Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([F:8])=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[C:5]([F:8])=[CH:6][N:7]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CNC(=O)c1ccccc1N
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1F
Yield: 33 %

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-fluoropyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in isopropyl alcohol (no microwave −20° C., 24 hours) to afford 2-(2-chloro-5-fluoropyrimidin-4-ylamino)-N-methyl-benzamide as a white solid in 33% yield. Mp: 225° C. (dec); MS: 281.23 (M+H); 1H NMR (chloroform-d): δ 11.78 (br s, 1H), δ 8.80 (d, J=8 Hz, 1H), δ 8.11 (s, 1H), δ 7.60 (t, J=8 Hz, 1H), δ 7.52 (d, J=8 Hz, 1H), δ 7.15 (t, J=8 Hz, 1H), δ 6.31 (br s, 1H), δ 3.06 (dd, J=2.5 Hz, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:12]=1[O:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[F:24])[CH2:9][C:8]([CH3:31])=[CH:7]2)([CH3:3])[CH3:2].[H-].[K+].[Cl:34][Si:35](Cl)([CH3:37])[CH3:36]>C1COCC1>[Cl:34][Si:35]([CH:7]1[C:6]2[C:10](=[C:11]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:12]([O:13][C:14]3[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=3[F:24])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)[CH:9]=[C:8]1[CH3:31])([CH3:37])[CH3:36]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=Cc2cc(C(C)C)c(Oc3c(F)c(F)c(F)c(F)c3F)c(-c3ccccc3)c2C1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1=Cc2c(cc(C(C)C)c(Oc3c(F)c(F)c(F)c(F)c3F)c2-c2ccccc2)C1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a solution of 8.61 g (20.0 mmol) of 5-isopropyl-2-methyl-6-(pentafluorophenoxy)-7-phenyl-1H-indene in 200 ml of THF cooled to −25° C., 885 mg (22.1 mmol) of potassium hydride was added. The resulting mixture was stirred overnight at room temperature, filtered through glass frit (G3) to remove an excess of KH, then cooled to −25° C., and 13.0 g (101 mmol, 5 eq.) of dichlorodimethylsilane was added in one portion. The resulting solution was stirred overnight at room temperature, then evaporated to dryness. The residue was dissolved in 200 ml of toluene, and the formed suspension was filtered through glass frit (G3). The precipitate was additionally washed by 2×30 ml of toluene. The combined filtrate was evaporated to dryness to give 10.5 g (99%) of the title product which was further used without an additional purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.S(O[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:30]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[N:35]1([C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:27][N:1]2[CH2:5][CH2:4][CH2:3][C@@H:2]2[CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CS(=O)(=O)OCCc1cccc(N2CCCC2)c1
Reactant: c1ccc2c(c1)COc1ccccc1N2C[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: c1cc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc(N2CCCC2)c1
Temperature: 90 °C

Procedure:
(R)-5,11-dihydro-5-(2-pyrrolidylmethyl)dibenzo[b,e][1,4]oxazepine (240 mg, 0.85 mmol, prepared by a method disclosed in International Patent No. 9912925A1), 3-pyrrolidinophenethyl mesylate (253 mg, 0.94 mmol), sodium carbonate (106 mg, 1.0 mmol) and sodium iodide (10 mg, 0.07 mmol) were added to acetonitrile (20 ml), and they were heated at 90° C. under reflux for 6.5 hours. The solvent was evaporated under reduced pressure, and the residue was distributed into ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (15:1) and then with hexane and ethyl acetate (2:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(3-pyrrolidinophenethyl)pyrrolidin-2-ylmethyl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oily substance (208 mg, 54%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[C:7](=O)[CH:6]([C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:5]1)(=[O:3])[CH3:2].Cl.[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([NH:35][NH2:36])=[CH:34][C:29]=2[O:28][CH2:27]1>C(O)(=O)C>[C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=2[C:7]2[N:35]([C:33]3[CH:32]=[CH:31][C:30]4[O:26][CH2:27][O:28][C:29]=4[CH:34]=3)[N:36]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: NNc1ccc2c(c1)OCO2
Reactant: CCOC(=O)C(=O)C1CN(C(C)=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CN(C(C)=O)c1ccc([N+](=O)[O-])cc1-2
Temperature: 60 °C
Yield: 78 %

