Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C([C:6]1[C:7]([F:27])=[C:8]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=O)=[N+]=[N-].[CH3:28][C:29]1[N:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.C[N:37]([CH:39]=[O:40])C>CCOC(C)=O>[F:27][C:7]1[C:6]([NH:37][C:39]([NH:35][C:32]2[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=2)=[O:40])=[C:25]([F:26])[CH:24]=[CH:23][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)c(C(=O)N=[N+]=[N-])c2F)CC1
Reactant: CN(C)C=O
Reactant: Cc1ccc(N)cn1
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)Nc2c(F)ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2F)cn1
Yield: 32 %

Procedure:
A solution of tert-butyl 4-(3-(azidocarbonyl)-2,4-difluorobenzyl)piperazine-1-carboxylate (2.52 g, nominally 5.4 mmol, 1.0 equiv) and 6-methylpyridin-3-amine (389 mg, 3.6 mmol, 0.66 equiv) in 7 mL of DMF was stirred at room temperature over 72 h, after which, the reaction mixture was diluted with EtOAc and washed repeatedly with water. After the EtOAc layer was washed with aq. satd. NaHCO3 and brine, it was dried over sodium sulfate, filtered and concentrated in vacuo. Reverse phase chromatography provided tert-butyl 4-(2,4-difluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate (800 mg, 32% over 4 steps). LCMS m/z (APCI)=462.2 (M+H).
Reaction SMILES: [CH:1]1([C:7]([N:9]([CH3:37])[CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([NH:25][C:26]3[S:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:30]=3)[C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl.O>C1COCC1.CO.O>[CH:1]1([C:7]([N:9]([CH3:37])[CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([NH:25][C:26]3[S:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:30]=3)[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@H](Cc1ccc(OCCN(C)C(=O)C2CCCCC2)cc1)Nc1nc(-c2ccccc2)cs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCOc1ccc(C[C@H](Nc2nc(-c3ccccc3)cs2)C(=O)O)cc1)C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42 %

Procedure:
The crude product from Step B was dissolved in a THF/MeOH/H2O mixture (6:0.1:1; 2 ml). Aqueous 1M LiOH solution (1.6 ml) was added and the mixture was stirred for 3 days at room temperature. Then the reaction mixture was neutralized with 1M HCl, a small amount of water was added and the mixture extracted with ethyl acetate. The solvent was evaporated. The product was purified by chromatography (SiO2, ethyl acetate/hexane). The yield was 42%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]2[C:7]3[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]=3[CH:15]=[CH:16][CH:17]=2)(=[O:4])=[O:3].[H-].[Na+].Br[CH:21]([CH3:23])[CH3:22]>CN(C)C=O>[CH3:22][CH:21]([N:10]1[C:11]2[C:7]3[C:6](=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]1=[O:14])[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=2)[CH3:23]
Reactant: CC(C)Br
Reactant: CS(=O)(=O)c1ccc2c3c(cccc13)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)c2cccc3c(S(C)(=O)=O)ccc1c23

Procedure:
A mixture of 2.5 g of 6-(methylsulfonyl)-benz[cd]indol-2(1H)-one (Example 3), 0.6 g of sodium hydride and 2.7 ml of 2-bromopropane in 100 ml of N,N-dimethylformamide is reacted for 18 hours under argon using the conditions of Example 4 to yield 2.24 g of the desired product as a yellow solid, m.p. 164°-165° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[CH:4]([CH3:13])[CH2:3]1>C(O)C.[Pd]>[OH:1][CH:2]1[CH2:11][CH2:10][CH:9]2[CH:5]([CH2:6][CH2:7][CH:8]2[CH3:12])[CH:4]([CH3:13])[CH2:3]1
Reactant: CC1=C2CCC(O)CC(C)C2CC1
Agent: [Pd]
Solvent: CCO
Product: CC1CCC2C(C)CC(O)CCC12
Yield: 68.7 %

Procedure:
3.6 g of 6-hydroxy-1,4-dimethyl-2,3,3a, 4,5,6,7,8-octahydroazulene were hydrogenated in 25 ml of ethanol with 500 mg of palladium-on-carbon (10%). The reaction mixture was filtered, the filtrate evaporated and distilled under reduced pressure in a bulb-tube. There were obtained 2.5 g of 6-hydroxy-1,4-dimethyl-perhydroazulene; b.p.0.005 ca 82°; IR(film):νmax = 3360, 1460, 1375, 1030, 975 cm-1. The compound has a fresh, woody, earthy odour somewhat reminiscent of vetiver.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1.[CH3:14][C:15]([CH3:17])=O.C(O)(=O)C>CO.C(Cl)Cl>[CH:15]([NH:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH3:5])[CH:8]=1)([CH3:17])[CH3:14]
Reactant: CC(C)=O
Reactant: COc1cccc(N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COc1cccc(NC(C)C)c1

