Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:37])([C:6](=[O:36])[C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[N:14]=2)[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:8]=1)[CH2:3][CH:4]=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:1][C:2]([CH3:37])([CH2:3][CH2:4][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:6]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)[N:14]=2)[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:33])[CH3:34])[CH:8]=1)=[O:36]
Reactant: COc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)CC=O)cn3COCC[Si](C)(C)C)cc(OC)c1OC
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)CCN2CCOCC2)cn3COCC[Si](C)(C)C)cc(OC)c1OC
Reaction time: 15 h
Yield: 13.1 %

Procedure:
A mixture of crude 3,3-dimethyl-4-oxo-4-[2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butyraldehyde (0.161 g, 0.305 mmol), morpholine (0.029 mL, 0.34 mmol), and sodium triacetoxyborohydride (0.129 g, 0.610 mmol) in 3 mL of 1,2-dichloroethane was stirred for 15 h. A sat. aq. NaHCO3 solution (10 mL) was added, and the mixture stirred for 10 min. The layers were separated, and the aqueous layer was extracted with two 20 mL portions of ethyl acetate. The three combined organic layers were dried over MgSO4, filtered, and concentrated to a residue. Column chromatography (0→10% MeOH/CH2Cl2) afforded 0.024 g (13%) of 2,2-dimethyl-4-morpholin-4-yl-1-[2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butan-1-one as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:11]([C:12]3[C:13](=[O:19])[NH:14][C:15](=[O:18])[NH:16][CH:17]=3)[C:10]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1.I[CH3:26]>>[CH3:26][N:16]1[CH:17]=[C:12]([CH:11]2[C:4]3[O:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=[CH:8][C:9]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:10]2=3)[C:13](=[O:19])[NH:14][C:15]1=[O:18]
Reactant: Cc1ccc2c(c1)C=Cc1nc(C)oc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: CI
Product: Cc1ccc2c(c1)C=Cc1nc(C)oc1C2c1cn(C)c(=O)[nH]c1=O

Procedure:
The title compound was prepared from the product of example 13 step (vii) (0.66 g) and iodomethane (0.49 ml) according to the method of example 1 step (viii). Purification was by chromatography eluting with 5% methanol in dichloromethane.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:36])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:35])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:34])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:33])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH2:3][CH2:4][OH:5].[C:37](OC(=O)C)(=[O:39])[CH3:38].O>N1C=CC=CC=1>[C:37]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:36])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:35])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:34])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:33])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)CCO
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCC(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Reaction time: 1 h

Procedure:
3.5 g of 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenol was dissolved in 20 ml of pyridine, and 10 ml of acetic anhydride was added. After 20 g of iced water was added, the solution was stirred for one hour and extraction was then made using 100 ml of n-hexane. The extract was washed with 1N hydrochloric acid and then with water, dried and concentrated. The concentrate was refined by silica gel column chromatography, providing 3 g of the captioned 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenyl acetate in a colorless oily form.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]([CH3:33])=[C:24]([CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:25]=2)=[CH:17][CH:16]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][C:23]([CH3:33])=[C:24]([CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[N:25]=3)=[CH:17][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1oc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)nc1CCN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 35 starting from 3-Methylsulfonylbenzene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 411.1 (M+1)
Reaction SMILES: [CH3:1][C:2](=[CH2:9])[CH2:3][CH:4]([CH2:7][OH:8])[CH2:5][OH:6]>ClCCl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:9][C:2]1([CH3:1])[O:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3]1
Reactant: C=C(C)CC(CO)CO
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC(CO)CO1
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-(2-methylallyl)propane-1,3-diol (2.00 g) and silver trifluoromethanesulfonate (197 mg) in dichloromethane (40 mL) was stirred at 80° C. for 2 days. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure to give the title compound (2.00 g) as a brown oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][C:13](OC)=[O:14])=[CH:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][OH:14])=[CH:3]1
Reactant: COC(=O)CCc1cn(C)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cn1cc(CCCO)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
To a solution of methyl 3-(1-methyl-3-indolyl)propionate (300 mg, 1.38 mmol) in Et2O (3.0 mL) was added LiAlH4 at 0° C. under N2 atmosphere. The reaction mixture was stirred for 30 min at 0° C. and quenched by careful addition of H2O. EtOAc was added to the quenched reaction mixture. The organic layer was separated, washed with brine and dried over MgSO4. It was then concentrated in vacuo and chromatographed on a silica gel column by elution with EtOAc/Hexanes to give 3-(1-methyl-3-indolyl)-1-propanol (250 mg, 96%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ1.28 (t, 1H, J=6.2 Hz), 1.98 (qu, 2H, J=7.7 Hz), 2.85 (t, 2H, J=7.3 Hz), 3.70-3.78 (m, 4H), 6.86 (s, 1H), 7.10 (dt, 1H, J=1.1, 7.0 Hz), 7.22 (dt, 1H, J=1.1, 7.5 Hz), 7.29 (d, 1H, J=8.1 Hz), 7.60 (d, 1H, J=7.7 Hz) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:11])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[CH:20]([Si:23](OS(C(F)(F)F)(=O)=O)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[O:11][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:20]([CH3:22])[CH3:21])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: OC1CCc2ccc(Br)cc21
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)[Si](OC1CCc2ccc(Br)cc21)(C(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
To 6-Bromo-2,3-dihydro-1H-inden-1-ol (300 mg, 1.41 mmol) in CH2Cl2 (4 mL) was added 2,6-lutidine (151 μL, 1.41 mmol) followed by triisopropylsilyltriflate (378 μL, 1.41 mmol) at room temperature. The reaction was stirred for 30 min then added to 1N HCl and extracted. The organic layer was washed with saturated sodium bicarbonate then brine and dried over MgSO4. The solvent was removed in vacuo and the crude material purified by column chromatography.
Reaction SMILES: N([O-])=O.[Na+].C(O)(=O)C.[F:9][C:10]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:11]=1N.O.[BrH:19]>S(=O)(=O)(O)O.[Cu]Br>[Br:19][C:11]1[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:10]=1[F:9]
Reactant: Br
Reactant: Nc1ccc(I)cc1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Fc1cc(I)ccc1Br
Reaction time: 1 h

Procedure:
51.2 g of sodium nitrite was dissolved in 390 ml of sulfuric acid, and 454 ml of acetic acid was added thereto at 10° C. or lower. The solution was kept at 20° to 25° C., and 124 g of 2-fluoro-4-iodoaniline was added thereto over a period of one hour and stirred for 2 hours. The solution was dropwise added to a solution of 130 g of copper(I) bromide as dissolved in 390 ml of 48% hydrobromic acid and stirred overnight. Next, 1000 ml of water was added to this, which was then extracted with chloroform and washed three times with water. Chloroform was removed by distillation, and the residue was distilled under reduced pressure (b.p. 120° to 125° C./13 mmHg) and recrystallized from methanol to obtain 114 g of 1-bromo-2-fluoro-4-iodobenzene.
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([N:14]([CH2:26][C:27]([OH:29])=[O:28])[CH2:15][CH2:16][N:17]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][C:19]([OH:21])=[O:20])[CH2:4][N:5]([CH2:10][C:11]([OH:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8].N(CC(O)=O)(CC(O)=O)CC(O)=O>O>[CH2:15]([N:14]([CH2:26][C:27]([O-:29])=[O:28])[CH2:3][CH2:4][N:5]([CH2:6][C:7]([O-:9])=[O:8])[CH2:10][C:11]([O-:13])=[O:12])[CH2:16][N:17]([CH2:22][C:23]([O-:25])=[O:24])[CH2:18][C:19]([O-:21])=[O:20].[Na+:2].[Na+:2].[Na+:2].[Na+:2].[Na+:2]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Agent: O=C(O)CN(CC(=O)O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CCN(CC(=O)[O-])CC(=O)[O-]
Yield: 40 %

Procedure:
A 40% aqueous pentasodium diethylenetriaminepentaacetate solution was prepared by mixing together sodium hydroxide, deionized water and the diethylenetriaminepentaacetic acid (as obtained in Example 1) having the reduced total content of the nitrilotriacetic acid (salt).
Reaction SMILES: [NH2:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[N:9]([CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]=[O:11]>O1CCOCC1>[O:8]=[C:3]1[NH:4][C:5](=[O:7])[CH2:6][N:2]1[NH:1][C:10]([NH:9][CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11]
Reactant: CCOC(=O)C(N=C=O)c1ccccc1
Reactant: NN1CC(=O)NC1=O
Solvent: C1COCCO1
Product: CCOC(=O)C(NC(=O)NN1CC(=O)NC1=O)c1ccccc1
Temperature: 25 °C

Procedure:
1.15 g. (0.01 mol.) of 1-amino-2,4-dioxoimidazolidine are dissolved in 50 ml. of dioxane while heating. The solution is permitted to cool to room temperature while stirring, wherein a portion of the 1-amino-2,4-dioxoimidazolidine crystallizes out. 2.05 g. (0.01 mol.) of α-isocyanatobenzeneacetic acid, ethyl ester are added and the reation mixture is stirred overnight at room temperature. On the next day the mixture is concentrated and the residue is triturated with ether. 3.0 g. of α-[[[(2,4-dioxo-1-imidazolidinyl)amino]-carbonyl] amino]benzeneacetic acid, ethyl ester are obtained, m.p. 148°-151°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:17])([CH3:16])[CH2:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.[I-].[CH3:19][S+](C)(C)=O.[H-].[Na+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:17])([CH3:16])[CH2:9][C:10]2([C:11]([F:13])([F:14])[F:12])[CH2:19][O:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cccc(Br)c1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(CC1(C(F)(F)F)CO1)c1cccc(Br)c1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3-bromophenyl)-1,1,1-trifluoro-4-methylpentan-2-one (68 mg, 2.2 mmol) in 2.9 mL of anhydrous DMSO was added over 5 minutes a solution the ylide of trimethylsulfoxonium iodide (3.3 mL of a 0.8M DMSO solution prepared from 2.66 g (12.1 mmol) of trimethylsulfoxonium iodide in 15 mL of anhydrous DMSO and 483 mg of 60% NaH in mineral oil (12.1 mmol) added in portions and aged for 30 minutes). The mixture stirred 2 hours and quenched with water and ethyl acetate. The organic phase was washed with water and brine, and dried over sodium sulfate. Removal of the volatiles in vacuo afforded the yellow oil 2-[2-(3-bromophenyl)-2-methylpropyl]-2-trifluoromethyloxirane which was used without further purification.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[C:15]([OH:18])(=[O:17])[CH3:16].O[CH2:20][C@@:21]12[C@@H:38]3[C@H:29]([C@H:30]4[C@@:34]([CH2:36][CH2:37]3)([CH3:35])[C:33](=[O:39])[CH2:32][CH2:31]4)[CH2:28][CH2:27][C:26]1=[CH:25][C:24](=[O:40])[CH2:23][CH2:22]2.[OH-].[Na+].OO.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:15]([O:18][CH2:20][C@@:21]12[C@@H:38]3[C@H:29]([C@H:30]4[C@@:34]([CH2:36][CH2:37]3)([CH3:35])[C@@H:33]([OH:39])[CH2:32][CH2:31]4)[CH2:28][CH2:27][C:26]1=[CH:25][C@H:24]([OH:40])[CH2:23][CH2:22]2)(=[O:17])[CH3:16]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Reactant: CC(=O)O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=C([O-])[O-]
Agent: OO
Solvent: C1CCOC1
Product: CC(=O)OC[C@]12CC[C@@H](O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1 M solution of lithium tri-sec-butylborohydride in tetrahydrofuran under nitrogen is cooled in a dry iceacetone bath to about -78° C. and 19-hydroxyandrost-4-ene-3,17-dione acetate in tetrahydrofuran is slowly added. The reaction mixture is stirred for a period of 2 hours at this temperature, warmed to 0° C., and stirring continued for an additional two hours. The reaction mixture is decomposed by the addition of 3 N sodium hydroxide followed by the addition of a 30% hydrogen peroxide solution. Care is taken that the solution temperature remains below 10° C. during decomposition. Solid potassium carbonate is added and the tetrahydrofuran decanted. The solid residue is washed with tetrahydrofuran and the combined solutions are dried over sodium sulfate, filtered and evaporated. The residue which remains is crystallized from acetone to yield 4-androstene-3α,17β,19-triol 19-acetate.
Reaction SMILES: C[N:2]([CH3:20])/[CH:3]=[C:4](/[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1F)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28](N)C)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[I:17][C:15]1[CH:16]=[C:11]2[C:12](=[CH:13][CH:14]=1)[N:2]([CH2:20][CH2:28][CH:25]1[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]1)[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]2=[O:19]
Reactant: CC(N)C1CCN(C)CC1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(CCC2CCN(C)CC2)c2ccc(I)cc2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (Intermediate 24, 1 g, 2.56 mmol) dissolved in THF (5.5 mL) was added 2-(1-methylpiperidin-4-yl-ethanamine (0.406 mL, 2.56 mmol). The reaction mixture was stirred at 60° C. for 2 h. Potassium carbonate was added (1.06 g, 7.67 mmol), and the reaction was stirred for 18 h and cooled down to room temperature. The reaction was quenched with 1 N HCl and partitioned between dichloromethane (10 mL) and water (20 mL). The aqueous layer was extracted with dichloromethane (2×10 mL), and the organics were dried over sodium sulfate and concentrated to give ethyl 6-iodo-1-(2-(1-methylpiperidin-4-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as a light yellow solid (1.08 g, 90%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:25]2[CH2:29][CH2:28][CH2:27][S:26]2(=[O:31])=[O:30])[CH:3]=1.[CH2:32]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1)[CH3:33]>>[O:30]=[S:26]1(=[O:31])[CH2:27][CH2:28][CH2:29][N:25]1[C:4]1[CH:3]=[C:2]([N:35]2[C@H:34]([CH2:32][CH3:33])[CH2:38][O:37][C:36]2=[O:39])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: CC[C@@H]1COC(=O)N1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CC)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 84.8 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (507 mg) described in Preparation Example 180 and (R)-4-ethyloxazolidin-2-one (138 mg) described in Preparation Example 26, the title compound (459 mg) was obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.[Br:10][C:11]1[N:16]=[C:15](Br)[C:14]([C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:13][N:12]=1>CCO>[Br:10][C:11]1[N:16]=[C:15]([NH:9][C:7]2[CH:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:5][N:6]=2)[C:14]([C:18]#[C:19][Si:20]([CH3:21])([CH3:23])[CH3:22])=[CH:13][N:12]=1
Reactant: C[Si](C)(C)C#Cc1cnc(Br)nc1Br
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: CCO
Product: C[Si](C)(C)C#Cc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Reaction time: 12 h
Yield: 39.9 %

