Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]([NH:12][CH2:13][CH2:14][C:15]1[C:19]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=2[NH:17][CH:16]=1)=[O:11].[OH-].[Na+]>C(O)(=O)C>[CH3:9][C:10]([NH:12][CH2:13][CH2:14][C:15]1[C:19]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=2[NH:17][C:16]=1[Br:1])=[O:11]
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(Br)c(CCNC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
N-bromo succinimide (0.89 g, 5 mmol) was added to a solution of melatonin (1.16 g, 5 mmol) in acetic acid (20 mL). The reaction mixture was stirred under N2 at room temperature for 4 h, then cooled at 0° C., neutralized with a 50% solution of NaOH and extracted with ethyl acetate. The combined organic layers were washed with NaCl solution, dried (Na2SO4) and concentrated. Purification by flash chromatography (silica gel; ethyl acetate/cyclohexane 6:4) and crystallization gave 0.467 g (30% yield) of 4k as white solid, mp 141°-142° C. IR νmax : 3460, 3300, 1650. 1H NMR: 1.99 (s, 3H, COCH3); 2.92(t, 2H, β -CH2), 3.54(q, 2H, α-CH2), 3.86(s, 3H, OCH3), 5.53(br s, 1H, NH), 6.85-7.23(m, 3Harom), 8.15(br s, 1H, NHindole).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([OH:13])[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:15](OCC)=[O:16].Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10](=[O:11])[NH:12][C:15](=[O:16])[O:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)N(O)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(=O)n(-c2ccc(Cl)c(Cl)c2)o1
Reaction time: 0.5 h

Procedure:
1-(3,4-Dichlorophenyl)-1-hydroxyurea (6.0 grams) dissolved in aqueous sodium hydroxide (13 ml; 2.0 M) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of 10° to 15°C and ethyl chloroformate (2.5 ml) is slowly added with stirring resulting in the formation of a white precipitate. After the addition is completed stirring is continued for a period of about 1/2 hour. After this time the reaction mixture is poured into a water-ice mixture and is treated with 6 N hydrochloric acid until the mixture is acidic. The solid product is then recovered by filtration and is dissolved in methylene chloride. The resulting solution is dried over anhydrous magnesium sulfate and is stripped of solvent. The remaining solid residue is then recrystallized from toluene to yield the desired product 2-(3,4-dichlorophenyl)-1,2,4-oxadiazolidin-3,5-dione having a melting point of 126° to 127.5°C.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([CH3:23])=[CH:13][C:14]([CH:21]=C)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.CC(C)=[O:28].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][C:11]3[C:12]([CH3:23])=[CH:13][C:14]([CH:21]=[O:28])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:24][CH:25]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)=O
Reactant: C=Cc1cc(C)c(Cc2ccc(-n3cccn3)cc2)cc1C(=O)OC
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-methyl-2-vinylbenzoate (0.31 g) in a mixed solvent of acetone (6.20 mL)-acetonitrile (6.20 mL)-water (6.20 mL) were added osmium oxide (fixed catalyst I) (0.12 g) and sodium periodate (1.00 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.16 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: CS[C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)([CH3:7])[C:4]([OH:6])=[O:5].[Na].C(O)C>C(O)(C)(C)C.O1CCCC1>[O:14]([C:10]1[CH:9]=[C:8]([CH:3]([CH3:7])[C:4]([OH:6])=[O:5])[CH:13]=[CH:12][CH:11]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CSC(C)(C(=O)O)c1cccc(Oc2ccccc2)c1
Agent: [Na]
Solvent: CC(C)(C)O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
α-Methylthio-α-(m-phenoxyphenyl)propionic acid (288 mg) was dissolved in a mixture of 1 ml of t-butanol and 4 ml of tetrahydrofuran, and 100 mg of metallic sodium was added. The mixture was stirred at room temperature for 10 minutes. The mixture was heated under reflux for an additional 1.5 hours with stirring. After cooling, a small amount of ethanol was added to consume the unreacted metallic sodium completely. Water (20 ml) was added, and the pH of the mixture was adjusted to 1 with conc. hydrochloric acid. The mixture was extracted three times with 27 ml of diethyl ether. The extract was washed twice with 20 ml of water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and chromatographed on a silica gel column using methylene chloride as an eluent to afford 234 mg of α-(m-phenoxyphenyl)propionic acid in a yield of 97%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH:13]C(OCC2C=CC=CC=2)=O)[CH:5]=1.O>[Pd].CO>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH2:13])[CH:5]=1
Reactant: CCOc1cc(NC(=O)OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCOc1cc(N)cc(C(=O)OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A mixture of 3-benzyloxycarbonylamino-5-ethoxy-benzoic acid methyl ester (D47) (15 g, 45.5 mmol, 1 equiv), 10% palladium on charcoal (50% wet, 1.5 g, 5% w/w) and NH4COOH (15 g, 455 mmol, 10 equiv) H2O (50 ml) and MeOH (200 ml) was stirred at 50° C. for 2 h. The mixture was cooled to room temperature and the catalyst was filtered off through a pad of celite. Most of the MeOH was removed in vacuo and the residue was partitioned between saturated aqueous NaHCO3 solution and AcOEt. The aqueous phase was re-extracted with AcOEt. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give 3-amino-5-ethoxy-benzoic acid methyl ester (D49) (8.8 g, 99%) as a pale green solid which was used in the next step without further purification. [M+H]+=196.1, RT=2.49 min
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]=[CH:9][CH:8]=[C:7]2[OH:15])[CH3:2].[Br:16]Br>C(O)(=O)C.S(=O)(O)[O-].[Na+]>[Br:16][C:8]1[CH:9]=[N:10][C:11]2[C:6]([C:7]=1[OH:15])=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[C:13]([CH3:14])[N:12]=2
Reactant: BrBr
Reactant: CCOc1cc2c(O)ccnc2nc1C
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1cc2c(O)c(Br)cnc2nc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 6-ethoxy-7-methyl-1,8-naphthyridin-4-ol, (5.0 g) in glacial acetic acid (60 ml) was stirred at between 15°-20° C. while a solution of bromine (2.4 ml) in glacial acetic acid (10 ml) was added dropwise over 10 minutes. The mixture was stirred at ambient temperature for 1.5 hours and then filtered. The residue was washed with water, ground up in water and the mixture basified with sodium bicarbonate and filtered. The solid obtained was ground in sodium bisulphite solution and filtered to give 3-bromo-6-ethoxy-7-methyl-1,8-naphthyridin-4-ol, m.p. 266°-267° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:20]([O:19][C:17](=[O:18])[NH:16][CH2:15][CH2:14][C@H:11]1[CH2:10][CH2:9][C@@H:8]([NH2:7])[CH2:13][CH2:12]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CCNC(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@@H](CCNC(=O)OCc2ccccc2)CC1
Yield: 90.5 %

