Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCCc2ccc(O)cc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCCCc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 104.8 %

Procedure:
To 3-hydroxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (1.76 g, 10.0 mmol) dissolved in DMF (10 ml) were added potassium carbonate (2.76 g, 20.2 mmol) and benzyl bromide (1.308 ml, 11.0 mmol), and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with water (20 ml) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 35 g, ethyl acetate/hexane=1/9). The objective fractions were concentrated under reduced pressure to obtain 3-benzyloxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (2.79 g).
Reaction SMILES: C([O:4][C@@H:5]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7][C@H:6]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])(=O)C.[O:25]=[C:26]1[NH:34][C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[N:27]1[CH:35]1[CH2:40][CH2:39][N:38]([C:41](OC2C=CC([N+]([O-])=O)=CC=2)=[O:42])[CH2:37][CH2:36]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C)C=O>[O:25]=[C:26]1[NH:34][C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[N:27]1[CH:35]1[CH2:36][CH2:37][N:38]([C:41]([O:16][C@H:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C@@H:5]([OH:4])[C@H:6]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])[CH2:7][CH2:8]2)=[O:42])[CH2:39][CH2:40]1
Reactant: CC(=O)O[C@@H]1c2cccnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](O)c2cccnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 1 h

Procedure:
In an oven-dried 100 mL round-bottom flask was suspended (5S,6S,9R)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-yl acetate (96.7 mg, 0.290 mmol) (azeotroped with dry benzene) and 4-nitrophenyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (167 mg, 0.435 mmol) in dimethylformamide (3 mL) under nitrogen. After cooling to −15° C. (ice-methanol bath), NaHMDS (0.870 mL, 0.870 mmol) was added dropwise. The resulting dark-red solution was stirred under nitrogen at −15° C.˜0° C. for 1 h. LCMS showed desired product and possible over-hydrolysed product. After another 1 h at room temperature, complete hydrolysis was not yet achieved. The reaction was quenched with sodium bicarbonate solution and volatiles were removed. The mixture was diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried with sodium sulfate, and concentrated to give a yellow oil. Purification by FCC up to 10% methanol/methylene chloride afforded the acetate-protected product (2nd peak, 51 mg, 30%, not pure) as well as the target alcohol (3rd peak, 20 mg, 13%). In a 250 mL round-bottom flask was (5S,6S,9R)-5-acetoxy-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (51 mg, 0.088 mmol) (acetate protected product from above) in methanol (1 mL) to give a colorless solution. Potassium carbonate (122 mg, 0.883 mmol) was added, and the mixture was stirred at room temperature for 1 h. LCMS indicated complete conversion. Methanol was removed in vacuo. The residue was partitioned between water and ethyl acetate. The layers were separated (no product in aqueous layer by LCMS). The organic layer was washed with brine, dried, and concentrated to give a white solid. Purification by FCC up to 10% methanol/methylene chloride afforded the desire product (28 mg, 56%) as a light yellow solid. 1H and 19F NMR spectra were obtained and matched that of example 4.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([F:25])(=[O:24])=[O:23])C1C=CC=CC=1.B(F)(F)F.CCOCC>C(S)(S)C>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([F:25])(=[O:24])=[O:23]
Reactant: O=S(=O)(F)CCCCCCCc1ccccc1OCc1ccccc1
Agent: CC(S)S
Agent: FB(F)F
Solvent: CCOCC
Product: O=S(=O)(F)CCCCCCCc1ccccc1O
Yield: 70.8 %

Procedure:
7-(2-Hydroxy-phenyl)-heptanesulfonyl fluoride (14.3) was synthesized as described in 14.1 using 13.3 (0.065 g, 0.17 mmol) in ethanedithiol (5 mL) and BF3.Et2O (0.092 g, 0.65 mmol). Purification by flash column chromatography gave 14.3 (0.033 g, 70% yield) as a viscous liquid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][N:12]=[C:13]([C:19]([O:21]CC)=[O:20])[C:14]([O:16]CC)=[O:15])[CH3:4]>C(O)C>[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][N:12]=[C:13]([C:19]([OH:21])=[O:20])[C:14]([OH:16])=[O:15])[CH3:4]
Reactant: CCOC(=O)C(=NNc1ccccc1CC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccccc1NN=C(C(=O)O)C(=O)O

