Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[C:16]3[CH:17]=[CH:18][C:19]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:20][C:15]=3[N:14]=[CH:13]1)[CH:8]=[CH:7]2.[OH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:25][O:24][CH2:23][CH2:22][O:21][C:19]1[CH:18]=[CH:17][C:16]2[N:12]([C:9]3[CH:8]=[CH:7][C:6]4[C:11](=[C:2]([C:30]5[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=5)[CH:3]=[CH:4][CH:5]=4)[N:10]=3)[CH:13]=[N:14][C:15]=2[CH:20]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: COCCOc1ccc2c(c1)ncn2-c1ccc2cccc(Br)c2n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COCCOc1ccc2c(c1)ncn2-c1ccc2cccc(-c3ccc(O)cc3)c2n1
Temperature: 105 °C
Yield: 60.3 %

Procedure:
8-Bromo-2-[5-(2-methoxy-ethoxy)-benzoimidazol-1-yl]-quinoline 61F (585 mg, 1.47 mMol), was dissolved in 10 mL of dioxane under an atmosphere of dry N2. To this solution were added 4-hydroxyphenyl boronic acid (240 mg, 1.74 mMol), potassium phosphate (620 mg, 2.92 mMol) and tetrakis(triphenylphosphine)palladium (0) (85 mg, 0.074 mMol). The reaction mixture was heated to 105° C. and reacted at this temperature for 48 hours. The reaction mixture was then cooled to ambient temperature, concentrated under vacuum and partitioned between DCM and aqueous saturated NaHCO3. The DCM layer was then washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to give a yellow residue. The residue was chromatographed on flash silica gel eluting with MeOH/DCM/NH4OH (297.90.1) to give 365 mg of a white foam as the title compound 61.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH:11]1[CH:12]=[CH:13][N:14]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2ncc[nH]2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2ncc[nH]2)cc1

Procedure:
A solution of 95 mg (0.5 mmol) of 2-(4-nitrophenyl)-1H-imidazole in 3 ml of ethanol was hydrogenated in the presence of 20 mg of palladium (10% on activated carbon) at RT and standard pressure. The reaction mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure and dried. Yield: 91 mg (quant.)
Reaction SMILES: [NH2:1][C:2]1([C:5]2[C:6]([F:25])=[CH:7][C:8]3[C:18](=[O:19])[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][N:10]4[C@@H:11]([CH3:15])[CH2:12][O:13][C:14]=2[C:9]=34)[CH2:4][CH2:3]1.[C:26](OC(=O)C)(=[O:28])[CH3:27].O>C(Cl)Cl>[C:26]([NH:1][C:2]1([C:5]2[C:6]([F:25])=[CH:7][C:8]3[C:18](=[O:19])[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][N:10]4[C@@H:11]([CH3:15])[CH2:12][O:13][C:14]=2[C:9]=34)[CH2:3][CH2:4]1)(=[O:28])[CH3:27]
Reactant: CCOC(=O)c1cn2c3c(c(C4(N)CC4)c(F)cc3c1=O)OC[C@@H]2C
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cn2c3c(c(C4(NC(C)=O)CC4)c(F)cc3c1=O)OC[C@@H]2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
In 33 ml of methylene chloride was suspended 6.43 g of ethyl (S)-10-(1-aminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine- 6-carboxylate. To the resulting suspension was added 2.27 g of acetic anhydride with ice-cooling. The resulting mixture was stirred at room temperature for 1 hour, and 30 ml of water was added to the reaction mixture. The resulting crystals were collected by filtration to obtain 5.85 g (yield: 81.1%) of ethyl (S)-10-(1-acetylaminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH:14]2[C:22]3[C:17](=[CH:18][C:19]([C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[C:25]#[N:26])=[CH:20][CH:21]=3)[CH2:16][CH2:15]2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C[Sn]([N:35]=[N+:36]=[N-:37])(C)C>C1(C)C(C)=CC=CC=1>[CH2:1]([C:3]1[N:13]([CH:14]2[C:22]3[C:17](=[CH:18][C:19]([C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[C:25]4[NH:37][N:36]=[N:35][N:26]=4)=[CH:20][CH:21]=3)[CH2:16][CH2:15]2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1C1CCc2cc(-c3ccccc3C#N)ccc21
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCc1nc2c(C)cc(C)nc2n1C1CCc2cc(-c3ccccc3-c3nnn[nH]3)ccc21
Temperature: 23 °C
Yield: 39.7 %

