Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:8]=2)[NH:3]1.[OH-].[Na+:20].[O:21]1CCOCC1>O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:8][C:9]=1[CH2:10][C:2]([O-:21])=[O:1].[Na+:20]
Reactant: O=C1Cc2cc(Oc3ccccc3Cl)ccc2N1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(Oc2ccccc2Cl)cc1CC(=O)[O-]

Procedure:
A mixture of 2-oxo-5-(2-chlorophenoxy)indoline (3.2 g.), sodium hydroxide (2 g.), dioxane (20 ml.) and water (40 ml.) was refluxed under heating for 5 days with stirring. After cooling, the reaction mixture was filtered. The filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate under warming and filtered. The filtrate was cooled in an ice bath and the precipitating crystals were collected by filtration, washed with ethyl acetate and then recrystallized from a mixture of methanol and ethyl acetate to give the captioned compound (3.2 g.). mp 105° to 115° C.
Reaction SMILES: [N:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][N:27]=1)#[CH:25]>C(Cl)Cl>[N:17]1([CH2:16][CH:12]2[CH2:13][CH2:14][CH2:15][N:10]([C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:1]4[CH:25]=[C:24]([C:26]5[C:34]6[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=6)[NH:28][N:27]=5)[N:3]=[N:2]4)=[CH:23][CH:22]=3)=[O:9])[CH2:11]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)N2CCCC(CN3CCCC3)C2)cc1
Reactant: C#Cc1n[nH]c2ccccc12
Solvent: ClCCl
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1)N1CCCC(CN2CCCC2)C1

Procedure:
The title compound was prepared following procedure described for intermediate 10, but starting from 1-(4-azidobenzoyl)-3-(pyrrolidin-1-ylmethyl)piperidine (420 mg; 1.34 mmol; 1.0 eq.) and 3-ethynyl-1H-indazole (190 mg; 1.34 mmol; 1.0 eq.). After purification by preparative HPLC, it was obtained as the formic acid salt. The salt was solubilized in DCM and washed with a saturated solution of NaHCO3 then brine. Organic phase was dried over magnesium sulfate, filtered and concentrated. The resulting oil was suspended in EtOH, and concentrated to dryness to afford the title compound as a yellow powder. 1H NMR (300 Mz, DMSO-d6) δ: 13.37 (s, 1H), 9.37 (s, 1H), 8.36 (d, J=8.1 Hz, 1H), 8.15 (d, J=8.7 Hz, 2H), 7.61 (m, 3H), 7.43 (m, 1H), 7.26 (m, 1H), 4.48 (m, 0.4H), 4.25 (m, 0.6H), 3.70 (m, 0.6H), 3.52 (m, 0.4H), 3.04 (m, 0.4H), 2.91 (m, 0.6H), 2.74 (m, 0.4H), 2.20-2.43 (m, 4H), 2.02 (m, 0.6H), 1.69 (m, 6H), 1.48 (m, 4H), 1.20 (m, 1H). HPLC (Condition A): Rt 2.69 min (purity 99.9%). MS (ESI+): 456.4, MS (ESI−): 454.5.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=O.[NH2:19][C@H:20]([C:24]([N:26]([CH3:55])[C@H:27]([C:31]([N:33]1[CH2:54][CH2:53][CH2:52][C@H:34]1[C:35]([N:37]1[CH2:51][CH2:50][CH2:49][C@H:38]1[C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:23])[CH3:22].Cl.C(N(CC)CC)C>CN(C=O)C>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([NH:19][C@H:20]([C:24]([N:26]([CH3:55])[C@H:27]([C:31]([N:33]1[CH2:54][CH2:53][CH2:52][C@H:34]1[C:35]([N:37]1[CH2:51][CH2:50][CH2:49][C@H:38]1[C:39]([NH:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:5]
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](N)C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)NCc1ccccc1)C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1)C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)NCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3.74 g Z-D-Pro-OH (15 mmol, BACHEM) and 8.25 g H-Val-MeVal-Pro-Pro-NHBn×HCl (15 mmol) were dissolved in 80 ml dry DMF. After cooling to 0° C., 2.4 g DEPCN (2.25 ml, 15 mmol) and 4.2 ml triethylamine (30 mmol) were added. The reaction mixture was stirred at 0° C. for several hours and room temperature overnight, then the DMF was evaporated under reduced pressure. The residue was diluted with ethyl acetate and thoroughly washed with dilute aqueous HCl (pH 2), water, dilute aqueous NaOH (pH 9-10), and water. The organic phase was dried over sodium sulfate and evaporated to dryness to yield 9.2 g of the desired protected pentapeptide.