Procedure:
(Step 4) A solution of 3-cyclopropyl-1H-pyrazol-5-amine (12.241 g, 99.39 mmol, 1.5 equiv.) in EtOH was added to a solution of compound 2,4-dibromo-5-((trimethylsilyl)ethynyl) pyrimidine (22.136 g, 66.26 mmol,) in EtOH (220 mL) at 20° C. After 12 h, EtOH was evaporated under reduce pressure. The residue was purified by silica-gel column chromatography (mobile phase: petroleum ether/ethyl acetate=20/1˜5/1) to afford solid product 2-Bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethylsilyl)ethynyl) pyrimidin-4-amine (9.948 g, 40%). LC-MS (m/z)=377.0 [M+H]+.
Reaction SMILES: O=P(Cl)(Cl)Cl.[NH2:6][C:7]1[S:11][N:10]=[C:9]([C:12]([NH2:14])=O)[C:8]=1[C:15]([NH2:17])=O.[CH3:18][N:19]([CH3:22])[CH:20]=O>>[CH3:18][N:19]([CH3:22])[CH:20]=[N:6][C:7]1[S:11][N:10]=[C:9]([C:12]#[N:14])[C:8]=1[C:15]#[N:17]
Reactant: CN(C)C=O
Reactant: NC(=O)c1nsc(N)c1C(N)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=Nc1snc(C#N)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
10.1 parts of phosphorus oxytrichloride are added dropwise to 30 parts of dimethylformamide at 0° C., and the mixture is then stirred for a further 0.5 hour at this temperature. 3.7 parts of 5-aminoisothiazole-3,4-dicarboxamide are then introduced, a little at a time, into this solution while cooling with ice. The mixture is stirred for a further 2 hours at room temperature, after which it is poured into 100 parts of ice water. The precipitate is filtered off under suction, washed with water and dried to give 3.8 parts (93% of theory) of N,N-dimethyl-N'-(3,4-dicyanoisothiazol-5-yl)-formamidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][C:18](OCC)=[O:19].B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][OH:19]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2c(Br)cccc12
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of EXAMPLE 1A (1.85 g) in THF (50 mL) was added 1M borane•THF (30 mL). The mixture was stirred at room temperature for 16 hours, quenched with methanol (10 mL) and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5-25% ethyl acetate/hexanes.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])=[CH:17][CH:16]=1.NN>C(O)C>[NH2:3][CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][CH:35]=3)=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])=[CH:17][CH:16]=1
Reactant: O=C(Nc1ccc(/C=C/CN2C(=O)c3ccccc3C2=O)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: NN
Solvent: CCO
Product: NC/C=C/c1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)cc1
Yield: 126.1 %