Procedure:
The material of Step 3 (1.1 g, 0.00331 mol) and 1-(1,3-benzodioxol-5-yl)hydrazine hydrochloride (500 mg, 0.00265 mol) were combined in acetic acid (10 mL) and heated to 60° C. for 5 hours. The suspension was then cooled and filtered to give the product as a brown solid. 930 mg (MW=450.4 g/mol, 78% yield). LC/MS m/z=451.5 (m+1).
Reaction SMILES: [H-].[Na+].O1CCOCC1.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].[F:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([F:29])[C:27]=1F)[N:24]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH:23]=[C:22]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:21]2=[O:42]>O>[C:9]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:27]1[C:26]([F:29])=[C:25]2[C:20]([C:21](=[O:42])[C:22]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:23][N:24]2[C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[CH:19][C:18]=1[F:17])#[N:10]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2c(F)c(C(C#N)C(=O)OCC)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.12 g of sodium hydride are initially introduced into 15 ml of dioxane. 0.51 g of ethyl cyanoacetate is added and the mixture is first stirred for one hour at room temperature. 1.1 g of ethyl 6,7,8-trifluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinoline-carboxylate are then added in portions. The mixture is boiled for 3 hours, diluted using water and acidified. It is extracted using methylene chloride.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N.[C:12]1([CH2:18][CH2:19][CH:20]=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[C:12]1([CH2:18][C:19]2[C:6]3[C:5](=[C:4]([O:3][CH3:2])[CH:9]=[CH:8][CH:7]=3)[NH:10][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CCCc1ccccc1
Reactant: COc1ccccc1NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c(Cc3ccccc3)c[nH]c12
Temperature: 0 °C

Procedure:
A mixture of 15 gm (0.086 mol) of 2-methoxyphenylhydrazine hydrochloride and 12 mL (0.09 mol) of 3-phenylpropionaldehyde in 300 mL of toluene was refluxed for 1.5 hours with azeotropic removal of water. The suspension was cooled, evaporated in vacuo and the residue dissolved in 500 mL of dichloromethane and stirred with 9 mL (0.09 mol) of phosphorous trichloride for 18 hours. The solution was poured into ice-water, stirred well, and made basic with sodium bicarbonate. The organic phase was washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a gradient hexane/5-15% ethyl ether to give product, 8.0 gm, 40%, as a viscous oil. 1H NMR (CDCl3) δ: 3.95 (s, 3H), 4.10 (s, 2H), 6.65 (d, 1H), 6.90 (s, 1H), 7.00 (t, 1H), 7.10 (d, 1H), 7.20 (m, 1H), 7.30 (m, 4H), 8.20 (br s, 1H)
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]1([C:23]2[CH2:27][CH2:26][CH2:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:28]([C:24]3[CH2:25][CH2:26][CH2:27][C:23]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:29])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: O=C(O)C1=C(c2ccccc2)CCC1
Solvent: CO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)C2=C(c3ccccc3)CCC2)[C@@H]1O

Procedure:
The title compound was prepared from (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (the title B compound of Example 1) and 2-phenyl-1-cyclopentenecarboxylic acid (the title C compound) by the same method as described for the compound of Example 2 to give a white powder, m.p. 156°-158° C. [α]D =+36.8° (c=0.72, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][O:22][CH3:23])[C:5]([NH:7][C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6].CN(CCN(C)C)C.CN([CH:35]=[O:36])C>C1COCC1>[Cl:1][C:2]1[C:19]([O:20][CH2:21][O:22][CH3:23])=[CH:18][CH:17]=[C:4]2[C:3]=1[CH:35]([OH:36])[N:7]([C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:5]2=[O:6]
Reactant: CN(C)C=O
Reactant: COCOc1ccc(C(=O)NC(C)(C)c2ccccc2)cc1Cl
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COCOc1ccc2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 98.1 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-chloro-4-methoxymethoxy-N-(1-methyl-1-phenylethyl)benzamide (2.83 g, 8.48 mmol) was dissolved in THF (110 mL), and the solution was treated with TMEDA (4.10 mL, 27.2 mmol), sec-butyl lithium-hexane solution (1.01 mol/L, 27.0 mL, 27.2 mmol) and DMF (1.40 mL, 18.1 mmol), followed by purification by flash column chromatography (chloroform/methanol=100/0 to 97/3) to obtain 4-chloro-5-methoxymethoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (3.01 g, yield 98%).
Reaction SMILES: [CH:1]1([N:4]2[CH2:13][C:12]([CH3:15])([CH3:14])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[CH:17])[CH:10]=3)[CH2:5]2)[CH2:3][CH2:2]1.[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:17]#[C:16][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH2:5][N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:13][C:12]3([CH3:14])[CH3:15])=[CH:26][CH:27]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CN(C1CC1)C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CN(C2CC2)C3)cc1
Yield: 23.4 %

