Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:5]=1
Reactant: OCCc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(CCO)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol (5 g) in acetone (45 mL) was added anhydrous potassium carbonate (6.5 g) at room temperature, and the mixture was stirred for 30 minutes. Ethyl bromoacetate (4.4 mL) was added dropwise to the reaction mixture at 40-45° C. of internal temperature, and the mixture was stirred at 40° C. for 8 hours. After the insoluble materials were filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate) to give ethyl 2-[4-(2-hydroxyethyl)phenoxy]acetate (5.8 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH:27][CH2:28][C:29]2[N:33](CC3C=CC(OC)=CC=3)[N:32]=[N:31][CH:30]=2)=[CH:22][CH:21]=1>FC(F)(F)C(O)=O>[F:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH:27][CH2:28][C:29]2[N:33]=[N:32][NH:31][CH:30]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(Cn2nncc2CNCc2ccc(-c3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3F)cc2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(CNCc4c[nH]nn4)cc3)c(F)c2)C(=O)O1
Temperature: 67.5 °C
Reaction time: 12 h

Procedure:
A solution of the crude regioisomeric mixture of (5S)—N-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-1-ylmethyl}-acetamide hydrochloride and (5S)—N-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide hydrochloride (1013 and 1014, 29.17 g, 49.07 mmol) in trifluoroacetic acid (TFA, 150 mL) was warmed up to 65-70° C., and the resulting reaction mixture was stirred at 65-70° C. for 12 h. When TLC and HPLC/MS showed that the deprotection reaction was complete, the solvents were removed in vacuo. The residual solids were then treated with ethyl acetate (EtOAc, 100 mL) and H2O (150 mL) before being treated with a saturated aqueous solution of sodium carbonate (30 mL) at room temperature. The resulting mixture was then stirred at room temperature for 1 h before the solids were collected by filtration, washed with EtOAc (2×50 mL) and H2O (2×50 mL), and dried in vacuo at 40-45° C. to afford the crude, (5S)—N-[3-(2-fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (1 as the free base, 18.9 g, 21.49 g theoretical, 87.9%) as off-white powders, which by HPLC/MS and 1H NMR was found to be one pure regioisomer and this regioisomer was found to be identical as the material obtained from deprotection of 1013 alone by the same method. For 1 as the free base: 1H NMR (300 MHz, DMSO-d6) δ 1.85 (s, 3H, COCH3), 3.44 (t, 2H, J=5.4 Hz), 3.74 (s, 2H), 3.77 (s, 2H), 3.79 (dd, 1H, J=6.4, 9.2 Hz), 4.17 (t, 1H, J=9.1 Hz), 4.72-4.81 (m, 1H), 7.39-7.62 (m, 7H, aromatic-H), 7.73 (s, 1H, triazole-CH), 8.29 (t, 1H, J=5.8 Hz, NHCOCH3), 9.72 (br. s, 2H, ArCH2N+H2), 15.20 (br. s, 1H, triazole-NH); C22H23FN6O3, LCMS (EI) m/e 439 (M++H) and 461 (M++Na).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[C:11]([O:14]CC)(=[O:13])C.CCC[CH2:20][CH2:21][CH3:22]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C:21]([CH3:20])([CH3:22])[C:11]([OH:14])=[O:13]
Reactant: CCOC(C)=O
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: CCCCCC
Product: Cc1cc(C)c(C)c(OC(C)(C)C(=O)O)c1
Yield: 65 %

Procedure:
Using 2,3,5-trimethylphenol, the title compound was synthesized in the same manner as in Reference Example 36. Yield 65%. Melting point: 91-94° C. (ethyl acetate-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[C:17]([F:20])[CH:16]=[CH:15][CH:14]=3)[C:5]([CH2:8][CH2:9]Cl)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[CH2:8][CH2:9][N:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[C:17]([F:20])[C:18]=4[CH:19]=[C:11]3[C:4]=2[CH:3]=1
Reactant: Fc1cccc2[nH]c(-c3cc(Br)cnc3CCCl)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cccc2c1cc1n2CCc2ncc(Br)cc2-1
Yield: 83.7 %

Procedure:
A solution of 2-(5-bromo-2-(2-chloroethyl)pyridin-3-yl)-4-fluoro-1H-indole (800 mg, 2.26 mmol) and cesium carbonate (1.47 g, 4.52 mmol) in 25 mL of DMF was heated at 80° C. for 1 hour. The mixture was concentrated in vacuo to remove DMF, and then the residue was suspended in water and EA. After extraction with EA, the combined organic phase was washed with brine, dried over sodium sulfate and concentrated to afford crude 2-bromo-11-fluoro-5,6-dihydroindolo[2,1-f][1,6]naphthyridine (600 mg, yield: 83.6%) which was used directly in the next step without further purification. 1H-NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 8.11 (s, 1H), 7.11˜7.17 (m, 2H), 6.97 (s, 1H), 6.78˜6.82 (m, 1H), 4.34˜4.37 (m, 2H), 3.34˜3.37 (m, 2H). MS (M+H)+: 317/319.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.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>C1(C)C=CC=CC=1.C(OCC)C.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]>[N:13]1([C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)Cc1cccc(N2CCOCC2)c1
Temperature: 100 °C
Yield: 23 %