Procedure:
A solution of cis-[4-(2-benzyloxycarbonylamino-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (5.26 g, 14 mmol) in 50% TFA in CH2Cl2 (60 mL) was stirred at ambient temperature for 1 hr. The mixture was concentrated and the residue was diluted with saturated aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2 (therr times). The organic layer was dried over Na2SO4 and concentrated to give cis-[2-(4-amino-cyclohexyl)-ethyl]-carbamic acid benzyl ester (3.5 g, 91%) as a colorless oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.C(O[C:17](=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=2)[NH:26][C:25]1=[O:36])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C>CN(C=O)C>[N:1]1([CH2:6][C:7]2[CH:13]=[CH:12][C:10]([NH:11]/[C:17](=[C:24]3\[C:25](=[O:36])[NH:26][C:27]4[C:32]\3=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:9][CH:8]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: Nc1ccc(CN2CC=CC2)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CN2CC=CC2)cc1)c1ccccc1

Procedure:
Prepared from 4-(2,5-dihydro-pyrrol-1-ylmethyl)aniline and 3-(1-ethoxy-1-phenylmethylidene)-5-nitro-2-indolinone in DMF.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1.[NH2:19][C:20]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:21]=1[C:22]([N:24]([CH3:26])[CH3:25])=[O:23]>>[ClH:1].[Cl:31][C:28]1[CH:29]=[CH:30][C:20]([NH:19][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[CH2:7][CH2:6]2)=[C:21]([CH:27]=1)[C:22]([N:24]([CH3:26])[CH3:25])=[O:23]
Reactant: CN(C)C(=O)c1cc(Cl)ccc1N
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Product: COc1ccccc1N1CCN(CCCNc2ccc(Cl)cc2C(=O)N(C)C)CC1
Product: Cl