Procedure:
48 ml of 2 N aqueous sodium hydroxide solution was added over 15 minutes to a stirred, refluxing mixture of 22.5 g of 53A in 48 ml of ethanol. A further 192 ml of 1 N aqueous sodium hydroxide solution was added over 20 minutes to the gently refluxing mixture. Then the mixture was filtered through Celite, and the filtrate was poured into a stirred mixture of 30 ml of concentrated hydrochloric acid, 90 ml of water and about 100 g of ice. The mixture was filtered. The solid was washed with water, dried under reduced pressure, and dissolved in methylene chloride. The solution was dried (MgSO4), filtered and stripped of solvent under reduced pressure. The residue was recrystallized from ethanol/water, and dissolved in methylene chloride. The solution was dried (MgSO4) and the solvent was evaporated to give ((2-ethylphenyl)hydrazono)malonic acid (53B), as a solid, m.p.: 135°-136° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([N:21]([CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:43])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.F[C:45](F)(F)[C:46](O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([N:21]([CH:35]([CH2:45][CH3:46])[C:36]([OH:38])=[O:37])[CH:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=4)[CH2:26][CH2:27]3)[C:17](=[O:43])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: Cc1cc(N2CCC(N(CC(=O)OC(C)(C)C)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3=O)CC2)ccn1
Reactant: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCC(C(=O)O)N(C1CCN(c2ccnc(C)c2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl {[4-(6-chloronaphthalene-2-sulfonyl)-2-oxo-1-piperazinyl][1-(2-methyl-4-pyridinyl)-4-piperidinyl]amino}acetate (135 g) obtained in Example 144 and toluene (1 ml) was combined with trifluoroacetic acid (1 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified on a CHP-20 column (water→1% conc. aqueous ammonia-containing 25% aqueous solution of acetonitrile) to obtain the title compound (0.75 mg) as a colorless powder.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C@@H:17]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:26]=3)[CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].CCOC(C)=O>N1C=CC=CC=1>[ClH:1].[C:39]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C@@H:17]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:26]=3)[CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)(=[O:41])[CH3:40]
Reactant: COc1ccc([C@@H](Cc2ccncc2)c2ccc(Oc3ccc(N)cc3)cc2)cc1OC1CCCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H](Cc2ccncc2)c2ccc(Oc3ccc(NC(C)=O)cc3)cc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of the free base of compound of Example 7 (322 mg, 0.67 mmol) in pyridine (10 ml) was heated with acetic anhydride (126 μl) and the mixture stirred at RT for 24 h. The solvent was removed in vacuo, the residue azeotroped twice with toluene and partitioned between aqueous NaOH (pH 13) and EtOAc. The aqueous layer was further extracted with EtOAc and the combined organic layer dried (Na2SO4) then concentrated in vacuo to give an off-white glass. Chromatography (SiO2 ; EtOAc) afforded the title compound free base (303.6 mg) as an off-white glass.
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:15])([CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])[CH3:9])[C:4](=[O:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:9])([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH3:15])[C:4](=[O:16])[C:3]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(O)C(C)C)CO1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)C(C)C)CO1
Reaction time: 5 h
Yield: 49.7 %