Procedure:
A round bottom flasked flushed with argon was charged with methyl 3-bromophenyl-acetate (2.29 g, 10 mmol) (prepared from 3-bromophenylacetic acid as described in example 2, step 1), morpholine (1.05 mL, 1.2 eq.), CsCO3 (4.55 g, 1.4 eq.), Pd2(dba)3 (92 mg, 0.01 eq) and BINAP (93 mg, 0.15 eq.) in toluene (20 mL). The resulting mixture was heated at 100° C. overnight and then diluted with diethyl ether (120 mL). The precipitates were filtered through a Celite pad and the filtrate was concentrated and purified on a silica-gel column with 20% EtOAc in hexane to give methyl 3-(morpholin-4-yl)phenylacetate (0.55 g, 23%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:25]=[CH:24][C:13]([O:14][CH:15]([CH3:23])[C:16](=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:26][C:27]([F:52])([F:51])[C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]2[CH:50]=[CH:49][C:38]([O:39][CH:40]([CH3:48])[C:41](=[O:47])[CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:37][CH:36]=2)=[N:32][CH:33]=1.[BH4-].[Na+]>>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH:15]([CH3:23])[CH:16]([OH:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:24][CH:25]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:51][C:27]([F:26])([F:52])[C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]2[CH:50]=[CH:49][C:38]([O:39][CH:40]([CH3:48])[CH:41]([OH:47])[CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:37][CH:36]=2)=[N:32][CH:33]=1
Reactant: COC(=O)CC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reactant: COC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: COC(=O)CC(O)C(C)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1

Procedure:
Each of the compounds, methyl 4-[4-(3,5-dichloropyridyloxy)phenoxy]-3-oxopentanoate and methyl 4-[4-(5-trifluoromethylpyridyloxy)phenoxy]-3-oxopentanoate is reacted with NaBH4 by the procedure of Example 17 to yield methyl 4-[4-(3,5-dichloropyridyloxy)phenoxy]-3-hydroxypentanoate and methyl 4-[4-(5-trifluoromethylpyridyloxy)phenoxy]-3-hydroxypentanoate, respectively.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C@@H:10]([C@@:14]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:20][CH2:19][C:18](=[O:21])[N:17]([CH3:22])[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]2=3)[C:11]([OH:13])=[O:12])[N:3]=1.[CH3:33]O>O.C=O.[Pd]>[CH3:22][N:17]1[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[C@:14]([C@H:10]([O:9][C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=2)[C:11]([OH:13])=[O:12])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:20]([CH3:33])[CH2:19][C:18]1=[O:21]
Reactant: Cc1cc(C)nc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCC(=O)N(C)c3ccccc32)n1
Reactant: CO
Agent: [Pd]
Agent: C=O
Solvent: O
Product: Cc1cc(C)nc(O[C@H](C(=O)O)[C@]2(c3ccccc3)c3ccccc3N(C)C(=O)CN2C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pd/C (100 mg, 10% Pd) is added to a solution of (±)-(S*)-(4,6-dimethyl-pyrimidin-2-yloxy)-((5S*)-1-methyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-acetic acid (100 mg, 0.231 mmol, Example 49) in water (8 ml), methanol (8 ml) and aq. formaldehyde solution (0.2 ml, 36%). The mixture is stirred at rt under 3 atm H2 for 18 h before the catalyst is filtered off. The organic solvent of the filtrate is evaporated and the remaining aq. phase is extracted three times with DCM. The organic phase is evaporated and the product is purified by chromatography on prep. tlc-plattes with DCM:methanol 9:1 to give (±)-(S*)-((5S*)-1,4-dimethyl-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl)-(4,6-dimethyl-pyrimidin-2-yloxy)-acetic acid (57 mg) as a white powder. LC-MS2: tR=3.40 min, [M+1]+=447.10, [M−1]−=445.14.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:13](=[O:31])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([N:17]([CH3:32])[CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:22][CH2:23]2)[C:13](=[O:31])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)N1CCN(C(=O)OCc2ccccc2)CC1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of 4-benzyloxycarbonyl-1-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-2-piperazinone (9.00 g), potassium carbonate (3.46 g) and methyl iodide (29.81 g) in DMF (100 ml) was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was combined with water (200 ml) and extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1, 120 ml×3). The extract was washed with water and brine, dried and concentrated. The residue was crystallized from diisopropyl ether to obtain the title compound (8.55 g) as colorless crystals.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][OH:25])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].C([O-])(=O)C.[Na+].[CH2:32]=[C:33]1[O:37][C:35](=[O:36])[CH2:34]1.C(OCC)(=O)C>ClCCl>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:25][C:35](=[O:36])[CH2:34][C:33](=[O:37])[CH3:32])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CO
Reactant: C=C1CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CC(C)=O

