Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[N:25]([CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[CH:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1>O1CCCC1.Cl>[ClH:1].[ClH:1].[ClH:1].[NH2:28][CH2:27][CH2:26][N:25]1[C:18]2[C:17]([NH:16][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=4)=[C:2]([Cl:1])[CH:3]=3)=[N:22][CH:21]=[N:20][C:19]=2[CH:23]=[CH:24]1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccn(CCNC(=O)OC(C)(C)C)c34)cc2Cl)cn1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccn(CCN)c34)cc2Cl)cn1
Temperature: 60 °C
Reaction time: 16 h
Yield: 394.5 %

Procedure:
tert-Butyl {2-[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate (643 mg) was dissolved in tetrahydrofuran (19.5 mL)/2N hydrochloric acid (9.75 mL), and the mixture was stirred at 60° C. for 16 hrs. The reaction mixture was concentrated under reduced pressure, ethanol (50 mL) was added to the residue and the mixture was concentrated again under reduced pressure. Ethyl acetate was added to the residue and the solid was collected by filtration and dried under reduced pressure to give the title compound (646 mg) as a solid powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[O:20]1[CH2:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[O:20]1[CH2:21][CH:22]=[C:23]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]3)[CH2:24][CH2:25]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1CCCc2cc(C3=CCOCC3)ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (1.4 g, 4.76 mmol) in dioxane (6 mL) was added 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.0 g, 4.76 mmol), Pd(dppf)Cl2DCM (408 mg, 0.5 mmol) and sat. NaHCO3 solution (2 mL). The mixture was stirred at 100° C. for 2 h under nitrogen. The mixture was cooled to rt and diluted with EtOAc, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=4:1) to give 930 mg (86%) of the title compound as yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.13-2.16 (2H, m), 2.53 (2H, s), 2.65 (2H, t, J=6.4 Hz), 2.96 (2H, t, J=6.0 Hz), 3.94 (2H, t, J=5.6 Hz), 4.34 (2H, s), 6.26 (1H, s), 7.25 (1H, d, J=5.6 Hz), 7.33 (1H, d, J=8.4 Hz), 7.99 (1H, d, J=8.0 Hz). [M+H] Calc'd for C15H16O2, 229. Found, 229.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:31])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)[CH:15]=1.[I-].C[SiH](C)C>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:31])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][NH2:23])[CH:15]=1
Reactant: Cc1cc(O)c(C(=O)C=Cc2cccc(OCCNC(=O)OC(C)(C)C)c2)c(=O)n1C
Agent: C[SiH](C)C
Agent: [I-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(OCCN)c2)c(=O)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
To a mixture of 70 mg of 4-hydroxy-3-[3-[3-[N-(t-butoxycarbonyl)-2-aminoethoxy]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone and 7 ml of chloroform was added 23 μl of trimethylsilane iodide, this was stirred at room temperature for 30 minutes, 46 μl of trimethylsilane iodide was further added, and this was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the resulting crystals were filtered, and washed to obtain 25 mg of 4-hydroxy-3-[3-[3-(2-aminoethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (52a)] as a yellow crystal.
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](I)=[CH:11][C:10]=2F)=[C:5](F)[C:4]=1F.C([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)CC.OCC(C)(CO)C.CC(C)=O>CC(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:6]1([C:9]2[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: C[Si](C)(C)c1ccc(-c2ccc(I)cc2F)c(F)c1F
Reactant: CCCc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(CO)CO
Solvent: CC(C)O
Solvent: CC(C)=O
Product: c1ccc(-c2ccccc2-c2ccccc2)cc1
Yield: 89 %

Procedure:
A solution of (2 mmol) of 8, (2.2 mmol) of 4-propylphenylboronic acid, 250 mg (2.40 mmol) of neopentyl glycol, 1.53 g (4.84 mmol) of Ba(OH)28 H2O, 1.35 ml (0.103 mmol, 5 mol %) of a 76 mM acetone solution of Pd(OAc)2 in 20 ml of 95% i-PrOH is stirred at 80° C. for 12 hours. The solvent is subsequently removed under reduced pressure. 5 ml of 2 M HCl are added to the residue, and the mixture is extracted with dichloromethane (3×5 ml). The combined organic phases are dried over MgSO4 and filtered through SiO2. The solvent is removed under reduced pressure, and the residue is converted into 10 (yield: 89%).
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[CH3:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)=[O:7].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][CH2:3][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH3:5])=[CH:9][CH:10]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: COCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1ccc(C(C)=O)cc1
Temperature: 25 °C