Procedure:
A mixture of 2-[1-(2-ethyl-5,7-dimethyl-imidazo[4,5-b]pyridin-3-yl)-indan-5-yl]-benzonitrile (100 mg, 0.26 mmol) and trimethyltin azide (110 mg, 0.51 mmol) in xylene (3.0 mL) was heated under reflux for 48 hours. The reaction mixture was cooled to 23° C. and the solvent was removed in vacuo. The crude residue was chromatographed on SiO2 -gel using 10% MeOH/CH2Cl2 to afford 45 mg of the tetrazole, mp-181 ° C. 1H NMR (250 MHz, d6 -DMSO): d 7.64 (m, 1 H), 7.53 (m, 1 H), 7.15 (s, 1 H), 6.91 (s, 1 H), 6.80 (d, 1 H), 6.70 (d, 1 H), 6.48 (m, 1 H), 3.04 (m,2 H), 2.68 (2H, m) 2.49 (s, 3 H), 2.42 (s, 3 H), 1.25 (t, 3 H); MS (M+): 435
Reaction SMILES: [Cl:1][CH:2]1[CH:12]=[CH:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=[O:7].BrBr.ClCl.Br>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C2CC(Cl)C=CC12
Agent: Br
Agent: BrBr
Agent: ClCl
Solvent: Clc1ccccc1
Product: O=C1OC(=O)c2cc(Cl)ccc21
Temperature: 105 °C
Yield: 86 %

Procedure:
A mixture of 93 g (0.5 moles) of 4-chlorotetrahydrophthalic anhydride and 30 g of monochlorobenzene was heated and maintained at 105° C. TO 135° C. while 80 g (0.5 moles) of bromine was added over a three hour period. Simultaneously, chlorine gas (0.5 moles) was added to the vapor space above the organic liquid. As the HBr off-gas from the reaction of bromine with 4-chlorotetrahydrophthalic anhydride exited, it contacted the chlorine gas and the resultant bromine was condensed back into the organic liquid phase for reuse. A total of 36.45 g (0.5 moles) of chlorine were consumed during this time. The reaction mixture was finally heated to 165°-175° C. for an additional 5 hours. The crude reaction mixture was distilled resulting in isolation of 86% of 4-chlorophthalic anhydride.
Reaction SMILES: [S:1]1[C:5]2[S:6](=[O:12])(=[O:11])[CH2:7][CH2:8][C:9](=[O:10])[C:4]=2[CH:3]=[CH:2]1.C1([C@]2(CO)CCCN2C2C=CC=CC=2)C=CC=CC=1.B.CSC.B>C1COCC1>[S:1]1[C:5]2[S:6](=[O:12])(=[O:11])[CH2:7][CH2:8][C@@H:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1CCS(=O)(=O)c2sccc21
Agent: B
Agent: OC[C@@]1(c2ccccc2)CCCN1c1ccccc1
Solvent: C1CCOC1
Solvent: CSC
Product: O=S1(=O)CC[C@@H](O)c2ccsc21
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5,6-Dihydro-4H-thieno[2,3-b]-thiopyran-4-one-7,7-dioxide (12) (1.00 g, 4.94 mmol) in dry THF (14 mL) was added (S)-diphenylprolinol-borane complex from Example 12 (132 mg, 0.494 mmol). The solution was cooled to -15° C. and a solution of borane-dimethyl sulfide (10M, 0.4 mL, 4.0 mmol) in dry THF (6.8 mL) was added at a rate to maintain the internal temperature at -151° C. The solution was stirred at -15° C. for 1 hour then at 22° C. for 6 hours. The product was isolated by the method decribed in Example 34 Step E. The enantiomeric ratio of the purified product was 95:5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([NH:9][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(=O)OC(C)=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Br)ccc1F

