Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:12]([C:5]1([CH2:15][CH2:16][CH3:17])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[CH:3]=2)[S:8][CH2:7][CH2:6]1)[CH2:13][CH3:14]
Reactant: CCCC1(CCC)CCSc2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCC1(CCC)CCSc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 0 °C

Procedure:
A mixture of 2.04 g (6.54 mmol) of 6-bromo-4,4-dipropylthiochroman (Compound 29), 0.12 g(0.64 mmol) of copper (I) iodide and 5.4 g (54 mmol) of triethylamine was degassed using argon for 15 minutes at -78° C. To the suspension was added 1.95 g (19.8 mmol) of (trimethylsilyl)acetylene then 0.41 g (58 mmol) of bis(triphenylphosphine)palladium (II) chloride. The solution was degassed with argon for an additional 5 minutes and the resulting mixture was allowed to warm to 0° C. The tube was sealed and the mixture heated to 55° C. for 15 hours.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C@@H:7]([NH:12][CH3:13])[CH2:8][CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:24]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:1]([O:5][C:6](=[O:14])[C@@H:7]([N:12]([CH2:32][C:31]1[CH:34]=[CH:35][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][CH:30]=1)[CH3:13])[CH2:8][CH:9]([CH3:10])[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CN[C@@H](CC(C)C)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)OC(C)(C)C)N(C)Cc1ccc(C(C)(C)C)cc1
Temperature: 40 °C
Yield: 50 %

Procedure:
(S)-4-Methyl-2-methylamino-pentanoic acid tert-butyl ester (6 g, 29.8 mmol) was dissolved in THF (250 mL) and treated with diisopropylethylamine (7.8 mL, 44.7 mmol) and p-t-butyl-benzyl bromide (6.03 mL, 32.8 mL). The reaction was heated to 40° C. overnight, then filtered and concentrated. The residue was chromatographed on silica gel eluting with 5% EtOAc/hexanes to give 5.1 g (50%) of (S)-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[NH:13][C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=1)=[N:10][CH:11]=2.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[N:13]([CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=1)=[N:10][CH:11]=2
Reactant: COc1ccc(Cn2c(=O)[nH]c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Reactant: ICCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(=O)n(CCN3CCOCC3)c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
500 mg (0.980 mmol) of the compound from example 82A were dissolved in 10 ml of DMF, 414 mg (1.270 mmol) of cesium carbonate and 259 mg (1.08 mmol) of 4-(2-iodoethyl)morpholine were added and the mixture was stirred at RT for 18 h, at 40° C. for 18 h and at 100° C. for 8 h. After cooling, water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The purification was effected by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 102 mg (17% of theory) of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[CH2:14][NH:15][CH2:16][CH2:17][O:18][C:12]=3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[C:29]([O:33][C:34]([NH:36][CH2:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](O)=[O:42])=[O:35])([CH3:32])([CH3:31])[CH3:30].Cl.C(N=C=NCCCN(C)C)C>C(#N)C.C(OCC)(=O)C.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH2:14][N:15]([C:41]([C:40]4[CH:39]=[C:38]([CH:46]=[CH:45][CH:44]=4)[CH2:37][NH:36][C:34](=[O:35])[O:33][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:42])[CH2:16][CH2:17][O:18][C:12]=3[N:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Reactant: Fc1ccc(-c2ccnc3c2CNCCO3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCc1cccc(C(=O)N2CCOc3nccc(-c4ccc(F)cc4)c3C2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.8 %

Procedure:
To a solution of 6-(4-fluorophenyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.20 g) obtained in Reference Example 13C, 1-hydroxy-1H-benzotriazole (0.15 g), triethylamine (0.083 g) and 3-(tert-butoxycarbonylaminomethyl)benzoic acid (0.205 g) in acetonitrile (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.314 g), and the mixture was stirred at room temperature for 20 hrs. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound (0.35 g) as a colorless amorphous powder.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[NH:24][C:23](=S)[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:26]>CO>[C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:26])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C1CCCCC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)N1
Reactant: N
Solvent: CO
Product: NC1=NC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)CCCC1
Temperature: 50 °C

