Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH:4]=[N:5][C:6]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])C.[C:22]([O:26][C:27](=[O:31])[CH2:28][C:29]#[N:30])([CH3:25])([CH3:24])[CH3:23]>C(O)(C)(C)C>[C:22]([O:26][C:27](=[O:31])[C:28]([C:29]#[N:30])=[CH:4][NH:5][C:6]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: CCOc1cc(N=CN(C)C)c(C(=O)OC)cc1[N+](=O)[O-]
Solvent: CC(C)(C)O
Product: CCOc1cc(NC=C(C#N)C(=O)OC(C)(C)C)c(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A 3-L round-bottomed flask under N2 equipped with an overhead stirrer, a condenser and a thermocouple is charged with 2-[[(dimethylamino)methylene]amino]-4-ethoxy-5-nitrobenzoic acid, methyl ester (68 g, 230 mmol), t-butanol (500 mL) followed by t-butylcyanoacetate (65 g, 460 mmol). The reaction mixture is heated to reflux. After 4 hours the reaction is cooled to room temperature and the suspension is filtered. The filter cake is washed with heptane (2×100 mL) and dried under vacuum (50 mm Hg) at 40° C. to provide the title compound as a beige solid (83 g, 91% yield, >98% purity by NMR). 1H NMR (300 MHz, DMSO-d6): 12.7 (d, J=12.9 Hz, 1H), 8.77 (d, J=12.9 Hz, 1H), 8.50 (s, 1H), 7.47 (s, 1H), 4.37 (q, J=7 Hz, 2H), 3.91 (s, 3H), 1.52 (s, 9H), 1.40 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]=2[C:6](=[O:16])[C:5]2[C:17](=O)[C:18]3[C:23]([C:4]1=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:2].Cl.[NH2:26][OH:27]>C(N(CC)CC)C.C(O)C>[CH2:1]([N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]=2[C:6](=[O:16])[C:5]2[C:17](=[N:26][OH:27])[C:18]3[C:23]([C:4]1=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:2]
Reactant: NO
Reactant: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)C(=O)c1ccccc1-2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)C(=NO)c1ccccc1-2

Procedure:
5-Ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (300 mg, 0.95 mmol) was dissolved in a solution of hydroxylamine hydrochloride (525 mg, 7.6 mmol) and triethylamine (0.5 mL) in 20 mL of ethanol. The solution was refluxed overnight and then concentrated dryness. The residue was diluted with water and extracted with chloroform twice. The combined organic layers were washed with saturated sodium chloride solution, dried with sodium sulfate followed by evaporation to remove the solvent. The title compound was obtained by subjecting the resulting residue to silica gel-chromatography (chloroform:actone=20: 1) and then to crystallization from diethyl ether. 1H-NMR(CDCl3)δ 1.32(6H,d,CH(CH3)2, 1.73(3H,t,NCH2CH3), 3.03(1H,septet,CH), 4.79(2H,q,NCH2), 7.41-8.00(6H,m,Ar-H), 8.25(1H,s,H-9), 15.31(1H,s,N═OH)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([S:9][CH3:10])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][S:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:2]=2)[CH:8]=1
Reactant: CSc1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 66.7 %

Procedure:
2-Cyano-4-methylthiopyridine (2.36 g, 15.7 mmol) and methyl thiosalicylate (5.28 g, 31.4 mmol) were dissolved in toluene (100 ml), and triethylamine (9.9 ml, 70.7 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (3.00 g, 68%) as pale yellow crystals.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23].C(N(CC)CC)C>CC(N(C)C)=O>[CH3:21][Si:22]([C:25]#[C:26][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(I)cn2)CC1
Reactant: C#C[Si](C)(C)C
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#C[Si](C)(C)C)cn2)CC1
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
To a stirred solution of tert-butyl 4-(5-iodopyridin-2-yl)piperazine-1-carboxylate (1.0 g, 2.57 mmol, prepared as in Example 1), trimethylsilyl acetylene (0.73 mL, 5.14 mmol), triethylamine (1.11 mL, 7.71 mmol), and cuprous iodide (196 mg, 1.03 mmol) in DMA (20 mL) at 25° C. was added tetrakistriphenylphosphine palladium (0) (149 mg, 5 mol %). The reaction was stirred for 10 minutes. Volatiles were removed in vacuo. The residue was then dissolved in ethyl acetate (250 mL) and washed with water (100 mL). The layers were then separated and the aqueous phase extracted with ethyl acetate (250 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 10% EtOAc in hexanes) to give tert-butyl 4-{5-[(trimethylsilyl)ethynyl]pyridin-2-yl}piperazine-1-carboxylate as a pale brown solid (652 mg, 1.81 mmol, 70%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][CH2:11][S:12][C:13]([F:16])([F:15])[F:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1.N#N>[C:36]1([NH:35][C:17]([C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][CH2:11][S:12][C:13]([F:14])([F:15])[F:16])=[O:19])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCSC(F)(F)F)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CCSC(F)(F)F)C(=O)Nc1ccccc1
Yield: 67.6 %