Procedure:
4-Bromo-1-fluoro-2-nitrobenzene (5.81 g), iron powder (6.20 g) and acetic anhydride (5 ml) were stirred in acetic acid (50 ml) at 60° C. for 16 h. Acetic acid was evaporated under reduced pressure and water and ethyl acetate were added. The organic layer was washed with aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (3.56 g) as colorless prism crystals.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2[CH:27]=[C:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[C:20]3[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=2)=[O:16])=[N:12][CH:13]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(Cl)Cl>[OH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2[CH:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:33][CH:34]=3)[C:20]3[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=2)=[O:16])=[N:12][CH:13]=1
Reactant: CC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Nc3ccc(C(C)(C)O[SiH2]C(C)(C)C)cn3)cc2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Nc3ccc(CO)cn3)cc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To a solution of 4-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid [5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-amide (22b) (85 mg, 0.15 mmol) in CH2Cl2 (5 mL) was added TBAF in THF (220 uL, 0.22 mmol). The reaction mixture was stirred at room temperature for 1 hr, quenched with H2O (20 mL), and extracted with CH2Cl2 (2×20 mL). The organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 50% EtOAc in hexanes to give a white solid (23 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1 H) 8.34 (d, J=8.34 Hz, 1 H) 8.30 (s, 1 H) 7.93 (d, J=8.84 Hz, 2 H) 7.74-7.83 (m, 1 H) 7.08-7.17 (m, 4 H) 4.72 (s, 2 H) 3.09 (s, 3 H) 2.91 (s, 2 H) 1.51 (s, 6 H); LCMS for C24H24N2O6S m/z 469.10 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:35])[CH:13]([CH2:31][C:32]([OH:34])=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[N+](=[CH2:38])=[N-]>CCOCC>[CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:35])[CH:13]([CH2:31][C:32]([O:34][CH3:38])=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCCCCCCCCCCCCCCCCC(CC(=O)O)C(=O)Nc1cccc2cnccc12
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCC(CC(=O)OC)C(=O)Nc1cccc2cnccc12

Procedure:
Commercially available N-(isoquinolin-5-yl)-2-(carboxymethyl) nonadecanoic amide was esterified with diazomethane in ether to give the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2.[OH-].[Na+].CN(C)[CH:26]=[O:27]>>[Br:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:26]=[O:27]
Reactant: Brc1ccncc1-c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccc(-c3cnccc3Br)cc12
Temperature: 25 °C

Procedure:
In a 100-ml round-bottom flask is placed 2.8 mL of dimethylformamide (2.74 g, 3.74 mmol). The flask and the content was cooled in an ice-salt bath for about 0.5 hour and 0.86 mL (1.44 g, 94 mmol) of freshly distilled phosphorusoxychloride is subsequently added with stirring to the dimethylformamide dropwise. Then a solution of 2 (1.00 g, 3.66 mmol) in 1 mL of dimethylformamide is added to the above solution slowly. After the addition, the temperature of the solution is brought to 40° C. and allowed to stir for an hour. At this time, 1 N NaOH (10 mL) was added to the reaction mixture dropwise. The resulting mixture is heated rapidly to the boiling point and allowed to cool to room temperature. The resulting precipitate is collected on a filter and the solid was further washed with water. Compound 3 obtained from this procedure was pure enough for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:15]1([CH3:33])[CH:20]=[CH:19][C:18]([CH:21]([NH2:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:32][CH:21]([C:18]2[CH:17]=[CH:16][C:15]([CH3:33])=[CH:20][CH:19]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: Cc1ccc(C(N)c2cccc(C(F)(F)F)c2)cc1
Product: Cc1ccc(C(NC(=O)CNC(=O)c2ccc(F)cc2)c2cccc(C(F)(F)F)c2)cc1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-p-tolyl-C-(3-trifluoromethyl-phenyl)-methylamine (example 4.6).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C@H:7]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:8]([OH:10])=O.Br.[CH2:23]([O:30][C:31]([C:33]1[N:34]=[CH:35][O:36][C:37]=1[CH2:38][CH2:39][NH2:40])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C.CN(C)C=O>[CH2:23]([O:30][C:31]([C:33]1[N:34]=[CH:35][O:36][C:37]=1[CH2:38][CH2:39][NH:40][C:8](=[O:10])[C@@H:7]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(N[C@@H](Cc1cccs1)C(=O)O)OCc1ccccc1
Reactant: NCCc1ocnc1C(=O)OCc1ccccc1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1cccs1)C(=O)NCCc1ocnc1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
A mixture of 2.56 g of (2S)-3-(2-thienyl)-2-(benzyloxycarbonylamino)propionic acid, 2.39 g of 4-benzyloxycarbonyl-5-(2-aminoethyl)oxazole.hydrobromide, 1.42 g of 1-hydroxybenzotriazole hydrate and 30 ml of dimethylformamide was cooled to -20° C., and 1.77 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.hydrochloride was added thereto. After 10 minutes, 0.93 g of triethylamine was added to the mixture, and the temperature of the mixture was gradually returned to room temperature and the mixture was stirred overnight. The solvent was removed, and ethyl acetate was added to the residue. The mixture was washed and dried, and then the solvent was removed. The residue was purified by silica gel column chromatography (solvent: chloroform:ethyl acetate=19:1) to obtain 3.5 g of 4-benzyloxycarbonyl-5-{2-[N-((2S)-3-(2-thienyl)-2-(benzyloxycarbonylamino)propionyl)amino]ethyl}oxazole as syrup.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]1[C:22]([SH:23])=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.ClCCl>[Cl:9][C:5]1[N:4]=[N:3][C:2]([S:23][C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:16])=[N:7][C:6]=1[Cl:8]
Reactant: Clc1nnc(Cl)c(Cl)n1
Reactant: Cc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccccc1Sc1nnc(Cl)c(Cl)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 116.5 %

