Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:33]=[CH:34][CH:35]=1)[CH2:18][CH2:19][NH:20][C:21]1[C:22](=[O:32])[N:23]([CH2:28][C:29](O)=[O:30])[C:24]([CH3:27])=[CH:25][N:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([CH2:46][NH2:47])[CH:44]=2)[NH:39][CH:38]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN1CCOCC1>CN(C)C=O>[CH3:27][C:24]1[N:23]([CH2:28][C:29]([NH:47][CH2:46][C:43]2[CH:44]=[C:45]3[C:40](=[CH:41][CH:42]=2)[NH:39][CH:38]=[C:37]3[CH3:36])=[O:30])[C:22](=[O:32])[C:21]([NH:20][CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([CH:35]=[CH:34][CH:33]=2)[O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:26][CH:25]=1
Reactant: Cc1c[nH]c2ccc(CN)cc12
Reactant: Cc1cnc(NCCc2cccc(OC[C@H]3CCCN3C(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NCCc4cccc(OC[C@H]5CCCN5C(=O)OC(C)(C)C)c4)c3=O)cc12
Yield: 102.8 %

Procedure:
A mixture of 2-[3-[(3-{[(2R)-1-(tert-butoxycarbonyl)pyrrolidinyl]methoxy}phenethyl)amino]-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid (preparation 136) (65 mg, 0.13 mmol), (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (25 mg, 0.16 mmol), HOBT (20 mg, 0.15 mmol), WSCDl.HCl (31 mg, 0.16 mmol) and N-methylmorpholine (40 mg, 0.40 mmol) in N,N-dimethylformamide (2.5 ml), was stirred at room temperature for 20 hrs. The reaction mixture was partitioned between ethyl acetate and water and the phases separated. The organic layer was washed with water, brine, then dried over MgSO4 and evaporated under reduced pressure to give the title compound, (84 mg, 100%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(#N)C>[CH3:26][S:27]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[N:8]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 6-(hydroxymethyl)pyridin-2-ylcarbamate 78 (3.0 g, 13.4 mmol) and diisopropylethylamine (5.0 g, 40 mmol) in acetonitrile (30 mL) was added methanesulfonyl chloride (2.0 g, 17.4 mmol) over a period of 30 min at 0° C. and the mixture was stirred for 2 h at room temperature. The reaction was quenched by adding saturated aqueous NaHCO3 and extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford quantitative yield of crude 79.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:11]([C:21](=O)[C:22]([CH3:32])([CH3:31])[CH2:23][O:24]C3CCCCO3)=[C:10](O)[C:9]2=[O:35])=[CH:4][CH:3]=1.O.[NH2:37][NH2:38].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:11]3[C:21]([C:22]([CH2:23][OH:24])([CH3:32])[CH3:31])=[N:38][NH:37][C:10]=3[C:9]2=[O:35])=[CH:4][CH:3]=1
Reactant: COc1ccccc1C1C(C(=O)C(C)(C)COC2CCCCO2)=C(O)C(=O)N1c1ccc(Br)cc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1C1c2c(C(C)(C)CO)n[nH]c2C(=O)N1c1ccc(Br)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A mixture of 1-(4-bromophenyl)-4-(2,2-dimethyl-3-tetrahydro-2H-pyrane-2-yloxypropionyl)-3-hydroxy-5-(2-methoxyphenyl)-1,5-dihydropyrrole-2-one (1.51 g, 2.77 mmol), hydrazine hydrate (0.204 mL, 4.16 mmol) and acetic acid (3 mL) was stirred at 95° C. for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution (150 mL) was poured into the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was triturated with ethyl acetate to give 5-(4-bromophenyl)-3-(1-hydroxymethyl-1-methylethyl)-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazole-6-one (1.02 g, yield: 81%) as colorless solid.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[C:21]([CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)#[N:22]>>[NH2:22][C:21]1[N:12]2[N:13]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:11]2[CH:10]=[C:24]([C:25]2[CH:26]=[CH:27][C:28]([S:31]([NH:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:23]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Reactant: N#CC=Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Product: Nc1cc(-c2ccc(S(=O)(=O)Nc3ccccc3)cc2)cc2nc(-c3ccco3)nn12