Procedure:
Proceeding as in Example 26, but reacting 1-chloro-3-[4-(2-methoxyphenyl)-piperazin-1-yl]propane with 2-amino-5-chloro-N,N-dimethylbenzamide gave 5-chloro-2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamino}-N,N-dimethylbenzamide hydrochloride, m.p. 100°-108° C.; Anal.: Calcd. for C23H31ClN4O2.(HCl)2.(H2O)0.75 : C, 57.38; H, 7.02; N, 11.65%; Found: C, 57.47; H, 6.94 ; N, 11.48%;
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]#[C:17][Si](C)(C)C)[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]([NH:22]C(=O)C(C)(C)C)[NH:3]1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CO.O>[NH2:22][C:4]1[NH:3][C:2](=[O:1])[C:11]2[C:10]3[CH:12]=[C:13]([C:16]#[CH:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(C#C[Si](C)(C)C)cc3c2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: C#Cc1ccc2ccc3nc(N)[nH]c(=O)c3c2c1
Yield: 58.5 %

Procedure:
A solution of N-(1,2-dihydro-1-oxo-9-(trimethylsilylethynyl)benzo[f]quinazolin-3-yl)pivalamide (0.24 g, 0.61 mmol) and K2CO3 (0.50 g, 3.6 mmol) in methanol (˜50 ml) was stirred at reflux for 2.5 hours. The solution was then diluted with water (˜20 ml) acidified with acetic acid, and the resulting solid filtered and dried at 90° C. under reduced pressure. The solid was resuspended in ethanol (˜20 ml), filtered, and dried to give 3-amino-9-ethynyl benzo[f]quinazolin-1(2H)-one (0.084 g) as a tan solid. 1H NMR (DMSO-d, 200 MHz) δ: 4.26 (s, 1H, ethynylCH), 6.63 (br s, 2H, NH2), 7.32 (d, J=9 Hz, 1H, Ar), 7.47 (dd, J=8, 2 Hz, 1H, Ar), 7.87 (d, J=8 Hz, 1H, Ar), 8.02 (d, J=9 Hz, 1H, Ar), 9.78 (s, 1H, Ar), 11.34 (br s, 1H, NH). Mass spectrum (CI-CH4): 236 (M+1, 100%). Anal. Calculated for C14H9N3O: C, 71.48; H, 3.86; N, 17.86. Found: C, 71.30; H, 3.92; N, 17.68.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23]>CO.C(Cl)Cl>[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH:23][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)CN
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CNC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and glycine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=158-160° C.). The reaction was monitored by tlc (Rf=0.61 in 10%MeOH/DCM) and the product was purified by silica gel chromatography.
Reaction SMILES: Cl[C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:15])[CH:3]=1.[CH3:16][S:17]([O-:19])=[O:18].[Na+].O.Cl>CN(C)C=O>[CH3:16][S:17]([C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:15])[CH:3]=1)(=[O:19])=[O:18]
Reactant: CS(=O)[O-]
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)O
Temperature: 0 °C
Yield: 53.9 %

Procedure:
6 kg of 4-chloro-2-methyl-5-(methylsulfonyl)benzoic acid are dissolved in 15 l of N,N-dimethylformamide (DMF) at room temperature (25°) and subsequently warmed to 50°. 3.6 kg of sodium methanesulfinate are added to this solution. The internal temperature is then raised to 120° and stirred at this temperature for 2 days, with a further 3 kg of sodium methanesulfinate being added after 24 hours. After cooling to 25°, the reaction mixture is introduced into 40 l of water, and 300 g of activated carbon and 1 kg of kieselguhr are added. 5 l of ice are added to the filtrate, and 3.5 l of concentrated hydrochloric acid are added dropwise (pH=1). Recrystallisation from 2-propanol gives 3.8 kg of 4,5-bismethanesulfonyl-2-methylbenzoic acid; m.p. 234-235°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:11].[C:12]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)(OC(C)(C)C)=O.[C:26]1(=O)[CH2:29]C[CH2:27]1.O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[S:38]([C:35]1[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=1)([OH:41])(=[O:40])=[O:39].[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH:22]1[CH2:21][CH2:20][N:19]([CH:12]2[CH2:29][CH2:26][CH2:27]2)[CH2:24][CH2:23]1)[NH2:8]
Reactant: O=C1CCC1
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Nc1ccc(OC2CCN(C3CCC3)CC2)c(Br)c1