Procedure:
3,5,6-Trichloro-1,2,4-triazine (0.50 g) was dissolved in dry tetrahydrofuran (8 ml) and dry potassium carbonate (0.37 g) and 4Å molecular sieves (180 mg, activated overnight at 180° C.) were added. The stirred mixture was cooled to 0° C. and a solution of o-thiocresol (0.36 g) in dry tetrahydrofuran (4 ml) was added dropwise. After 45 minutes at 0-5° C. and standing overnight at 10° C., the mixture was diluted with dichloromethane (20 ml) and filtered through Hyflo Supercel filter aid covered with a layer of Merck silica 60. The filtrate was concentrated under reduced pressure to afford a single dichloro-(2-methylphenylthio)-1,2,4-triazine (unidentified regioisomer) as a yellow oil (0.86 g) which crystallised on standing. Recrystallisation from ether-n-hexane yielded a pale yellow powder (0.57 g, 77%); m.p. 93-95° C.; IR max (nujol mull): 1460, 1250 cm-1 ; 1H NMR: δ2.38 (3H,s), 7.24-7.37(1H,m), 7.37-7.54(3H,m) ppm.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:28]([N:30]3[CH2:35][CH2:34][S:33][CH2:32][CH2:31]3)=[O:29])[CH2:12]2)[O:8][N:7]=1.ClC1C=CC=C(C(OO)=[O:44])C=1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:21][CH:22]=3)[CH2:14][N:13]([C:28]([N:30]3[CH2:35][CH2:34][S:33](=[O:44])[CH2:32][CH2:31]3)=[O:29])[CH2:12]2)[O:8][N:7]=1
Reactant: COCCOc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COCCOc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCS(=O)CC3)C2)n1
Yield: 17.9 %

Procedure:
60.0 mg (0.116 mmol) of the compound from Example 42 were reacted according to General Method 2 with 36.1 mg (0.105 mmol) of meta-chloroperbenzoic acid. Enantiomer separation of the racemate according to Method 2D gave 10.0 mg of the title compound of Example 43 (enantiomer 1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>>[NH:10]([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)[NH2:11]
Reactant: Cc1ccnc(Cl)c1
Reactant: NN
Solvent: O
Product: Cc1ccnc(NN)c1
Temperature: 150 °C
Yield: 50.1 %