Procedure:
The title compound, MS m/e (%): 430 (M—H−, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 4-(2-cyano-vinyl)-N-phenyl-benzenesulfonamide
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:3]=1[NH2:4].[O:14]=[C:15](Cl)OC(Cl)(Cl)Cl>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:3]=1[N:4]=[C:15]=[O:14]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(N)c(F)cc1Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N=C=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A solution of 2-fluoro-4-chloro-5-methoxycarbonylaniline (1.0 g, 5 mmol) in THF (10 mL) was added dropwist to a solution of diphosgene (2.0 g, 10 mmol) in toluene (20 mL) with stirring at room temperature. The reaction mixture was stirred at room temperature for one hour and then heated to reflux for 4 hours. The mixture was then cooled to room temperature and the solvents were evaporated under reduced pressure to give 1.1 g of 2-fluoro-4-chloro-5-methoxycarbonylphenyl isocyanate as a solid. This was used for the next step without further purification.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:30])[C@:7]1([OH:29])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([Cl:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@@H:8]1[CH3:28])(=O)C.Cl(O)(=O)(=O)=O.C([O-])(=O)C.[Na+]>CO>[Cl:26][C@H:22]1[CH2:23][C@@:24]2([CH3:25])[C@@H:10]([CH2:9][C@H:8]([CH3:28])[C@:7]2([OH:29])[C:6](=[O:30])[CH2:5][OH:4])[C@H:11]2[C@H:21]1[C@:19]1([CH3:20])[C:14]([CH2:13][CH2:12]2)=[CH:15][C:16](=[O:27])[CH:17]=[CH:18]1
Reactant: CC(=O)OCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@]2(C)[C@@]1(O)C(=O)CO

Procedure:
A solution of 21-acetoxy-11β-chloro-17-hydroxy-16β-methylpregna-1,4-diene-3,20-dione (100 mg.) in methanol (7 ml.) was treated with 60% aqueous perchloric acid (0.2 ml.) at room temperature. After 24 hours sodium acetate (100 mg.) was added and about half of the solvent was evaporated in vacuo. Purification of the remaining solution by preparative thin layer chromatography and crystallisation from methanol afforded 11β-chloro-17,21-dihyroxy-16β-methylpregna-1,4-diene-3,20-dione as needles, m.p. 202°-204° decomp (Kofler).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]([NH2:7])[CH3:6].C(N(CC)CC)C.[NH2:15][C:16]1[C:21]([Cl:22])=[C:20]([Cl:23])[N:19]=[C:18](Cl)[N:17]=1>C1(C)C=CC=CC=1>[NH2:15][C:16]1[C:21]([Cl:22])=[C:20]([Cl:23])[N:19]=[C:18]([NH:7][CH:5]([CH3:6])[CH2:4][CH2:3][O:2][CH3:1])[N:17]=1
Reactant: Nc1nc(Cl)nc(Cl)c1Cl
Reactant: COCCC(C)N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COCCC(C)Nc1nc(N)c(Cl)c(Cl)n1

Procedure:
3.4 g (0.033 mole) of 3-methoxy-1-methylpropylamine and 3.3 g (0.033 mole) of triethylamine are successively added dropwise to a solution of 6.5 g (0.033 mole) of 4-amino-2,5,6-trichloropyrimidine in 200 ml of toluene and the mixture is heated to the boil for five hours. When it has cooled, the reaction mixture is washed with water and the organic phase is dried over sodium sulphate and concentrated. The crude product thus obtained is purified by chromatography over silica gel (length of column: 80 cm, diameter: 5 cm), using ethyl acetate and petroleum ether (1:1). In addition to 4-amino-6-(3-methoxy-1-methylpropylamino)-2,5-dichloropyrimidine (1st fraction, melting point 62° C.), 1.5 g (17.2% of theory) (2nd fraction, melting point 96° C.) of the desired pyrimidine are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]([CH3:13])[C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].[Cl:17][S:18](O)(=[O:20])=[O:19].O>ClCCCl>[F:1][C:2]1[CH:16]=[CH:15][C:14]([S:18]([Cl:17])(=[O:20])=[O:19])=[C:4]([CH2:5][N:6]([CH3:13])[C:7](=[O:12])[C:8]([F:10])([F:11])[F:9])[CH:3]=1
Reactant: CN(Cc1cccc(F)c1)C(=O)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: ClCCCl
Solvent: O
Product: CN(Cc1cc(F)ccc1S(=O)(=O)Cl)C(=O)C(F)(F)F
Temperature: 70 °C