Procedure:
In 30 ml of dichloromethane is dissolved 0.8 g of 16β-ethyl-17β-glycoloyloxy-4-estren-3-one, and 0.24 g of anhydrous sodium acetate and 0.3 ml of diketene are added. The mixture is refluxed for 4 hours. After cooling, 100 ml of ethyl acetate is added and the mixture is washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following serial passage of 400 ml of diisopropyl ether and 400 ml of diisopropyl ether-ethyl acetate (10:1), elution is carried out with 600 ml of isopropyl ether-ethyl acetate (2:3). The eluate is evaporated under reduced pressure to remove the solvent, giving 1.0 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].[CH2:12]1N2CCN(CC2)C1>CCOC(C)=O.O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[CH:4]=1)#[N:2]
Reactant: N#Cc1c[nH]c2ccccc12
Reactant: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cc(C#N)c2ccccc21
Temperature: 25 °C
Yield: 987.8 %

Procedure:
To a solution of 3-cyanoindole (1.0 g, 7.03 mmol) in DMC (10 mL), DABCO (0.079 g, 0.70 mmol) is added and the resulting solution is heated to reflux for 8 h. The reaction is cooled to RT, and diluted with EtOAc (40 mL) and H2O (40 mL). The organic layer is separated and washed in sequence with H2O (50 mL), 10% aqueous citric acid (2×40 mL) and H2O (4×40 mL). The organic layer is dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 3-cyano-1-methylindole (about 1.08 g, 98%) as an oil: 1H NMR (CDCl3) δ7.74 (d, 1H), 7.53 (s, 1H), 7.40-7.28 (m, 3H), 3.83 (s, 3H); 13C NMR (CDCl3) 136.0, 135.6, 127.8, 123.8, 122.1, 119.8, 116.0, 110.4, 85.4, 33.6; MS m/z 156 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:18]1([NH:24][C:25]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:25](=[S:26])[NH:24][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:11][CH:10]=3)=[O:7])=[CH:4][CH:3]=2)=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ccc(NC(=O)c2ccc(N)cc2)cc1
Solvent: CC(C)=O
Product: O=C(Nc1ccc(NC(=S)Nc2ccccc2)cc1)c1ccc(NC(=S)Nc2ccccc2)cc1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
4,4'-Diaminobenzanilide (0.658 g, 2.5 mM) was dissolved in 20 ml of acetone, and 2 equivalents of phenylisothiocyanate (0.676 g, 5 mM) was added. The mixture was stirred at 55° C. for 10 minutes. After cooling, the reaction mixture was filtered, and washed with acetone/n-hexane to obtain 0.90 g (72.3% yield) of a colorless crystal of compound A-15.
Reaction SMILES: [C:1](Cl)(=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:19]1([NH:25][C:26]2([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClC(Cl)Cl>[C:19]1([NH:25][C:26]2([C:32]([O:34][CH3:35])=[O:33])[CH2:27][CH2:28][N:29]([C:1]([O:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:10])[CH2:30][CH2:31]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1(Nc2ccccc2)CCNCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(Nc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3.7 parts of (phenylmethyl) carbonochloridate and 2.1 parts of N,N-diethylethanamine in 75 parts of trichloromethane is added dropwise a solution of 4.6 parts of methyl 4-(phenylamino)-4-piperidinecarboxylate in 30 parts of trichloromethane (exothermic reaction: cooling with ice-water is necessary to keep the temperature below 25° C.). Upon completion, stirring is continued for 5 hours at room temperature. The reaction mixture is washed twice with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol, yielding 4.2 parts of O4 -methyl O1 -(phenylmethyl) 4-(phenylamino)-1,4-piperidinedicarboxylate; mp. 105.8° C.
Reaction SMILES: [CH2:1]1[CH2:26][O:25][C:3]2([CH2:20][CH2:19][C@@:18]3([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C@@H:12]3[OH:22])[C:4]2([CH3:24])[CH3:23])[O:2]1.C1C[O:30]CC1>>[CH2:26]1[CH2:1][O:2][C:3]2([CH2:20][CH2:19][C@@:18]3([CH3:21])[C@@:5]([OH:30])([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C@@H:12]3[OH:22])[C:4]2([CH3:24])[CH3:23])[O:25]1
Reactant: C1CCOC1
Reactant: CC1(C)C2=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC12OCCO2
Product: CC1(C)C2(CC[C@]3(C)[C@H]4CC[C@]5(C)[C@@H](O)CC[C@H]5[C@@H]4CC[C@@]13O)OCCO2
Reaction time: 24 h
Yield: 23 %