Procedure:
2-Chloro-4-methylpyridine (3.43 mL, 39.19 mmol) and hydrazine hydrate (19.07 mL, 391.9 mmol) were suspended together in a flask and heated to 150° C. for 72 hours. The mixture was concentrated in vacuo to an oil. The oil was taken up in EtOAc and the resulting solid was removed by vacuum filtration. The organic filtrate was washed with 40% aqueous NaOH (2×50 mL) and dried over Na2SO4, filtered and concentrated to provide the desired product (2.42 g, 54%) as a white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.ClCCl>[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)=[CH:8][CH:7]=1)=[O:5]
Reactant: CON(C)C(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C=O)cc2)CC1
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A solution of EXAMPLE 88A (0.8 g, 2.3 mmol) in tetrahydrofuran (5 mL) was cooled to −78° C. and treated with lithium aluminum hydride (0.25 g, 6.6 mmol). The mixture was stirred for 30 minutes and treated with water (1 mL) and 15% sodium hydroxide (0.25 mL). Dichloromethane was added and the mixture dried over magnesium sulfate and filtered through silica gel. The solution was concentrated and purified by flash chromatography on silica gel using 1:1 hexane/ethyl acetate to provide the title compound (0.18 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([NH:24][CH2:25][CH2:26][P:27](=[O:34])([O:31]CC)[O:28]CC)(=[O:23])=[O:22])=[CH:16][CH:15]=1.Br[Si](C)(C)C.[OH-].[Na+]>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([NH:24][CH2:25][CH2:26][P:27](=[O:28])([OH:31])[OH:34])(=[O:23])=[O:22])=[CH:16][CH:15]=1
Reactant: CCOP(=O)(CCNS(=O)(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1)OCC
Agent: C[Si](C)(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NS(=O)(=O)NCCP(=O)(O)O)cc2)C1
Temperature: 39 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of diethyl 2-(N-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfamoylamino)ethylphosphonate (100 mg, 0.18 mmol, 1.00 equiv) in dichloromethane (5 mL) and bromotrimethylsilane (275 mg, 1.80 mmol, 9.89 equiv). The resulting solution was stirred overnight at 39° C. The resulting mixture was concentrated under vacuum and the residue was dissolved in dichloromethane (5 mL). This was followed by the addition of a solution of sodium hydroxide (14.5 mg, 0.36 mmol, 2.00 equiv) in methanol (0.2 mL) dropwise with stirring. The solids were collected by filtration and dried under reduced pressure. This gave 40 mg (40%) of a sodium salt of the title compound as a white solid. 1H-NMR (300 MHz, d6-DMSO, ppm): δ 9.78 (1H, brs), 7.54 (1H, s), 7.47 (1H, brs), 7.09-7.17 (4H, m), 6.82 (1H, s), 4.31 (1H, brs), 3.88 (2H, brs), 3.13 (1H, brs), 3.04 (2H, brs), 2.90 (1H, brs), 2.58 (3H, s), 1.65-1.77 (2H, m). MS (m/z): 494 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:20][C:19]2[C:10](=[C:11]3[C:16](=[C:17]([O:21][CH3:22])[CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)[C:9](=[O:23])[CH:8]=1)=[O:6].[CH2:24](I)[CH3:25]>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([O:23][CH2:24][CH3:25])[C:10]2[C:19]([N:20]=1)=[CH:18][C:17]([O:21][CH3:22])=[C:16]1[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]1)=[O:6]
Reactant: CCI
Reactant: COC(=O)c1cc(=O)c2c(cc(OC)c3ncccc32)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)nc2cc(OC)c3ncccc3c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.2 g of sodium hydride (50% suspension in mineral oil) is added to a solution of 6.5 g of 6-methoxy-1-oxo-1,4-dihydro-4,7-phenanthroline-3-carboxylic acid methyl ester in 50 ml of absolute dimethylformamide, whilst stirring at 40° in an inert gas atmosphere. After 30 minutes the reaction mixture is allowed to cool to room temperature, 4.3 g of ethyl iodide are added in portions, the mixture is stirred for 6 hours, 200 ml of ice-water are added, the mixture is extracted by shaking with 50 ml of petroleum ether and then extracted three times with 200 ml of chloroform each time. The chloroform extracts are combined, washed with water, dried over sodium sulphate and concentrated by evaporation under reduced pressure. 1-ethoxy-6-methoxy-4,7-phenanthroline-3-carboxylic acid methyl ester is obtained which, after recrystallisation from ethanol, melts at 188°-190°.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[OH:6][C@@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:21]2[C:20](=O)[CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:27]([OH:29])=[O:28])[CH2:8]1.Cl>C(O)C.O>[OH:6][C@@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:21]2[C:20](=[N:2][OH:3])[CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:27]([OH:29])=[O:28])[CH2:8]1
Reactant: NO
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=NO)[C@@H]12
Yield: 63.8 %

Procedure:
Hydroxylamine hydrochloride (4 g) was added to a water cooled solution of sodium hydroxide (50%; 16 ml). This mixture was added to a solution of 3α-hydroxy-11-oxo-5α-androstane-17β-carboxylic acid (1.5 g) in ethanol (70 ml). The mixture was heated at reflux for 24 h, cooled and brought to pH 1 with concentrated HCl solution. Water (800 ml) was added and the precipitate (1.42 g) was collected by filtration, washed with water (2×300 ml) and dried. Crystallisation from ethyl acetate gave the title compound (1 g) m.p. 250°-253° C. (dec) [α]D +124° (EtOH C=1%).