Procedure:
A solution of 3-fluoro-N-methyl-N-(trifluoroacetyl)benzylamine (Intermediate 159, 0.497 g) in DCE (0.5 mL) was added to stirred, cooled chlorosulfonic acid (3 mL). The mixture was allowed to come up to room temperature and then heated at 70° C. for 3 hours. After cooling, the mixture was added carefully to a mixture of ice and water, then extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 2.5-10% to give 4-fluoro-2-[N-methyl-N-(2,2,2-trifluoroacetyl)aminomethyl]-benzenesulfonyl chloride (0.21 g) as a clear oil.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=1)(=[O:44])=[O:43])([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.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=1)(=[O:43])=[O:44])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 93 %

Procedure:
Methyl 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and collected resulting precipitate by filtration. Obtained 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid (white-yellow solid) in 93% yield. HRMS calc for [C38H33Cl3N2O6S2−H] 793.07728. found 793.07629
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].Br[C:14]1[CH:15]=[C:16]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:20][C:17]2=[N:18][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[O:20][C:17]3=[N:18][CH:19]=[C:14]([C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:1]([OH:3])=[O:2])[CH:15]=[C:16]3[CH:22]=2)=[CH:28][CH:27]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Fc1ccc(-c2cc3cc(Br)cnc3o2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Temperature: 95 °C
Yield: 29.8 %

Procedure:
3-Carboxyphenylboronic acid (700 mg, 4.22 mmol), 5-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridine (750 mg, 2.57 mmol), Pd(Ph3P)4 (30 mg, 0.026 mmol), and Cs2CO3 (1.25 g, 3.84 mmol) were combined in dioxane (20 mL) and water (4 mL). The mixture was evacuated/backfilled with nitrogen (3×). The reaction was heated to 95° C. under N2 (g) overnight. The mixture was partitioned between EtOAc and 1 N HCl. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated to give a brown solid which was triturated with Et2O to give the expected product 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (255 mg, 30% yield) consistent by LCMS. LC-MS retention time: 1.83 min; m/z (MH+): 334. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:25][CH3:26])[C:10](=[O:24])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH3:22])[C:16](=[O:23])[C:12]3=2)[C:7]1=[O:27].[H][H]>[Pd].C(O)C>[F:31][C:30]1[CH:2]=[CH:3][C:4]([CH2:5][N:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([O:25][CH3:26])[C:10](=[O:24])[N:11]4[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH3:22])[C:16](=[O:23])[C:12]4=3)[C:7]2=[O:27])=[CH:28][CH:29]=1
Reactant: [H][H]
Reactant: COc1c2c(c3n(c1=O)CCCCN(C)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: [Pd]
Solvent: CCO
Product: COc1c2c(c3n(c1=O)CCCCN(C)C3=O)CCN(Cc1ccc(F)cc1)C2=O

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (52 mg, 0.12 mmol) and 10% palladium on charcoal (70 mg) in ethanol (6 mL) was stirred at room temperature under a balloon of hydrogen overnight. The reaction mixture was filtered and concentrated under vacuum. ES MS M+1=480
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.N1C=CN=C1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[Si:30]([O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 18 h
Yield: 98.8 %

Procedure:
To a solution of estrone (11, 8.10 g, 30.0 mmol) in DMF (25 mL) were added imidazole (3.07 g, 45 mmol) and tert-butyldimethyl-chlorosilane (5.42 g, 36 mmol) at room temperature. The reaction mixture was stirred for 18 h, and then quenched with H2O (100 mL). The precipitate was collected by filtration and washed with H2O to afford 11.4 g of 29 (99% yield) mp: 171-172° C.
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=2)O1>>[OH:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[C:6]([CH3:7])=[C:2]([C:26]3[CH:27]=[CH:28][C:29]([NH:32][S:33]([CH3:36])(=[O:34])=[O:35])=[CH:30][CH:31]=3)[C:3]([CH3:17])=[N:4]2)=[CH:9][CH:10]=1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1ccc(NS(C)(=O)=O)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamide: MS (EI) m/z 385 [M]+, 1H-NMR (CDCl3) δ 7.44-7.26 (8H, m), 3.92-3.90 (2H, br), 3.08 (3H, s), 2.94 (2H, t, J=6.6 Hz), 2.32 (3H, s), 2.29 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7]2)([O-:3])=[O:2].[CH3:14][NH:15][CH3:16].O>C1COCC1>[CH3:14][N:15]([CH3:16])[C:8]1[CH2:9][C:10]2[C:6]([CH:7]=1)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2
Reactant: CNC
Reactant: O=C1Cc2ccc([N+](=O)[O-])cc2C1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C1=Cc2cc([N+](=O)[O-])ccc2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.9 %

