Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: C1CCNC1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)N4CCCC4)cc3C)cc12

Procedure:
(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)(pyrrolidin-1-yl)methanone was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and pyrrolidine following the procedures described for Example 117. 1H NMR (methanol-d4): δ 8.60 (s, 1H), 8.42 (s, 1H), 8.09 (d, 1H), 7.34 (s, 1H), 7.23 (s, 1H), 7.05-7.15 (m, 3H), 3.49 (t, 2H), 3.27 (t, 2H), 3.05-3.17 (m, 4H), 2.42 (s, 3H), 2.26 (s, 3H), 1.88-1.91 (m, 2H), 1.73-1.77 (m, 2H). LRMS [M+H]=425.2
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.I[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1>>[CH2:14]([O:13][C:11](=[O:12])[C:10]1[CH:16]=[CH:17][C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1)[CH3:15]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: c1cn[nH]c1
Product: CCOC(=O)c1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg, 3.0 mmol) is coupled with ethyl 4-iodobenzoate (336 μL, 2.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=80/20) to provide 400 mg (93% isolated yield) of the desired product as a white solid.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=[O:25])=[CH:19][CH:18]=1>>[C:1]([C:5]1[C:6]([NH:14][C:24](=[O:25])[CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:27])([F:15])[F:28])=[CH:22][CH:21]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Product: CC(C)(C)c1c(NC(=O)Cc2ccc(C(F)(F)F)cc2)nn2cccnc12

Procedure:
The product from Example 105B and 2-(4-(trifluoromethyl)phenyl)acetic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (400 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.87 (dd, J=6.9, 1.0 Hz, 1H), 8.49 (dd, J=4.0, 1.8 Hz, 1H), 7.67-7.75 (m, 2H), 7.51-7.64 (m, 2H), 7.01 (dd, J=7.0, 4.0 Hz, 1H), 3.75-3.80 (bs, 2H), 1.39 (s, 9H); MS (ESI) m/z 377 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[F:9].[Br:10]Br>[Fe]>[Br:10][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([F:9])[C:4]=1[CH3:8]
Reactant: BrBr
Reactant: Cc1cccc(F)c1F
Agent: [Fe]
Product: Cc1c(Br)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1,2-difluoro-3-methylbenzene (5 g, 39.0 mmol, commercially available from e.g. Sigma-Aldrich, Apollo or Fluorochem) containing iron (0.131 g, 2.342 mmol) was added bromine (2.011 ml, 39.0 mmol) dropwise maintaining a temperature of <30° C. with ice cooling. The mixture was stirred at room temperature overnight. The mixture was partitioned between water (50 mL) and diethyl ether (100 mL). The aqueous phase was extracted with diethyl ether (3×50 mL), combined organic extracts were washed with water (50 mL), 5% sodium thiosulfate solution (50 mL), water (50 mL), brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to afford product in 8.07 g. (Caution: by of product=68-70° C. @ 57 mBar).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[CH2:22][CH2:21][CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:29])([F:28])[F:1])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CNC
Product: CN(C)CCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1, Methanesulfonic acid 5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and dimethylamine were converted to yield Dimethyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amine as off-white solid, MS: 389 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12].[CH3:15][O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([C@H:30]3[CH2:32][C@H:31]3[CH2:33][CH2:34]O)[CH2:26][CH2:25]2)=[N:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[CH3:14][O:13][C:11](=[O:12])[CH2:10][C:3]1[C:2]([F:1])=[CH:7][C:6]([O:8][CH2:34][CH2:33][C@@H:31]2[CH2:32][C@@H:30]2[CH:27]2[CH2:28][CH2:29][N:24]([C:21]3[N:20]=[CH:19][C:18]([CH2:17][O:16][CH3:15])=[CH:23][N:22]=3)[CH2:25][CH2:26]2)=[CH:5][C:4]=1[F:9]
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Reactant: COC(=O)Cc1c(F)cc(O)cc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)OC)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of methyl (2,6-difluoro-4-hydroxyphenyl)acetate (1.46 g, 7.22 mmol) in 10 ml anhydrous dichloromethane at RT was added a solution of 2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethanol (2.10 g, 7.22 mmol) in 20 ml anhydrous dichloromethane, followed by triphenylphosphine (polymer-bound, 3.79 g, 11.4 mmol), and di-tert-butyl azodicarboxylate (1.83 g, 7.94 mmol). The reaction mixture was stirred at RT for 3 hours. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage column, 50 g) using a gradient eluent of 0-40% ethyl acetate in hexanes (900 ml) to afford the title compound. LC/MS (m/z) 476.4 (M+H)+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][NH:11][CH3:12]>COCCOC>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:11]([CH3:12])[CH3:10])[N:7]=1
Reactant: CNC
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: COCCOC
Product: CN(C)c1nc(Cl)nc(Cl)n1
Temperature: -5 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
Cyanuric chloride (11.0 g, 59.6 mmol) was dissolved in ethylene glycol dimethyl ether (100 ml), cooled to -5° C. and gradually added dropwise with 50% aqueous dimethylamine solution (10.8 ml, 120 mmol). This reaction mixture was stirred at the same temperature for 2 hours and then stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The obtained residue was added with dichloromethane and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 11.0 g (yield: 95.4%) of 2,4-dichloro-6-dimethylamino-1,3,5-triazine as colorless crystals having melting point of 122.5° C.-123° C. (2) The obtained 2,4-dichloro-6-dimethylamino-1,3,5-triazine (1.93 g, 10.0 mmol) was dissolved in DMF (8 ml), added with anhydrous potassium carbonate (1.40 g, 10.1 mmol) and cooled to -5° C.-0° C. This mixture was gradually added with imidazole (695 mg, 10.2 mmol). The reaction mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was added with ethyl acetate and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography, using ethyl acetate and methanol (95:5) as eluant, to obtain 873 g (yield: 38.8%) of 2-chloro-4-(1-imidazolyl)-6-dimethylamino-1,3,5-triazine as colorless crystals having melting point of 88° C.-92° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH2:5]O.[BrH:14]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH2:5][Br:14]
Reactant: Br
Reactant: O=[N+]([O-])c1cc(CO)cc(O)c1O
Product: O=[N+]([O-])c1cc(CBr)cc(O)c1O

