Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[CH2:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].S(=O)(=O)(O)[OH:23]>>[C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:21][C:14](=[O:23])[CH2:13][CH:12]2[C:20]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:11]1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)N1CCC(=C2CC(=O)c3ccccc32)CC1
Reactant: O=S(=O)(O)O
Product: CCOC(=O)N1CCC2(CC1)OC(=O)CC2c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-Carboxy-β-phenyl-4-piperidinehydracrylic acid diethyl ester (60 g, 0.17 mol; mp 73°-75° C.), prepared by the general procedures described in Example 1, is added portionwise to a stirred mixture of 600 ml of concentrated sulfuric acid, and stirring at room temperature is continued for 4 hours. The solution is poured onto ice, and the mixture is extracted with a copious volume of diethyl ether. The ether extract is washed with water, dried and evaporated; the residue is collected as a solid (34 g) with the aid of a small volume of ether. This product mixture is purified by partition chromatography on a Celite® diatomaceous earth column developed with a hexane-methanol solvent system. The two main fractions separated on the partition column are each, in methylene chloride solution, passed through a short column of alumina (Woelm, Activity II) and the columns are eluted with methylene chloride and then with ethylacetate. Evaporation of the eluates gives the two products described above. The more polar product is the saturated spirolactone product of the example (17 g); mp. 112° -114° C. Recrystallization from acetone-hexane gives analytically pure material, mp. 121°-122° C. The second product, present in lesser amount, is the less polar 4-(3-oxo-1-indanylidene)-1-piperidinecarboxylic acid ethyl ester described above, mp. 118°-122°; recrystallization from aqueous methanol gives the analytical sample, mp. 114°-116° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([NH:24][NH2:25])[CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S.O1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[C:29]1([C:28]2[NH:18][C:16](=[O:15])[N:24]([CH:21]3[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:14][CH:12]4[C:13]5[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)=[O:17])[CH2:19][CH2:20]3)[N:25]=2)[CH:30]=[CH:31][CH:13]=[CH:1][CH:2]=1
Reactant: NNC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: C1CCOC1
Agent: S
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(n2nc(-c3ccccc3)[nH]c2=O)CC1

Procedure:
The solutions of 5.56 g (0.0165 mol) of [1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-hydrazine in 60 ml of tetrahydrofuran and 3.7 g (0.0177 mol) of N-(ethoxycarbonyl)-benzothionamide in 30 ml of tetrahydrofuran were combined and refluxed for 1 hour, whereupon hydrogen sulphide was released. The solvent was distilled off in vacuo, the oily residue remaining was boiled with a little acetonitrile. The mixture was allowed to cool, then additionally cooled from outside with ice water and the resulting precipitate was suction filtered. 4.0 g (52% of theory) of colourless crystals were obtained, melting point 142° C. and Rf=0.38 (eluant 4).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][C:13]2[N:23]=[CH:22][CH:21]=[CH:20][C:14]=2[C:15]([O:17][CH2:18]C)=[O:16])=[CH:2]1.C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:32])C>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[C:13]3[N:23]=[CH:22][CH:21]=[CH:20][C:14]=3[C:15](=[O:16])[O:17][C:18]2=[O:32])=[CH:2]1
Reactant: CCOC(=O)c1cccnc1NCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Product: O=c1oc(=O)n(CCc2c[nH]c3ccccc23)c2ncccc12

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 60A for the product of Example 3A (0.164 g, 53%). MS (DCI) m/z 325 (M+NH4)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[ClH:21]>>[ClH:21].[ClH:21].[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1
Reactant: CC1CCN(C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Product: CC1CCN(C2CCNCC2)CC1
Yield: 36.3 %