Procedure:
To a microwave tube charged with a stirring bar was added sodium cyanoborohydride (0.10 g, 1.6 mmol) and m-anisidine (0.075 mL, 0.8 mmol) in methanol (1 mL). To this solution was the added acetone (0.5 mL) and glacial acetic acid (0.5 mL). Once the gas evolution had subsided, the tube was crimped and subjected to microwave irradiation at 130° C. for 15 minutes. The solution was diluted with CH2Cl2, washed once with 1N NaOH, and the organic layer was dried (Na2SO4), filtered and concentrated to a yellow liquid. This was purified via silica gel chromatography with an ethyl acetate/hexanes gradient (Rf=0.60 in 4:1 Hex/EtOAc) to give N-isopropyl-3-methoxybenzenamine as a colorless oil. FIA MS 166 (M+1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[CH2:22][CH2:21]1)[C:15](=[O:36])[N:14]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)[C:13]2=[O:48].CCN(CC)CC>C(Cl)Cl>[C:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:22][CH2:21]1)[C:15](=[O:36])[N:14]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)[C:13]2=[O:48])(=[O:3])[CH3:2]
Reactant: COc1ccc(Cn2c(=O)c3cc(CN)ccc3n(C3CCN(C(=O)OCc4ccccc4)CC3)c2=O)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c3cc(CNC(C)=O)ccc3n(C3CCN(C(=O)OCc4ccccc4)CC3)c2=O)cc1OC
Reaction time: 1 h
Yield: 107.5 %

Procedure:
0.049 g of acetic anhydride is added to a solution of 0.09 g of benzyl 4-[6-(aminomethyl)-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carboxylate obtained in stage 5.5 and 0.09 ml of NEt3 in 3 ml of DCM and the mixture is stirred at AT for 1 h 00. DCM is added and the solution is washed with a saturated NH4Cl solution, then with a 1N HCl solution, then with a 2N NaOH solution and then with water. The organic phase is dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure to give 0.104 g of the expected product.
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:40][O:41][CH2:42][C:43]1[S:47][C:46]([CH2:48][N:49]2[N:53]=[C:52]([NH2:54])[CH:51]=[N:50]2)=[CH:45][CH:44]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:41][CH2:42][C:43]1[S:47][C:46]([CH2:48][N:49]2[N:53]=[C:52]([NH:54][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:51]=[N:50]2)=[CH:45][CH:44]=1
Reactant: COCc1ccc(Cn2ncc(N)n2)s1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: COCc1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-phenyloxazole-4-carboxylic acid (120 mg, 0.62 mmol) in CH2Cl2 (4.0 mL) was treated at rt with DMAP (19 mg, 0.15 mmol), HOBt (103 mg, 0.74 mmol), EDC (301 mg, 1.54 mmol) and DIPEA (0.5 mL, 2.77 mmol) and the resulting mixture was stirred for 15 min at rt. A solution of 2-((5-(methoxymethyl)thiophen-2-yl)methyl)-2H-1,2,3-triazol-4-amine (131 mg, 0.61 mmol) in CH2Cl2 (8.0 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (15.0 mL), the layers were separated and the org. phase was washed with 1N HCl (15.0 mL), water (15.0 mL), followed by brine (15.0 mL) and dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (gradient from 85:15 hept-EA to 70:30 hept-EA) gave the title compound as a white solid. TLC: rf (7:3 hept-EA)=0.2. LC-MS-conditions 07: tR=0.90 min, [M+H]+=396.03
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2([NH2:11])[CH2:10][CH2:9]2)[CH:7]=1.Br[C:21]1[C:22](=[O:39])[N:23]([C:28]2[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=2[CH3:38])[C:31]([O:33][CH3:34])=[O:32])[CH:24]=[C:25]([Br:27])[N:26]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1.Cl>[CH3:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:34][O:33][C:31](=[O:32])[C:30]1[CH:35]=[CH:36][C:37]([CH3:38])=[C:28]([N:23]2[CH:24]=[C:25]([Br:27])[N:26]=[C:21]([NH:11][C:8]3([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:9][CH2:10]3)[C:22]2=[O:39])[CH:29]=1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Reactant: NC1(c2cc(F)ccc2OCc2ccccc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCCC(C)C
Product: COC(=O)c1ccc(C)c(-n2cc(Br)nc(NC3(c4cc(F)ccc4OCc4ccccc4)CC3)c2=O)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 151.2 %

