Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([C@@H:29]2[CH2:31][O:30]2)[CH:26]=[CH:27][CH:28]=1>C(O)C>[CH2:1]([N:8]([CH2:31][C@@H:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=1)[OH:30])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Reactant: Clc1cccc([C@@H]2CO2)c1
Solvent: CCO
Product: COc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)c1cccc(Cl)c1)CCC2
Yield: 86.1 %

Procedure:
A mixture of N-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (0.30 g) and (R)-3-chlorophenyl oxirane (0.18 g) in ethanol (0.6 ml) was refluxed overnight. The reaction mixture was evaporated in vacuo, and the residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (5:1). The product (0.43 g) was treated with 4N hydrogen chloride in ethyl acetate and powdered from diisopropyl ether to afford (1R)-2-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-1-(3-chlorophenyl)ethanol (0.40 g).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][NH2:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[C:11]([O:15][C:16]([NH:18][C:19]([CH3:24])([C:21](O)=[O:22])[CH3:20])=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[F:1][C:2]1[C:3]([NH:9][NH:10][C:21](=[O:22])[C:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:24])[CH3:20])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NNc1ncc(F)cc1F
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)NNc1ncc(F)cc1F

Procedure:
This compound was prepared (66%) from 3,5-difluoro-2-hydrazinopyridine and N-(tert-butoxycarbonyl)-2-methylalanine following the experimental procedure described for the synthesis of Intermediate 21, step a.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[N+:12]([O-])([O-:14])=[O:13].[K+]>OS(O)(=O)=O>[F:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(C(=O)O)ccc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(C(=O)O)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.6 %

Procedure:
To a solution of 4-fluoro-3-methylbenzoic acid (3.7 g, 24 mmol) in conc. H2SO4 (50 mL) at 0° C. was added KNO3 (3.6 g, 36 mmol) in one portion and the mixture was stirred at rt for 2 h. The reaction mixture was poured into ice water (200 mL) and extracted with DCM (100 mL×2). The organic layer was washed with brine, dried and concentrated to give the crude 4-fluoro-5-methyl-2-nitrobenzoic acid (5 g) as white solid. It was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:12]2[C:7](=[C:8]([NH2:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:7]=2[N:6]=[CH:5][CH:4]=[C:3]3[C:2]([F:1])([F:14])[F:15])(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1
Reactant: Nc1cccc2c(C(F)(F)F)ccnc12
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Nc1cccc2c(C(F)(F)F)ccnc12
Yield: 60.5 %

Procedure:
In a similar fashion using route 14 general procedure 27, 4-trifluoromethyl-quinolin-8-ylamine (Intermediate 469) (325 mg, 1.53 mmol), 4-chloro-2-nitrobenzenesulfonylchloride (Intermediate 454) (507 mg, 1.99 mmol), DMAP (cat.), pyridine (0.5 ml), and DCM (5 ml) gave the title compound (400 mg, 60%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [OH-].[K+].[CH:3]1([O:9][N:10]2[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([O:18]C(=O)C)[CH2:12][C:11]2([CH3:23])[CH3:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>CO>[CH:3]1([O:9][N:10]2[C:11]([CH3:22])([CH3:23])[CH2:12][CH:13]([OH:18])[CH2:14][C:15]2([CH3:17])[CH3:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC(=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1

Procedure:
24 g (428 mmol) of potassium hydroxide are dissolved in 600 ml of methanol in a conical flask. 85 g (286 mmol) of 1-cyclohexyloxy-2,2,6,6-tetramethyl-4-acetoxypiperidine are poured into the warm solution with stirring. The mixture is subsequently poured onto ice and extracted with diethyl ether. After the diethyl ether solution has been dried over sodium sulfate, the ether is evaporated and the viscous residue is dissolved in 300 ml of warm acetonitrile. The solution is filtered and allowed to crystallize; yield: 50 g (68%). The colourless substance has a melting point of 78.5° C.; purity according to GC analysis: 96%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:6]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[C:5]2[CH3:23].Cl>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH:6]([CH2:18][CH2:19][N:20]([CH3:21])[CH3:22])[CH:5]2[CH3:23]
Reactant: Cc1c(CCN(C)C)n(-c2ccc(Cl)cc2)c2ccc(Cl)cc12
Agent: Cl
Solvent: CC(C)=O
Product: CC1c2cc(Cl)ccc2N(c2ccc(Cl)cc2)C1CCN(C)C