Procedure:
N-Boc-trifluoromethionine (200 mg, 0.659 mmol) was dissolved in 6.6 ml of dry THF in the presence of N2, and the temperature was adjusted to −78° C. Subsequently, N-methylmorpholine (0.09 ml, 0.794 mmol) was added thereto, and the mixture was stirred. Two minutes later, isobutyl chloroformate (0.10 ml, 0.794 mmol) was added thereto, and the mixture was stirred for 2 minutes. Finally, aniline (0.07 ml, 0.794 mmol) was added thereto. TLC was performed to confirm disappearance of the starting compound, and the solid matters were filtered, followed by distillation of THF under reduced pressure. The residue was purified by column chromatography (hexane/ethyl acetate=80/20 then 70/30), thereby the product (168.6 mg, 65%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C@@H:15]([CH:16]=O)[CH2:14][C:13]([CH3:19])([CH3:18])[C:12]1=[O:20])[CH3:2].COP([CH2:28][C:29](=[O:39])[C:30]1[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1)(=O)OC.[Cl-].[Li+].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C@@H:15](/[CH:16]=[CH:28]/[C:29](=[O:39])[C:30]2[O:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=2)[CH2:14][C:13]([CH3:19])([CH3:18])[C:12]1=[O:20])[CH3:2]
Reactant: COP(=O)(CC(=O)c1ccc(C(F)(F)F)o1)OC
Reactant: CCOC(=O)CCCCCCN1C(=O)C(C)(C)C[C@@H]1C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCCCCCN1C(=O)C(C)(C)C[C@@H]1/C=C/C(=O)c1ccc(C(F)(F)F)o1
Temperature: 25 °C

Procedure:
To a stirred solution of 7-((R)-5-formyl-3,3-dimethyl-2-oxo-pyrrolidin-1-yl)-heptanoic acid ethyl ester. (360 mg, 1.21 mmol) and [2-oxo-2-(5-trifluoromethyl-furan-2-yl)-ethyl]-phosphonic acid dimethyl ester (344 mg, 1.21 mmol)(prepared from 5-trifluoromethyl-furan-2-carboxylic acid as described herein) in acetonitrile (14 mL), were added lithium chloride (62 mg, 1.21 mmol) and diisopropylethyl amine (0.214 mL, 1.21 mmol). The reaction flask was left stirring at room temperature over the weekend. The reaction was then quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was then washed with brine and dried over magnesium sulfate, and the crude was purified on silicagel column using hexane:ethyl acetate 2:1. Evaporation of the solvent gave 280 mg of 7-{(R)-3,3-dimethyl-2-oxo-5-[(E)-3-oxo-3-(5-trifluoromethyl-furan-2-yl)-propenyl]-pyrrolidin-1-yl}-heptanoic acid ethyl ester.
Reaction SMILES: Cl[C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[NH:11][C:12]([O:14]C(C)(C)C)=[O:13].C(OCC)C>C(Cl)(Cl)Cl>[O:13]1[C@H:2]2[C:10]3[C:5]([CH2:4][C@H:3]2[NH:11][C:12]1=[O:14])=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@H]1Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=C1N[C@@H]2Cc3ccccc3[C@@H]2O1
Yield: 92.6 %

Procedure:
A solution of (±) trans-1-chloro-2-tert-butoxycarbonylaminoindane (10.0 g, 0.037 mol) in chloroform (200 ml) was heated under reflux in an argon atmosphere for 23 h. The mixture was concentrated in vacuo to give a brown solid. Trituration with diethyl ether afforded the title compound as a beige solid (6.0 g, 92%) m.p. 205°-206° C. which was used without further purification.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]=[N:9][C:8]=1[C:19](=[O:21])[NH2:20].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([NH:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]=[N:9][C:8]=1[C:19](=[O:21])[NH:20][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC(=O)c1nnn(Cc2ccccc2)c1N
Reactant: O=C(Cl)c1ccccc1
Agent: O=S(=O)(O)O
Product: O=C(NC(=O)c1nnn(Cc2ccccc2)c1NC(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Concentrated sulphuric acid (1.5 ml.) was added dropwise, under anhydrous conditions, to an ice-cooled, stirred suspension of 5-amino-1benzyl-4-carbamoyl-1,2,3-triazole (2.17 g.; prepared as described by J. R. E. Hoover and A. R. Day, J.Amer.Chem.Soc., 1956, 78, 5832) in benzoyl chloride (24 ml.). Stirring was continued at room temperature overnight. The clear solution which formed was then poured into ice-water, the precipitated solid was filtered off, washed well with water and diethyl ether to give 5-benzamido-4-benzoylcarbamoyl-1-benzyl-1,2,3-triazole (1.8 g.), m.p. 171°-173° C., suitable for use in the next stage of the preparation. An aliquot was recrystallised from ethanol to give pure 5-benzamido-4-benzoylcarbamoyl-1-benzyl-1,2,3-triazole, m.p. 182°-186° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].[Cl:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[Cl:18].[OH-].[K+].O>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:19][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10]
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C)c(Oc2ccc(Cl)c(Cl)c2)c1C=O
Temperature: 150 °C
Yield: 54.8 %