Procedure:
1,1-Dimethylethyl 4-methyl-1,4′-bipiperidine-1′-carboxylate (33.0 g, 117 mmol) in HCl (60.0 mL, 4M in MeOH, 240 mmol) was refluxed at 60° C. for 1 h. The reaction was concentrated and the residue was taken up in MeOH (100 mL), filtered and concentrated to provide the title compound of step B (10.8 g, 42.5 mmol, 36%). 1H NMR (300 MHz, D2O) δ ppm 0.85 (d, J=6.22 Hz, 3H), 1.22-1.41 (m, 2H), 1.51-1.70 (m, 1H), 1.80-1.91 (m, 4H), 2.21-2.31 (m, 2H), 2.91-3.11 (m, 4H), 3.40-3.61 (m, 5H).
Reaction SMILES: N.[Na].C1([P:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)C=CC=CC=1.Cl[C:23]1[NH:24][C:25](=[O:33])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>O1CCCC1>[C:16]1([P:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:23]2[NH:24][C:25](=[O:33])[C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=c1[nH]c(Cl)cc2ccccc12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: O=c1[nH]c(P(c2ccccc2)c2ccccc2)cc2ccccc12
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 61 %

Procedure:
At −78° C., 130 ml of ammonia were condensed in and 2.10 g of sodium (91.3 mmol) were dissolved therein within 5 min. The dark blue solution was admixed with 11.70 g of triphenylphosphine (44.6 mmol) in portions and stirred at −78° C. for 2 h. After 100 ml of dry tetrahydrofuran had been added, the cold bath was removed and the ammonia evaporated off within 2 h. After the orange-colored solution had been warmed to room temperature, it was admixed with 4.0 g (22.3 mmol) of 3-chloroisoquinolin-1(2H)-one from example 16.4 in portions and heated to 60° C. for 20 h. After the mixture had been cooled, it was admixed with 50 ml of dist. H2O, and the aqueous phase was extracted three times with 100 ml each time of dichloromethane, and the combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The resulting solid was digested with dichloromethane, filtered off and dried. The filtrate was concentrated and the resulting solid again digested with dichloromethane, filtered off and dried. The solids were combined. 4.47 g (13.6 mmol, 60.9%) of 3-(diphenyl-phosphino)isoquinolin-1(2H)-one were obtained. The filtrate was concentrated under reduced pressure and the resulting solid purified by column chromatography (5:1 dichloromethane/ethyl acetate). A further 0.216 g (0.66 mmol, 2.9%) of 3-(diphenylphosphino)isoquinolin-1(2H)-one was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:15]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[O:1][CH2:13][CH2:14]1
Reactant: OCCO
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 150 °C
Reaction time: 18 h
Yield: 97.6 %

