Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23](S(C)(=O)=O)[N:22]=1.[CH2:37]([OH:40])[CH2:38][OH:39].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:39][CH2:38][CH2:37][O:40][C:23]1[N:22]=[C:21]([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=1
Reactant: OCCO
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(OCCO)n1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a solution of N-(4-methyl-3-(2-(methylsulfonyl)-6-morpholinopyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzamide (1.0 equiv.) and ethylene glycol (1.0 equiv.) in acetonitrile (0.10M) was added potassium carbonate (1.0 equiv.) and the allowed to stir at 120° C. for 24 hours. LCMS analysis indicated formation of the desired product. The volatiles were removed in vacuo. The crude material was purified via preparative reverse phase HPLC. Upon lyophilization of the pure fractions, N-(4-methyl-3-(2-(methylsulfonamido)-6-morpholinopyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzamide was isolated as the TFA salt in 6% yield. LCMS (m/z) (M+H)=536.3, Rt=0.80 min, 1H NMR (400 MHz, <cd3od>) δ ppm 2.37 (s, 3H) 3.79-3.85 (m, 4H) 3.86-3.97 (m, 6H) 4.60-4.65 (m, 2H) 6.78 (s, 1H) 7.41 (d, J=8.22 Hz, 1H) 7.67 (dd, J=8.22, 2.35 Hz, 1H) 7.74 (t, J=7.83 Hz, 1H) 7.91 (d, J=8.22 Hz, 1H) 7.94 (d, J=1.96 Hz, 1H) 8.21 (d, J=7.83 Hz, 1H) 8.26 (s, 1H). LCMS (m/z) (M+H)=503.1, Rt=0.73 min. The compounds listed below were prepared using methods similar to those described above using the appropriate starting materials.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[O:8]=[S:9]1(=[O:26])[CH2:14][CH2:13][N:12]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:11]2=[N:10]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[C:11]3=[N:10][S:9](=[O:26])(=[O:8])[CH2:14][CH2:13][N:12]3[CH:15]=[CH:16][CH:17]=2)=[CH:24][CH:23]=1
Reactant: Clc1ccccn1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccn4)cc3)C2=N1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
2-Chloropyridine (0.132 mL) was added to a solution of 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (300 mg) and potassium carbonate (390 mg) in DMSO (6 mL). The mixture was stirred at 120° C. under nitrogen overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and crystallized from THF-IPE to give the title compound (3.3 mg) as colorless crystals.
Reaction SMILES: [Na].[Na].[Na].S(C1C=C(P(C2C=CC=C(S(O)(=O)=O)C=2)C2C=CC=C(S(O)(=O)=O)C=2)C=CC=1)(O)(=O)=O.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[CH3:45].Br[C:47]1[CH:48]=[CH:49][C:50]([CH2:63][CH3:64])=[C:51]([CH:53]2[C:59](=[O:60])[CH:58]3[CH2:61][CH:55]([CH2:56][CH2:57]3)[C:54]2=[O:62])[CH:52]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:47]2[CH:48]=[CH:49][C:50]([CH2:63][CH3:64])=[C:51]([CH:53]3[C:54](=[O:62])[CH:55]4[CH2:61][CH:58]([CH2:57][CH2:56]4)[C:59]3=[O:60])[CH:52]=2)=[CH:38][C:37]=1[CH3:45]
Reactant: CCc1ccc(Br)cc1C1C(=O)C2CCC(C2)C1=O
Reactant: Cc1cc(B(O)O)ccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: CCc1ccc(-c2ccc(Cl)c(C)c2)cc1C1C(=O)C2CCC(C2)C1=O
Temperature: 160 °C
Reaction time: 0.08 h