Procedure:
A solution of 1-[5-fluoro-2-(phenylmethoxy)phenyl]-cyclopropanamine (Example 278a, 1.7 g) in dioxane (200 mL) was treated with 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 1.99 g) and N-ethyldiisopropylamine (1.7 ml,) under nitrogen. The resulting solution was stirred at 100° C. for 8 h. The cooled reaction mixture was diluted with 2M HCl (300 mL), and extracted with diethyl ether (3×300 mL). The combined organics were dried (MgSO4) filtered and evaporated to afford crude product. Trituration with iso-hexane gave the subtitle compound (2.89 g).
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[F:11][C:12]([F:42])([F:41])[C:13]1[CH:14]=[C:15]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]1[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:17].[I-].[K+].C(N(C(C)C)CC)(C)C>C(#N)C>[F:40][C:37]([F:38])([F:39])[C:35]1[CH:34]=[C:15]([CH:14]=[C:13]([C:12]([F:11])([F:41])[F:42])[CH:36]=1)[C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:1][C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])[CH2:20][C@H:19]1[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:17]
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
A mixture of phenacyl bromide (0.88 g), (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (2 g), potassium iodide (catalytical), diisopropyl-ethylamine (0.77 mL), and acetonitrile (20 mL) was stirred at room temperature overnight. After cooling to room temperature the solvent was removed in vacuo, and the residue treated with dichloromethane and NaOH (2N). The layers were separated, the organic layer was dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH 97/3) to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(2-phenyl-2-ethanon-1-yl)piperazine 2.16 g (85%). MH+ 574, Rf 0.44 (CH2Cl2/MeOH 97/3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[O:14][CH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1
Reactant: Cc1ccc(Nc2nccs2)cc1O
Reactant: BrCc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1ccc(Nc2nccs2)cc1OCc1nccs1
Yield: 51 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-methyl-5-(thiazol-2-ylamino)phenol (158 mg, 0.48 mmol) and Cs2CO3 (158 mg, 0.48 mmol) in acetone (4.4 mL) was treated with 2-bromomethylthiazole (86 mg, 0.48 mmol) at RT. Reaction control by TLC showed full conversion after 2.5 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 4/6) in 51% yield (75 mg).
Reaction SMILES: C([O:5][P:6]([C:13]([F:37])([F:36])[C:14]1[CH:35]=[CH:34][C:17]([CH2:18][CH:19]([C:30]([O:32][CH3:33])=[O:31])[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1)([O:8]C(C)(C)C)=[O:7])(C)(C)C.[H-].[Na+].Br[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([F:57])([F:56])[C:49]([O:51]C(C)(C)C)=[O:50])=[CH:44][CH:43]=1>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[C:19]([CH2:18][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:37])([F:36])[P:6]([OH:7])([OH:8])=[O:5])=[CH:35][CH:34]=1)([C:30]([O:32][CH3:33])=[O:31])[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([C:48]([F:56])([F:57])[C:49]([OH:51])=[O:50])=[CH:46][CH:47]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)C(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)C(Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(C(F)(F)C(=O)O)cc1)(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To starting 1-benzyl 3-methyl 2-{4-[(di-tert-butoxyphosphoryl) (difluoro)methyl]benzyl}malonate (0.12 g) in DMF(5.0 mL) was added NaH (55 mg). The reaction was stirred at r.t. for 30 min. Then tert-butyl 2-[4-(bromomethyl)phenyl]-2,2-difluoroacetate(0.085 g, prepared according the procedures described by J. W. Tilley et al, J. Med. Chem. 1991, 34. 1125) was added to the mixture. After stirring for 2 h, the mixture was quenched with H2O and extracted with EtOAc (50 mL). The extract was dried over Na2SO4 and evaporated to dryness. The residue was treated with a solution of TFA/H2O (3 mL, 9:1) for 3 h at r.t. and evaporated to dryness. The crude was purified on reverse phase HPLC to give 12 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[N:12][C:11]=2[CH2:16][CH3:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:20][N:14]1[C:10]([S:9][C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[C:11]([CH2:16][CH3:17])[N:12]=[C:13]1[CH3:15]
Reactant: CCc1nc(C)[nH]c1Sc1cc(C)cc(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(C)n(C)c1Sc1cc(C)cc(C)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 67.2 %

