Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([NH:14][C:15]([C@H:17]2[O:19][C@@H:18]2[C:20](O)=[O:21])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[N:24]1C(=O)C[CH2:26][C:25]1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.C(N)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:25]([NH:24][C:20]([C@@H:18]1[C@@H:17]([C:15](=[O:16])[NH:14][CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:19]1)=[O:21])[CH3:26]
Reactant: O=C(O)[C@H]1O[C@@H]1C(=O)NC(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@H]1O[C@@H]1C(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S, 3S)-3-diphenylmethylcarbamoyloxirane-2-carboxylic acid (1.80 g, 6.05 mmol.) and N-hydroxysuccinimide (696 mg, 6.05 mmol) in methylene chloride (10 mL) was added a solution of N,N'-dicyclohexylcarbodiimide (1.25 g, 6.05 mmol.) in methylene chloride (7 mL) under chilling with ice. The mixture was stirred for 30 minutes at room temperature. To the mixture was then added under chilling with ice a solution of ethylamine hydrochloride (493 mg, 6.05 mmol.) and triethylamine (0.84 mL, 6.05 mmol) in methylene chloride (7 mL). The resulting mixture was stirred overnight at 5° C. The solvent was distilled off under reduced pressure, and N,N'-dicyclohexylurea (DC-Urea) was removed by filtration after addition of ethyl acetate (10 mL). The solution was washed successively with water, 0.5N hydrochloric acid, an aqueous sodium hydrogen carbonate saturated solution, and an aqueous sodium chloride saturated solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (chloroform/methanol=1/0 to 50/1), to give the desired compound as a white crystalline powdery product (928 mg, yield: 47%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[CH:27]([CH3:29])[NH:26][CH2:25][CH2:24]3)=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[C:19]([C:16]5[CH:17]=[CH:18][O:14][CH:15]=5)[CH:20]=[CH:21][CH:22]=4)[CH:27]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cccc(-c3ccoc3)c21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2c(cccc2-c2ccoc2)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Furan-3-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[CH:30]1([CH2:33][N:34]2[CH2:39][CH2:38][N:37]([C:40]3[CH:45]=[C:44]([CH2:46][NH2:47])[CH:43]=[C:42]([C:48]4[CH:53]=[CH:52][C:51]([O:54][C:55]([F:58])([F:57])[F:56])=[CH:50][CH:49]=4)[N:41]=3)[CH2:36][CH2:35]2)[CH2:32][CH2:31]1>C1COCC1>[CH:30]1([CH2:33][N:34]2[CH2:35][CH2:36][N:37]([C:40]3[CH:45]=[C:44]([CH2:46][NH:47][C:5](=[O:7])[C:4]([N:3]([CH2:1][CH3:2])[S:9]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)(=[O:11])=[O:10])=[CH2:8])[CH:43]=[C:42]([C:48]4[CH:53]=[CH:52][C:51]([O:54][C:55]([F:56])([F:58])[F:57])=[CH:50][CH:49]=4)[N:41]=3)[CH2:38][CH2:39]2)[CH2:32][CH2:31]1
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(F)cc1
Reactant: NCc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCN(CC3CC3)CC2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCN(CC3CC3)CC2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.2 %