Procedure:
A solution of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2,4-dimethylpentan-3-ol (1.7 g) in dichloromethane was added to a stirred mixture of pyridinium chlorochromate (1.81 g) and powdered molecular sieve (4A) in dichloromethane at 20° C. After 5 hours, ether was added, the mixture filtered through hyflo and evaporated. The residue was purified by dry column chromatography on silica gel, eluting with dichloromethane/ethyl acetate to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2,4-dimethylpentan-3-one (Compound 1, 0.84 g) as a white solid, m-p. 98.6-101.6° C.
Reaction SMILES: [CH:1]1([CH:4]([NH:17][S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[C:5]([F:16])([F:15])S(C2C=CC=CC=2)(=O)=O)[CH2:3][CH2:2]1.CC([O-])=O.[Na+].CC(O)=O.[Mg]>CN(C=O)C.O>[CH:1]1([CH:4]([NH:17][S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH:5]([F:16])[F:15])[CH2:3][CH2:2]1
Reactant: CC(C)(C)S(=O)NC(C1CC1)C(F)(F)S(=O)(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Mg]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)S(=O)NC(C(F)F)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[1-cyclopropyl-2,2-difluoro-2-(phenylsulfonyl)ethyl]-2-methylpropane-2-sulfinamide (0.8 g, 2.2 mmol) in DMF (30 mL) was added a solution of NaOAc (4.5 g, 55 mmol) in AcOH (4.5 g, 75 mmol) and H2O (7.0 mL). Magnesium turning (0.8 g, 33 mmol) was added in portions at room temperature under a water bath. The reaction mixture was stirred at room temperature overnight. Water (90 mL) was added to the solution, and the aqueous layer was extracted with EtOAc. The combined organics were washed with sat. NaHCO3, dried, concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (400 MHz, CDCl3) 5.75 (t, 1H); 3.50 (d, 1H); 2.58-2.70 (m, 1H); 1.18 (s, 9H); 0.90-1.00 (m, 1H); 0.58-0.70 (m, 2H); 0.35-0.50 (m, 2H).
Reaction SMILES: O([Si](C)(C)C)[Na].[Cl:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16](=[O:18])[CH3:17])=[C:10](F)[C:9]=1[N+:20]([O-:22])=[O:21].[O:23]1CCC[CH2:24]1>O1CCOCC1.CO>[Cl:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16](=[O:18])[CH3:17])=[C:10]([O:23][CH3:24])[C:9]=1[N+:20]([O-:22])=[O:21]
Reactant: C1CCOC1
Reactant: CC(=O)Nc1c(F)cc(Cl)c([N+](=O)[O-])c1F
Agent: C[Si](C)(C)O[Na]
Solvent: C1COCCO1
Solvent: CO
Product: COc1c(NC(C)=O)c(F)cc(Cl)c1[N+](=O)[O-]
Yield: 63 %

Procedure:
A solution of 72.5 g (647 mmol) of NaOSi(CH3)3 in 25 ml of tetrahydrofuran was added dropwise at approximately 20° C. to a solution of 81 g (323 mmol) of N-(4-chloro-2,6-difluoro-3-nitro-phenyl)acetamide in 490 ml of dioxane and 50 ml of methanol. The mixture was subsequently heated for two hours at reflux temperature. After cooling and concentrating, the crude product (black oil) was stirred into ice-cold 10% strength hydrochloric acid. The resulting product of value was then extracted with ethyl acetate (3 times). The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The residue was stirred once with water. The insoluble components were removed and washed three times with water. After drying, 52.1 g (63%) of the product of value were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([F:22])[CH:14]=1.BrC1C=CC(C(NC2C=CC=C(C(C)(C)C)C=2)=O)=CC=1F>>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)=[O:18])=[C:15]([F:22])[CH:14]=1
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)cc2F)c1

Procedure:
4-Bromo-N-(3-tert-butyl-phenyl)-2-fluoro-benzamide was synthesized from 3-tert-butyl-phenylamine and 4-bromo-2-fluoro-benzoic acid in a manner similar to the one described in the synthesis of 4-bromo-N-(3-tert-butyl-phenyl)-3-fluoro-benzamide above. LCMS calcd for C17H17FNO (m/e) 349, obsd 350 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][C:5]=1[Br:12].[CH2:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=[N:31][OH:32])=[CH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:32]/[N:31]=[CH:30]/[C:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:22]=2)=[CH:6][C:5]=1[Br:12]
Reactant: COC(=O)c1ccc(CBr)cc1Br
Reactant: ON=Cc1cn(Cc2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CO/N=C/c2cn(Cc3ccccc3)c3ccccc23)cc1Br
Temperature: 25 °C
Yield: 33.6 %