Procedure:
3-bromo-4-[(1-cyclobutylpiperidin-4-yl)oxy]aniline was obtained according to the method of Example 94, using 2-bromo-4-nitrophenol, N-Boc-4-piperidinol and cyclobutanone as starting materials. By treating this with 1 Eq of p-toluenesulfonic acid monohydrate, the target compound was obtained as a colorless solid. 2-bromo-4-nitrophenol was manufactured by the method described in the literature (J. Org. Chem., Vol. 62, 1997, p. 4504).
Reaction SMILES: CN1C(C)(C)C(=O)N(C)C1=O.[F:12][C:13]1[CH:30]=[C:29]2[C:16]([S:17](=[O:32])(=[O:31])[NH:18][C:19]3[C:28]2=[CH:27][CH:26]=[C:25]2[C:20]=3[N:21]=[CH:22][CH:23]=[CH:24]2)=[CH:15][CH:14]=1.C(Cl)(Cl)[Cl:34]>>[Cl:34][C:26]1[CH:27]=[C:28]2[C:19](=[C:20]3[C:25]=1[CH:24]=[CH:23][CH:22]=[N:21]3)[NH:18][S:17](=[O:31])(=[O:32])[C:16]1[C:29]2=[CH:30][C:13]([F:12])=[CH:14][CH:15]=1
Reactant: ClC(Cl)Cl
Reactant: O=S1(=O)Nc2c(ccc3cccnc23)-c2cc(F)ccc21
Agent: CN1C(=O)N(C)C(C)(C)C1=O
Product: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Temperature: 70 °C
Yield: 69 %

Procedure:
1,3-dimethyl-5,5-dimethylhydantoin (0.73 g, 36.7 mmol) was added to a solution of 9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 187 (1.0 g, 33.3 mmol) in chloroform (40 ml) and the reaction was heated at 70° C. until the starting material was consumed (LCMS). After cooling, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with sodium metabisulfate, water and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (99:1) as the eluent to give the title compound (0.8 g, 69%).
Reaction SMILES: [Si](OC[C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:26]([CH2:27][CH2:28][C@:11]12C)[C@:24]1([CH3:25])[C@H:19]([CH:20]=[C:21]([C:29]([O:31][CH3:32])=[O:30])[CH2:22][CH2:23]1)[CH2:18][CH2:17]3)(C(C)(C)C)(C)C.C[C:34]([CH3:36])=[O:35].[OH:37]S(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[C:29]([C:21]1[CH2:22][CH2:23][C@@:24]2([CH3:25])[CH:19]([CH2:18][CH2:17][C@@H:16]3[C@@H:26]2[CH2:27][CH2:28][C@@:11]2([CH3:10])[C@H:13]3[CH2:14][CH2:15][C@@H:36]2[C:34]([OH:37])=[O:35])[CH:20]=1)([O:31][CH3:32])=[O:30]
Reactant: CC(C)=O
Reactant: O=S(=O)(O)O
Reactant: COC(=O)C1=C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](CO[Si](C)(C)C(C)(C)C)CC[C@@H]34)[C@@]2(C)CC1
Agent: O=[Cr](=O)=O
Solvent: CC(C)O
Product: COC(=O)C1=CC2CC[C@H]3[C@@H]4CC[C@H](C(=O)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Yield: 99 %