Reaction SMILES: O=[C:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6]CC)=O.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17]>C(O)C>[CH2:9]([C:2]1[CH:3]=[C:4]([OH:6])[N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NNc1ccccn1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Solvent: CCO
Product: Oc1cc(Cc2ccccc2)nn1-c1ccccn1
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
Compound 2a (1.03 g, 5.0 mmol) prepared in Step 1 of Example A-1 was charged in a 25 mL round-bottom flask and dissolved in 6 mL of ethanol. A solution of 2-hydrazinopyridine (0.55 g, 5.0 mmol, manufactured by Aldrich) in 5 mL of ethanol at 50° C. was gradually added thereto over 30 minutes, followed by reaction for 1 hour. After completion of the reaction was confirmed by TLC, the reaction solution was concentrated by evaporation, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography [n-Hex/EtOAc=3/1 (v/v)] to afford a compound of 3-benzyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol (3a).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH:5]=[C:4]([Br:13])[CH:3]=1.[CH2:14]([O:16][C:17](=[O:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][C:21]=1[CH3:27])[CH3:15].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>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].CN1C(=O)CCC1>[CH2:14]([O:16][C:17](=[O:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:2]2[CH:7]=[C:6]([O:8][CH2:9][CH:10]3[CH2:12][CH2:11]3)[CH:5]=[C:4]([Br:13])[CH:3]=2)=[CH:22][C:21]=1[CH3:27])[CH3:15]
Reactant: CCOC(=O)COc1ccc(S)cc1C
Reactant: Brc1cc(Br)cc(OCC2CC2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCC3CC3)c2)cc1C
Temperature: 140 °C
Reaction time: 1 h

Procedure:
1,3-Dibromo-5-cyclopropylmethoxy-benzene (5.27 g; 17.23 mmol), (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (3 g; 13.26 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.36 g; 0.40 mmol), and 1,1′-bis-(diphenylphosphineo)ferrocene (0.44 g; 0.80 mmol) was added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (7.45 mL) and NMP (8 mL) was added, and the reaction mixture was stirred in a microwave oven for 1 h at 140° C. A 5% aqueous citric acid solution (150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (4×100 mL). The pooled organic phases were dried and evaporated in vacuo. The crude reaction product was purified by flash chromatography (heptane: ethyl acetate (20:1→7:3). Yield 2.8 g; 47%). HPLC-MS: m/z: 451.0 (M+); Rt: 2.85 min
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([N:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=3)[O:15][CH:14]([OH:25])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].CN(C1C=CC=CN=1)C.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>ClCCl>[C:41]([O:25][CH:14]1[CH2:13][CH:12]([C:4]2[CH:5]=[C:6]([O:10][CH3:11])[C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=2)[C:21]2[C:16](=[CH:17][C:18]([N:22]([CH3:23])[CH3:24])=[CH:19][CH:20]=2)[O:15]1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C2CC(O)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C2CC(OC(C)=O)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(3-bromo-4,5-dimethoxyphenyl)-7-dimethylamino-2-hydroxy-chroman (9 mg, 0.022 mmol), dimethylamino-pyridine (catalytic) and pyridine (0.1 ml) in dichloromethane at 0° C. was added acetic anhydride (0.05 ml). The mixture was stirred overnight at room temperature. To the mixture was added ice and the mixture was extracted with dichloromethane. The extract was washed with 1N HCl, saturated NaHCO3 and saturated sodium chloride solution, dried and the solvent was evaporated. The title compound was obtained upon chromatography of the crude material over a bond-elute (hexane:ethyl acetate=9:1 and 4:1 as eluent) (6.0 mg; 61%). 1H NMR (CD3OD): 6.99 (d, J=1.9 Hz), 6.86 (broad signal) and 6.85 (d, J=1.8 Hz) (2H), 6.72 (d, J=8.8 Hz) and 6.54 (d, J=8.5 Hz) (1H), 6.47 (t, J=2.3 Hz) and 6.42 (dd, J=2.2, 9.2 Hz) (1H), 6.35 (overlapping dd, J=2.5, 8.7 Hz) (1H), 6.26 (d, J=2.3 Hz) and 6.22 (d, J=2.5 Hz) (1H), 4.14 (overlapping dd, J=6.0, 11.9 Hz; 1H), 3.76-3.80 (s, 6H), 2.87 and 2.91 (s each, 6H), 2.40-2.45 and 2.11-2.32 (m each; 2H), 2.08 and 1.79 (s each, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH2:10](N(CC)CC)[CH3:11]>CN(C)C=O>[C:10]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])#[CH:11]