Procedure:
To a solution of 2-bromo-4-bromomethyl-benzoic acid methyl ester (0.50g, 1.62 mmol) and 1-benzyl-1H-indole-3-carbaldehyde oxime (0.43 g, 1.70 mmol) in acetone (50 mL) was added cesium carbonate (2.12 g, 6.49 mmol). The mixture was heated to reflux for 6 hours and allowed to cool back to room temperature. The mixture was partitioned between ethyl acetate and brine and the layers were then separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 20/80) to give an off-white solid. This solid was recrystallized one time from ethyl acetate/hexanes (1/6) to give 4-[({[(1E)-(1-benzyl-1H-indol-3-yl)methylidene]amino}oxy)methyl]-2-bromobenzoic acid methyl ester (0.26 g, 34%) as off-white crystals. 1H NMR (400 MHz, CDCl3); δ 8.12 (s, 1H), 7.76 (m, 4H), 7.68 (s, 1H), 7.35 (d, 1H), 7.28 (m, 3H), 7.23 (m, 2H), 7.11 (d, 2H), 5.33 (s, 2H), 5.27 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:17][CH2:16][C@H:15]([NH:18][S:19]([C:22]4[S:30][C:29]5[C:24](=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[C:14]3=[O:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C1(O)C=CC=CC=1.C([O-])(=O)C.[NH4+:43]>>[NH2:43][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:17][CH2:16][C@H:15]([NH:18][S:19]([C:22]4[S:30][C:29]5[C:24](=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[C:14]3=[O:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C1[C@@H](NS(=O)(=O)c2cc3ncccc3s2)CCN1Cc1ccc2ccnc(Cl)c2c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Oc1ccccc1
Product: Nc1nccc2ccc(CN3CC[C@H](NS(=O)(=O)c4cc5ncccc5s4)C3=O)cc12
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
Thieno[3,2-b]pyridine-2-sulfonic acid [1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (1.36 g, 2.88 mmol) and phenol (2.22 g, 23.6 mmol) are melted together with stirring at 70° C. for 5 minutes. Ammonium acetate (2.71 g, 28.8 mmol) is added and the reaction mixture is heated to 90° C. and stirred overnight. Additional ammonium acetate (0.50 g, 5.31 mmol) is added and the reaction is heated for 20 more hours. The reaction is cooled and the residue is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN. The appropriate product fractions are lyophilized to provide the title compound as a white solid. The enantiomeric purity is 90.5% ee as determined by analytical AS RP-HPLC.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][N:15]=2)=[CH:10][CH:9]=1)=[O:6].C[O-].[Na+]>CN(C=O)C>[O:6]1[CH2:2][CH2:3][N:4]=[C:5]1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: O=C1CCC(c2ccc(NC(=O)NCCCl)cc2)=NN1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc(NC3=NCCO3)cc2)=NN1
Temperature: 100 °C
Yield: 76.1 %