Procedure:
Chloromethyl methyl ether (19.2 mL, 252 mmol) was added dropwise to a 0° C. solution of 4-hydroxyacetophenone (6.855 g, 50.35 mmol) and triethylamine (8.4 mL, 60.42 mmol) in dichloromethane (100 mL). The solution was then allowed to warm to rt overnight, quenched with MeOH (40 mL), filtered and the filtrate concentrated and purified by flash chromatography to give the title compound which was used as is in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][C:13]([N+:19]([O-])=O)=[C:12]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=2)[CH:11]=1.Cl.[C:33](=N)(O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CO>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([NH2:16])=[CH:14][C:13]2[N:19]=[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:22]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=3)[C:12]=2[CH:11]=1
Reactant: N=C(O)c1ccccc1
Reactant: COC(=O)CCCCCOc1cc(Nc2ccc(C)c(C)c2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccc(C)c(C)c1

Procedure:
2.45 g of 6-[[3-[(3,4-dimethylphenyl)amino]-4,6-dinitrophenyl]oxy]hexanoic acid methyl ester was hydrogenated in methanol according to general operating instructions 1. 500 mg of the crude product was reacted with benzimidate hydrochloride according to general operating instructions 4. Contrary to general operating instructions 4, after being taken up in solvent, the crude product was not washed with aqueous hydrochloric acid.
Reaction SMILES: [CH:1]1([CH:4](O)[CH:5]2[C:9](=[O:10])[C:8]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:7]([O:20][CH3:21])[CH2:6]2)[CH2:3][CH2:2]1.CCN(CC)CC.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH:1]1([CH:4]=[C:5]2[C:9](=[O:10])[C:8]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:7]([O:20][CH3:21])[CH2:6]2)[CH2:2][CH2:3]1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)C2CC2)C1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(=CC2CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
To a solution of 5-(Cyclopropyl-hydroxy-methyl)-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (622 mg, 2.1 mmol) in CH2Cl2 (10 ml) at 0 C were added dropwise Et3N (0.59 ml, 4.2 mmol) followed my methane sulfonyl chloride (0.33 ml, 4.2 mmol). The reaction was allowed to warm to room temperature over 10 minutes and then quenched by addition of 1M HCl (10 ml). The layers were separated and the organic phase was evaporated to dryness under reduced pressure. The crude mesylate was dissolved in MeOH (10 ml) and K2CO3 (580 mg, 4.2 mmol) was added in a single portion. The reaction was stirred at room temperature for 2 hours and then the solvent was removed under reduced pressure. The crude material was partitioned between EtOAc (20 ml) and H2O (20 ml), the organic phase was washed with brine (20 ml), dried over MgSO4, filtered and evaporated to dryness under reduced pressure. The crude material was purified by flash chromatography over SiO2 using a 100% isohexane to 100% EtOAc gradient to give the desired product as a colourless oil (83 mg).
Reaction SMILES: C[C:2](C)(C)[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2F)=[N:12]1)=[O:10])[C:4](NC)=O.F[C:33]1C=C(C2C3CN(C(OC(C)(C)C)=O)CCC=3NN=2)C=CC=1F.C(N)(C)(C)C>>[C:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:22]=[CH:23][C:24]([F:28])=[C:25]([F:27])[CH:26]=2)=[N:12]1)=[O:10])([CH3:33])([CH3:4])[CH3:2]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Solvent: CC(C)(C)N
Product: CN1CCc2c(c(-c3ccc(F)c(F)c3)nn2C(=O)NC(C)(C)C)C1