Procedure:
Following general procedure F and using 2-cyclopropyl-4,4-dimethyl-6-ethynyl-1,2,3,4-tetrahydro-isoquinoline(Intermediate 27, 0.13 g, 0.571 mmol), 4-iodo phenyl acetic acid methyl ester (Reagent B, 0.16 g, 0.58 mmol), triethyl amine (0.5 mL), anhydrous tetrahydrofluran (2 mL), copper(I)iodide (0.04 g, 0.21 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.12 g, 0.17 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, 0.05 g of the title compound was obtained as an oil. It was further purified by preparative normal phase HPLC on a partisil-10 silica column using 10% ethyl acetate in hexane as the mobile phase (0.01 g, 6%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[CH2:13][C:12]2([CH2:18][CH2:17][N:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:11][CH2:10][CH2:9]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:7][N:8]1[CH2:13][C:12]2([CH2:14][CH2:15][N:16]([C:19]3[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=3)[CH2:17][CH2:18]2)[O:11][CH2:10][CH2:9]1
Reactant: CN1CCOC2(CCN(c3ccc(C#N)cc3)CC2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN1CCOC2(CCN(c3ccc(CN)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 106.7 %

Procedure:
Lithium aluminum hydride (2 g) was suspended in THF (40 ml) and a solution of 4-(4-methyl-1-oxa-4,9-diazaspiro[5,5]undecan-9-yl)benzonitrile (12 g) in THF (100 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hr 40 min and a saturated aqueous sodium sulfate solution was added portionwise under ice-cooling. The precipitated solid was filtrated and washed with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and, after drying, the solvent was evaporated under reduced pressure to give the objective 4-(4-methyl-1-oxa-4,9-diazaspiro[5,5]undecan-9-yl)phenylmethylamine (13 g), which was used in the next Starting Material Synthetic Example 185 without purification.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH3:12])[CH2:5][P:6](=[O:11])([O:9][CH3:10])[O:7][CH3:8].C(NC1C=CC(S([N:26]=[N+:27]=[N-])(=O)=O)=CC=1)(=O)C>C1C=CC=CC=1.C1COCC1>[N+:26](=[C:5]([P:6](=[O:11])([O:9][CH3:10])[O:7][CH3:8])[C:4](=[O:3])[CH3:12])=[N-:27]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COP(=O)(CC(C)=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a suspension of 4.1 g of NaH (washed with hexane) in 110 mL of benzene and 25 mL of THF at 5° C., was added 15.5 g of dimethyl 2-oxopropylphosphonate (Formula 13) in 15 mL of benzene. The resulting solution was stirred at 5-10° C. for 1 hour. A solution of 24.7 g of 4-acetamidobenzenesulfonyl azide (Formula 14) in 25 mL of benzene and 50 mL of THF was then added and the mixture was stirred at room temperature for 2 hours. The yellow suspension was filtered through celite and washed with ethyl ether. The filtrate was concentrated to give 18 g of dimethyl 1-diazo-2-oxopropylphosphonate (Formula 15) as a light yellow oil.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]#[CH:10])[N:6]=[N:5][C:4]2=[C:11]([C:14](=[S:16])[NH2:15])[N:12]=[CH:13][N:3]12.Br[CH2:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)=O>CC#N>[CH2:8]([N:7]1[C:2](=[O:1])[N:3]2[CH:13]=[N:12][C:11]([C:14]3[S:16][CH:18]=[C:19]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)[N:15]=3)=[C:4]2[N:5]=[N:6]1)[C:9]#[CH:10]
Reactant: C#CCn1nnc2c(C(N)=S)ncn2c1=O
Reactant: O=C(CBr)c1cccs1
Solvent: CC#N
Product: C#CCn1nnc2c(-c3nc(-c4cccs4)cs3)ncn2c1=O
Yield: 73 %