Procedure:
To a microwave vial is added palladium(II) acetate (3.7 mg, 0.016 mmol), tris(3-sulfophenyl)phosphine trisodium salt (23 mg, 0.041 mmol), 4-chloro-3-methylphenyl boronic acid (0.167 g, 0.97 mmol), 3-(5-bromo-2-ethyl-phenyl)-bicyclo[3.2.1]octane-2,4-dione (0.209 g, 0.65 mmol) and potassium phosphate (0.691 g, 3.26 mmol). A degassed mixed solution of acetonitrile/distilled water (1.6 ml, 1:1 ratio) is next added (washing-down any solids from the slides of the vial), followed by stirring for 5 minutes and flushing with nitrogen. This mixture is then heated at 160° C. under microwave irradiation for 15 minutes. After cooling to room temperature the reaction mixture is diluted with N,N-dimethylformamide (1 ml), then partitioned between 2M hydrochloric acid and dichloromethane. After the organic phase is separated the aqueous phase is again washed with dichloromethane, then all organic fractions are combined and concentrated in vacuo to afford a crude gum. This crude product is then purified by preparative reverse-phase HPLC to afford 3-(4′-chloro-4-ethyl-3′-methylbiphen-3-yl)bicyclo[3.2.1]octane-2,4-dione.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:30])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])[C:3]=1[O:31][CH:32]([CH3:34])[CH3:33].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:30])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])[C:3]=1[O:31][CH:32]([CH3:34])[CH3:33]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(/C=C/C(F)=C(/C)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)C)=C\C(=O)O

Procedure:
As described in General Procedure J-1, ethyl (2E,4E,6E)-7-(4-bromo-3-isopropoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-6-fluoro-3-methyl-octa-2,4,6-trienoate (Compound A-161, 189 mg, 0.35 mmol) in ethanol was treated with a solution of 1 N NaOH to produce the title compound after purification by recrystallization from acetonitrile.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])/[CH:6]=[CH:7]\[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3].[S:12](=[O:15])([OH:14])[O-:13]>O>[C:8]([CH:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH2:6][C:5]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:11])([OH:10])=[O:9]
Reactant: C=CCNC(=O)/C=C\C(=O)O
Reactant: O=S([O-])O
Solvent: O
Product: C=CCNC(=O)CC(C(=O)O)S(=O)(=O)O

Procedure:
Allylamine reacts readily with maleic anhydride in THF to give N-allylmaleamic acid (VIII) in quantitative yield. VIII reacts with bisulfite in water to form 3-carboxy-3-sulfo-N-allyl propionamide (IX). At 160° C., (IX) cyclolyzes slowly to form N-allyl-sulfo-succinimide (X).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:14](N)[CH2:15][NH2:16]>O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>[NH:5]1[CH2:14][CH2:15][N:16]=[C:4]1[C:3]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:2]=1[NH2:1]
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: NCCN
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Product: COc1cc(N)c(C2=NCCN2)cc1OC
Reaction time: 8 h
Yield: 82.3 %

Procedure:
2-Amino-4,5-dimethoxybenzonitrile (5.0 g, 28 mmol) was added to ethylenediamine (7.9 g, 131 mmol) at room temperature. The resulting solution was warmed to 40., and a catalytic amount of diphosphorus pentasulfide (50 mg) was added. The mixture was heated to 80-90, and the stirring was continued overnight. The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration to give 2-(4,5-dihydro-1H-imidazol-2-yl)-4,5-dimethoxyaniline (5.1 g, 82%) as a solid.
Reaction SMILES: NC1C=CC(C(C)(C)C)=CC=1S(N)(=O)=O.C(N=C=S)(C)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:24]=1[S:33]([NH:36][C:37]([NH:39][CH:40]([CH3:42])[CH3:41])=S)(=[O:35])=[O:34].C(Cl)(Cl)=O>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]2[NH:22][C:37]([NH:39][CH:40]([CH3:42])[CH3:41])=[N:36][S:33](=[O:35])(=[O:34])[C:24]=2[CH:25]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)NC(=S)NS(=O)(=O)c1cc(C(C)(C)C)ccc1N
Agent: CC(C)(C)c1ccc(N)c(S(N)(=O)=O)c1
Agent: CC(C)N=C=S
Agent: O=C(Cl)Cl
Product: CC(C)NC1=NS(=O)(=O)c2cc(C(C)(C)C)ccc2N1