Procedure:
To a solution of 5-nitro-2-indanone (885 mg, 5 mmol) in THF (15 mL) was added dimethylamine (2N in THF, 5 mL, 10 mmol) dropwise. The reaction mixture was stirred at r.t. for 5 h. Water was added and the reaction mixture was extracted with EtOAc. Combined organic layers were washed with water and brine and dried over Na2SO4. The concentrated crude product was filtered through a short pad of silica gel (EtOAc:hexane=1:1) and the filtrate was concentrated to give dimethyl-(5-nitro-1H-inden-2-yl)-amine as a dark red solid (1.0 g, 98%). Dimethyl-(5-nitro-1H-inden-2-yl)-amine (1.0 g, 4.9 mmol) was hydrogenated using Pd/C (10% dry, ca. 300 mg) and H2 in MeOH:THF (1:1, 30 mL) at 1 atm at r.t. for 5 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. The concentrated filtrate was further purified via short silica gel column chromatography (EtOAc: MeOH=6:4) to give the title compound as a yellow solid (830 mg, 82%).
Reaction SMILES: [CH2:1]([C:5]1([CH2:21][CH2:22][CH2:23][CH3:24])[C:17]2[CH:16]=[C:15]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:29](Cl)(=[O:31])[CH3:30].O>[N+](C1C=CC=CC=1)([O-])=O>[CH2:1]([C:5]1([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]2[CH:7]=[C:8]([C:29](=[O:31])[CH3:30])[CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)Cl
Reactant: CCCCC1(CCCC)c2ccccc2-c2ccc([N+](=O)[O-])cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CCCCC1(CCCC)c2cc(C(C)=O)ccc2-c2ccc([N+](=O)[O-])cc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
After 7.0 g of 9,9-di-n-butyl-2-nitrofluorene (5) (21.7 mmol) was dissolved in 200 ml of anhydrous nitrobenzene and 5.77 g of anhydrous aluminum chloride (43.4 mmol) was added thereto, the reaction mixture was heated to 45° C., and a solution in which 3.40 g of acetyl chloride (43.3 mmol) was dissolved in 40 ml of anhydrous nitrobenzene was slowly added thereto for 1 hour, followed by stirring at 65° C. for 1 hour. Thereafter, the reaction mixture was cooled to room temperature, 100 ml of distilled water was added thereto and stirred for about 30 minutes, followed by extracting the product with 200 ml of dichloromethane. The extracted organic layer was sequentially washed with 100 ml of saturated aqueous sodium bicarbonate solution and 100 ml of distilled water. Then, a solid product obtained by drying the recovered organic layer over anhydrous magnesium sulfate and distilling a solvent under reduced pressure was dispersed in a small amount of ether and stirred at room temperature for 30 minutes, followed by filtering and drying, thereby obtaining 5.44 g of 1-(9,9-di-n-butyl-7-nitrofluorene-2-yl)-ethanone (6) (68.7%) as a light yellow product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1>>[CH3:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:20][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=3)[CH2:13][CH2:14]2)=[O:19])=[CH:27][CH:26]=1
Reactant: Cc1ccc(COC(=O)N2CCC(CN)CC2)cc1
Reactant: CSc1nccc(Cl)n1
Product: CSc1nccc(NCC2CCN(C(=O)OCc3ccc(C)cc3)CC2)n1

Procedure:
The 4-[(2-methylsulfanyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid 4-methyl-benzyl ester was prepared as described in EXAMPLE 13, Step 2, but replacing 6-chloropurine with 4-chloro-2-methylthiopyrimidine and replacing benzyl 4-(aminomethyl)-1-piperidinecarboxylate with 4-methylbenzyl 4-(aminomethyl)-1-piperidinecarboxylate. M.S. (M+1): 387
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19].[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH:18][S:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccc(F)cc3)c2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.53 mmol) and 4-fluoro-benzenesulfonyl chloride (98 mg, 0.63 mmol) were dissolved in pyridine (5 ml). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified on column chromatography using petroleum ether/ethyl acetate=5:1 as eluent to afford N-[3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-4-fluoro-benzenesulfonamide (135 mg, yield: 46%) as yellow solid. MS (ESI+APCI) M+1=445.1.