Procedure:
The title compounds are produced in analogous manner to Example 2, using 5-chloro-1-p-chlorophenyl-2-(2-dimethylaminoethyl)-3-methylindole as starting compound. The major product is the cis compound. M.Pt. of the hydrochloride: 187°-190°. The trans compound is isolated from the mother liquor. M.Pt. of the hydrochloride: 163°-168° (both from acetone).
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([C:6]([CH2:8][CH2:9][CH2:10]Cl)=[O:7])[S:3][CH:2]=1.[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][NH:13]1>>[O:7]=[C:6]([C:4]1[S:3][CH:2]=[CH:1][CH:5]=1)[CH2:8][CH2:9][CH2:10][N:13]1[CH2:14][CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12]1
Reactant: O=C(CCCCl)c1cccs1
Reactant: c1ccc2c(c1)CCNC2
Product: O=C(CCCN1CCc2ccccc2C1)c1cccs1
Yield: 58 %

Procedure:
Prepared in standard fashion from commercially available 4-chloro-2′-butyrothienone and 1,2,3,4-tetrahydroisoquinoline. Purified by flash chromatography, eluting with 1:1 EtOAc/hexane to provide 17A (58% yield) as a yellow oil. 1H NMR(300 MHz, CDCl3, δ): 7.72-7.70 (m, 1H), 7.60-7.58 (m, 1H), 7.15-6.98 (m, 5H), 3.62 (s, 2H), 3.01 (t, 2H, J=7 Hz), 2.87 (t, 2H, J=6 Hz), 2.72 (t, 2H, J=6 Hz), 2.59 (t, 2H, J=7 Hz), 2.10-2.00 (m, 2H). 13C NMR(300 MHz, CDCl3, δ): 193.10, 144.56, 134.92, 134.43, 133.34, 131.79, 128.64, 128.05, 126.59, 126.08, 125.58, 57.37, 56.10, 50.83, 37.01, 29.19, 22.14. . IR(KBr, cm−1): 1662 (s). UV (MeOH): max 282 nm, ε 260. MS(CI, NH3) m/e 286 (base, M+H ). HRMS(CI, NH3) m/e Calc'd for (M+H+): 286.1266. Found: 286.1259.
Reaction SMILES: ClN1C(=O)CCC1=O.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.[CH3:20][S:21][CH3:22]>ClCCl>[CH3:20][S:21]([CH3:22])=[N:15][C:14]1[CH:16]=[CH:17][C:11]([C:10]([F:18])([F:19])[F:9])=[CH:12][CH:13]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CS(C)=Nc1ccc(C(F)(F)F)cc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
A solution of N-chlorosuccinimide (12-43 g, 93.1 mmol) in ˜170 mL of dichloromethane was added to a mixture of 4-(trifluoromethyl) aniline (15 g, 93.1 mmol) and dimethyl sulfide (6.35 g, 102 mmol) in 230 mL of dichloromethane at −5-0° C. After the addition was complete, the mixture was stirred at 0-5° C. for 1 h, and N-chlorosuccinimide (0.02 g, 4.64 mmol) was added. After a further 30 minutes, the mixture was washed with 500 mL of 1N sodium hydroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([CH2:16][CH3:17])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:35]=[C:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([F:46])[CH:39]=1)[CH3:37]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:35]=[C:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([F:46])[CH:39]=1)[CH3:37])[C:6]1[CH:11]([CH2:16][CH3:17])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: CCC1c2[nH]c3ccc(Cl)cc3c2CCN1C
Reactant: COc1ccc(C(C)=CBr)cc1F
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCC1c2c(c3cc(Cl)ccc3n2C=C(C)c2ccc(OC)c(F)c2)CCN1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (84 mg, 0.34 mmol) was dissolved in DMF (5 mL). To this solution was added CuI (6 mg, 0.034 mmol), L-proline (8 mg, 0.068 mmol), K3PO4 (145 mg, 0.68 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 4-(1-bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100 mg, 0.408 mmol). The reaction mixture was heated at 80° C. for 18 h. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 21 mg of 6-chloro-1-ethyl-9-(2-(3-fluoro-4-methoxyphenyl)prop-1-enyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (CD3OD) TFA SALT 7.60 (d, 1H), 7.42 (m, 2H), 7.20 (m, 3H), 7.0 (s, 1H), 4.60 (m, 1H), 3.90 (s, 3H), 3.8 (m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 3.05 (s, 3H), 2.10 (m, 2H), 1.90 (s, 3H), 1.10 (t, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH:6]1[C:8]([O:10]C)=[O:9])=[O:4].CO.[OH-].[Na+]>O>[Cl:19][C:14]1[CH:13]=[C:12]([C:5]2([C:3]([OH:4])=[O:2])[CH2:7][CH:6]2[C:8]([OH:10])=[O:9])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: COC(=O)C1CC1(C(=O)OC)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CC1(C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 72.5 °C
Reaction time: 2 h