Procedure:
To a solution of ethyl 4-oxocyclohexanecarboxylate (10.0 g, 58.8 mmol) in toluene (196 mL), ethylene glycol (3.6 mL, 64.6 mmol) and p-toluenesulfonic acid monohydrate (1.12 g, 5.88 mmol) were added, and the obtained solution was heated to reflux at 150° C. The resulting solution was stirred for 18 hours. The reaction was quenched by adding a saturated sodium bicarbonate solution to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (12.3 g, 57.4 mmol, 98%) as a colorless oily compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9]C.[CH3:11][O:12][CH:13](Cl)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:13]([O:12][CH3:11])=[C:4]([CH:5]=1)[CH:3]=[O:9]
Reactant: COc1ccc(Cl)cc1C
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(C)cc(Cl)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Titanium tetrachloride (21.6 g, 0.114 mole) was added to a solution of 2-methyl-4-chloroanisole (9 g, 0.057 mole) in methylene chloride at 0° C. Then, 1,1-dichloromethyl methyl ether (7.24 g, 0.063 mole) was added dropwise over a three minute period and the reaction mixture stirred at 0° C. for 30 minutes. The reaction was quenched by carefully pouring it into water (600 ml). The organic layer was separated and the aqueous phase extracted with methylene chloride (2×100 ml). The combined organic layer and extracts was washed with brine, dried (MgSO4) and concentrated under reduced pressure to a pale yellow solid (10.1 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>ClCCl>[CH3:19][S:20]([O:1][CH2:2][CH2:3][NH:4][C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1 g (6.2 mmol) tert.-butyl (2-hydroxyethyl)carbamate and 0.75 g (7.44 mmol) triethylamine are dissolved in 250 ml dichloromethane and the solution is cooled to 0° C. 0.78 g (6.82 mmol) methanesulfonyl chloride are added slowly. The reaction mixture is stirred at 0° C. for one hour, then water is added, and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate, evaporated to dryness in vacuo, and the crude product is purified by column chromatography (silica, eluent: cyclohexane/ethyl acetate 5:1→2:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:10]1=[O:22].[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:35].C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([C@H:14]4[CH2:15][CH2:16][C@H:17]([O:20][CH3:21])[CH2:18][CH2:19]4)[C:10]3=[O:22])=[C:6]([Cl:23])[CH:5]=2)=[CH:38][CH:37]=1)=[O:35]
Reactant: CO[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN([C@H]4CC[C@H](OC)CC4)C3=O)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Mix trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-trans-1-(4-methoxy-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenyl ester (2.134 g, 4.24 mmol), (4-methoxycarbonylphenyl)boronic acid (0.926 g, 5.09 mmol), tetrakis(triphenylphosphine)palladium(0) (0.490 g, 0.42 mmol) and 6.36 ml of 2M solution of K2CO3 in DME (10 mL). Stir for 12 hours at 80° C. Quench the reaction with water and extract with ethyl acetate. Wash the extract with brine and dry over magnesium sulfate. Purify by flash chromatography to recover 1.68 g (81%) of the title compound: MS (m/z): 490 (M+).
Reaction SMILES: Br.Br.[CH3:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:11]=2)[CH2:6][CH2:5]1.CCN(CC)CC.Cl[CH2:33][C:34]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:35]>C(Cl)Cl>[CH3:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([N:19]3[CH2:24][CH2:23][N:22]([CH2:33][C:34]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[O:35])[CH2:21][CH2:20]3)[N:11]=2)[CH2:6][CH2:5]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: CC1CCN(c2nc(N3CCNCC3)ccc2[N+](=O)[O-])CC1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCN(c2nc(N3CCN(CC(=O)N4CCOCC4)CC3)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
A solution of 4-methyl-3′-nitro-6′-piperazin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl dihydrobromide (as prepared in Example 67, step (c), 0.10 g, 0.21 mmol) in CH2Cl2 (5 mL) was treated with Et3N (0.10 mL, 0.75 mmol) and 2-chloro-1-morpholin-4-yl-ethanone (as prepared in the previous step, 39 mg, 0.24 mmol). The reaction stirred at room temperature for 18.5 h. The reaction was diluted with CH2Cl2 and washed with water. The aqueous layer was further extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (0.11 g, 117%, some salt remains) as a yellow solid, which was used directly in the next step without further purification. 1H-NMR (CDCl3; 400 MHz): δ 8.19 (d, 1H, J=9.2 Hz), 6.02 (d, 1H, J=9.2 Hz), 3.76-3.67 (m, 8H), 3.26 (br s, 2H), 3.14-3.07 (m, 2H), 3.03-2.93 (m, 2H), 2.63 (br s, 4H), 1.74-1.65 (m, 2H), 1.65-1.58 (m, 1H), 1.45-1.39 (m, 3H), 1.37-1.24 (m, 3H), 0.97 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z): Calcd. for C21H32N6O4, 433.2 (M+H), found 433.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][O:9][C:5]=2[CH:4]=1.Br[C:13]1[CH:14]=[N:15][C:16]([N:19]([CH3:21])[CH3:20])=[N:17][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.[Pd]>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[C:8]([C:13]3[CH:14]=[N:15][C:16]([N:19]([CH3:21])[CH3:20])=[N:17][CH:18]=3)[O:9][C:5]=2[CH:4]=1
Reactant: CN(C)c1ncc(Br)cn1
Reactant: COc1ccc2ncoc2c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3cnc(N(C)C)nc3)oc2c1