Procedure:
A solution of acid 4B (273.28 mg, 1 mmol) in THF (10 mL) was added with DEPC (0.15 mL, 1.1 mol eq) and the mixture was stirred at room temperature for about 5 minutes. Then [2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 27F (405 mg, 1.04 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (40 mL) and washed with water (50 mL) and brine. The separated organic phase was dried over Na2SO4 and evaporated under reduced pressure and the residue was purified by flash chromatography (9:1 EtOAc:methanol) to afford a white solid (200 mg) after crystallization from diethyl ether. Yield=30%, 1HNMR (DMSO, 200 MHz) δ 0.05 (m, 2H), 0.45 (bm, 2H), 0.82 (m, 1H), 1.08 (t, 3H), 2.17 (d, 2H, J=6.4), 3.34 (bm, 4H), 3.49 (bm, 4H), 4.43 (d, 2H, J=6.2), 5.13 (s, 1H); 6.09 (s, 1H), 6.80 (s, 1H), 7.30 (s, 1H), 7.47 (m, 4H), 7.85 (m, 4H), 8.74 (t, 1H). [M+1] 662.90 (C32H35F4N5O4S requires 661.71).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[CH2:5][CH3:6])[CH3:3].O1CCOCC1.[CH:23]1([N:28]2[C:32]3=[N:33][C:34]([CH2:38][C:39]4[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=4)=[N:35][C:36](=[O:37])[C:31]3=[C:30]([CH2:46][CH3:47])[NH:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1.O>C(OCC)(=O)C>[CH:23]1([N:28]2[C:32]3=[N:33][C:34]([CH2:38][C:39]4[CH:40]=[CH:41][C:42]([O:13][C:12]([C:11]5[CH:10]=[CH:9][C:8]([CH2:7][N:4]([CH2:5][CH3:6])[CH2:2][CH3:3])=[CH:16][CH:15]=5)=[O:14])=[CH:43][CH:44]=4)=[N:35][C:36](=[O:37])[C:31]3=[C:30]([CH2:46][CH3:47])[NH:29]2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc(O)cc3)nc(=O)c1-2
Reactant: CCN(CC)Cc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc(OC(=O)c4ccc(CN(CC)CC)cc4)cc3)nc(=O)c1-2
Temperature: 25 °C
Yield: 58.1 %

Procedure:
A mixture of 4-diethylaminomethyl benzoic acid hydrochloride (360 mg, 1.5 mmol), N,N'-carbonyldiimidazole (264 mg, 1.5 mmol) and dioxane (20 ml) was heated on an oil bath for 1 hour. The reaction mixture was cooled to room temperature and 1-cyclopentyl-3-ethyl-6-(4-hydroxyphenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one (500 mg, 105 mmol) and dioxane (10 ml) were added and the reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled, the solvent was stripped and then water and ethyl acetate were added. The ethyl acetate layer was separated, then washed with 2 N HCl (4×150 ml). The aqueous layers were combined, treated with concentrated NH4OH and then extracted with ethyl acetate (2×). The ethyl acetate layer was washed with brine, dried over MgSO4, filtered and stripped to afford crude product. The crude product was combined with the crude product from a similar experimental run and the mixture was recrystallized from ether to afford 0.46 g of 1-cyclopentyl-3-ethyl-6-[4-[4-(diethylaminomethyl)phenylcarbonyloxy]phenylmethyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 143-145° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]([NH2:14])=[S:13].O>CO>[NH2:14][C:12]1[S:13][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:11]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1ccccc1
Solvent: O
Solvent: CO
Product: Nc1nc(-c2ccccc2)cs1
Yield: 85.1 %

Procedure:
A solution of 19.9 g (0.10 mol) of α-bromo-acetophenone and 11.4 g (0.15 mol) of thiourea in 75 ml of methanol is refluxed for 2 h. It is evaporated to dryness under reduced pressure and the evaporation residue is taken up with water. The resulting solution, heated to the reflux temperature, is treated with CXA charcoal and then rendered alkaline with aqueous ammonia. The precipitate formed is isolated by filtration and purified by recrystallization from isopropanol, with CXA charcoal treatment. to give 15 g (yield: 85.15%) of the expected product in the form of water-insoluble white needles. M.p. (inst.)=150° C.
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12]1([S:18][C:19]2[N:20]=[CH:21][N:22]3[CH:26]=[CH:25][S:24][C:23]=23)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:27]([Sn:31](Cl)([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Cl-].[NH4+]>C1COCC1>[C:12]1([S:18][C:19]2[N:20]=[CH:21][N:22]3[CH:26]=[C:25]([Sn:31]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:27][CH2:28][CH2:29][CH3:30])[S:24][C:23]=23)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1ccc(Sc2ncn3ccsc23)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(Sc3ccccc3)c2s1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
A 1.59 N n-butyl lithium/n-hexane solution (0.189 ml) was added dropwise at −73° C. in an argon atmosphere to a solution of 66.5 mg of 7-phenylthioimidazo[5,1-b]thiazole in 3 ml of THF. Subsequently, 0.098 ml of tri-n-butylstannyl chloride was added to the mixture. The mixture was stirred at the same temperature for 15 min. The temperature of the system was raised to −40° C. A 1.0 N lithiumbis(trimethylsilyl)amide/THF solution (0.11 ml) was added thereto. The mixture was stirred for one hr. An aqueous ammonium chloride solution was added to the reaction solution. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give 115 mg of the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].BrCCCCCC(O[C:16]([CH3:19])([CH3:18])[CH3:17])=O>C=C(C)C>[C:16]([CH:3]([CH2:2][Br:1])[C:4]([OH:6])=[O:5])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)CCCCCBr
Reactant: O=C(O)CCBr
Agent: C=C(C)C
Product: CC(C)(C)C(CBr)C(=O)O
Yield: 36 %