Procedure:
Compound 46 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15, and replacing tert-leucine methylamide with tert-butylamine. 1H NMR (CDCl3) δ 7.47-7.52 (m, 1H), 7.21-7.31 (m, 2H), 4.06 (s, 2H), 3.43 (t, J=6.1 Hz, 2H), 3.20 (t, J=6.1 Hz, 2H0, 2.75 (3H), 1.48 (s, 9H). LCMS (+ESI) m/z=349.2 [M+H]+.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:26])[C:6]1[CH:15]=[C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:13]=[C:8]([C:9]([O:11]C)=[O:10])[CH:7]=1.Cl>O.CCO>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[C:14]1[CH:13]=[C:8]([C:9]([OH:11])=[O:10])[CH:7]=[C:6]([CH:15]=1)[C:5]([OH:26])=[O:4]
Reactant: COC(=O)c1cc(C(=O)OC)cc(-c2ccc3ccccc3c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(C(=O)O)cc(-c2ccc3ccccc3c2)c1
Temperature: 25 °C

Procedure:
A solution of LiOH (1.5 mmol) in water (1 ml) was added to 5-(naphthalene-2-yl)-isophthalic acid dimethylester (160 mg, 0.5 mmol) suspended in 5 ml EtOH. The mixture was stirred at room temperature. The reaction was monitored by TLC until completion. 1.5 ml 1 M HCl solution was added and the precipitation was collected. The product was used in next step without further purification
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.BrN1C(=[O:18])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([CH:11]=[O:18])[C:6]=2[N:7]=1.[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1csc2cnc(Cl)nc12
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1csc2cnc(Cl)nc12
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-7-methyl-thieno[3,2-d]pyrimidine (1.8 g), N-bromosuccinimide (1.8 g), 2,2′-azobis(2-methylpropionitrile) (0.1 g) in carbon tetrachloride (50 mL) was heated at reflux for 1 hour. The resulting mixture was cooled, the solid was filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved in acetonitrile (20 mL) and diisopropylethylamine (2.0 mL) was added, followed by pyridine-N-oxide (3 g) and the resulting mixture was heated at 100° C. for 30 minutes. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc) to afford 0.25 g of 2-chloro-thieno[3,2-d]pyrimidine-7-carbaldehyde and 1 g of 2-chloro-7-methyl-thieno[3,2-d]pyrimidine starting material.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[N:18]([CH3:19])[C:17]2[C:20]([N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]=1.[C-:31]#[N:32].[K+]>CS(C)=O.O>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([NH:13][C:14]2[N:18]([CH3:19])[C:17]3[C:20]([N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=[CH:23][C:16]=3[N:15]=2)=[C:6]([CH:11]=1)[O:5][CH:4]([CH2:3][CH3:2])[C:31]#[N:32]
Reactant: [C-]#N
Reactant: CCCN(CCC)c1cccc2nc(Nc3ccc(Cl)cc3OCCCBr)n(C)c12
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCN(CCC)c1cccc2nc(Nc3ccc(Cl)cc3OC(C#N)CC)n(C)c12
Temperature: 25 °C
Yield: 106.5 %

Procedure:
To a solution of 80 mg (0.16 mmol) of N2-[2-(3-bromopropoxy)-4-chlorophenyl]-1-methyl-N7,N7-dipropyl-1H-benzimidazole-2,7-diamine in 2 mL of dimethylsulfoxide was added 13 mg (0.19 mmol) of potassium cyanide. The reaction was stirred at room temperature for several hours, diluted with 10 mL water, and extracted twice with 10 mL ethyl acetate. The organics were washed with water, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography eluting with a solution of 20% acetone/hexanes to give 75 mg (100%) of the title compound.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N2CCCCC2)ncn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 77.1 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 85 mg of piperidine was added therein, and the mixture was stirred for 5 hours at 80° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 178 mg of 4-(2-butynyloxy)-6-piperidinopyrimidine (hereinafter, referred to as Compound (16)).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(OP([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(OCC)=O)C.[Cl:25][C:26]1[CH:43]=[CH:42][C:29]2[N:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:31](O)[CH2:32][O:33][C:28]=2[CH:27]=1.O>C1COCC1>[Cl:25][C:26]1[CH:43]=[CH:42][C:29]2[N:30]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH:31]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:32][O:33][C:28]=2[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1c2ccc(Cl)cc2OCC1O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC1COc2cc(Cl)ccc2N1C(=O)OC(C)(C)C
Yield: 106.6 %

Procedure:
A 1 M solution of LiHMDS (23.0 mL, 23.0 mmol) in THF was a added dropwise to a solution of ethyl 2-(diethoxyphosphoryl)acetate (4.57 mL, 23.0 mmol) in THF (30 mL) at 0° C. under nitrogen and the resulting mixture was stirred for 10 min where after tert-butyl 7-chloro-3-hydroxy-2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate (Intermediate 17, 3.29 g, 11.5 mmol) dissolved in THF (30 mL) was added dropwise at 0° C. The reaction mixture was stirred under nitrogen at rt for 1 h where after water (100 mL) was added and the mixture was extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine (100 mL), dried by passage through a phase separator and concentrated giving crude the title compound (4.36 g, 106%) as a brown oil.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:23]=[CH:22][C:13]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.B.[Na]>O1CCOCC1.O>[N:1]1([CH:6]([C:10]2[CH:23]=[CH:22][C:13]([CH:14]([OH:15])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(c1ccc(C(=O)c2ccccc2)cc1)n1ccnc1
Agent: B
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(c1ccc(C(O)c2ccccc2)cc1)n1ccnc1

Procedure:
By reduction of the ketone of example 17 with sodium boron hydride in dioxane/water (90:10); boiling point 250° C./0.03 mbar.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([OH:26])[C:22]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:29]=2)([CH3:27])[CH2:21]1)([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.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[Si:1]([O:18][CH2:19][CH:20]1[CH2:25][CH2:24][C:23](=[O:26])[C:22]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([C:35]([F:38])([F:36])[F:37])[CH:29]=2)([CH3:27])[CH2:21]1)([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: CC1(c2ccc(Cl)c(C(F)(F)F)c2)CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCC1O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(c2ccc(Cl)c(C(F)(F)F)c2)CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 99.5 %

Procedure:
A solution of (1RS,2RS,4RS)-4-((tert-butyldiphenylsilyloxy)methyl)-2-(4-chloro-3-(trifluoromethyl)phenyl)-2-methylcyclohexanol (1.35 g, 2.406 mmol) in dichloromethane (40 mL) was treated with Celite (1.5 g, 24.97 mmol) and pyridinium chlorochromate (0.778 g, 3.61 mmol). The resulting mixture was stirred at rt for 19.5 h, then diluted with Et2O and stirred vigorously at rt. The resulting slurry was filtered through a pad of Florisil and the solids were rinsed thoroughly with Et2O. The filtrate was concentrated under vacuum, taken up in dichloromethane and concentrated. The resulting residue was purified by column chromatography on silica gel, eluting with 0-15% ethyl acetate-hexane, to provide (2RS,4RS)-4-((tert-butyldiphenylsilyloxy)methyl)-2-(4-chloro-3-(trifluoro-methyl)phenyl)-2-methylcyclohexanone as a colorless gum (1.338 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.66 (m, 4 H), 7.53 (d, J=2.0 Hz, 1 H), 7.43 (m, 7 H), 7.26 (m, 1 H), 3.58 (dd, J=9.8, 5.5 Hz, 1 H), 3.48 (dd, J=9.8, 7.1 Hz, 3 H), 2.79 (dt, J=14.6, 3.0 Hz, 1 H), 2.33 (m, 2 H), 2.07 (m, 1 H), 1.93 (m, 1 H), 1.49 (dd, J=14.6, 12.6 Hz, 1 H), 1.41 (m, J=12.5, 4.9 Hz, 1 H), 1.26 (s, 3 H), 1.09 (s, 9 H).
Reaction SMILES: C([O:3][C@@H:4]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[CH:6]([C:7](=[O:24])[CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:23])[CH2:5]1)=O.C([O-])([O-])=O.[K+].[K+].Cl>CO>[OH:3][C@@H:4]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[CH:6]([C:7](=[O:24])[CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:23])[CH2:5]1
Reactant: C[C@]12CC[C@@H](OC=O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@]12CC[C@@H](O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3α-formyloxyandrostane-6,17-dione (2.20 g) in MeOH (100 mL), K2CO3 (2.70 g) was added and the mixture stirred at room temperature for 10 minutes, then HCl 1N (20 mL) was added, the phases were separated and the aqueous one extracted with EtOAc (2×). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness to give 3α-hydroxyandrostane-6,17-dione (quantitative yield), which was used in the next step without purification. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.35 (1H, d), 3.40 (1H, m), 2.40-0.95 (20H, m), 0.80 (3H, s), 0.69 (3H, s).
Reaction SMILES: C([N:8]([C@@H](C1C=CC=CC=1)C)[C@@H:9]1[CH2:13][CH2:12][CH2:11][C@:10]1([CH2:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])C1C=CC=CC=1.C(O)=O>CO.[Pd]>[NH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@:10]1([CH2:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15]
Reactant: CC[C@]1(C(=O)OC)CCC[C@H]1N(Cc1ccccc1)[C@H](C)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CC[C@]1(C(=O)OC)CCC[C@H]1N
Yield: 70.3 %