Procedure:
65 mg of 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione (compound A1) are suspended in 4.3 ml of methanol containing ammonia (strength: 7.0 M) and heated at 50° C. for 90 hours. Subsequently, the reaction mixture is evaporated to dryness and purified by flash chromatography on LiChroprep-NH2® (eluent gradient: dichloromethane/0-100 vol. % methanol), and lyophilized from 2.0 ml of water, 5.0 ml of dioxane to afford 29.5 mg of the title compound as an amorphous, colorless solid of m.p. 117° C. (decomp.). ESI-MS: 334.3 (MH+). TLC: Rf=0.35 (LiChroprep-NH2® HPTLC, methanol/water 10:1 parts by volume).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:22])[CH2:19][C:20]#[N:21])[CH3:16].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:15]([O:17][C:18](=[O:22])[C:19](=[C:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)[C:20]#[N:21])[CH3:16]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)CC#N
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C1CCN(Cc2ccccc2)CC1

Procedure:
To a solution of 1-benzyl-piperidin-4-one (75.1 g, 0.40 mol) in toluene (400 ml), cyano-acetic acid ethyl ester (50.6 ml, 0.48 mol) and acetic acid (18.2 ml, 0.32 mol) are added at ambient temperature. The reaction mixture is refluxed for 4 h, quenched with ice-water and extracted with diethyl ether. The combined extracts are washed with H2O, brine and dried over sodium sulphate to give (1-benzyl-piperidin-4-ylidene)-cyano-acetic acid ethyl ester in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:16])=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.[CH3:18][Mg]Br.C(OCC)C.C(Cl)(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:16])=[CH:9][CH:10]=3)[C:5](=[CH2:18])[C:4]=2[CH:3]=1
Reactant: C[Mg]Br
Reactant: O=c1c2cc(Br)ccc2oc2ccc(Cl)nc12
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C1c2cc(Br)ccc2Oc2ccc(Cl)nc21
Temperature: 0 °C

Procedure:
To a suspension of 8-bromo-2-chloro-10H-chromeno[3,2-b]pyridin-10-one (20 g, 64.4 mmol) in 500 mL of THF at −78° C. was added dropwise methylmagnesium bromide 3.0 M in diethyl ether (13.82 mL, 116 mmol). The reaction was allowed to slowly warmed up to 0° C. in about 2 h. The reaction was quenched with NH4Cl solution, extracted with EtOAc, dried over Na2SO4, filtered and evaporated to give the corresponding crude tertiary alcohol. This solid residue was re-dissolved in 100 mL of THF and treated with mL of chloroform and the resulting solution was evaporated on a 75° C. water bath for 10 min to give crude 8-bromo-2-chloro-10-methylene-10H-chromeno[3,2-b]pyridine as a brownish solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:26]([CH2:32][CH2:33][CH3:34])=[N:25][C:19]=3[C:20]([NH2:24])=[N:21][C:22]=2[CH:23]=1.N12CCCN=C1CCCCC2.O>C(Cl)(Cl)Cl>[O:6]=[S:5]1(=[O:7])[CH2:4][CH2:3][CH2:2][N:9]1[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:27]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:26]([CH2:32][CH2:33][CH3:34])=[N:25][C:19]=3[C:20]([NH2:24])=[N:21][C:22]=2[CH:23]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCc1nc2c(N)nc3cc(OCCCN)ccc3c2n1CC(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1nc2c(N)nc3cc(OCCCN4CCCS4(=O)=O)ccc3c2n1CC(C)C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
3-Chloropropanesulfonyl chloride (0.206 mL, 1.69 mmol) was added dropwise to a suspension of 7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.41 mmol) in chloroform (17 mL), and the reaction was stirred for 30 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in DMF (17 mL). 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.316 mL, 2.11 mmol) was then added, and the reaction was stirred for 18 hours. The reaction was poured into water, and the mixture was extracted twice with dichloromethane. The combined organic fractions were washed sequentially with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 97:3 dichloromethane:methanol) followed by recrystallization from acetonitrile to provide 0.237 g of 7-[3-(1,1-dioxidoisothiazolidin-2-yl)propoxy]-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as needle-like, white crystals, mp 142-144° C.
Reaction SMILES: [C:1]1([C:7]2([NH2:16])[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([NH:27][CH2:28][C:29](O)=[O:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[C:17]([NH:27][CH2:28][C:29]([NH:16][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15]1)=[O:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: NC1(c2ccccc2)Cc2ccccc2C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)OCc1ccccc1)NC1(c2ccccc2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a stirred solution of 2,3-dihydro-2-phenyl-1H-inden-2-amine (10.2 g, 0.049 mol) in chloroform (200 mL) were added N-CBZ-glycine (10.8 g. 0.052 mol) and then a solution of dicyclohexylcarbodiimide (11.1 g, 0.053 mol) in chloroform (70 mL). The mixture was stirred for 18 hours at ambient temperature. The mixture was filtered and the solvent was evaporated. The residue was dissolved in ethyl acetate (200 mL) and filtered again. The filtrate was washed with 1N hydrochloric acid (2×100 mL), 2N sodium carbonate (2×100 mL), brine (100 mL) and dried over magnesium sulfate. The solvent was then evaporated. The residue was recrystallized from ethyl acetate (75 mL) and cyclohexane (150 mL) to provide 17.1 g of 2-[(carbobenzoxy)amino]-N-(2,3-dihydro-2-phenyl-1H-inden-2-yl)acetamide, mp 63°-70° C. To a solution of the latter (14.3 g, 0.037 mol) in methanol (200 mL), tetrahydrofuran (75 mL) and IN hydrochloric acid (70 mL), was added 10% palladium on carbon (1.4 g). The mixture was shaken on a Parr apparatus for 1.5 hours. The catalyst was removed by filtration, the solvents evaporated and the residue dissolved in chloroform (200 mL) and 2N sodium carbonate (200 mL). The aqueous layer was extracted with chloroform (2×100 mL). The combined chloroform extracts were washed with brine (100 mL), dried over magnesium sulfate, and the solvent evaporated. The residue was dissolved in methanol (50 mL) and 2-propanol (75 mL) and acidified with HCl gas. The solid which formed was collected by filtration and vacuum dried at 80° C. for 3 days to provide 7.3 g of 2-amino-N-(2,3-dihydro-2-phenyl-1H-inden-2-yl)acetamide, mp 275°-276° C.
Reaction SMILES: Cl.C([N:9]1[CH2:17][C:16]2[C:15]([Cl:18])=[N:14][C:13]([Cl:19])=[N:12][C:11]=2[CH2:10]1)C1C=CC=CC=1.C(N(CC)CC)C.ClC(OC(Cl)C)=O.O>ClCCCl>[ClH:18].[Cl:19][C:13]1[N:14]=[C:15]([Cl:18])[C:16]2[CH2:17][NH:9][CH2:10][C:11]=2[N:12]=1
Reactant: Clc1nc(Cl)c2c(n1)CN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1nc(Cl)c2c(n1)CNC2
Yield: 54 %

