N1CCNC(C)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: COc1cncnc1N1CCN(CCCc2csc3ccccc23)C(C)C1

Procedure:
The title compound was prepared (0.80 g, 85%, mp 200°-205° C.) in a manner analogous to the preparation of 1-[3-(benzo[b]thien-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)-2-methylpiperazine hydrochloride (Example 41) by the reaction of 3-benzo[b]thienepropanol tosylate with 1-(5-methoxy-4-pyrimidinyl)-3-methylpiperazine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2oc(-c3ccc(C)cc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc3cc(C(=O)O)ccc3o2)cc1

Procedure:
A solution containing 16.0 g. (0.06 mole) of methyl 2-(4-methylphenyl)-5-benzoxazolecarboxylate (1a), 4.0 g. (0.1 mole) of sodium hydroxide, and 50 ml. of water in 275 ml. of ethanol was stirred at 25° for 16 hours. The reaction mixture was poured into 1 l. of water. Acidification gave a white precipitate which was filtered, washed with water, and when air-dried amounted to 14.44 g. (95%) of 2-(4-methylphenyl)-5-benzoxazolecarboxylic acid (1b). The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][C:16]4([CH3:29])[CH3:28])[CH2:13][CH2:12][C:11]=2[CH:10]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[CH2:17][C:16]4([CH3:29])[CH3:28])[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC(C)(C)[C@@H]12
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C(C)(C)C[C@@H]2O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 85.5 %

Procedure:
Lithium aluminum hydride (30 mg; 0.79 mmol) was added to a solution of the dimethyl ketone (4) (50 mg; 0.16 mmol) in dry tetrahydrofuran (2 ml) at 0° C. The mixture was stirred at 0° C. for 5 min. Saturated aqueous sodium hydrogen carbonate was added and the mixture was filtered. Work-up of the filtrate (ethyl acetate) gave 3-methoxy-15,15-dimethylestra-1,3,5(10)-trien-17β-ol (12) (43 mg; 85%), m.p. 87°-91° C. (from chloroform-hexane), [α]D +75° (c 1.1); νmax 3606 cm-1 (OH); δ0.92 (3H, s, 13β-Me), 1.06 (1H, d, J 11.2 Hz, 14α-H), 1.11 and 1.14 (each 3H, s, 15α- and 15β-Me), 1.61 and 1.90 (each 1H, dd, J 13.0 and 10.2, and 13.0 and 7.9 Hz, 16α- and 16β-H), 2.86 (2H, m, 6-H2), 3.71 (1H, dd, J 10.2 and 7.9 Hz, 17α-H), 3.77 (3H, s, 3-OMe), 6.62 (1H, d, J 2.7 Hz, 4-H), 6.71 (1H, dd, J 8.6 and 2.7 Hz, 2-H), and 7.21 (1H, d, J 8.6 Hz, 1-H); δc 13.5 (C-18), 25.6 (15-Me), 26.1 (C-11), 28.5 (C-7), 29.9 (C-6), 35.0 (C-12), 36.2 (C-15), 37.1 (C-8), 38.8 (15-Me), 44.9 (C-9), 45.6 (C-13), 50.1 (C-16), 55.2 (3-OMe), 58.1 (C-14), 79.8 (C-17), 111.4 (C-2), 113.6 (C-4), 126.3 (C-1), 132.9 (C-10), 137.7 (C-5), and 157.5 (C-3) (Found: C, 80.0; H, 9.5%; M+, 314. C21H30O2 requires C, 80.2; H, 9.6%; M, 314).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5](N)[CH:4]=1.N([O-])=O.[Na+].[CH3:14][N:15]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]1=[O:21].C1C=CC=CC=1>Cl.O.CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[C:16]([N:15]([CH3:14])[C:19](=[O:20])[CH:18]=2)=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: CN1C(=O)C=CC1=O
Reactant: COc1cccc(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: COc1cccc(C2=CC(=O)N(C)C2=O)c1
Temperature: 0 °C

Procedure:
A 92.3 g portion of m-anisidine is dissolved in 225 ml of concentrated hydrochloric acid, 150 ml of water and 150 g of ice and cooled to 0° C. This mixture is diazotized carefully with vigorous stirring at 0°-5° C. with 52.5 g of sodium nitrite in 120 ml of water. This mixture is then added to 83.25 g of N-methylmaleimide in 225 ml of acetone at 0° C. The pH is adjusted to 3.0 and 25.5 g of cuprous chloride dihydrate is added in one portion followed by 200 ml of acetone, with stirring. Evaporation of the acetone and decantation of the aqueous layer leaves a black residue which is boiled with one liter of benzene, dried over magnesium sulfate and filtered through a Buchner funnel containing 50 g of activated magnesium silicate. The residue is boiled with one liter of benzene and filtered through activated magnesium silicate. The dark filtrate is evaporated under reduced pressure and then heated for 10 minutes with 100 ml of 2,6-lutidine to insure dehydrochlorination. This solution is combined with 500 ml of water and 400 ml of pyridine and filtered. The crystalline cake is pressed free of dark oil and then boiled with 500 ml of 90% ethanol. This is cooled and filtered giving 2-(m-methoxyphenyl)-N-methylmaleimide as orange crystals, m.p. 138°-146° C.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:16]([O:19][C:20]1[C:28]([O:29][CH3:30])=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][C:21]=1[O:31][CH3:32])[C:17]#[CH:18]>C(OCC)(=O)C>[CH:1]1([CH2:7][NH:8][C:24](=[O:25])[C:23]2[CH:22]=[C:21]([O:31][CH3:32])[C:20]([O:19][CH2:16][C:17]#[CH:18])=[C:28]([O:29][CH3:30])[CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Reactant: NCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOc1c(OC)cc(C(=O)NCC2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A mixture of 3.6 g of cyclohexylmethylamine, 3.5 g of triethylamine and 10 ml of ethyl acetate was added dropwise under ice cooling to a mixture of 75 ml of ethyl acetate and 7.4 g of 4-(2-propynyloxy)-3,5-dimethoxybenzoyl chloride. The mixture obtained was stirred at room temperature for 4 hours. Then, ethyl acetate was added to the reaction mixture and it was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7.7 g of N-cyclohexylmethyl-4-(2-propynyloxy)-3,5-dimethoxybenzamide (hereinafter, described as the compound 1 of the present invention) represented by the formula: