Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26](O)=[O:27])[CH:22]=[CH:23][CH:24]=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.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[Br:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26]([NH:17]/[N:16]=[C:7]2\[NH:8][C:9](=[O:15])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:6]\2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCn1/c(=N/NC(=O)Cc2cccc(Br)c2)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
The mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (0.30 g, 1.3 mmol), (3-bromophenyl)acetic acid (0.30 g, 1.4 mmol), benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (0.62 g, 1.4 mol) and triethylamine (0.53 mL, 3.8 mmol) in DMF (10 mL) were stirred at rt overnight. The reaction mixture was diluted with EtOAc. The solid was filtered, washed with EA and dried to yield the desired product (430 mg, 78.2%). LCMS calculated for C18H22BrN6O2 (M+H): 433.1. found: 433.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][NH2:5].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.C(Cl)Cl>[CH2:13]([NH:5][CH2:4][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:12])[CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)C(CN)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)C(CNCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 3-methyl-2-phenyl-butylamine (1.3 g, 8 mmol), benzaldehyde (271 μL, 2.66 mmol) and CH2Cl2 (50 mL) is stirred for 20 min at RT. NaBH(OAc)3 (840 mg, 3.96 mmol) and acetic acid (154 μL, 2.69 mmol) are added. After 2 h the same amounts as indicated above of benzaldehyde, NaBH(OAc)3 and acetic acid are added once again. This procedure is repeated after 4 h. After stirring for 16 h at RT, saturated NaHCO3 solution is added, the CH2Cl2 layer is removed and the aqueous phase is extracted twice with fresh CH2Cl2. The combined organic layers are dried (Na2SO4), evaporated in vacuo and the residue is purified by flash chromatography (hexane/ethyl acetate). The combined pure fractions are evaporated to afford the title compound as a colourless oil. MS: 254.3 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.03 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[CH:4][CH:3]=1.[C:33]([NH2:41])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C=O.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:33])[C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[CH:4][CH:3]=1.[C:33]([NH2:41])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CCCC[C@@H]1NCc1ccc(Cl)cc1
Agent: C=O
Agent: NC(=O)c1ccccc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CN(Cc1ccc(Cl)cc1)[C@H]1CCCC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 93 %

Procedure:
The title benzamide from Example 1 (21 mg) was dissolved in THF prior to the addition of Hunigs's base (0.01 mL). Next, 37% formaldehyde (0.017 mL) was added along with 4A molecular sieves. After 3 h, NaHB(OAc)3 (38 mg) was added. This mixture was stirred an additional 2 h before the reaction was quenched-with NaHCO3 solution. This was extracted with EtOAc. The EtOAc was dried and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title benzamide N-[2-[[(1S,2S)-2-[(4-chlorobenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide (10 mg). MS found: (M+H)+=482.3.
Reaction SMILES: FC1C=C2C(=CC=1)C=NC([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=O)=[O:14])=C2.[F:20][C:21]1[C:30]2[CH:29]=[N:28][C:27]([OH:31])=[CH:26][C:25]=2[C:24]([C:32]#[N:33])=[CH:23][CH:22]=1>>[C:32]([C:24]1[CH:23]=[CH:22][C:21]([F:20])=[C:30]2[C:25]=1[CH:26]=[C:27]([O:31][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:14])=[O:12])[N:28]=[CH:29]2)#[N:33]
Reactant: N#Cc1ccc(F)c2cnc(O)cc12
Reactant: O=S(=O)(Oc1cc2cc(F)ccc2cn1)C(F)(F)F
Product: N#Cc1ccc(F)c2cnc(OS(=O)(=O)C(F)(F)F)cc12