Procedure:
6-Benzyl-2,4-dichloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride (0.500 g, 0.00158 mol) prepared according to Process Step 2 was dissolved in 1,2-dichloroethane (15 mL), and the solution was mixed with triethylamine (0.160 g, 0.00158 mol) added dropwise under ice-cooling. The resulting solution was mixed with 1-chloroethyl chloroformate (0.680 g, 0.00478 mol) added dropwise at room temperature, followed by stirring under reflux for three hours. The reaction mixture was mixed with water (20 mL), followed by shaking and separation. The organic layer was dried over anhydrous magnesium sulfate, and was concentrated under reduced pressure. The residue was dissolved in methanol (15 mL), followed by reflux of the solution for one hour. After standing the reaction mixture to cool, methanol was distilled off under reduced pressure, to thereby yield 2,4-dichloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride (0.19 g, in a yield of 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].[Br:35][CH2:36][CH2:37]Br.O>CN(C)C=O>[Br:35][CH2:36][CH2:37][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:2]([Cl:1])[CH:7]=3)=[CH:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1Cl
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCBr)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N′-propylurea, 100 mg), potassium carbonate (172 mg), and 1,2-dibromoethane (0.086 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give an intermediate (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-propylurea). The intermediate, potassium carbonate (138 mg), and morpholine (0.17 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 70 mg (yield 54%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[C:32]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.[C:43](Cl)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:43]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[C:32]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CN)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CNC(=O)c3ccccc3)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1