Procedure:
Starting from 2-amino-5-tert-butylbenzenesulfonamide and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amino-5-tert-butylbenzenesulfonyl)-N′-isopropylthiourea was prepared; m.p. 128-130° C. Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound; m.p. 290-293° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[C:14]1([CH2:20][CH2:21][C:22](Cl)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>ClC(Cl)C>[C:14]1([CH2:20][CH2:21][C:22]([C:3]2[C:4]3[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=[CH:8][C:9]=3[NH:1][CH:2]=2)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc2[nH]cc(C(=O)CCc3ccccc3)c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of methyl indole-4-carboxylate (250 mg, 1.43 mmol) in dichloroethane (3 mL) was treated with 3-phenylpropionyl chloride (361 mg, 2.14 mmol) at room temperature. The orange solution was cooled to 0° C. and treated with aluminum chloride (572 mg, 4.29 mmol). The reaction mixture was stirred at room temperature for 2 h, then poured into ice-cold 1M aqueous HCl. The aqueous solution was adjusted to pH=8 with 1M NaOH, and extracted with CH2Cl2 (10 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated to give methyl 3-(3-phenylpropionyl)-indole-4-carboxylate as a pale-yellow solid, 395 mg (90%). A solution of the 3-(3-phenylpropionyl)-4-carboxy indole (95.5 mg, 0.31 mmol) in MeOH (3 mL) and HCl (0.1 mL) was treated with hydrazine hydrate (47 mg, 0.93 mmol) and the solution was heated at reflux for 8 h. The solution was cooled in an ice/water bath and the precipitated solid was collected by filtration to give 1,5-dihydro-3-phenethyl-[1,2]diazepino[4,5,6-cd]-indol-6-one, 60.2 mg (71%). The crude product was purified by radial chromatography (2 mm SiO2, 5:1 hexanes:EtOAc) to give a yellow solid. mp 182-183.5° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.80 (m, 2H), 2.84 (m, 2H), 7.22 (m, 2H), 7.31 (m, 4H), 7.54 (m, 2H), 7.81 (s, 1H), 10.19 (s, 1H), 11.92 (br s, 1H); Anal. (C10H7N3O.0.1 H2O) C, H, N.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([N:18]([CH3:20])[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[OH:22])[CH:8]=2)[N:3]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].CC[O-].[Na+].C[O-].[Na+]>CCO.CO>[CH3:19][N:18]([CH3:20])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[OH:22])[CH:8]=2)[N:3]=[C:2]([O:36][CH2:35][CH3:37])[C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]
Reactant: CN(C)c1c(-c2ccccc2)c(Cl)nc2ccc(C(O)(c3ccncc3)c3cncn3C)cc12
Agent: CC[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCOc1nc2ccc(C(O)(c3ccncc3)c3cncn3C)cc2c(N(C)C)c1-c1ccccc1

Procedure:
The title compound was prepared using (2-chloro-4-(dimethylamino)-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanol (Example 47) and NaOEt in EtOH in place of (3-chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(pyridin-3-yl)methanol and NaOMe in MeOH, respectively, according to the procedure described in Example 79. 1H NMR (400 MHz, MeOH-d4) δ 9.07 (s, 1H), 8.82 (d, J=5.62 Hz, 2H), 8.09 (s, 1H), 7.99 (d, J=5.38 Hz, 2H), 7.87 (d, J=8.56 Hz, 1H), 7.63 (dd, J=1.96, 8.56 Hz, 1H), 7.41-7.48 (m, 2H), 7.39 (d, J=7.09 Hz, 1H), 7.24 (d, J=7.82 Hz, 2H), 7.17 (s, 1H), 4.42 (q, J=7.01 Hz, 2H), 3.72 (s, 3H), 2.57 (s, 6H), 1.24 (t, J=6.97, 3H); MS m/e 480.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10]([CH3:16])([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:20][CH:17]2[CH2:19][CH2:18]2)[C:10]([CH3:16])([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC1(C)CN(Cc2ccccc2)CCC1NC1CC1
Reaction time: 6 h

Procedure:
1-Benzyl-3,3-dimethyl-4-piperidone (10.0 g, 46.0 mmol), was added to the stirred solution cyclopropylamine (13.1 g, 230.0 mmol) in methanol (150 ml) and stirred for 6 hr. Sodium cyanoborohydride (2.9 g, 46.0 mmol) was added to it and reaction mixture was stirred for 15 hr. The reaction mixture was concentrated to dryness, triturated with water, extracted with chloroform, dried (Na2SO4) and concentrated. The obtained crude product was purified over silica gel column. Eluted from 5% ethyl acetate in hexane gave 1-benzyl-4-cyclopropylamino-3,3-dimethyl piperidine. Yield 8.0 g (67.3%), C17H26N2, m/z 259 (M+1), PMR (CDCl3): 0.4 (m, 2H), 0.82 (s, 3H), 1.06 (s, 3H), 1.16 (m, 2H), 1.5 (bs, 1H, D2O exchangeable), 1.7 (m, 2H), 1.9-2.95 (m, 5H), 3.3-3.6 (m, 3H), 7.22 (m, 5H).
Reaction SMILES: CN1CCCC1=O.Cl[C:9]1[N:10]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([C:24]1[C:25]([CH3:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1)[N:12]=2.[NH:36]1[CH2:44][CH2:43][CH:39]([C:40]([NH2:42])=[O:41])[CH2:38][CH2:37]1>O>[NH2:30][C:27]1[N:26]=[C:25]([CH3:31])[C:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([N:36]4[CH2:44][CH2:43][CH:39]([C:40]([NH2:42])=[O:41])[CH2:38][CH2:37]4)[N:10]3[CH2:32][CH:33]3[CH2:35][CH2:34]3)=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)=[CH:29][N:28]=1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Reactant: NC(=O)C1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(N3CCC(C(N)=O)CC3)n(CC3CC3)c2n1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 69 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and isonipecotamide (191 mg, 1.5 mmol) and the resulting mixture was stirred at 120° C. for 2.5 hours. The reaction mixture was left standing to cool followed by the addition of water and the insoluble matter was collected by filtration and dried to give 1-[2-(2-amino-4-methylpyrimidin-5-yl)-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-8-yl]piperidine-4-carboxamide (85 mg, 69%) as a pale yellow solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-])=O)[CH:29]=2)=[CH:26][N:27]=1)([CH3:22])[CH3:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl>C(OCC)(=O)C.[Pd]>[Si:1]([O:18][CH2:19][C:20]([C:23]1[S:24][C:25]([C:28]2[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=2)[NH2:34])=[CH:26][N:27]=1)([CH3:22])[CH3:21])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ncc(-c2cccc([N+](=O)[O-])c2)s1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ncc(-c2cccc(N)c2)s1
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of the product of Step 2 (461 mg, 0.892 mmol) in ethyl acetate (9 mL) was added Pd/C (10 wt %, 190 mg, 0.178 mmol), and the reaction vessel was charged with H2 (balloon) and stirred overnight, at which point LCMS analysis indicated complete conversion. Dichloromethane was added to deactivate the catalyst, and the mixture was filtered through a pad of Celite (ethyl acetate rinse) and concentrated in vacuo to provided 393 mg (0.807 mmol, 91%) of 3-[2-(1-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropan-2-yl)-1,3-thiazol-5-yl]aniline as a light yellow oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].I[CH2:22][CH2:23][CH2:24][C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29].O>O1CCCC1>[CH2:3]([C:10]([CH2:22][CH2:23][CH2:24][C:25]([F:36])([F:37])[C:26]([F:34])([F:35])[C:27]([F:32])([F:33])[C:28]([F:29])([F:31])[F:30])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCI
Reactant: C=CCCCCCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.6 %

Procedure:
60% sodium hydride (0.54 g, 13.5 mmol) was added to a solution of diethyl 2-(6-heptenyl)malonate (3.0 g, 11.7 mmol) in tetrahydrofuran (30 ml) followed by stirring for 30 minutes at room temperature. 1-Iodo-4,4,5,5,6,6,7,7,7-nonafluoroheptane (5.45 g, 14.04 mmol) was added to the mixture followed by stirring for 12 hours at room temperature. After the reaction was completed, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/25) to give diethyl 2-(6-heptenyl)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)malonate (6.14 g, quantitative) as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[O:35]1CC(O)O[CH2:37][CH:36]1O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:30]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:20][C:19]1[CH:33]=[CH:34][C:16]([CH2:15][N:7]([CH2:6][C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)[CH2:8][C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=2)=[CH:17][CH:18]=1)[CH2:37][CH2:36][OH:35])[CH2:31][CH3:32]
Reactant: OC1COC(O)CO1
Reactant: CCCN(CCC)CCCCNCc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN(CCO)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 76.8 %

Procedure:
The compound (209 mg) obtained in Example 1-8 was dissolved in anhydrous methanol (8.4 ml) and added with [1,4]-dioxan-2,5-diol (54.0 mg) and sodium cyanoborohydride (56.6 mg). Then, the solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 19.5 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution (1.0 ml) and subjected to extraction with chloroform, followed by drying with magnesium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (175.8 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([C@@H:12]1[C@:29]2([CH3:30])[C@H:15]([C:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19]([CH2:20][C@@H:21]([O:36][C:37]([O:39][CH3:40])=[O:38])[CH2:22][C@@H:23]2[O:31][C:32]([O:34][CH3:35])=[O:33])=[CH:18][CH:17]=3)[CH2:14][CH2:13]1)[CH2:3][S:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH:41]O>CO.O>[CH3:1][CH:2]([C@@H:12]1[C@:29]2([CH3:30])[C@H:15]([C:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19]([CH2:20][C@@H:21]([O:36][C:37]([O:39][CH3:40])=[O:38])[CH2:22][C@@H:23]2[O:31][C:32]([O:34][CH3:35])=[O:33])=[CH:18][CH:17]=3)[CH2:14][CH2:13]1)[CH2:3][S:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:41])=[O:5]
Reactant: OO
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CS(=O)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Solvent: CO
Solvent: O
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CS(=O)(=O)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 29 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)-21-phenylsulfinylpregna-5,7-diene in 1 ml of methanol was added 0.5 ml of a 30% aqueous solution of hydrogen peroxide and the mixture was stirred at ambient temperature for 6 hours. The reaction mixture was diluted with water and the methanol was distilled off under reduced pressure. The residue was extracted with methylene chloride, the extract was washed with an aqueous solution of sodium thiosulfate, water and an aqueous solution of sodium chloride, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 13 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)-21-phenylsulfonylpregna-5,7-diene, whose 1H NMR spectrum was identical with that obtained in Example 5.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:8]
Reactant: O=[N+]([O-])c1c(O)cccc1Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(O)cccc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A mixture of 3-chloro-2-nitrophenol(250 mg, 1.4 mmol) and tin (II) chloride (1.2 g, 5.3 mmol) in ethanol(50 mL) was heated at 80° C. under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(143 mg, 69%). 1H NMR (CD3OD): δ 6.75 (t, 1H), 6.70 (d, 1H), 6.65 (d, 1H).
Reaction SMILES: [CH3:1][Mg]I.[C:4]1([C:10]23[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:18][CH:12]([C:13]4=[O:20])[CH2:11]2)[CH2:17]3)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCOCC.C1COCC1>[CH3:1][C:13]1([OH:20])[CH:12]2[CH2:18][CH:16]3[CH2:17][C:10]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)([CH2:19][CH:14]1[CH2:15]3)[CH2:11]2
Reactant: C[Mg]I
Reactant: O=C1C2CC3CC1CC(c1ccccc1)(C3)C2
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)C2CC3CC1CC(c1ccccc1)(C3)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Freshly prepared methylmagnesium iodide in ether (1 M, 85 mL), was added through a canola to 5-phenyladamantan-2-one (9.6 g, 42.5 mmol) obtained in step II, in THF (85 mL) at 0° C. After stirring at 0° C. for 0.5 h, the reaction mixture was quenched by adding sat. aq. NH4Cl solution. The organic layer was separated and the aqueous layer was extracted with diisopropylether. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to obtain 2-methyl-5-phenyl-adamantan-2-ol (9.9 g) as an off-white solid in 97% yield. M.R: 98-100.4° C. m/z (M+23) 265; 1H NMR (CDCl3) 300 MHz δ 7.42-7.28 (m, 4H), 7.24-7.18 (m, 1H), 2.47-2.26 (m, 2H), 2.14-2.09 (m, 3H), 1.96-1.70 (m, 6H), 1.61-1.57 (m, 2H), 1.42 (s, 3H). 13C NMR (CDCl3) 75 MHz δ 150.0, 128.1 (2C), 125.7, 124.8 (2C), 73.3, 44.0 (2C), 40.5 (2C), 39.6 (2C), 35.9, 32.0, 27.6.