Procedure:
Following the procedure for trifluoromethanesulfonic acid 6-fluoroisoquinolin-3-yl ester, using 8-fluoro-3-hydroxyisoquinoline-5-carbonitrile in place of 6-fluoroisoquinolin-3-ol, the title compound was obtained as a yellow solid. MS (ES+): m/z=321.06 [MH+]. HPLC: tR=3.58 min (ZQ2, polar—5 min).
Reaction SMILES: [CH2:1]([O:4][C:5]([CH3:9])([CH3:8])[CH2:6][OH:7])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:18])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:8][C:5]([O:4][CH2:1][CH:2]1[CH2:3][O:18]1)([CH3:9])[CH2:6][OH:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOC(C)(C)CO
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(CO)OCC1CO1
Temperature: 0 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A solution of 2-allyloxy-2-methyl-propionic acid ethyl ester (1.72 g, 10 mmol) in anhydrous tetrahydrofuran (40 mL) was stirred at room temperature under nitrogen. Lithium borohydride (44 mg, 20 mmol) was added portion-wise and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was cooled to 0° C. and saturated ammonium chloride solution was cautiously added followed by hydrochloric acid (2 M) to acidify the reaction mixture to pH 2. The mixture was extracted with diethyl ether and the organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford 2-allyloxy-2-methyl-propan-1-ol (10 mmol) which was used crude in the next step. LCMS (m/z) 153.2 [M+Na], Tr=1.16 min. A suspension of 2-allyloxy-2-methyl-propan-1-ol (10 mmol) in dichloromethane (40 mL) was stirred at 0° C. Meta-chloroperbenzoic acid (70% pure containing 20% water and 10% meta-chlorobenzoic acid, 2.9 g, 12 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 24 h. The reaction mixture was cooled to 0° C. and saturated sodium hydrogen carbonate solution and sodium thiosulfate solution were added and the mixture was stirred at 0° C. for 15 min. The organic layer was separated and the aqueous layer was extracted with dichloromethane (4×). The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford 2-methyl-2-oxiranylmethoxy-propan-1-ol (10 mmol) which was used crude in the next step. LCMS (m/z) 169.2 [M+Na], Tr=0.72 min. A solution of 2-methyl-2-oxiranylmethoxy-propan-1-ol (10 mmol) in dichloromethane (50 mL) and racemic camphor-10-sulfonic acid (765 mg, 3.3 mmol) was stirred at room temperature for 18 h. Saturated sodium hydrogen carbonate solution was added and the organic layer separated. The aqueous layer was extracted with dichloromethane and the organic extracts were combined, filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 2:3 to 1:4 to afford the title compound (826 mg, 57% over 3 steps) as a yellow oil. 1H NMR (300 MHz, d6-DMSO): δ 1.02 (s, 3H), 1.20 (s, 3H), 3.23 (d, J=11.1 Hz, 1H), 3.30-3.50 (m, 6H), 4.68 (t, J=5.4 Hz, 1H). LCMS (m/z) 169.2 [M+Na], Tr=0.72 min.
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.[CH3:14][CH:15]1[C:28]2[C:19](=[C:20]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][CH2:22][O:21]3)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH:15]([CH3:14])[C:28]4[C:19](=[C:20]5[C:25](=[CH:26][CH:27]=4)[O:24][CH2:23][CH2:22][O:21]5)[CH2:18][CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c1ccc1c2OCCO1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc3c(c2CCN1C(=O)c1cc2ncc(Br)cn2n1)OCCO3

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-Methyl-2,3,5,6,7,8-hexahydro-1,4-dioxa-7-aza-phenanthrene to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1.[Cl:24][C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1>>[O:9]=[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][CH2:11]1)[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:30]([C:28]2[S:29][C:25]([Cl:24])=[CH:26][CH:27]=2)=[O:31])[S:3][CH:4]=1
Reactant: Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1
Reactant: O=C(O)c1ccc(Cl)s1
Product: O=C(Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1)c1ccc(Cl)s1

Procedure:
37.5 Using general procedure D, 2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone was coupled with 5-chlorothiophene-2-carboxylic acid to give 5-chloro-thiophene-2-carboxylic acid (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide. Light yellow amorphous solid. MS 482.4 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[C:9]2[N:10]([N:15]=[CH:16][CH:17]=2)[C:11](I)=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[C:9]2[N:10]([N:15]=[CH:16][CH:17]=2)[C:11]([C:19]#[N:20])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)n2nccc12
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)Nc1ccc(C#N)n2nccc12
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 93 %

Procedure:
A mixture of (7-iodo-pyrazolo[1,5-a]pyridin-4-yl)-carbamic acid tert-butyl ester (36 mg, 0.1 mmol), zinc cyanide (24 mg, 0.2 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), and anhydrous DMF (1 mL) was degassed with argon. Then, the mixture was stirred at 80° C. for 4.5 h, cooled to rt, mixed with EtOAc (6 mL), and filtered. The filtrate was concentrated under reduced pressure. Purification by silica gel flash chomatography eluting with EtOAc/heptane (gradient from 1:4 to 1:2 ratio) gave compound 777E (24 mg, 93%) as a white solid. HPLC: 93% at 3.64 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10–90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 259 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16](Br)[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][N:10]3[CH:20]=[CH:21][CH:22]=[C:9]23)[CH2:4][CH2:3]1.C1C=CC=CC=1.[C-:29]#[N:30].[Na+].O>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([C:29]#[N:30])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][N:10]3[CH:20]=[CH:21][CH:22]=[C:9]23)[CH2:4][CH2:3]1
Reactant: [C-]#N
Reactant: CN1CCC(=C2c3cc(Br)ccc3C=Cn3cccc32)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O
Product: CN1CCC(=C2c3cc(C#N)ccc3C=Cn3cccc32)CC1
Reaction time: 1 h
Yield: 87 %

Procedure:
1-Methyl-4-(9-bromo-11H-pyrrolo[2,1-b][3]benzazepin-11-ylidene)piperidine (6.3 g, 0.019 mole) and cuprous cyanide (3.2 g, 0.035 mole) in 25 ml of dry dimethylformamide are refluxed under nitrogen for five hours. The mixture is cooled to an internal temperature of 50° and treated with 60 ml each of benzene and aqueous saturated sodium cyanide solution. After stirring one hour the contents are transferred to a separatory funnel with the aid of additional benzene and water. The aqueous phase is extracted two times with benzene, once with ether and the combined benzene-ether extracts are washed successively with dilute sodium cyanide, water, dilute ammonium hydroxide, and water. Upon drying over sodium sulfate the solvents are evaporated in vacuo to give 1-methyl-4-(9-cyano-11H-pyrrolo[2,1-b][3]benzazepin-11-ylidene)piperidine as an oil (5.0 g, 87%). Trituration with acetonitrile gives a solid (3.6 g, m.p. 156°-159°). An analytical sample is obtained after one recystallization from acetonitrile, m.p. 158°-161°.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.[CH2:18]([S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21])[CH3:19].C(N(CC)CC)C>C(#N)C>[CH2:18]([S:20]([N:23]1[CH2:24][CH2:25][N:26]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:6]=[N:5][N:4]=2)[CH2:27][CH2:28]1)(=[O:22])=[O:21])[CH3:19]
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: FC(F)(F)c1ccc(-n2nnnc2CCl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCS(=O)(=O)N1CCN(Cc2nnnn2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
5-(Chloromethyl)-1-[4-(trifluoromethyl)phenyl]-1H-tetrazole (79 mg, 0.301 mmol, commercially available from UkrOrgSynthesis, Kiev, Ukraine) and 1-(ethylsulfonyl)piperazine (53.6 mg, 0.301 mmol, Sigma-Aldrich) were dissolved in acetonitrile (1.5 ml). Triethylamine (0.046 ml, 0.331 mmol) was added, and the mixture was heated at 120° C. in a microwave with stirring for 20 min. The reaction mixture was concentrated in vacuo and the residue was purified by high pH MDAP to yield the title compound as a colourless solid (89 mg).
Reaction SMILES: C[C@]12CC[C@H]3[C@@H](C=CC4[C@]3(C)CCC(=O)C=4)[C@@H]1CCC2=O.CC(C)=O.[OH:26][C@H:27]1[C@@:43]2([CH3:44])[C@@H:39]([CH2:40][CH2:41][C:42]2=[O:45])[C@H:38]2[C@@H:29]([C@:30]3([CH3:47])[C:35]([CH2:36][CH2:37]2)=[CH:34][C:33](=[O:46])[CH2:32][CH2:31]3)[CH2:28]1>CCCCCC.C(OCC)(=O)C>[OH:26][C@H:27]1[C@@:43]2([CH3:44])[C@@H:39]([CH2:40][CH2:41][C:42]2=[O:45])[C@H:38]2[C@@H:29]([C@:30]3([CH3:47])[C:35]([CH:36]=[CH:37]2)=[CH:34][C:33](=[O:46])[CH2:32][CH2:31]3)[CH2:28]1
Reactant: C[C@@]12C(=O)CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(C)[C@H]1C[C@H]2O
Agent: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C[C@@]12C(=O)CC[C@H]1[C@@H]1C=CC3=CC(=O)CC[C@]3(C)[C@H]1C[C@H]2O

Procedure:
Product C is seen to contain compounds of low polarity. A portion (26 g) is chromatographed on silica gel using a gradient of acetone in chloroform to separate the components. From the eluate comprising 10% acetone a fraction containing IV is obtained. This is re-chromatographed on silica gel with equal parts of hexane and ethyl acetate as eluent and provides a fraction which on recrystallising the product from aqueous ethanol gives pure IV, seen to be androsta-4,6-diene-3,17-dione, melting point 171.5°-172.5° C. (0.65 g). Similarly an eluate comprising 15% acetone is seen to contain a mixture of products, V and VI. On re-chromatography as above with hexane-ethyl acetate the compound V elutes first and on recrystallising this product from aqueous ethanol gives pure V, shown to be 12β-hydroxyandrost-4-ene-3,17-dione, melting point 169°-70° C. (8.2 g). The product VI elutes soon after and on recrystallising the product from aqueous ethanol gives pure VI, 12β-hydroxyandrosta-4,6-diene-3,17-dione, melting point 195°-6° C. (0.75 g). Similarly, an eluate comprising 20-25% acetone is seen to contain a mixture of II and VII. On re-chromatography as before, component II elutes first and then VII. On recovering this latter component and re-crystallising from aqueous ethanol gives pure VII, seen to be 12α-hydroxyandrosta-1,4-diene-3,17-dione melting point 202°-3° C. (0.34 g). Similarly the eluate comprising 30-35% acetone is seen to contain III and VIII. On re-chromatography of this product with ethyl acetate-hexane the first component eluting is VIII. On recovering this product and recrystallising from aqueous ethanol pure VIII is obtained, shown to be 7α-hydroxyandrost-4-ene-3,17-dione melting point 248°-50° C. (0.22 g). Similarly the eluate comprising 35-40% acetone is seen to contain IX and X, eluting separately. The first product is recovered and on recrystallising from aqueous ethanol pure IX is obtained shown to be 12β,17β-dihydroxyandrost-4-ene-3,17-dione melting point 118°-19° C. (1.6 g). The second product is also recovered and on recrystallising from aqueous ethanol pure X is obtained, shown to be 12β,17β-dihydroxyandrosta-1,4-diene-3-one, melting point 174°-5° C. (0.79 g).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1.Br[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]([C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1)[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]
Reactant: CN[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Reactant: N#Cc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(c1cccc(C#N)c1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 25 °C