Procedure:
4-Oxo-3-(prop-2-ynyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide (0.43 mmol) and 2-bromo-1-(2-thienyl)-1-ethanone (0.43 mmol) were stirred in dry MeCN (2 mL) at room temperature overnight. A precipitate formed which was filtered off and treated with basic ion exchange resin. After removal of the resin, the liquor was recombined with the original filtrate and evaporated to dryness before being purified by column chromatography eluting with 5% MeCN/DCM to give the title compound. Yield 73%. δH (DMSO-d6) 8.95 (1H, s), 8.16 (1H, s) 7.67 (1H, dd, J=3.6, 1.2), 7.58 (1H, dd, J=4.8, 1.2), 7.16 (1H, dd, J=4.8, 3.6), 5.14 (2H, d, J=2.4), 3.53 (1H, t, J=2.4).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([OH:15])([CH3:14])[C:12]#[CH:13].O1CCCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:13]#[C:12][C:11]([OH:15])([CH3:14])[CH3:10])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(C#N)cc1
Yield: 105.3 %

Procedure:
50 g (274.7 mmol) 4-bromobenzonitrile, 46.2 g (550 mmol) 3-methyl-1-butyne-3-ol, 0.97 g (1.38 mmol) bis(triphenylphosphine) dichloropalladium, 0.26 g (1.38 mmol) copper iodide and 2 g (7.6 mmol) triphenyl phosphine were added in a nitrogen stream, and 100 ml tetrahydrofuran (THF) and 20 ml triethylamine were added thereto, and the mixture was reacted at 80 ° C. for 15 hours. The reaction solution was concentrated and partitioned by adding 300 ml ethyl acetate and 300 ml water, and the organic layer was washed twice with 100 ml water and dried over magnesium sulfate anhydride. The solvent was distilled away, and about 250 ml heptane was added to the residual paste and stirred for a while, and the precipitated crystals were filtered to give 53.6 g crystals.
Reaction SMILES: C[C@@]12[C@](O)(C)CC[C@H]1[C@@H]1CC[C@H]3CC(=O)OC[C@]3(C)[C@H]1CC2.[CH3:23][C@@:24]12[C@H:34]3[CH2:35][CH2:36][C@:37]4([CH3:44])[C@:41]([OH:43])([CH3:42])[CH2:40][CH2:39][C@H:38]4[C@@H:33]3[CH2:32][CH2:31][C@H:30]1[CH2:29][C:27](=[O:28])[CH2:26][CH2:25]2>>[OH:43][C@@:41]1([CH3:42])[CH2:40][CH2:39][C@H:38]2[C@H:33]3[C@H:34]([CH2:35][CH2:36][C@:37]12[CH3:44])[C@:24]1([CH3:23])[C@H:30]([CH2:29][C:27](=[O:28])[CH:26]=[CH:25]1)[CH2:31][CH2:32]3
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(C)O
Agent: C[C@]12COC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(C)O
Product: C[C@]12C=CC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(C)O

Procedure:
The present invention relates to a process for the synthesis of oxandrolone from mestanolone. In one aspect of the present invention, a process is provided comprising the steps of: (a) oxidizing mestanolone to form 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one; (b) hydroxylating the 17β-hydroxy-17α-methyl-5α-androst-1-en-3-one to form 1α, 2α, 17β-trihydroxy-17α-methylandrostan-3-one; (c) cleaving the 1≢, 2α, 17β-trihydroxy-17α-methylandrostan-3-one to form 17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid; and (d) reducing the 17β-hydroxy-17α-methyl-1-oxo-1,2,-seco-A-nor-5α-androstan-2-oic acid to form oxandrolone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][O:16][CH2:17][CH2:18][OH:19])[CH:5]=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[O:21].[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH3:39][C:29]1[CH:34]=[CH:33][C:32]([S:35]([O:19][CH2:18][CH2:17][O:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6]2[CH:5]=[CH:4][C:3]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:21])=[C:2]([Cl:1])[CH:7]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2COCCO)cc1Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCc2ccccc2Nc2ccc(C(=O)c3ccccc3C)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 156 (1.0 g, 2.55 mmol) was dissolved in pyridine (1.3 mL) under an argon atmosphere. The solution was cooled on an ice bath and p-toluenesulfonyl chloride (0.56 g, 2.9 mmol) was added. The suspension was stirred for 3 h at room temperature. The reaction was quenched with water and the water phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography eluting with EtOAc/petroleum ether 1:2. This afforded the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12](Cl)(=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1COCC1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)=[O:21])=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc2c(c1)CCC2=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc3c(c2)CCC3=O)cc1
Yield: 76 %