Procedure:
Methyl 17β-(t-butyldimethylsilyloxymethyl) -5α-androst-3-ene-3-carboxylate (500 mg), was dissolved in 150 ml acetone. Jones reagent was added until a red color persisted. Isopropanol was then added to quench excess Jones reagent. The acetone was decanted off and the residual chromium salts were then dissolved in water and washed 3 times with dichloromethane. The organic layers were combined and passed through a plug of florosil and concentrated to give 360 mg (99%) of 3-carbomethoxy-3-androstene-17β-carboxylic acid.
Reaction SMILES: [CH:1]1([C@@:4]2([CH2:11][NH:12]C(=O)OC(C)(C)C)[C:8](=[O:9])[NH:7][C:6](=[O:10])[NH:5]2)[CH2:3][CH2:2]1.[ClH:20]>CO.O1CCOCC1.C1(C)C=CC=CC=1>[ClH:20].[NH2:12][CH2:11][C@@:4]1([CH:1]2[CH2:2][CH2:3]2)[NH:5][C:6](=[O:10])[NH:7][C:8]1=[O:9]
Reactant: CC(C)(C)OC(=O)NC[C@@]1(C2CC2)NC(=O)NC1=O
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: NC[C@@]1(C2CC2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
tert-butyl N-[[(4R)-4-cyclopropyl-2,5-dioxo-imidazolidin-4-yl]methyl]carbamate (310 g, 1151 mmol) is dissolved in MeOH (3.1 L) at 6° C. 4M HCl in dioxane (310 mL) is added and the mixture warmed to 25° C. After stirring for 22 h, a second portion of 4M HCl in dioxane (110 mL) is added and stiffing continued for an additional 16 h. The reaction is then allowed to sit with no agitation for 2 days. The mixture is then diluted with toluene (6 L). The title compound is collected by filtration of the mixture as a white solid (180 g).
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1.Cl.[CH3:17][O:18][C:19](=[O:26])[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1>Cl.B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]>[CH3:5][O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([N:14]=[N:1][C:23]2[NH:24][CH:25]=[C:21]([CH2:20][C:19]([O:18][CH3:17])=[O:26])[N:22]=2)=[CH:10][CH:9]=1
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COC(=O)Cc1c[nH]cn1
Agent: Cl
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Product: COC(=O)Cc1c[nH]c(N=Nc2ccc(C(=O)OC)cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution (5.1 mL) of sodium nitrite (4.5 mmol, 311 mg) was cooled in an ice bath and added to a mixture of 694 mg (4.5 mmol) of 4-amino-benzoic acid methyl ester in 2.36 N aq. HCl (7.5 mL) at 0° C. The mixture was stirred at 0° C. for 30 min, and the reaction mixture was added to a mixture of 795 mg (4.5 mmol) of (1H-imidazol-4-yl)-acetic acid methyl ester hydrochloride in saturated aqueous sodium tetraborate solution (150 mL). The mixture was stirred at 0° C. for 1.5 h and slowly warmed up to room temperature. The 4-(4-Methoxycarbonylmethyl-1H-imidazol-2-ylazo)-benzoic acid methyl ester was obtained after filtering and washing with water in a quantitative yield. LCMS: 303 (M+1)+.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[ClH:22].[C:23]1([C:29]2[NH:30][C:31]([CH3:37])=[C:32]([CH:34]([Cl:36])[CH3:35])[N:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.O>[ClH:36].[ClH:22].[ClH:36].[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH:34]([C:32]3[N:33]=[C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[NH:30][C:31]=3[CH3:37])[CH3:35])[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Cc1[nH]c(-c2ccccc2)nc1C(C)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1[nH]c(-c2ccccc2)nc1C(C)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
14 Grams (0.052 mol) of N-(diphenylmethyl)piperazine and 6 grams (0.15 mol) of sodium hydroxide were dissolved in 180 ml of a mixture of ethanol:water 60:40. The mixture was heated to reflux, then 2-phenyl-4-(1-chloroethyl)-5-methylimidazole hydrochloride in 180 milliliters of ethanol:water 60:40 were added dropwise. After 4 to 5 hours under reflux, the reaction mixture was allowed to cool to room temperature. The oil that separated was washed twice with water, then dissolved in ether and hydrochloric acid was added. The precipitate was recrystallized from ethanol to give 1-diphenylmethyl-4-[1-(2-phenyl-5-methyl-1H-imidazol-4-yl)ethyl]piperazine trihydrochloride, which melted at 215° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]#[C:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.Cl[CH2:34][C:35]1[CH:44]=[C:43]([O:45][CH3:46])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]=1[O:47][CH3:48]>>[CH3:48][O:47][C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]([O:45][CH3:46])=[CH:44][C:35]=1[CH2:34][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]#[C:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC#CCOc3ccccc3)cc2)C(O)C1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCC#CCOc3ccccc3)cc2)c(OC)c2ccccc12

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(4-phenoxy-but-2-ynyloxy)-phenyl]-piperidine-1-carboxylate with 2-chloromethyl-1,4-dimethoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-[4-(4-phenoxy-but-2-ynyloxy)-phenyl]-piperidine-1-carboxylate as a pale yellow solid; MS: 638 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[NH:17])[NH:15]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[H][H]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[NH:15])[NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Reactant: [H][H]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(C(=N)N)CC1
Yield: 114.6 %

Procedure:
Dissolve 4-(N-Hydroxycarbamimidoyl)-piperidine-1-carboxylic acid tert-butyl ester (9.7 g 1.00 equiv; 39.9 mmoles) in methanol (300 mL) and add acetic acid (2 equiv, 79.73 mmoles; 4.6 mL), and methanol washed Raney Nickel (2.7 g). Heat the reaction to 50° C., then hydrogenate with 1 ATM hydrogen gas for 4.5 hours. Filter the reaction mixture through Celite and concentrate under reduced pressure. Suspend the solid in diethyl ether, filter and dry under reduced pressure to give 10.39 g of 4-carbamimidoyl-piperidine-1-carboxylic acid tert-butyl ester.