Procedure:
12.2 g of 3,4-dihydroxy-5-nitrobenzyl alcohol was dissolved in 100 ml of 47% hydrobromic acid at 50° C. After cooling the product was filtered and washed with 47% hydrobromic acid. The crude product was dissolved in dichloromethane and dried over Na2SO4. The mixture was filtered and the solvent was evaporated in vacuo. Yield 7.1 g.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][NH2:14])[CH:11]=2)[CH2:6][CH2:5]1.[CH3:15][CH2:16][N:17](CC)CC>CCO>[NH2:14][CH2:13][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH2:5][CH:4]2[NH:3][C:16](=[NH:17])[CH3:15])=[CH:8][CH:9]=1
Reactant: CCN(CC)CC
Reactant: NCc1ccc2c(c1)C(N)CC2
Agent: Cl
Solvent: CCO
Product: CC(=N)NC1CCc2ccc(CN)cc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
6-Cyanoindan-1-one (prepared using the procedure of Allinger and Jones, JOC 1962, p70. vol 27 for the tetralone analogue) (3.86 g, 24.5 mmol) was converted to the 1-oxime-O-benzyl ether and reduced with BH3-THF by the methods described in example 59 to give 1-amino-6-(aminomethyl)indane. The diamine was isolated in 31% yield as the 2 HCl salt by treatment of an ether solution with 4.0N HCl in dioxane. 1-Amino-6-aminomethylindane 2HCl (0.5 g, 2.1 mmol) was stirred in EtOH (20 ml), cooled to 0° C. and treated with NEt3 (0.59 ml, 4.2 mmol). Intermediate A (0.43 g, 2.1 mmol) was added and the mixture was allowed to warm to 20° C. and stir overnight. The white crystaline product was collected and washed with a small volume of ether and dried in vacuo to give N-(6-(Aminomethyl)-1-indanyl)acetamidine (0.27 g, 35%) as the 2 HCl salt NMR (D2O) 7.45-7.25 (m, 3H), 4.8 (m, 1H), 4.45 (s, 2H), 3.2-2.85 (m, 2H), 2.6)m, 1H), 2.2 (s, 3H, CH3), 2.1 (m, 1H).
Reaction SMILES: [N:1]1([C:5]([C:7]2[O:8][C:9]3[C:15]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=[CH2:31])[N:25]=1.C(O)(=O)C>CO>[N:1]1([C:5]([C:7]2[O:8][C:9]3[C:15]([N:16]4[CH2:17][CH2:18][N:19]([CH2:31][CH2:30][C:26]5[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[N:25]=5)[CH2:20][CH2:21]4)=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: C=Cc1cccc(OC)n1
Reactant: O=C(c1cc2cccc(N3CCNCC3)c2o1)N1CCC1
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc(CCN2CCN(c3cccc4cc(C(=O)N5CCC5)oc34)CC2)n1
Temperature: 120 °C

Procedure:
Azetidin-1-yl(7-(piperazin-1-yl)benzofuran-2-yl)methanone (0.070 g, 0.25 mmol) was dissolved in methanol (1 mL). 2-Methoxy-6-vinylpyridine (0.066 g, 0.49 mmol) and acetic acid (0.014 mL, 0.25 mmol) were added. The mixture was heated by microwave irradiation to 120° C. for 10 h. The product was purified by preparative HPLC to give the title compound. Yield: 0.044 g (43%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(F)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2ccc(F)c(F)c2)CCNC1
Reaction time: 4 h

Procedure:
Preparation according to Preparation 2: tert-Butyl 3-(3,4-difluorophenyl)-3-hydroxy-pyrrolidin-1-carboxylate (2.6 g, 8.69 mmol), dichloromethane (3 mL) and trifluoroacetic acid (3 mL). Stirred for 4 h. Yield: 1.32 g. MS m/z (relative intensity, 70 eV) 199 (M+, 876), 141 (bp), 127 (58), 113 (99), 63 (55).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(O)c([N+](=O)[O-])c1)c1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(OC(=O)c2ccccc2)cc1[N+](=O)[O-]
Yield: 60.4 %

Procedure:
A mixture of 4-hydroxy-3-nitrophenyl benzoate (48.8 g, 0.19 mol), methyl bromoacetate (28.8 g, 0.19 mol), anhydrous potassium carbonate (33.8 g, 0.24 mol) and acetone (700 mL) was heated at reflux for 24 h. The mixture was evaporated in vacuo and the residue partitioned between aqueous NaOH (1 M, 1 L) and dichloromethane (3×200 mL). The combined organic extracts were washed with aqueous NaOH (1 M, 500 mL), water (500 mL) and brine (250 mL), then dried (Na2SO4) and evaporated in vacuo to give a solid. Crystallisation from methanol following decolourisation with charcoal gave the title compound (38 g, 61%) as pale yellow needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[Cl:21][C:15](=[O:17])[CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (3.84 g, 15.78 mmol) (prepared using M from ethyl 2-(piperidin-4-yl)acetate (Oakwood), Z) in DCM (79 mL) at ambient temperature were added oxalyl chloride (1.658 mL, 18.94 mmol) and DMF (0.115 g, 1.58 mmol). The reaction mixture was stirred at ambient temperature for about 3 h. The solvent was removed under reduced pressure to afford tert-butyl 4-(2-chloro-2-oxoethyl)piperidine-1-carboxylate (4.13 g, 100%) as a light yellow solid. The product was used in the next step without further purification.
Reaction SMILES: [S:1]([Cl:5])(=O)(=[O:3])[OH:2].[C:6]1([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[O:15]1[CH2:16][CH2:17][N:12]([C:6]2[CH:11]=[CH:10][C:9]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:8][CH:7]=2)[CH2:13][CH2:14]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(N2CCOCC2)cc1
Product: O=S(=O)(Cl)c1ccc(N2CCOCC2)cc1
Temperature: 90 °C
Reaction time: 20 h
Yield: 14.7 %

Procedure:
Sulfurochloridic acid (71.0 g, 612.07 mmol) was cooled to 0° C. and 4-phenylmorpholine (20.0 g, 122.53 mmol) was added in several batches, while keeping the temperature at 0° C. The resulting solution was then stirred at 90° C. for 20 hours. The reaction mixture was then added dropwise to 200 mL of ice/salt. The resulting solution was extracted with ethyl acetate (2×200 mL) and the organic layers were combined, dried (MgSO4) and filtered. The filtrate was concentrated, and the residue was purified by column chromatography using a 20:1 ethyl acetate/petroleum ether solvent system to give 4.7 g of 4-morpholinobenzene-1-sulfonyl chloride as a yellow solid. 1H NMR (CDCl3) δ 7.9 (d, 2H), 6.9 (d, 1H), 7.5 (d, 2H), 3.87 (t, 2H), 3.4 (t, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:11]2[C:6](=[CH:7][C:8]([O:31][CH3:32])=[C:9]([O:29][CH3:30])[CH:10]=2)[N:5]=1.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>ClCCl>[CH2:33]([N:35]([CH2:2][CH2:3][C:4]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:11]2[C:6](=[CH:7][C:8]([O:31][CH3:32])=[C:9]([O:29][CH3:30])[CH:10]=2)[N:5]=1)[CH2:36][CH3:37])[CH3:34]
Reactant: CCNCC
Reactant: CCOC(=O)c1c(CCBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Solvent: ClCCl
Product: CCOC(=O)c1c(CCN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 25.5 %

Procedure:
A mixture of ethyl 2-(2-bromoethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (0.45 g), diethylamine (0.326 g) and dichloromethane (10 ml) was stirred under reflux for 14 hours. The reaction mixture was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-methanol (20:1, v/v) gave ethyl 2-[2-(N,N-diethylamino)ethyl]-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (0.113 g, 26%). This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 76°-78° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][N:13]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:9]2)=[N:4]1)[CH3:2].NN.O>CO>[CH2:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][NH2:13])=[CH:9]2)=[N:4]1)[CH3:2]
Reactant: CCn1cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2n1
Agent: NN
Solvent: O
Solvent: CO
Product: CCn1cc2cc(CN)ccc2n1
Temperature: 50 °C
Yield: 52 %

Procedure:
To a suspension of 2-((2-ethyl-2H-indazol-5-yl)methyl)isoindoline-1,3-dione (step-3 of Example 13, mixture) in MeOH (7 mL) was added hydrazine-H2O (0.5 mL), and the mixture was heated at 50° C. for 4 hrs. The mixture was concentrated, the residual white solid was added 2 M aqueous NaOH, and extracted with DCM, dried over Na2SO4, filtered and concentrated. The residual oil was diluted with MeOH and applied onto a strong cation exchange cartridge (BondElute (registered trademark) SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix was rinsed with MeOH (6 mL). The crude mixture was eluted with 1 M NH3 in MeOH (6 mL) and concentrated to give 68 mg (52% yield in 2 steps) of the titled compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:17]([Cl:24])=[C:18](N)[CH:19]=[CH:20][C:21]=1Br)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]1[CH:21]=[CH:20][C:19]([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:34]=2)=[CH:18][C:17]=1[Cl:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1c(Br)ccc(N)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(Cl)c2)CC1
Temperature: 80 °C