Procedure:
In dry dimethylformamide (4 ml)was dissolved 200 mg (0.8 mmol)of 5-(3,5-dimethylphenylthio)-4-ethyl-2-methylimidazole (5c), followed by addition of 49 mg (1.2 mmol)of 60% sodium hydride under ice-cooling, and the mixture was stirred for 5 minutes. Then, 138 mg (1.00 mmol)of methyl iodide was added and stirred for 30 minutes. The reaction mixture was poured in ice-water and extracted with diethyl ether, and the organic layer was dried over sodium sulfate. The solvent was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:methylene chloride=1:1). From the first fraction, 40 mg (yield 19%)of positional isomer (6e')of the target compound was obtained as oil. From the latter fraction, 140 mg of 1,2-dimethyl-5-(3,5-dimethylphenylthio)-4-ethylimidazole (Compound I-5)was obtained as oil (yield 66%).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Cl:18])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[C:5](=[O:6])[NH:4][C:2](=[S:3])[NH:1]2)[CH:14]=[C:15]([Cl:18])[C:16]=1[OH:17]
Reactant: O=Cc1cc(O)c(O)c(Cl)c1
Reactant: O=C1CNC(=S)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1NC(=S)NC1=Cc1cc(O)c(O)c(Cl)c1
Temperature: 100 °C

Procedure:
A solution containing 1.16 g of thiohydantoin, 1.72 g of 3,4-dihydroxy-5-chlorobenzaldehyde and 0.2 ml of piperidine in 20 ml of acetic acid was heated for 4 h at 100° C. The product was filtered and washed with ether. Yield 1.0 g, mp 303°-304° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:13][CH2:14][C@H:15]1[O:21][CH:19](O)[C@H:18]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[C@@H:17]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@H:16]1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:12])[CH3:11]>ClCCCl.C(OCC)(=O)C>[C:10]([O:13][CH2:14][C@H:15]1[O:21][C@@H:19]([F:7])[C@H:18]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[C@@H:17]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@H:16]1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC[C@H]1OC(O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](F)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Under nitrogen gas atmosphere, diethylaminosulfur trifluoride (5.8 ml, 43.9 mmol) was added to a solution of Compound 23 (5.95 g, 11.2 mmol) in 1,2-dichloroethane (50 ml) under ice cooling, and the mixture was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, and dried over magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:ethyl acetate=4:1) to obtain Compound 24 (5.9 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].CS(O[CH:19]([C:21]1[CH:26]=[C:25]([Cl:27])[C:24]([CH3:28])=[C:23]([C:29]([NH:31][CH2:32][CH3:33])=[O:30])[C:22]=1[C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[CH:35]=1)[CH3:20])(=O)=O>CN(C)C=O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:19]([C:21]3[CH:26]=[C:25]([Cl:27])[C:24]([CH3:28])=[C:23]([C:29]([NH:31][CH2:32][CH3:33])=[O:30])[C:22]=3[C:34]3[CH:35]=[C:36]([F:41])[CH:37]=[C:38]([F:40])[CH:39]=3)[CH3:20])[N:3]=[C:2]([CH3:1])[C:10]=12
Reactant: CCNC(=O)c1c(C)c(Cl)cc(C(C)OS(C)(=O)=O)c1-c1cc(F)cc(F)c1
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)n2nc(C)c3c(N)ncnc32)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (from ChemBridge) (26 mg, 0.17 mmol) in N,N-dimethylformamide (0.5 mL) was added sodium hydride (14 mg, 0.35 mmol). After stirring at room temperature for 30 minutes, to the resulting mixture was added to a mixture of 1-{4-chloro-6-[(ethylamino)carbonyl]-3′,5′-difluoro-5-methylbiphenyl-2-yl}ethyl methanesulfonate (50 mg, 0.1 mmol) in N,N-dimethylformamide (0.5 mL). The reaction was stirred at room temperature overnight and then quenched with water. The resultant mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C24H24ClF2N6O (M+H)+: m/z=485.2; Found: 485.1
Reaction SMILES: Cl.ClC1N=C(Cl)C2CNCCC=2N=1.C1(C(Cl)=O)CC1.Cl[C:21]1[N:22]=[C:23](Cl)[C:24]2[CH2:30][N:29]([C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH2:28][CH2:27][C:25]=2[N:26]=1.[Cl:37][C:38]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:39]=1[CH2:40][NH2:41].[NH2:47][CH2:48][CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52]>>[Cl:37][C:38]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:39]=1[CH2:40][NH:41][C:23]1[C:24]2[CH2:30][N:29]([C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH2:28][CH2:27][C:25]=2[N:26]=[C:21]([NH:47][CH2:48][CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[N:22]=1
Reactant: O=C(C1CC1)N1CCc2nc(Cl)nc(Cl)c2C1
Reactant: NCc1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl
Agent: Clc1nc(Cl)c2c(n1)CCNC2
Agent: O=C(Cl)C1CC1
Product: CC(C)(C)OC(=O)NCCNc1nc2c(c(NCc3ccc(F)cc3Cl)n1)CN(C(=O)C1CC1)CC2