Procedure:
Reaction of 5-amino-indan-1-one (73 mg, 0.50 mmol) in THF (6 mL) with p-anisoyl chloride (88 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave 4-methoxy-N-(1-oxo-indan-5-yl)-benzamide (107 mg, 0.38 mmol, 76% yield) as a yellow powder after purification by chromatography on silica gel (eluent EtOAc/DCM 0/10 to 2/8).
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[C:32]2[C:31](=[O:33])[NH:30][C:29]([C:34]([O:36]CC)=O)=[N:28][C:27]=2[S:26][CH:25]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:82]2[CH:86]=[N:85][C:84]([O:87][CH2:88][CH2:89][O:90][C:91]3[CH:92]=[C:93]([CH2:97][NH2:98])[CH:94]=[CH:95][CH:96]=3)=[N:83]2)C=CC=CC=1>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[C:32]2[C:31](=[O:33])[NH:30][C:29]([C:34]([NH:98][CH2:97][C:93]3[CH:94]=[CH:95][CH:96]=[C:91]([O:90][CH2:89][CH2:88][O:87][C:84]4[N:85]=[CH:86][NH:82][N:83]=4)[CH:92]=3)=[O:36])=[N:28][C:27]=2[S:26][CH:25]=1
Reactant: CCOC(=O)c1nc2scc(-c3ccccc3Cl)c2c(=O)[nH]1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3ccccc3Cl)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(2-chlorophenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 70 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (68.2 mg, 44%).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:20]=[CH:21][C:22]([OH:24])=O)[CH:10]=[C:11]([O:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[C:12]=1[OH:13])[CH2:4][CH3:5])[CH3:2].[NH2:25][CH2:26][C:27]1[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:30]([OH:37])=[C:29]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCN(CC)CC.C(Cl)Cl>[CH2:16]([CH:15]([O:14][C:11]1[CH:10]=[C:9]([CH:20]=[CH:21][C:22]([NH:25][CH2:26][C:27]2[CH:28]=[C:29]([C:38]([CH3:39])([CH3:40])[CH3:41])[C:30]([OH:37])=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:32]=2)=[O:24])[CH:8]=[C:7]([O:6][CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[C:12]=1[OH:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CCC(CC)Oc1cc(C=CC(=O)O)cc(OC(CC)CC)c1O
Reactant: CC(C)(C)c1cc(CN)cc(C(C)(C)C)c1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)Oc1cc(C=CC(=O)NCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(OC(CC)CC)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To the solution of 3-[3,5-bis-(1-ethylpropoxy)-4-hydroxyphenyl]acrylic acid (30 mg, 0.09 mmol) in DMF (0.2 ml) and Et3N (10 μl), was added 4-aminomethyl-2,6-di-t-butylphenol (23 mg, 0.10 mmol) at 0° C. and was added the solution of BOP (44 mg, 0.10 mmol) in CH2Cl2 (0.6 ml). The solution was stirred for 30 minutes at 0° C. and then was stirred for 2 hours at room temperature. And then CH2Cl2 was evaporated in vacuo and the obtained residue was poured into ice water. The residue was extracted with EtOAc and washed with HCl (aq) and NaHCO3 (aq). And then the water was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was vacuum concentrated to give the residue, which was purified by column chromatography (EtOAc:Hexane=1:5), yielding 25 mg (50%) of the title compound as a yellow solid.