Procedure:
To a stirred solution of 3,3-ethylenedioxy-4,4-dimethyl-5-androsten-17β-ol (190 mg) in THF (3.5 ml) at 0° C., under N2, 1M BH3.THF complex in THF (3.3 ml) was added in five portions over 5 days. The reaction mixture was cautiously quenched by dropwise addition of H2O at 0° C. (1.5 ml), followed by 4N NaOH (0.16 ml) and by 30-32 wt. % H2O2 solution in water (0.056 ml). After 24 h, EtOAc and brine were added, the phases were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (SiO2, n-hexane/DCM/acetone 80/10/10) to give 3,3-ethylenedioxy-4,4-dimethylandrostan-5α,17β-diol (80 mg, 23%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Br:10]Br.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][C:7]=1[Br:10]
Reactant: N#Cc1ccc(N)cn1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N#Cc1ccc(N)c(Br)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
5-Aminopyridine-2-carbonitrile (2.38 g, 20 mmol) was dissolved in 6 mL of glacial acetic acid. A solution of bromine (1 mL, 20 mmol) in 2.5 mL of glacial acetic acid was added dropwise over a period of 30 minutes while the room temperature was maintained with a water bath. The resulting slurry was stirred for 1 hour at room temperature, treated with 50 mL of aqueous 20% sodium hydroxide solution and extracted with three 160 mL portions of dichloromethane. The combined organic layers were dried over sodium sulfate (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by crystallization from ethyl acetate-hexanes to give 5-amino-6-bromopyridine-2-carbonitrile (1.42 g, 35% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[SH:10][C:11]1[C:12]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:13]=2[S:14][C:15]=1[C:16]([NH2:18])=[O:17].C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[NH2:18][C:16]([C:15]1[S:14][C:13]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:12]=2[C:11]=1[S:10][CH:4]([CH2:3][CH3:2])[CH2:5][C:6]([O:8][CH3:9])=[O:7])=[O:17]
Reactant: COC(=O)CCCCBr
Reactant: COc1ccc2sc(C(N)=O)c(S)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC(=O)OC)Sc1c(C(N)=O)sc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
Methyl 5-bromovalerate (144 μL, 1.00 mmol) is added to a room temperature solution of 3-mercapto-5-methoxybenzo[b]thiophene-2-carboxamide (200 mg, 0.84 mmol) in 8 mL of THF followed by NaHCO3 (351 mg, 4.18 mmol) and the reaction mixture is stirred at room temperature overnight. Additional methyl 5-bromovalerate (100 μL) is added and the reaction mixture is stirred at room temperature for 3 days. The reaction mixture is diluted with ethyl acetate and washed with 1N HCl, water, saturated NaHCO3, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane gives methyl 3-[[2-(aminocarbonyl)-5-methoxybenzo[b]thien-3-yl]thio]pentanoate in 30% yield; mp=134.5°-135.5° C.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[C:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>CO.[Pd]>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[C:24]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:18][CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccccc1
Yield: 81.1 %

Procedure:
A mixture of intermediate (9) (0.1 mole) in methanol (500 ml) was hydrogenated for two hours with palladium-on-carbon (10%) (10 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in 2-propanol. The precipitate was filtered off and dried, yielding 29 g of N-[4-(1-piperazinyl)phenyl]-[1,1′-biphenyl]-2-carboxamide (intermediate 10, melting point 176° C.).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Cl[CH2:9][C:10]1[N:15]=[C:14]2[S:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2=[C:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:11]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32].O>CN(C)C=O>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([C:12]2[C:11]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:10]([CH2:9][N:3]3[CH:7]=[N:6][CH:5]=[N:4]3)[N:15]=[C:14]3[S:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=23)[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)c1c(CCl)nc2sc(C)c(C)c2c1-c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cn2cncn2)nc2sc(C)c(C)c2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
Sodium hydride (60% in oil, 0.171 g) was added to a solution of 1H-1,2,4-triazole (0.271 g) in N,N-dimethylformamide (DMF) (15 ml). The mixture was stirred for 15 minutes at room temperature, to which was added ethyl 6-chloromethyl-4-(3,4-dimethoxyphenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate (1.5 g). The mixture was stirred for 35 minutes at 80° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off. The residue was subjected to column chromatography on silica gel. From the fraction eluted with chloroform-methanol (30:1, v/v), ethyl 4-(3,4-dimethoxyphenyl)-2,3-dimethyl-6-(1,2,4-triazol-1-ylmethyl)thieno[2,3-b]pyridine-5-carboxylate (1.0 g, 62%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, m.p.136°-137° C.