Procedure:
3-Bromopropanoic acid (8.2 g, 53.6 mmol) and iso-butene (60 ml) were reacted by the same procedure as described in Example 1 for the preparation of tert-butyl 6-bromohexanoate and afforded the title material (4 g, 36%) as a colorless liquid.
Reaction SMILES: [C:1]1(=[O:11])C2C(=CC=CC=2)C=[CH:3][CH2:2]1.[C:12]1([OH:23])[C:21]2[CH2:20][CH2:19][CH:18]([OH:22])[CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1>>[O:11]1[CH2:1][CH:2]1[CH2:3][O:23][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[CH2:20][CH2:19][CH:18]([OH:22])[CH2:17]2
Reactant: Oc1cccc2c1CCC(O)C2
Reactant: O=C1CC=Cc2ccccc21
Product: OC1CCc2c(cccc2OCC2CO2)C1

Procedure:
Employing the procedure of Example 3a, but substituting a 6-alkoxy-1-tetralone as shown in the left hand (first) column of Table II for 6-methoxy-1-tetralone, a 6-alkoxy-1-naphthol is produced, which is converted as per Example 3b to the corresponding 5-hydroxy-3,4-dihydro-2(1H)-naphthalenenone shown in the middle column of Table II; employing the procedure of Example 3c the naphthalenone is converted to the corresponding 5,6,7,8-tetrahydro-1,6-naphthalenediol which is reacted with an epoxide of the structure ##STR52## in accordance with the procedure of Example 3d to form the corresponding 1,2,3,4-tetrahydro-5-[2,3-epoxy-propoxy]-2-naphthol which is reacted with an amine of the structure ##STR53## in accordance with the procedure of Example 3e to form the corresponding 1,2,3,4-tetrahydro-5-[2-hydroxy-3-(R1, R2 -substituted amino)propoxy]-2-naphthol (formula I) as shown in the right hand (third) column of Table II.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:8]1[CH:12]=[C:11]([C:13]2[CH:27]=[CH:26][CH:25]=[CH:24][C:14]=2[CH2:15][NH:16]C(=O)OC(C)(C)C)[N:10]=[CH:9]1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:8]1[CH:12]=[C:11]([C:13]2[CH:27]=[CH:26][CH:25]=[CH:24][C:14]=2[CH2:15][NH2:16])[N:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1cocn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccccc1-c1cocn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 142.8 %

Procedure:
Added trifluoroacetic acid (5 mL, 64.9 mmol) to a solution of tert-butyl 2-(oxazol-4-yl)benzylcarbamate (200 mg, 0.729 mmol) in Dichloromethane (DCM) (5 mL) and let stir at room temperature for 1 hour. Concentrated to dryness. Obtained 300 mg of (2-(oxazol-4-yl)phenyl)methanamine trifluoroacetate. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.88-4.50 (m, 2H) 7.38-7.60 (m, 4H) 8.00 (s, 1H) 8.10 (s, 1H) 8.19-8.56 (m, 2H). MS[MH]+=175.1
Reaction SMILES: [C:1]([NH:9][C:10](=[N:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[C:26]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH3:34])[N:28]=3)=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:16][CH:15]=1)SC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][NH2:36]>CCO>[CH3:34][NH:33][C:29]1[N:28]=[C:27]([C:26]2[C:21]([O:20][C:17]3[CH:18]=[CH:19][C:14]([NH:13][C:10]4[NH:9][C:1]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[N:36][N:35]=4)=[CH:15][CH:16]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:32]=[CH:31][N:30]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N=C(NC(=O)c3ccccc3)SC)cc2)n1
Reactant: NN
Solvent: CCO
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)[nH]3)cc2)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A slurry of 1-benzoyl-2-methyl-3-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)isothiourea (0.174 g, 0.37 mmol) and anhydrous hydrazine (0.35 ml, 11 mmol) in EtOH was sealed and heated to 80° C. After 16 h, a yellow precipitate formed. The reaction was cooled to ambient temperature, filtered, rinsing with 2×1 mL EtOH, and the solid was dried in vacuo to give N-methyl-4-(2-(4-(5-phenyl-4H-1,2,4-triazol-3-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amine as a white solid. MS m/z=437 [M+H]+. Calc'd for C24H20N8O: 436.5.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:15][OH:16].Cl.CC([O-])=O.[Na+]>C(O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:15][OH:16])=[CH:4][C:3]=1[CH2:10][C:11]([F:14])([F:13])[F:12]
Reactant: O=Cc1ccc(Br)c(CC(F)(F)F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(Br)c(CC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 4-bromo-3-(2,2,2-trifluoroethyl)benzaldehyde (700 mg, 2.62 mmol, 1.00 equiv) in ethanol:H2O (20:5 mL), NH2OH. hydrogen chloride (235 mg, 3.41 mmol, 1.30 equiv), NaOAc (279 mg, 3.40 mmol, 1.30 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 700 mg (crude) of N-[[4-bromo-3-(2,2,2-trifluoroethyl)phenyl]methylidene]hydroxylamine as yellow oil.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11]1(=[O:21])[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[Cl-].[NH4+]>O1CCCC1>[CH3:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:11]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])=[O:21]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1ccccc1C(=O)O
Temperature: -70 °C
Reaction time: 2.5 h
Yield: 88.4 %

Procedure:
A solution in tetrahydrofuran (17 ml) of a Grignard's reagent prepared from magnesium (120 mg, 5.1 mmol) and 2-bromoanisole (0.55 ml, 4.4 mmol) was added dropwise to a solution of phthalic anhydride (500 mg, 3.4 mmol) in tetrahydrofuran (12 ml) in an atmosphere of nitrogen at −70° C. over a period of 10 minutes. The reaction mixture was stirred at −70° C. for 2.5 hours, and aqueous saturated ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with aqueous saturated sodium chloride solution, dried and concentrated under reduced pressure to obtain crude 2-(2-methoxybenzoyl)benzoic acid (770 mg, yield: 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[NH2:32][CH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:32][CH:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35][CH2:34]3)=[O:22])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NC1CCc2ccccc21
Product: O=C(NC1CCc2ccccc21)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-aminoindan as in General Procedure 10 to give the title compound. LCMS: m/z=562.95 (M+H+); retention time=0.99 minutes.
Reaction SMILES: C(O[C:4](=[O:17])[C:5]([C:15]#[N:16])=[CH:6][NH:7][C:8]1[CH:9]=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=1)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:11]1[N:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[NH:7][CH:6]=[C:5]([C:15]#[N:16])[C:4]2=[O:17]
Reactant: CCOC(=O)C(C#N)=CNc1ccc(C)nc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc2[nH]cc(C#N)c(=O)c2n1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
The suspension of 2-cyano-3-(6-methyl-pyridin-3-ylamino)-acrylic acid ethyl ester (8.8 g, 38.05 mmol) in diphenylether (190 mL) was heated under refluxing for 5 hrs. After cooling to room temperature, the reaction mixture was poured into nHexane (800 mL) and the solid was collected by filtration and washed with cold THF to give 6-methyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carbonitrile (3.86 g, 54.8%). HR-MS-EI (+) m/e calcd for C10H7N3O (M+) 185.0589. found 185.0591.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccc(F)cc4)CC3)c(OC)nc2c1
Yield: 92 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 92%). 1H NMR (300 MHz, CDCl3): δ 3.17 (s, 4H), 3.75 (s, 4H), 3.89 (s, 3H), 4.12 (s, 3H), 6.86-7.01 (m, 4H), 7.13 (s, 2H), 7.32 (s, 1H), 7.72-7.74 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7](O)[CH:8]=[CH2:9]>Cl.CCCCCC>[CH2:9]([O:6][CH:5]1[CH2:4][CH2:3][CH2:2][O:1]1)[CH:8]=[CH2:7]
Reactant: C=CCO
Reactant: O=CCCCO
Agent: Cl
Solvent: CCCCCC
Product: C=CCOC1CCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
The procedure of Example 1 is followed with 4-hydroxybutanal (20.0 g of 11.5 wt. % solution, 26 mmol, 1.0 eq.), allyl alcohol (3.26 g, 56 mmol, 2.2 eq.), and hexanes (50 mL). Concentrated hydrochloric acid (2 drops) is used in place of the ion-exchange resin. After 3 h of stirring at room temperature, the hexane phase contains 8.8% of 2-allyloxytetrahydrofuran (3.1 g, 92.5% yield).
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[Cl:15][CH2:16][C:17]([NH:19][CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])=[O:18].O.Cl>O1CCCC1>[Cl:15][CH2:16][C:17]([NH:19][C@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:21]1[OH:30])=[O:18]
Reactant: O=C(CCl)NC1CCc2ccccc2C1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCl)N[C@H]1CCc2ccccc2[C@H]1O
Yield: 70.8 %

Procedure:
Lithium tri-sec-butylborohydride (1.0 M solution in tetrahydrofuran, 70 ml, 70 mmol) was added to a solution of 2-chloro-N-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (7.58 g, 31.9 mmol) in tetrahydrofuran (500 ml). When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by the addition of water and pH was adjusted to 5-6 with 3N aqueous hydrochloric acid. The residue was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 2-chloro-N-((1RS,2SR)-cis-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-acetamide (5.4 g, 22.6 mmol, 71%) as white crystals.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4](OCC)(=O)CC(OCC)=O.[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=1)[C:21](Cl)=[O:22].Cl>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:21]([C:20]1[CH:19]=[N:18][CH:17]=[C:16]([Br:15])[CH:24]=1)(=[O:22])[CH3:4]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1cncc(Br)c1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.3 %

Procedure:
1.24 g of ground magnesium chloride was suspended in 13 ml of toluene and 6.2 ml of triethylamine and 2.93 g of diethyl malonate were added in turn. After stirring at room temperature for 1.5 hours, a suspension of 4.08 g of 5-bromonicotinoyl chloride obtained in the step 1 in 10 ml of toluene was added dropwise over 15 minutes, followed by stirring at room temperature for 2 hours. After neutralizing with 40 ml of 1N hydrochloric acid, the aqueous layer was separated. The aqueous layer was further subjected to extraction with diethyl ether and the organic layers were combined, and then the solvent was distilled off under reduced pressure. To the resulting oily product, dimethyl sulfoxide-water (17 ml-0.7 ml) was added, followed by stirring with heating at 150 to 160° C. for 2 hours. The reaction solution was air-cooled, and then water was added. Then, the deposited crystals were collected by filtration. The deposited crystals were dissolved in ethyl acetate, washed in turn with water and an aqueous saturated sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulfate. 0.60 g of activated carbon (Kyoryoku Shirasagi MOIWY433) was added and, after standing for 10 minutes, activated carbon was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.89 g of the objective compound as pale yellow crystals.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[C:12]([C@:14]1([OH:35])[CH2:19][CH2:18][C@H:17]2[C@H:20]3[C:30](=[CH:31][CH2:32][C@:15]12[CH3:16])[C@:28]1([CH3:29])[C:23]([CH2:24][C:25](=[O:33])[CH2:26][CH2:27]1)=[C:22]([F:34])[CH2:21]3)#[CH:13]>C1COCC1>[C:12]([C@:14]1([OH:35])[CH2:19][CH2:18][C@H:17]2[C@H:20]3[C:30](=[CH:31][CH2:32][C@:15]12[CH3:16])[C@:28]1([CH3:29])[C:23](=[CH:24][C:25](=[O:33])[CH2:26][CH2:27]1)[C@@H:22]([F:34])[CH2:21]3)#[CH:13]
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CC(F)=C4CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Reaction time: 1 h

Procedure:
p-TSA (20 mg) is added to THF (5 ml) containing 17α-ethynyl-6-fluoro-17β-hydroxyandrost-5,9(11)-diene-3-one (VI, Example 5, 200 mg). After one hour at 20°-25°, the mixture is heated to reflux for 1.5 hrs. After cooling, the organic diluent is removed under reduced pressure. The residue is taken up in ethyl acetate, washed with aqueous sodium carbonate, the organic mixtures dried over sodium sulfate, and the organic diluent is removed under reduced pressure to give a solid. Filtration chromatography on silica dioxide (4 g), eluting with methylene chloride with increasing amounts of ethyl acetate, gives the title compound. Rf (ethyl acetate/hexane, 1/1)=0.7; NMR (CDCl3 +CD3OD) 0.8, 1.4, 2.6, 5.3, 5.7 and 6.1 δ.