Procedure:
5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (500.0 mg, 0.00315 mol), 3,4-dichlorophenol (565 mg, 0.00344 mol) and potassium hydroxide (265 mg, 0.00472 mol) were stirred in DMF (2.0 mL). Mixture was heated at 150° C. for 20 min using microwave. Water was added and resulting mixture was extracted with ethyl acetate. Organic layer was washed with brine twice, dried over MgSO4 and evaporated. The resulting oil was purified by column chromatography (10% to 20% ethyl acetate/heptane) to give 5-(3,4-dichlorophenoxy)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (492 mg, 54.7%) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:20][CH2:19][C:18]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:21]
Reactant: O=Cc1ccccc1Br
Reactant: NCC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(CNCc1ccccc1Br)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a stirring solution of 2-bromobenzaldehyde in dichloromethane (0.2 M) was added glycine benzyl ester (1.2 eq), sodium triacetoxyborohydride (2 eq) and acetic acid (4 eq). After stirring overnight, the solution was washed with 10% sodium carbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (silica; 30%-40% EtOAc/Hexanes) to afford a pale yellow oil. EI-MS m/z 334, 336 (M+H)+
Reaction SMILES: C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2(O)[CH2:34][CH2:33][CH:32]([CH:35]3[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][CH3:42])[CH2:36]3)[CH2:31][CH2:30]2)=[C:25]([F:44])[C:24]=1[F:45])[CH3:21]>O>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:34][CH2:33][CH:32]([CH:35]3[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][CH3:42])[CH2:36]3)[CH2:31][CH:30]=2)=[C:25]([F:44])[C:24]=1[F:45])[CH3:21]
Reactant: CCCC1CCC(C2CCC(O)(c3ccc(OCC)c(F)c3F)CC2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1CCC(C2CC=C(c3ccc(OCC)c(F)c3F)CC2)C1
Temperature: 25 °C
Yield: 82 %

Procedure:
Toluene (50 ml) and p-toluenesulfonic acid monohydrate (0.15 g) were added to 1-(4-ethoxy-2,3-difluorophenyl)-4-(3-propylcyclopentyl)cyclohexanol (5.0 g) obtained in the first step, in a reaction vessel equipped with a Dean-Stark apparatus under an atmosphere of nitrogen. The mixture was refluxed for 1.5 hour, while forming water was removed with a Dean-Stark apparatus. After the mixture had been cooled to room temperature, the reaction solution was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane=1/10 by volume) to give 1-ethoxy-2,3-difluoro-4-(4-(3-propylcyclopentyl)cyclohex-1-enyl)benzene (3.9 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([NH2:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:25][C:26]([CH3:28])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([NH:22][CH:26]([CH3:28])[CH3:25])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(N)c2ccncc2)CCN(C)C1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)c1c(n2CC(NC(C)C)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
2-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylamine (200 mg, 0.62 mmol) was dissolved in 15 mL DCM, acetone (108 mg, 1.87 mmol), acetic acid (0.5 mL) was added and the reaction mixture was stirred at RT overnight. Sodiumcyanoborohydride (117 mg, 1.87 mmol) was added and stirred at for 1 h. The reaction mixture was diluted with DCM (300 mL) and washed with saturated bicarbonate solution (200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 120 mg of [2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl]-isopropyl-amine as the TFA salt. 1H NMR (CD3OD, TFA salt): δ (ppm): 8.52 (m, 2H), 7.42 b (s, 2H), 7.30 b (s, 1H), 7.22 (s, 1H), 7.02 (m, 1H), 4.8 (m, 1H), 4.58 (m, 2H), 4.23 (t, 1H), 3.72 (m, 1H), 3.4 (m, 3H), 3.13 (m, 2H), 2.99 (d, 3H), 2.39 (s, 3H), 1.43 (d, 3H), 1.34 (d, 3H). Chiral HPLC separates the racemate into enantiomers II-10a-b.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:13]1[C:22]2[C:17](=[C:18]([CH:23]([CH3:27])[C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:24](=[O:25])[CH:23]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[CH:16]=[CH:15][N:14]=[CH:13]3)[CH3:27])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(tert-butyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 347 (M+H)+; MS (ESI−) m/z 345 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.56 (d, J 7.1, 3H), 4.22 (d, J 6.1, 2H), 4.57 (q, J 7.1, 1H), 7.10 (d, J 8.5, 2H), 7.29 (d, J 8.5, 2H), 7.98 (t, J 7.5, 1H), 8.13 (d, J 7.1, 1H), 8.34 (d, J 7.8, 1H), 8.56 (d, J 6.8, 1H), 8.69 (m, 2H), 9.78 (s, 1H); Anal. Calcd for C23H26N2O+1.1 HCl:C, 71.46; H, 7.07; N, 7.25. Found: C, 71.13; H, 7.17; N, 7.02.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[C:14]2[S:15][CH:16]=[C:17]([CH2:19][C:20]([OH:22])=O)[N:18]=2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:44]1[CH2:49][CH2:48][CH:47]([CH2:50][NH2:51])[CH2:46][CH2:45]1>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[C:14]2[S:15][CH:16]=[C:17]([CH2:19][C:20]([NH:51][CH2:50][CH:47]3[CH2:48][CH2:49][O:44][CH2:45][CH2:46]3)=[O:22])[N:18]=2)=[CH:4][CH:3]=1
Reactant: Cn1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: NCC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1-c1ccc(F)cc1
Yield: 65.3 %