Procedure:
In analogy to the procedure described under (d), from tert-butyl (3RS,4RS)-4-(4-aminomethyl-phenyl)-3-[4-(2-trimethylsilyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate by acylation with benzoyl chloride there was obtained crude tert-butyl (3RS,4RS)-4-[4-(benzoylamino-methyl)-phenyl]-3-[4-(2-trimethylsilyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate, which was used in the following step without further purification and characterization.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:12]([SH:15])[NH:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[CH2:23][CH:24]=[O:25]>C1COCC1.O.CCOC(C)=O.C([O-])(O)=O.[Na+]>[OH:25][CH:24]1[CH2:23][S:15][C:12]2=[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:14][N:13]12
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]c(S)c2-c2ccncc2)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2nn3c(c2-c2ccncc2)SCC3O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
5-(3-Nitro-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol (prepared as described in Example 1) (3.92 g, 13.14 mmol) was dissolved in a 1:1 THF/water mixture (130 mL). Chloroacetaldehyde (55% in water, 2.31 mL, 19.71 mmol, 1.5 eq) was added and the solution was stirred at room temperature overnight. The reaction mixture was diluted with AcOEt and saturated aqueous NaHCO3. The organic phase was washed with saturated aqueous NaHCO3 and brine, dried and evaporated to dryness. 3.25 g of crude product were obtained as yellow solid (72%), which was used in the following step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:13])[O:2][CH:3]1[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.[CH3:15][C:16]([NH2:29])([C:25]([O:27][CH3:28])=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.Cl.CCOC(C)=O.C(N(CC)CC)C>C1COCC1>[CH3:15][C:16]([C:25]([O:27][CH3:28])=[O:26])([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[NH:29][C:1]([O:2][CH:3]1[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)=[O:13]
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: COC(=O)C(C)(N)Cc1ccc(O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(Cc1ccc(O)cc1)NC(=O)OC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tricyclo[3.3.1.13,7 ]dec-2-yl carbonchloridate [5.77 g, 0.026 mmol, prepared from 2-adamantanol and his (trichloromethyl)carbonate (Horwell, D. C., et al, J. Med. Chem. 1991, 34,404-414)] in 60 mL THF, a solution of DL-α-methyltyrosine methyl ester (5.0 g, 0.0238 mol, prepared from the DL-α-methyltyrosine methyl ester hydrochloride using 1M K2CO3 and EtOAc) in 320 mL THF was added dropwise via an addition funnel, keeping the temperature below 25° C. A solution of triethylamine (4.81 g, 0.047 mol) in 120mL THF was then added dropwise and the heterogeneous reaction mixture was stirred for 16 hours at room temperature under a nitrogen atmosphere. The amine salt was filtered and the filtrate was concentrated in vacuo to givea tan, fluffy solid. Purification by flash chromatography (silica gel, 10% EtOAc/hexane) yielded the title compound. MS: 388 (MH+); 387 (M+).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.C[Li].[CH2:17](OCC)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][C:25]=1[C:34]([F:37])([F:36])[F:35]>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:6]2[CH:7]([CH3:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)(=[O:32])=[O:31])=[CH:26][C:25]=1[C:34]([F:37])([F:36])[F:35]
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: CCOCC
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(F)(F)F
Agent: [Li]C
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1C(F)(F)F
Yield: 44.2 %

Procedure:
The title compound was prepared from phenanthridine (5.38 g, 30 mmol), 1.4 M methyllithium in diethyl ether (21.8 mL, 30.5 mmol), and 4-methoxy-3-(trifluoromethyl)benzenesulfonyl chloride (8.24 g, 30 mmol) according to the procedure and in the same manner as described in Example 1, step a. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:8) to yield 5-{[4-methoxy-3-(trifluoromethyl)phenyl]sulfonyl}-6-methyl-5,6-dihydrophenanthridine (5.75 g, 13.27 mmol, 44%) as a white solid;
Reaction SMILES: [CH:1]1([CH2:5][C@@:6]2([CH3:19])[C:11](=[O:12])[O:10]C[C@H](C3C=CC=CC=3)[NH:7]2)[CH2:4][CH2:3][CH2:2]1>[OH-].[OH-].[Pd+2].C(O)C.O.FC(F)(F)C(O)=O>[NH2:7][C@@:6]([CH3:19])([CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)[C:11]([OH:12])=[O:10]
Reactant: C[C@@]1(CC2CCC2)N[C@@H](c2ccccc2)COC1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: O
Product: C[C@](N)(CC1CCC1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 12.7 %

Procedure:
Pearlman's catalyst (0.5 g) was added to a solution of (3S,5S)-3-(cyclobutylmethyl)-3-methyl-5-phenylmorpholin-2-one (0.445 g, 1.7 mmol, Preparation 5) in ethanol (15 ml), water (2 ml) and trifluoroacetic acid (0.5 ml). The reaction was stirred under hydrogen gas (414 kPa, 60 psi) at room temperature for 24 hours. The reaction mixture was filtered through Arbocel® and washed with ethanol (20 ml). The liquor was evaporated under reduced pressure and the residue was partitioned between dichloromethane (50 ml) and water (50 ml). The organic layer was removed and the aqueous phase was extracted with more dichloromethane (50 ml). The water layer was evaporated under reduced pressure to give a yellow solid. The product was purified by ion exchange chromatography on Dowex 50 WX8 resin, eluting with 0.88 aqueous ammonia:water (2:98 to 14:86) to give the title compound (0.034 g) as a white solid.