Procedure:
A mixture of the product of Example 60A (380 mg, 1.23 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (380 mg, 1.23 mmol) and sodium carbonate (391 mg, 3.69 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was degassed and heated at 80° C. for 16 hours. After cooling to ambient temperature and concentration, the residue was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate (3×35 mL). The combined organic phase was washed with saturated brine, dried over sodium carbonate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 8/1 petroleum/ethyl acetate to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:18]([N:22]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:25][C:24]([CH:34]=O)=[N:23]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([N:22]1[C:26]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[CH:25][C:24]([CH2:34][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Reactant: Cc1ccc(-c2cc(C=O)nn2C(C)(C)C)cc1
Product: COc1ccc(N2CCN(CCNCc3cc(-c4ccc(C)cc4)n(C(C)(C)C)n3)CC2)cc1
Yield: 95.9 %

Procedure:
Compound 45 was prepared using the same method as that Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 1-t-butyl-5-(4-methylphenyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.C(O)(=[O:35])C>Cl.C(O)C>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:35])[NH2:25])[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:31][CH:30]=1
Reactant: CC(=O)O
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccc(C#N)c1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccc(C(N)=O)c1
Temperature: 50 °C

Procedure:
A mixture of 4.5 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine in 50 cm3 of acetic acid and 50 cm3 of concentrated hydrochloric acid (d=1.18) is heated at 50° C. for 20 hours. The reaction medium is cooled to room temperature and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is taken up in 100 cm3 of ethanol and then the solution is concentrated to dryness under reduced pressure (2.7 kPa). The residue is precipitated in 60 cm3 of ethyl ether. The solid obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 25 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with dichloromethane and then a dichloromethane and ethanol mixture (99.5/0.5 by volume) as eluent and collecting 30 cm3 fractions. Fractions 35 to 46 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 15 cm3 of ethyl ether. 0.2 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a solid melting at 192° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH), 7.35 (4H, d, J=7 Hz, 4CH arom.), 7.45 (5H, d, J=7 Hz, 4CH arom. and 2 CONH2), 7.50 (2H, m, 2CH arom.), 7.85 (2H, m, 2CH arom.)].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:29][OH:30])[C:5]([CH2:21][O:22]C2CCCCO2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.C(N(C(C)C)C(C)C)C.[CH3:40][Si:41]([CH2:44][CH2:45][O:46][CH2:47]Cl)([CH3:43])[CH3:42]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:29][O:30][CH2:47][O:46][CH2:45][CH2:44][Si:41]([CH3:43])([CH3:42])[CH3:40])[C:5]([CH2:21][OH:22])=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(CO)cc(C)c32)cc1
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CO)c(COCOCC[Si](C)(C)C)cc(C)c32)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution (±)-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)methanol (200 mg, 0.466 mmol) and iPr2EtN (0.16 mL, 0.93 mmol) in CH2Cl2 (2 mL) was added SEMCl (0.124 mL, 0.69 mmol), and then the mixture was stirred at 40° C. for 1 hr. The reaction mixture was concentrated (during the concentration, the THP group was partially removed) and then purified by SiO2 column chromatography (heptane/EtOAc=1/0 to 1/3) to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 7.81 (d, J=3.79 Hz, 1H), 7.58 (d, J=8.30 Hz, 2H), 7.32 (d, J=8.30 Hz, 2H), 7.08 (s, 1H), 6.99 (d, J=3.79 Hz, 1H), 4.79 (d, J=5.81 Hz, 2H), 4.68 (s, 2H), 4.67 (s, 2H), 3.54-3.63 (m, 2H), 3.05 (t, J=5.80 Hz, 1H), 2.54 (s, 3H), 2.35 (s, 3H), 0.82-0.96 (m, 2H), 0.01 (s, 9H).