Procedure:
From 2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride prepared according to Reference Example 1 and cyclopropylcarbonyl chloride, 2,4-dichloro-6-cyclopropylcarbonyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine was prepared in the same way as Process Step 1 of Example 1. Further, 2,4-dichloro-6-cyclopropylcarbonyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine was allowed to sequentially react with 2-chloro-4-fluorobenzylamine and N-(2-aminoethyl)(tert-butoxy)carboxamide in the same way as Process Steps 2 and 3 of Example 1, to yield 4-(2-chloro-4-fluorobenzylamino)-6-cyclopropylcarbonyl-2-(2-tert-butoxycarbonylaminoethylamino)-5,6,7,8-tetrahydropyrido [4,3-d]pyrimidine.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:21])[C@:16]1([CH3:17])[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]1)=[CH:10][CH2:9]3.[BH4-].[Na+]>[Pd]>[CH3:1][C@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C@@H:3]1[OH:21])[C@:16]1([CH3:17])[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[CH3:1][C@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C@H:3]1[OH:21])[C@:16]1([CH3:17])[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]1)[CH2:10][CH2:9]3
Reactant: C[C@H]1C[C@H]2[C@@H]3CC=C4CCCC[C@]4(C)[C@H]3CC[C@]2(C)C1=O
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Product: C[C@H]1C[C@H]2[C@@H]3CC[C@H]4CCCC[C@]4(C)[C@H]3CC[C@]2(C)[C@@H]1O
Product: C[C@H]1C[C@H]2[C@@H]3CC[C@H]4CCCC[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1O

Procedure:
Similarly, catalytic hydrogenation over 5% palladium on carbon of the 16β-methyl-5-androsten-17-one produced in Example 5 followed by treatment with sodium borohydride affords 16β-methyl-5α-androstan-17α-ol and 16β-methyl-5α-androstan-17β-ol.
Reaction SMILES: [CH2:1]([N:4]1[CH2:15][CH:14]2[CH2:16][CH:6]([CH:7]([OH:19])[C:8]3[C:13]2=[CH:12][CH:11]=[CH:10][C:9]=3[CH2:17][OH:18])[CH2:5]1)[CH:2]=[CH2:3].ClCCl.O.C[N+]1([O-])CCOCC1>CCOC(C)=O.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([N:4]1[CH2:15][CH:14]2[CH2:16][CH:6]([C:7](=[O:19])[C:8]3[C:13]2=[CH:12][CH:11]=[CH:10][C:9]=3[CH:17]=[O:18])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CC2CC(C1)C(O)c1c(CO)cccc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCN1CC2CC(C1)c1cccc(C=O)c1C2=O
Reaction time: 18 h
Yield: 81.6 %

Procedure:
11-Allyl-6-hydroxymethyl-11-aza-tricyclo[7.3.1.02,7]trideca-2,4,6-trien-8-ol (93 mg, 0.36 mmol) was dissolved dichloromethane (8 mL) and treated with N-methylmorpholine N-oxide monohydrate (73 mg, 0.54 mmol), powdered 4 Å molecular sieves (180 mg) and TPAP (TETRAPROPYLAMMONIUM PERRUTHENATE) 6.0 mg, 0.02 mmol). After 18 h, the mixture was stripped, dissolved in EtOAc and filtered through a silica gel pad. The organic layer was washed with H2O (2×30 mL), saturated aqueous NaCl solution (30 mL), dried over MgSO4, filtered and concentrated to give an oil (75 mg, 81%). (TLC 30% EtOAc/hexanes Rf 0.70); 1H NMR (400 MHz, CDCl3) δ 10.62 (s, 1H), 7.62 (dd, J=7.9, 1.4 Hz, 1H), 7.54 (dd, J=7.9, 7.3 Hz, 1H), 7.43 (d, J=7.3 Hz, 1H), 5.46 (m, 1H), 4.93 (m, 2H), 3.19 (m, 2H), 2.82 (m, 3H), 2.73 (br s, 1H), 2.48 (dd, J=10.9, 2.4 Hz, 1H), 2.35 (m, 2H), 1.96 (ddd, J=12.8, 5.4, 2.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz, free base) δ 202.1, 194.5, 148.3, 138.0, 134.6, 134.0, 132.9, 131.6, 126.2, 117.3, 60.8, 57.8, 57.2, 44.1, 36.6, 32.0.