Procedure:
According to the procedure of Example 53, Step 2, using crude methyl (1S,2R)-2-{benzyl[(1R)-1-phenylethyl]amino}-1-ethylcyclopentanecarboxylate (1.103 g), 4.4% formic acid in methanol (30 mL) and 10% Pd/C (2 g), methyl (1S,2R)-2-amino-1-ethylcyclopentanecarboxylate (441 mg, 2.12 mmol, 21%) was obtained as a colorless solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.78 (t, J=7.45 Hz, 3H) 1.42 (ddd, J=21.10, 7.58, 7.45 Hz, 1H) 1.50-1.78 (m, 5H) 1.92 (ddd, J=21.03, 7.42 Hz, 1H) 2.01-2.12 (m, 1H) 2.16-2.26 (m, 1H) 3.31 (s, 1H) 3.68 (s, 3H) 8.15 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:10](S(O)(=O)=O)(O)[CH:11](S(O)(=O)=O)O.C(C=O)=O>O>[CH3:9][C:4]1[CH:3]=[C:2]2[C:7](=[CH:6][CH:5]=1)[N:8]=[CH:11][CH:10]=[N:1]2
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=S(=O)(O)C(O)C(O)S(=O)(=O)O
Agent: O=CC=O
Solvent: O
Product: Cc1ccc2nccnc2c1
Temperature: 60 °C
Yield: 77.8 %

Procedure:
A solution of 3,4-diaminotoluene (Aldrich, 100 g, 0.82 mol) in 600 mL of hot water (temp. 70-75° C.) was added rapidly to a 60° C. slurry of glyoxal-sodium bisulfite adduct (Aldrich, 239.5 g, 0.9 mol, 1.1 eq) in 400 mL of water. The resulting dark-brown clear solution was heated at 60° C. for 1 hr, then 5 g (0.02 mol) of additional glyoxal adduct was added. The mixture was allowed to cool to r.t. and filtered through a paper filter. The filtrate was neutralized with 5 M aq. NaOH to pH 7.5-7.8 and then extracted with ether (4×400 mL). The extract was dried over Na2SO4 and concentrated on a rotary evaporator to afford 92 g of brown oil which was distilled in vacuum (bp. 100-102° C. at 10 mm Hg; Cavagnol, J. C.; Wiselogle, F. Y. J. Am. Chem. Soc. 1947, 69, 795; 86° C. at 1 mm Hg). Yield 89 g (75%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=O)[CH2:11][C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N+:18]=[N-:19].C[O-].[Na+].[OH-].[Na+]>CO>[CH2:1]([O:8][CH2:9][C:10]1[N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[N:19][C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: COC(=O)CC(=O)COCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nnn(-c2ccccc2)c1COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
Methyl 4-(benzyloxy)-3-oxobutanoate (5.00 g) and azidobenzene (2.68 g) were dissolved in methanol (30 ml), sodium methanolate (28% methanol solution, 6.5 g) was added and the mixture was stirred at room temperature for 2 hr, and then heated under reflux for 18 hr. 1M Aqueous sodium hydroxide solution (10 ml) was added and the mixture was heated under reflux for 2 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water and washed with ethyl acetate-hexane (1:1, v/v). The obtained aqueous solution was acidified with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (6.03 g).