Reactant: COc1ccccc1I
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccccc1OC
Yield: 51 %

Procedure:
2-Iodoanisole (10.5 g) andtrimethylsilylacetylene (10.3 g) were reacted in dimethylformamide (50 ml), in the presence of dichloro-bis-triphenylphosphine palladium (1.0 g), cuprous iodide (0.5 g) and triethylamine (15 ml) in nitrogen atmosphere at 50° C. for 12 hr. The resulting reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was dissolved in methanol (100 ml), a 5N aqueous solution of sodium hydroxide (20 ml) was added thereto, and then reacted at 60° C. for 1 hr. The reaction solution was evaporated, and to the resulting residue were added ether and water. The resulting ether layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system) to give the title compound as a pale yellow oil (3.02 g, yield; 51%).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[CH2:15]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:16][CH2:17][CH3:18]>O.CO>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CCCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCNS(=O)(=O)c1ccc(N)cc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 6 %

Procedure:
Sodium dithionite (11.4 g, 65 mmol) and sodium carbonate (5.6 g, 53 mmol) were dissolved in water (65 mL) and heated to 70° C. A suspension of the above 4-nitrophenylsulfonamide (2.64 g, 10.2 mmol) in methanol (65 mL) was added and the resulting mixture was stirred at 70° C. for 1.5 hour. The cooled mixture was filtered and the volume of the filtrate was reduced by 50% in vacuo. The aqueous mixture was extracted with ethyl acetate (3×60 mL), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford 0.14 g (6%) of 4-amino-N-butylbenzenesulfonamide as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]([NH:11][CH2:12][CH:13]=[CH2:14])[CH:9]=[CH2:10]>>[CH2:8]([N:11]([CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH:9]=[CH2:10]
Reactant: C=CCNCC=C
Reactant: Clc1ccncc1
Product: C=CCN(CC=C)c1ccncc1
Temperature: 130 °C
Yield: 64.9 %

Procedure:
The title compound was prepared by hydrosilation of 4-diallylaminopyridine with dimethyl(ethoxy)silane, (ETO)Me2SiH. The 4-diallylaminopyridine was obtained by reaction of 4-chloropyridine with diallylamine. Thus, in an experiment similar to that described in Example 1, 4-chloropyridine (11.2 g; 0.10 mol) and diallylamine (14.6 g; 0.15 mol) were combined in an ampoule, degassed under vacuum, sealed and heated for three days at 130° C. The product mixture was dissolved in water, neutralized with 10% NaOH and extracted with several portions of diethyl ether. The ether solution was filtered, the solvent was evaporated, and the residue was distilled to give 4-diallylaminopyridine (11.3 g; 65%; b.p. 92° C. @0.25 torr). 4-Diallylaminopyridine (5.2 g; 0.030 mol), (ETO)Me2SiH (8.3g; 0.080 mol), and H2PtCl6 (60 μL; 0.080 mol/L in isopropylalcohol (i-PrOH); 4.6×10-6 mol) were combined as in Example 1 and heated for 10 hours at 130° C. After reaction the product mixture was distilled under vacuum to give Silane 2a, N,N[bis(3-(dimethyl(ethoxy)silyl)propyl)-4-aminopyridine, as a colorless liquid (5.75 g; 50%; b.p. 142°-146° C. @0.05 torr), which was also characterized by elemental analysis, infrared, 1H and 13C-NMR spectroscopy, and gas chromatography-mass spectrometry.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([OH:36])[C:33]3[C:28](=[CH:29][C:30]([CH3:37])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:45]([O:52][C:53](=[O:56])[CH2:54]Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH2:54][C:53]([O:52][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:56])[C:33]3[C:28](=[CH:29][C:30]([CH3:37])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Reaction time: 16 h