Procedure:
A mixture of intermediate (2) (0.005 mol) and an aqueous hydrazine solution (0.005 mol) in ethanol (30 ml) was stirred and refluxed for 2 hours. The precipitate was filtered and washed with ethanol. Water was added. The suspension was basified with NaOH and filtered over celite. Celite was washed with ethyl acetate. The filtrate was extracted with ethyl acetate and washed with K2CO3, then with NaCl. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried, yielding 2.5 g of N-[4-[(1E)-3-amino-1-propenyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 3; mp. 190° C.).
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17]C.C[C:22]1(C)[O:29][C:27](=[O:28])[CH2:26][C:24](=[O:25])O1.N1C=CC=CC=1>C(Cl)Cl>[O:25]=[C:24]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:26][C:27]([O:29][CH3:22])=[O:28]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)CC(=O)OC
Temperature: 25 °C
Yield: 87.1 %

Procedure:
Linoleoyl chloride (25.0 g, 83.6 mmol) was added, dropwise, to a cooled (0° C.) solution of Meldrum's acid (1) (13.3 g, 92.0 mol) and pyridine (14.8 mL, 184 mmol) in CH2Cl2 (180 mL) and the solution was allowed to warm (rt, 16 h). The reaction mixture was washed with an equal volume of HCl (5%, aq., 2×), dried (Na2SO4), filtered and concentrated. The residue was dissolved in dry methanol (200 mL) and heated at reflux (6 h). The solution was cooled (rt), concentrated and the crude oil was purified by flash chromatography (4% EtOAc-hexanes) to yield (11Z,14Z)-methyl 3-oxoicosa-11,14-dienoate (2) (24.5 g, 87%) as a pale yellow oil. Rf 0.38 (10% EtOAc-hexanes). FW 336.51, C21H36O3.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[CH3:22][C:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH3:22][C:23]1([N:26]=[C:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:5]([CH2:4][CH2:3][C@:2]23[CH3:1])[C@:15]2([CH3:21])[C:14]([CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16]2)=[CH:13][CH2:12]4)[CH2:25][CH2:24]1
Reactant: CC1(N)CC1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: CC1(N=C2CC[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]23C)CC1

Procedure:
Reaction of dehydroepiandrosterone with 1-methylcyclopropylamine according to the procedure described in Example 1 gives 17-(1-methylcyclopropylimino)androst-5-en-3β-ol. This is then reduced with sodium borohydride according to the procedure in Example 2 to give 17β-(1-methylcyclopropylamino)androst-5-en-3β-ol.