Procedure:
A solution of the compound (225 mg, 0.709 mmol) obtained in step 5, WSC (204 mg, 1.06 mmol), HOBt (163 mg, 1.06 mmol), TEA (0.198 mL, 1.42 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (98.0 mg, 0.851 mmol) in DMF (2.8 mL) was stirred at 100° C. for 1 hr. The reaction solution was cooled, added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 1→10% methanol/ethyl acetate) to give the title compound (192 mg, 65%) as a yellow powder.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([O:16]C)=O)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=O)C.C(OCC)(=O)C.[OH-].[NH4+:25]>CO>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([NH2:25])=[O:16])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: [NH4+]
Reactant: COC(=O)Cc1ccc2c(ccn2C(C)=O)c1
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)Cc1ccc2[nH]ccc2c1

Procedure:
A solution of 1-acetyl-1H-indole-5-acetic acid, methyl ester (1.46 g) in methanol (10 ml) and conc. ammonium hydroxide (20 ml) was stirred at ambient temperature for 48 h. The resulting solution was poured into ethyl acetate (100 ml). The layers were separated and the aqueous layer was washed with ethyl acetate (3×50 ml) and chloroform (3×50 ml). The organic layers were dried (MgSO4) and the solvent was evaporated to give a solid (0.72 g). Crystallisation from ethyl acetate gave the title compound as a white solid, (0.3 g) m.p. 146°-7°.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].C([O:32]O)(C)(C)C>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Cr]>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[O:32])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: [Cr]
Agent: [C-]#[O+]
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
A second method of preparing βAET has been developed which also used 3β,17βdiacetoxyandrost-5-ene as a starting material as before. This compound was oxidized with t-butylhydroperoxide in the presence of chromium hexacarbonyl (Cr(CO)6) to form 3β,17β-diacetoxyandrost-5-en-7-one as described by Pearson [Pearson, et al., J. Chem Soc. Perkin Trans, I, 267 (1985)]. The enone formed then was reduced with triisobutylaluminum (TIBA) to give the acetylated 7β-hydroxy (I) product.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:4]([O:21][CH3:22])[CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:27](Cl)=[O:28]>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:27](=[O:28])[C:26]2[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=[C:24]([F:23])[CH:25]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1NCC(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1cc(F)c(F)cc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine and 3-fluoro-5-(trifluoromethyl)benzoic acid chloride (CAS RN 171243-30-4) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light yellow foam (39%). MS (ESI): m/z=509.091 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH2:12][CH3:13])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([N:21]2[C:11]([CH2:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:19][CH:18]=1
Reactant: CCC(=O)CCC(=O)c1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(Cl)cc2)n1-c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 80.8 %

Procedure:
A mixture of 1-(4-chlorophenyl)hexane-1,4-dione (2.10 g, 9.35 mmol, as obtained in Step-1), 4-chloro aniline (1.31 g, 10.29 mmol), and p-toluene sulfonic acid (0.321 g, 1.80 mmol) in toluene (5.0 ml) was refluxed over molecular sieves or using a Dean Stark apparatus. The progress of the reaction was monitored by TLC and after three hours, toluene was removed under reduced pressure. The residue was dissolved in ethyl acetate (200 ml), washed with aqueous sodium bicarbonate solution (2×75 ml), followed by washing with water (2×50 ml) and brine (1×25 ml). The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent evaporated off. The solid so obtained was washed with hexane to give 2.39 g (81%) of the title compound.