Procedure:
A mixture of 1.8 g of N-(2-chloroethyl)-N'-[4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)phenyl]-urea and 0.7 g of NaOMe in 20 ml of DMF is heated at 100° C. for five hours. The DMF is distilled under reduced pressure, the residue is treated with water, and the pH of the solution is adjusted to 6. The solid is filtered, washed with water, and crystallized from DMF to yield 1.2 g of the product, 6-[4-[(4,5-dihydro-2-oxazolyl)amino]phenyl]-4,5-dihydro-3(2H)-pyridazinone, mp 332°-333° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:29])[N:18]=[C:19]([CH2:20][CH:21]([CH2:27][CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:12]2[N:11]=1)[CH3:2].[S:30](Cl)([Cl:33])(=[O:32])=[O:31]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:30]([Cl:33])(=[O:32])=[O:31])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:29])[N:18]=[C:19]([CH2:20][CH:21]([CH2:27][CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:12]2[N:11]=1)[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCC(CC)Cc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Product: CCCCCC(CC)Cc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 5.6 g (14.1 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-(2-ethylheptyl)-3H-imidazo-[5,1-f][1,2,4]-triazin-4-one (Example 19A). This gives 3.7 g (52.9%) of sulphonyl chloride as a slightly yellow foam which is directly reacted further.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]([CH:31]=O)[CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:31][C:23]2[CH:22]=[N:21][C:30]3[C:25]([CH:24]=2)=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cnc2ccccc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available quinoline-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.63 min.; [M+H]+: 391.18 g/mol.
Reaction SMILES: [CH2:1]1[CH:10]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:3][CH:2]1[N:11]1[CH2:27][CH2:26][C:14]2([N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:16][CH:15]2[OH:25])[CH2:13][CH2:12]1.[C:28]([O-:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([O-:33])=[O:32].[C:36](O)(=O)/C=C/C(O)=O>C(OCC)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH2:1]1[CH:10]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:3][CH:2]1[N:11]1[CH2:27][CH2:26][C:14]2([N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:16][CH:15]2[O:25][CH3:36])[CH2:13][CH2:12]1
Reactant: OC1CCN(c2ccccc2)C12CCN(C1CC3CCCCCC3C1)CC2
Reactant: O=C([O-])/C=C/C(=O)[O-]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Product: COC1CCN(c2ccccc2)C12CCN(C1CC3CCCCCC3C1)CC2

Procedure:
Methylation of 8-(decahydro-azulen-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (mixture of diastereoisomers) according to the general method of example 31 and formation of the fumarate with fumaric acid in diethyl ether yielded the title compound, white solid, m.p. 260° C. (dec.) and MS: m/e=383.3 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)O)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-]>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:17][C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[OH:8])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(O)c2cc(OC)ccc2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cc2cc(OC)ccc2O)cc1
Reaction time: 14 h
Yield: 91.5 %

Procedure:
To a solution of (2-benzyloxy-5-methoxyphenyl)-(4-methoxyphenyl)methanol (2.54 g, 7.25 mmol) in methanol (50 ml), a 20% palladium hydroxide catalyst (250 mg) was added and furthermore 36% HCl (0.25 mL) was added thereto. The mixture was stirred under a hydrogen atmosphere for 14 hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (1.62 g, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CN1C=CN=C1.Br[C:28]1[CH:33]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:31]=[CH:30][N:29]=1>[Cu]I.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:28]3[CH:33]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:31]=[CH:30][N:29]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)c1ccnc(Br)c1
Reactant: Brc1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]I
Agent: Cn1ccnc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccnc(-n2c3ccccc3c3ccc(Br)cc32)c1
Temperature: 120 °C
Reaction time: 96 h

Procedure:
To a pressure vessel equipped with a magnetic stir bar was added 2-bromo-9H-carbazole (2461 mg, 10.0 mmol, 1.0 eq), CuI (762 mg, 4.0 mmol, 0.4 eq), and K2CO3 (2764 mg, 20.0 mmol, 2.0 eq). Then the vessel was evacuated and back-filled with nitrogen, and the evacuation and back-fill procedure was repeated twice. Then solvent toluene (60 mL), 1-methyl-1H-imidazole (792 uL, 10.0 mmol, 1.0 eq) and 2-bromo-4-tert-butylpyridine (5353 mg, 25.0 mmol, 2.5 eq) were added under the protection of nitrogen. The mixture was stirred in an oil bath at a temperature of 115-125° C. for 4 days. Then the mixture was cooled to ambient temperature. The solvent was removed under reduced pressure and the residue was purified through column chromatography on silica gel using dichloromethane as an eluent to obtain the desired product, 2-bromo-9-(4-tert-butylpyridin-2-yl)-9H-carbazole, as a colorless sticky liquid (3635 mg in 96% yield). 1H NMR (DMSO-d6, 400 MHz): δ 1.39 (s, 9H), 7.36 (t, J=8.0 Hz, 1H), 7.48-7.55 (m, 3H), 7.71-7.73 (m, 2H), 7.94 (d, J=2.0 Hz, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.66 (d, J=5.5 Hz, 1H).