Procedure:
A mixture of 31.0 kg 1-(3,4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid dimethyl ester (from Step 2), 40 L water, 35 kg methanol and 18.0 kg 50% caustic soda was warmed to 70-75° C. (under reflux) and maintained at 70-75° C. for 1.5 hours. 10 L water was then added, and the mixture was kept at 75-77° C. for an additional 2 hours. Methanol was slowly distilled off in vacuo to 70° C. to give a heavy suspension, which was then mixed with 80 L water to effect solution. The free dicarboxylic acid was precipitated with 31 kg of 32% hydrochloric acid and extracted with 100 kg ethyl acetate. The lower aqueous phase was separated and washed with 20 kg ethyl acetate. The combined organic phases were washed with 50 L water, and then saturated aqueous sodium chloride. Distillation in vacuo to 80° C. with full vacuum yielded a concentrate of 1-(3,4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid, which was used “as is” for the next step, cyclization to the imide. A quantitative yield from the diester was assumed for calculation purposes.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH3:9][N:10]([CH2:12][C:13]1[O:17][C:16]([CH2:18][S:19][C:20](=N)N)=[CH:15][CH:14]=1)[CH3:11].ClC[CH2:25][NH:26][C:27]([NH:32][CH3:33])=[CH:28][N+:29]([O-:31])=[O:30].C(=O)([O-])[O-].[K+].[K+]>O.O1CCCC1>[CH3:11][N:10]([CH2:12][C:13]1[O:17][C:16]([CH2:18][S:19][CH2:20][CH2:25][NH:26][C:27]([NH:32][CH3:33])=[CH:28][N+:29]([O-:31])=[O:30])=[CH:15][CH:14]=1)[CH3:9]
Reactant: CN(C)Cc1ccc(CSC(=N)N)o1
Reactant: CNC(=C[N+](=O)[O-])NCCCl
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 120 h
Yield: 19 %

Procedure:
A mixture of 1-[[[5-[(dimethylamino)methyl]-2-furanyl]-methyl]thio]methanimidamide maleate (1:2) (2.23 g), N-(2-chloroethyl)-N'-methyl-2-nitro-1,1-ethenediamine (0.9 g) and potassium carbonate (3.46 g) in water (10 ml) and tetrahydrofuran (10 ml) was stirred under nitrogen at room temperature for 5 days. The suspension was evaporated in vacuo; the residue suspended in water (50 ml) and extracted with ether (2×40 ml). The aqueous fraction was evaporated in vacuo and magnesium sulphate and tetrahhydrofuran (100 ml) added. After 18 hours, the mixture was filtered and the filtrate evaporated to give a semi-solid which was chromatographed (silica/methanol). The appropriate eluate was evaporated in vacuo to give the title compound (0.3 g), which had an n.m.r. identical to that of the product according to Example 1 above.
Reaction SMILES: B(F)(F)F.CCOCC.[NH2:10][C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=O)[CH:20]=[C:21]([Cl:23])[CH:22]=2)=[CH:13][C:12]=1[C:32]1[N:33]=[N:34][N:35]([CH:37]([CH3:39])[CH3:38])[CH:36]=1.[BH4-].[Na+].CO>C1COCC1.O>[Cl:23][C:21]1[CH:22]=[C:17]([C:14]2[CH:13]=[C:12]([C:32]3[N:33]=[N:34][N:35]([CH:37]([CH3:39])[CH3:38])[CH:36]=3)[C:11]([NH2:10])=[N:16][CH:15]=2)[CH:18]=[C:19]([CH2:24][N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[CH:20]=1
Reactant: CC(C)n1cc(-c2cc(-c3cc(Cl)cc(C(=O)N4CCOCC4)c3)cnc2N)nn1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CC(C)n1cc(-c2cc(-c3cc(Cl)cc(CN4CCOCC4)c3)cnc2N)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
BF3.Et2O in THF (47-49%) (0.70 mL, 2.34 mmol) was added to a solution of [3-[6-amino-5-(1-isopropyltriazol-4-yl)-3-pyridyl]-5-chloro-phenyl]-morpholino-methanone (200 mg, 0.46 mmol) in THF (10.0 mL) at 0° C., then reaction mixture was stirred for 30 min, added NaBH4 (89 mg, 2.36 mmol) at 0° C., reaction mixture was slowly warmed to RT, stirred for 16 h. Reaction mixture was cooled to 0° C., added MeOH (5.0 mL) to the reaction mixture, heated to 70° C. for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. Crude product was purified by silica (100-200 mesh) column eluted with 2% MeOH in DCM to afford 39 mg (Yield: 20.2%) of the title compound. This was converted to its HCl salt by using HCl in ether (2M) to afford 45 mg as a pale gray solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:16][CH2:15][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:17]([C:19]1[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=1)=[CH2:18].[OH-].[K+]>CN1C(=O)CCC1>[OH:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:18][CH2:17][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=3)[C:5]3[CH2:15][CH2:16][N:2]([CH3:1])[CH2:3][C:4]=3[C:12]=2[CH:11]=1
Reactant: C=Cc1ccc(C(=O)O)nc1
Reactant: CN1CCc2[nH]c3ccc(CO)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(CO)ccc3n2CCc2ccc(C(=O)O)nc2)C1

Procedure:
The title compound is prepared from a mixture of (2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indol-8-yl)methanol, 5-vinylpyridine-2-carboxylic acid and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[CH:10]=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]Br>ClCCl>[CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([Br:26])=[C:9]1[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2cnnc(OCc3ccccc3)c2n1Cc1ccccc1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1c(Br)c2cnnc(OCc3ccccc3)c2n1Cc1ccccc1
Yield: 85 %

Procedure:
42.3 g (0.128 mol) of 1-benzyl-7-benzyloxy-2-methylpyrrolo[2,3-d]pyridazine and 6.6 ml (0.128 mol) of bromine are reacted in a total of 200 ml of dichloromethane as described for Example 3a. Yield: 85%, m.p.: 122°-123° C.
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:20]=1)[CH2:14][N:15]=[N+]=[N-])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H][H]>CO.CCOCC>[CH2:22]([O:21][C:19]1[CH:18]=[C:13]([CH:12]=[C:11]([O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:20]=1)[CH2:14][NH2:15])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCOc1cc(CN=[N+]=[N-])cc(OCCCCCCCCC)c1
Reactant: [H][H]
Solvent: CCOCC
Solvent: CO
Product: CCCCCCCCCOc1cc(CN)cc(OCCCCCCCCC)c1
Yield: 62.26 %

Procedure:
A thick walled glass bottle containing a stir bar was flushed with nitrogen gas. 5% Palladium on activated carbon (0.53 g, 10% by mass) was added and wetted with a solution of 50% methanol/ether (about 10 mL). A solution of 3,5-dinonoxybenzylazide (5.3 g, 12.68 mmol) in 50% methanol/ether (about 40 mL) was added. The mixture was hydrogenated with hydrogen gas at 40 psi for approximately 1 hour. The mixture was then filtered through celite with a controlled vacuum using.50% methanol/ether. The solvent was removed from the filtrate under reduced pressure and then the trace solvent was removed with using high vacuum. The starting material was still present in the resulting organic oil, so hydrogenation and celite filtration were repeated until there is no azide remained (3 times). There was a 7.3 g yield or a 62.26% yield of the derivative. The NMR characterization data for this derivative is as follows. 1NMR (300 MHz, CDCl3): 0.88 (t, J=6.3, 6H, CH2CH3), 1.1-1.55 (m, 28H, CH2(CH2)6), 1.76 (p, J=6.6, 4H, OCH2CH2), 3.78 (s, 2H,), 3.95 (t, J=6.6, 4H,), 6.33 (t, J=2.2, 1H, ArH), 6.44 (d, J=2.2, 2H, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:13](=[O:22])[CH:12]=[C:11]3[C:23]2[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34]>CN(C=O)C.C(NCC)C.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:13](=[O:22])[CH:12]=[C:11]3[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])[CH:24]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(I)c1)cc(=O)n2CC1CC1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1cccc(-c2cc(=O)n(CC3CC3)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
A solution of 6-(4chloro-benzoyl)-1-cyclopropylmethyl-4-(3-iodo-phenyl)-1H-quinolin-2-one (4.0 g, 7.41 mmol) in DMF/diethylamine (1:1, 80 mL) was treated with palladium (II) bis(triphenyl)phosphine chloride (0.26 9, 0.37 mmol), trimethylsilylacetylene (1.09 g, 11.1 mmol), and copper (I) iodide (0.21 g, 1.09 mmol). The reaction mixture was stirred at room temperature for 3 hours, concentrated in vacuo, poured into H2O (450 mL), and filtered to give a crude brown foam. Purification by flash column chromatography (silica, ether:petroleum ether 1:1) gave 6-(4-Chloro-benzoyl)-1-cyclopropylmethyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one (3.47 g, 92%) as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@@:12]34[C:13]5[CH:14]=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][C:18]=5[CH2:19][C@@H:6]2[C@:7]3([CH2:25][CH3:26])[CH2:8][CH2:9][C:10](=[O:24])[CH2:11]4)[CH2:3][CH2:2]1.[BH4-].[Na+].O>C(O)C>[CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@@:12]34[C:13]5[CH:14]=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][C:18]=5[CH2:19][C@@H:6]2[C@:7]3([CH2:25][CH3:26])[CH2:8][CH2:9][C@H:10]([OH:24])[CH2:11]4)[CH2:2][CH2:3]1
Reactant: CC[C@@]12CCC(=O)C[C@@]13CCN(CC1CC1)[C@@H]2Cc1ccc(OC)cc13
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC[C@@]12CC[C@H](O)C[C@@]13CCN(CC1CC1)[C@@H]2Cc1ccc(OC)cc13
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.95 g (2.7 mMol) of N-cyclopropylmethyl-14β-ethyl-3-methoxymorphinan-6-one (starting compound of example 11a) are dissolved in 70 ml of ethanol, then 0.53 g of NaBH4 (0.14 mol) are added, and the mixture stirred for 3 hours at room temperature. The reaction mixture is stopped with 20 ml of water and subsequent stirring for 30 minutes. The ethanol is distilled off and the residue is extracted three times with methylene chloride. After drying and concentrating, the organic phase yields a colorless oil, which is separated by chromatography on silica gel (methylene chloride/methanol/conc. ammonia 99:1:0.1) into the two compounds named in the title. Both compounds are isolated as colorless oils.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)=[O:15])=[CH:8][CH:7]=1)=[O:4].C(OC(N1CCNCC1)=O)C.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([C:19]2[CH:20]=[CH:21][C:16]([C:14](=[O:15])[CH2:13][CH2:12][C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:24])([F:23])[F:1])=[CH:7][CH:8]=3)=[CH:17][CH:18]=2)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(CCc1ccc(NC(=O)C(F)(F)F)cc1)c1ccc(F)cc1
Agent: CCOC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)CCc3ccc(NC(=O)C(F)(F)F)cc3)cc2)CC1
Yield: 64 %

Procedure:
Similarly following the procedure described in Example 5, but substituting 3-(4-amino-phenyl)-1-(4-fluorophenyl)propan-1-one with 2,2,2-trifluoro-N-{4-[3-(4-fluorophenyl)-3-oxopropyl]phenyl}acetamide, and 1-ethoxycarbonylpiperazine with 1-tert-butoxycarbonylpiperazine in Example 5a, gave the title compound as a beige colored solid (64%). The product was used in the next step without further purification.
Reaction SMILES: C[O-].[Na+].[I:4][C:5]1[C:6]([O:19][CH2:20][C:21]([C:23]2[S:27][CH:26]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH:24]=2)=O)=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.[Br-].[CH3:33]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CO.C1COCC1>[I:4][C:5]1[C:6]([O:19][CH2:20][C:21]([C:23]2[S:27][CH:26]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH:24]=2)=[CH2:33])=[CH:7][C:8]2[C:9]([CH3:17])([CH3:18])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1csc(C(=O)COc2cc3c(cc2I)C(C)(C)CCC3(C)C)c1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(COc1cc2c(cc1I)C(C)(C)CCC2(C)C)c1cc(C(=O)OC)cs1

Procedure:
A 30% solution of sodium methoxide in methanol (1.68 ml) was added over 8 hours to a mixture of methyl 5-[(3-iodo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-acetyl]-3-thiophenecarboxylate (4.1 g, 8 mmol) and methyltriphenylphosphine bromide (3.8 g, 10.8 mmol) in THF (50 ml).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH3:19][O:20][C:21]1[C:26]([NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: COc1ncccc1N
Product: COc1ncccc1NC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 2-methoxypyridine-3-amine as the starting materials.