Procedure:
To a solution of 26.4 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (prepared analogously as in example 1) in 150 ml of DMF, 18 g of cesium carbonate and 12.7 g of Bromo-acetic acid benzyl ester was added and stirred for 16 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×300 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 23.6 g.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[C:27](=[O:28])[C:26](OC)=[C:25]([C:31]3[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[CH:33][CH:32]=3)[CH:24]=[N:23]2)[CH:19]=[CH:20][CH:21]=1>O1CCCC1>[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[C:27](=[O:28])[C:26]([N:2]([CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH3:1])=[C:25]([C:31]3[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[CH:33][CH:32]=3)[CH:24]=[N:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: CNCc1ccccc1
Reactant: COc1c(-c2ccc(SC)cc2)cnn(-c2cccc(Cl)c2)c1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2N(C)Cc2ccccc2)cc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
To a rapidly stirred 0° C. mixture of N-methylbenzylamine (67.5 mg, 0.56 mmol) and tetrahydrofuran (3.7 mL) was slowly added dropwise an n-BuLi solution (0.235 mL, 0.59 mmol, 2.5 M in hexanes). The reaction mixture was stirred for 10 minutes at 0° C. and 1 hour at 23° C. The solution was cooled to −78° C., and a tetrahydrofuran (10–15 mL) solution of the 2-(3-chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (200 mg, 0.56 mmol) slowly added along the interior wall of the reaction vessel. This reaction mixture was stirred overnight, slowly warming to 23° C. as the cooling bath evaporated. The reaction was quenched with water and diluted with a large excess of ethyl acetate. The layers were separated, and the ethyl acetate layer washed with additional water and brine and dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 1:9) to provide 2-(3-chlorophenyl)-4-(N-methyl benzylamino)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 145 mg, 58%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:15][NH2:16])([F:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(F)(CN)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 4-[(1,3-dioxoisoindolin-2-yl)methyl]-4-fluoropiperidinecarboxylic acid tert-butyl ester was dissolved in ethanol (200 mL), and then hydrazine monohydrate (10.0 mL) was added. After stirring at room temperature for 2 hours, the precipitated solid was filtered out and the filtrate was concentrated under reduced pressure. The obtained crudely purified product was further purified by silica gel column chromatography (5% MeOH/CH2Cl2) to obtain 4-(aminomethyl)-4-fluoropiperidinecarboxylic acid tert-butyl ester. The compound was identified by 1H-NMR. The yield was 3.23 g (76%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.C(O[C:13]([CH:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1)=[O:14])C.[Cl-].[NH4+]>O1CCCC1>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:13]([C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)([CH:15]2[CH2:16][CH2:17][N:18]([S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:22])=[O:23])[CH2:19][CH2:20]2)[OH:14])=[CH:4][CH:5]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccccc2)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 2 h

Procedure:
To a suspension of 33.78 g (1.39 mole) of magnesium trimmings in 1 liter of tetrahydrofuran (dried over molecular sieves 5A) under an atmosphere of nitrogen and cooled in an ice bath was added dropwise a solution of 243.25 g (1.39 mole) of p-bromoflurobenzene in 150 of tetrahydrofuran. The mixture was stirred for 2 hr after the addition was completed. To this mixture was added 103 g (0.346 mole) of 1-(phenylsulfonyl)-4-piperidinecarboxylic acid ethyl ester as a solid, and the solution was stirred at ambient temperature for 5 hr. The reaction mixture was poured into an icy aqueous solution of ammonium chloride. The phases was separated, and the solvent was removed in vacuo from the organic phase. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate and was reduced in vacuo to ≃1 liter volume. The title compound was obtained by adding hexane and cooling, recrystallizing and the precipitate from ethyl acetate and hexane and drying the solid under high vacuum at 130° C. for 45 min at which time the product had partially melted, m.p. 142.5°-144° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:6]1.C(=O)(O)[O-:20].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[OH:20][CH:4]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH:6]=1)[C:3]([NH:2][CH3:1])=[O:18]
Reactant: O=C([O-])O
Reactant: CNC(=O)C=C1CC2(CCCC2)c2ccccc21
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)C(O)C1=CC2(CCCC2)c2ccccc21
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
N-Methyl-[spiro(cyclopentane-1,1'-indan)-3'-yliden]acetamide (9.6 g; Swedish Pat. No. 7203905-0) is dissolved in dichloromethane (200 ml) and added to sodium bicarbonate solution (30 ml; 0.5 M). The solution is treated with m-chloroperbenzoic acid (13.76 g of a 50% product) in small portions with stirring at about 20° C. After stirring for an additional 2 hours, the solution is washed with saturated sodium carbonate solution and water and dried with sodium sulphate. The solvent is evaporated and the remaining oil is dissolved in tetrahydrofuran (100 ml). Perchloric acid (70%, 10 drops) is added and the mixture is kept at about 20° C. for 1.5 hour. Evaporation of the solvent in vacuo gives the crude α-hydroxy-N-methyl-[spiro(cyclopentane-1,1'-indene)-3'-yl]acetamide as a viscous oil. A sample is triturated with diisopropyl ether and the crystalline product obtained is recrystallized from this solvent. A colourless product is obtained, melting at 136°-138° C. The crude hydroxyamide is dissolved in anhydrous diethyl ether (200 ml) and added dropwise to a suspension of lithium aluminium hydride (30 g) in anhydrous ether (500 ml). The mixture is stirred at room temperature for 5 days and the excess of hydride is destroyed with ethyl acetate, followed by saturated aqueous sodium sulphate solution. The ether phase is washed with water and dried. Evaporation of the solvent gives the crude title compound, which after crystallization from diisopropyl ether melts at 134° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH2:18][CH2:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>C(O)C.O>[CH2:21]([C:18]1[C:17](=[O:20])[C:7]2[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=[C:11]3[C:6]=2[N:5]([CH:19]=1)[C:4]1[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]3=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc2c3c(c1)c1ccc(Br)cc1n3CCC2=O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc2c(=O)c(Cc3ccccc3)cn3c4cc(Br)ccc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
9-bromo-5,6-dihydro-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 101, step 6 was suspended in ethanol (12 ml), and benzaldehyde (103 mg) and sodium hydroxide (190 mg) dissolved in water (1 ml) were added to the suspension. The mixture was stirred at room temperature for 12 hours, and approximately half of the solvent was evaporated under reduced pressure. The crystals precipitated were recovered by filtration, and washed with water, ethanol and ether in succession to obtain the title compound (217 mg, 87%).