Procedure:
Under N2, a mixture of (R)—N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (50 mg, 0.14 mmol), 3-bromobenzonitrile (39 mg, 0.21 mmol), Pd2(dba)3 (1 mg, 0.002 mmol), BINAP (5 mg, 0.008 mmol) and t-BuONa (27 mg, 0.28 mmol) in toluene (2 mL) was stirred at reflux for 6 hour, cooled to ambient temperature, diluted with EtOAc (50 mL), washed with brine (3×10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=20:1) to give the title compound. MS (m/z): 449 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([NH:12][CH2:13][C:14]#[CH:15])(=[O:11])[CH3:10]>C(NC(C)C)(C)C.C(OCC)(=O)C.[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>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[C:14][CH2:13][NH:12][C:9](=[O:11])[CH3:10])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#CCNC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CC(=O)NCC#Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.7 %

Procedure:
A mixture of 2,5-dibromopyridine (1-1) (1.19 g), N-acetyl-propargylamine (733 mg), CuI (10 mg), and Pd(PPh3)2Cl2 (73 mg) in diisopropylamine (20 mL) was stirred at ambient temperature under nitrogen atmosphere over 3 days. The mixture was diluted with ethyl acetate (50 mL). The solid was filtered and washed with ethyl acetate. The filtrate and wash were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate as eluant to give crystalline 1-2 (1.14 g).
Reaction SMILES: C(OC([N:11]1[CH2:14][CH:13]([C:15]2[O:19][C:18]([CH:20]3[CH:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:24][CH2:23][CH2:22][N:21]3[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:17][N:16]=2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:11]1[CH2:14][CH:13]([C:15]2[O:19][C:18]([CH:20]3[CH:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:24][CH2:23][CH2:22][N:21]3[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:17][N:16]=2)[CH2:12]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1c1nnc(C2CN(C(=O)OCc3ccccc3)C2)o1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1c1nnc(C2CNC2)o1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 2-(5-{1-[(benzyloxy)carbonyl]azetidin-3-yl}-1,3,4-oxadiazol-2-yl)-3-phenylpiperidine-1-carboxylate (200 mg, 0.39 mmol) in ethanol (10 ml) was added 10% palladium on carbon (20.0 mg). The reaction was charged with 1 atm hydrogen gas and allowed to stir for 1 h. The reaction was filtered through celite, and the filtrate was concentrated to yield tert-butyl 2-(5-azetidin-3-yl-1,3,4-oxadiazol-2-yl)-3-phenylpiperidine-1-carboxylate (100%). LCMS (M+H)=385.2.
Reaction SMILES: [H-].[H-].[H-].[H-].[Al+3].[Li+].[CH2:7]([C@@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=1)[C@@H:10]([CH3:16])[C:11]([N:13]([CH3:15])[CH3:14])=O)[CH3:8]>O1CCCC1>[CH2:7]([C@@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=1)[C@@H:10]([CH3:16])[CH2:11][N:13]([CH3:15])[CH3:14])[CH3:8]
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)C(=O)N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CN(C)C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Lithium aluminum tetrahydride (730 mg, 20 mmol) was suspended in tetrahydrofuran (10 ml), then it was cooled in an ice-water bath and the solution of product of Example 5 (3 g, 9.2 mmol) in tetrahydrofuran (10 ml) was added dropwise. The reaction was carried out for 2 hours and quenched by adding 10% NaOH aqueous solution, Then the reaction solution was extracted with ethyl acetate for three times, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give a pale yellow oil 2.7 g, yield: 93%. 1HNMR (300 MHz, CDCl3): δ 7.3-7.5 (5H, m), 7.2 (1H, t, J=7.6, 15.1), 6.8 (1H, d, J=8.5), 6.7 (2H, m), 5.0 (2H, s), 2.2-2.3 (2H, m), 2.2 (3H, s), 2.1 (3H, s), 1.8-1.9 (1H, m), 1.7-1.8 (1H, m), 1.5-1.6 (1H, m), 1.4-1.5 (1H, m), 1.0 (3H, d, J=6.2), 0.8 (3H, t, J=7.4, 14.7). ESI-MS: 312.3 (M+H).