Procedure:
6-Methoxy-1,3-benzoxazole (0.67 mmol), 5-bromo-N,N-dimethylpyrimidin-2-amine (0.80 mmol), CuBr (0.13 mmol), Cs2CO3 (0.67 mmol) and Pd(t-Bu3P)2 (0.067 mmol) in dry DMF (3 ml) was stirred 30 min at 160° C. in a microwave reactor. The reaction mixture was filtered through celite, washed through with CH2Cl2 and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography (CH2Cl2/CH2Cl2/MeOH (9:1) gradient) to give the title compound as an off white solid (108.2 mg). 1H NMR δ ppm 8.99 (s, 2H) 7.62 (d, 1H) 7.38 (d, 1H) 6.98 (dd, 1H) 3.83 (s, 3H) 3.23 (s, 6H); MS m/z 271 (M+H).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:11]1)=[O:7])(C)(C)C.[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32](C(O)=O)=[C:31]([O:39][CH3:40])[CH:30]=1>>[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:11]2)=[O:7])=[C:31]([O:39][CH3:40])[CH:30]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCn2c(=O)[nH]c3ccccc32)C1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCn2c(=O)[nH]c3ccccc32)C1

Procedure:
3-tert-Butoxycarbonylaminomethyl-1-(3-(2,3-dihydro-2-oxobenzimidazol-1-yl)propyl)pyrrolidine (1.31 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.7 g) to give 4-amino-5-chloro-N-(1-(3-(2,3-dihydro-2-oxobenzimidazol-1-yl)propyl)pyrrolidin-3-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]4[C:29](=O)[C:28]5[C:27]([C:31]([O:33]C)=O)=[CH:26][CH:25]=[CH:24][C:23]=5[NH:22][CH:21]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.[NH2:42][NH2:43]>CO>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]4[C:29]5=[N:42][NH:43][C:31](=[O:33])[C:27]6[CH:26]=[CH:25][CH:24]=[C:23]([C:28]=65)[NH:22][CH:21]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1cccc(C(=O)N3CCN(C(=O)C4CC4)CC3)c1)C(c1ccccc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: O=C(c1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1)N1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13 %

Procedure:
A mixture of methyl 3-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (64 mg, 0.12 mmol) in 85% hydrazine monohydrate (5 mL) and methanol (2 mL) was stirred at 25° C. for 4 hr. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by prep-HPLC to give 9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (8 mg, yield 13%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 0.73-0.81 (m, 4H), 1.18-1.19 (m, 1H), 3.20-3.71 (m, 8H), 4.23-4.25 (d, J=10.0 Hz, 1H), 4.59-4.61 (d, J=8.4 Hz, 1H), 7.08-7.26 (m, 10H), 7.45-7.54 (m, 2H); LC-MS (ESI) m/z: 520(M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2([CH2:22][NH2:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:12]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:23][CH2:22][C:17]1([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:6]
Reactant: NCC1(c2cccnc2)CCCC1
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccccc1C(=O)NCC1(c2cccnc2)CCCC1

Procedure:
From 2-methylbenzoic acid and C-(1-pyridin-3-yl-cyclopentyl)-methylamine. LCMS (MH+): m/z=357.0, tR (minutes, Method B)=1.16
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=[N:2]1.Cl.[CH3:10][O:11][NH:12][CH3:13].CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C.CN1CCOCC1.Cl>ClCCl>[CH3:10][O:11][N:12]([CH3:13])[C:6]([C:5]1[O:1][N:2]=[CH:3][CH:4]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1ccno1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccno1
Yield: 75.8 %

Procedure:
A solution of isoxazole 5-carboxylic acid (2.81 g), N-methoxy-N-methylamine hydrochloride (2.49 g), EDCI (4.96 g), dimethylaminopyridine (3.15 g) and 4-methylmorpholine (2.8 ml) in dichloromethane (20 ml) was stirred for 18 h. 2M Hydrochloric acid was added and the mixture was extracted with dichloromethane (three times). The organic layers were washed with aqueous sodium hydrogen carbonate and then brine, combined, dried (magnesium sulphate), evaporated and purified by chromatography on silica eluting with petrol-ether to give the sub-title compound as a colourless oil (2.94 g, 76%).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[NH2:19][CH2:20][C:21]([NH2:24])([CH3:23])[CH3:22]>C1COCC1>[NH2:24][C:21]([CH3:23])([CH3:22])[CH2:20][NH:19][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:18][CH:17]=2)=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Reactant: CC(C)(N)CN
Solvent: C1CCOC1
Product: CC(C)(N)CNC(=O)c1ccc(Oc2ccc(C#N)cc2)cc1
Yield: 38.5 %

Procedure:
4-(4′-Cyanophenoxy)benzoic acid (1.00 g, 4.2 mmol) was dissolved in THF (40 mL) followed by the addition of 1,1-carbonyldiimidazole (0.745 g, 4.6 mmol) in small portions. This mixture was stirred for 1 hour whereupon 1,2-diamino-2-methylpropane (0.48 mL, 4.6 mmol) was added and the resultant mixture stirred for 20 hours at RT. The mixture was then concentrated in vacuo and the residue chromatographed over silica (10% MeOH/CHCl3) to provide 0.50 g (38%) of the desired product. MS. (FD+) 310.2 m.p. 133–137° C.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.Cl.[OH:13][NH2:14].N1C=CC=CC=1>CO.C(Cl)(Cl)Cl>[C:9]1(=[N:14][OH:13])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH2:11]1
Reactant: NO
Reactant: O=C1CCCc2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: ON=C1CCCc2ccccc21
Yield: 88.4 %

Procedure:
To a solution of α-tetralone (5.21 g) in methanol (25 ml), hydroxyamine hydrochloride (5.28 g) and pyridine (25 ml) were added and heated under reflux for 2 hours. The reaction mixture was concentrated and crystallized from ethanol to give a first crystal. After a second crystal was further obtained from the filtrate, this filtrate was concentrated, dissolved in chloroform, washed sequentially with 1M aqueous hydrochloric acid and brine, and then dried over anhydrous sodium sulfate. The crystals obtained earlier were combined and dissolved in chloroform, washed sequentially with 1M aqueous hydrochloric acid and brine, and then dried over anhydrous sodium sulfate. The chloroform solution obtained from the filtrate and the chloroform solution obtained from the crystals were combined and concentrated. The resulting residue was converted into a powder form by addition of n-hexane. The crystal was collected by filtration to give 3,4-dihydronaphthalen-1(2H)-one oxime (5.08 g) as a light-brown powder. To polyphosphoric acid (74.1 g), 3,4-dihydronaphthalen-1(2H)-one oxime thus obtained (5.08 g) was added and stirred at 120° C. for 1 hour. After the reaction mixture was cooled to room temperature, ice-cold water was added under ice cooling and stirred. The precipitated crystal was collected by filtration, and the resulting crystal was dissolved in chloroform and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to give 1,3,4,5-tetrahydro-2H-1-benzoazepin-2-one (4.47 g) as a brown powder. 1,3,4,5-Tetrahydro-2H-1-benzoazepin-2-one thus obtained (4.47 g) was dissolved in tetrahydrofuran (100 ml), to which lithium aluminum hydride (2.12 g) was then added and heated under reflux for 4 hours. The reaction mixture was cooled to room temperature, diluted with 28% aqueous ammonia under ice cooling, and then filtered to remove insoluble materials. The filtrate was evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=20:1 to 9:1) to give the titled compound, i.e., 2,3,4,5-tetrahydro-1H-1-benzoazepine (2.92 g) as a light-yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:8])=[N+:4]([O-:17])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ncccc1Br
Solvent: ClCCl
Product: Cc1c(Br)ccc[n+]1[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 3-bromo-2-methylpyridine (5 g, 29.1 mmol) in DCM (50 ml) was added portionwise at 0° C. m-chloroperbenzoic acid (70%, 8.6 g, 34.9 mmol). The solution was stirred at 0° C. for three hours and then at room temperature overnight. The mixture was filtered, the residue was washed with DCM and the combined DCM phases were quenched with a 10% solution of sodium thiosulfate. The phases were separated, the organic phase was washed with a saturated solution of sodium bicarbonate and brine, dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by column chromatography (silica, diethyl ether, then DCM/methanol 95:5) to yield 4.44 g (23.6 mmol, yield 81%) MS (multi-mode) m/z=190.0 [M+1]+.