Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][NH:15][C@H:14](/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][N:15]([CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C@H:14](/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=Cc1cccnc1
Reactant: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1Cc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a mixture of (2S,4R)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]pyrrolidine (356 mg) and nicotinaldehyde (98.6 mg) in methanol (5 ml) were added acetic acid (0.1 ml) and sodium cyanoborohydride (58 mg) and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate (20 ml) was added to the solution and the aqueous solution was extracted with chloroform (50 ml). The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel (10 g) column with a mixture of chloroform and methanol (99:1) to give (2S,4R)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-1-(3-pyridylmethyl)pyrrolidine (340 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][N:17]=[C:18]2[C:21]2([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:24][CH2:23][CH2:22]2)=[CH:13][CH:12]=1)(C)(C)C.Cl>ClCCl.C(O)(C)C>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:21]2([C:18]3[C:19]4[C:14](=[CH:13][CH:12]=[C:11]([O:10][CH2:9][CH2:8][NH2:7])[CH:20]=4)[CH2:15][CH2:16][N:17]=3)[CH2:24][CH2:23][CH2:22]2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2
Temperature: 25 °C

Procedure:
tert-Butyl[2-({1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethyl]carbamate (2.5 g, 5.7 mmol) was dissolved in dichloromethane (30 mL) and 5N hydrochloric acid in isopropanol (20 mL) was added. After stirring over night at room temperature the solvent was evaporated in vacuo. Water (30 mL) was added and the aqueous phase was neutralized with saturated aqueous NaHCO3 and extracted with dichloromethane. The combined organic layers were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product (1.76 g) was used without purification for the next step.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[C:14]1([N:20]=[C:21]=[S:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:14]1([NH:20][C:21](=[S:22])[NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: S=C=Nc1ccccc1
Reactant: NCC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)CNC(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
A mixture of glycinamide hydrochloride (8.25 g), triethyl amine (10.0 g), phenyl-isothiocyanate (10.1 g), and methylene chloride (300 mL) was heated at reflux for 1 hour. The mixture was stirred at ambient temperature for 2 hours. The precipitate was collected by filtration, washed with methylene chloride, then with diethyl ether and air dried to give 2-(3-phenyl-thioureido)-acetamide (9.7 g), m.p. 150°-152° C. Anal. Calcd. for. C9H11N3O S: C, 51.66; H, 5.30; N, 20.08. Found: C, 51.41; H, 5.04; N, 20.02. Mass spectrum (EI, M.+) m/z 209. 1H-NMR (DMSO-d6; 400 MHz) δ9.88 (s, 1 H), 7.70 (t, 1 H), 7.52 (s, 1 H), 7.47 (d, 2 H), 7.31 (t, 2 H), 7.15 (s, 1 H), 7.09 (t, 1 H), and 4.08 ppm (d, 2 H).
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[N:69]1[CH:74]=[CH:73][C:72]([N:75]2[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]2)=[CH:71][CH:70]=1>CN(C=O)C>[CH3:25][C:24]([CH3:27])([O:23][C:21]([NH:1][C@H:2]([C:18]([N:78]1[CH2:79][CH2:80][N:75]([C:72]2[CH:73]=[CH:74][N:69]=[CH:70][CH:71]=2)[CH2:76][CH2:77]1)=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:22])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: c1cc(N2CCNCC2)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1

Procedure:
To a mixture of 18.8 g (0.0494 mol) of Boc-Lys(Z)-OH, 6.5 g (0.05 mol) of DIEA, 16 g (0.05 mol) of TBTU, 6.6 g (0.049 mol) of HOBt and 100 ml of dimethylformamide were added dropwise, with stirring, 8.1 g (0.0494 mol) of 1-(4-pyridinyl)piperazine, dissolved in 40 ml of DMF, and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate phase was then washed three times successively with 70 ml of saturated aqueous sodium hydrogen carbonate solution and once with 70 ml of saturated aqueous saline solution, dried over sodium sulphate and evaporated down in vacuo. 24.2 g (93.2% of theory) of a yellowish oil were obtained, which was used for the following reactions without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:23]2[CH:30]=[CH:29][S:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[CH3:20][C:17]1[CH:18]=[CH:19][N:6]2[C:7]=1[C:8](=[O:16])[N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([C@@H:2]([NH:1][C:22]1[C:23]3[CH:30]=[CH:29][S:28][C:24]=3[N:25]=[CH:26][N:27]=1)[CH3:3])=[N:5]2
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: Clc1ncnc2sccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4sccc34)n(-c3ccccc3)c(=O)c12
Yield: 57.5 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.16 mmol) was treated with 4-chlorothieno[2,3-d]pyrimidine (31 mg, 0.18 mmol) and N,N-diisopropylethylamine (171 μl, 0.98 mmol) in 1-butanol according to the method described in Example 17. The crude was purified using SP1® Purification (0% to 60%, hexane-ethyl acetate) to give 37 mg (56% yield) of the title compound as a solid. Purity 99%.
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[CH:9]3[CH:13]([CH2:14][CH2:15][C:7]=2[C:6]([O:18][CH3:19])=[C:5]([O:20][CH3:21])[CH:4]=1)[C:12](=[O:16])[NH:11][C:10]3=[O:17])[CH3:2].[CH2:22](I)[CH3:23]>>[CH2:22]([N:11]1[C:10](=[O:17])[CH:9]2[CH:13]([CH2:14][CH2:15][C:7]3[C:6]([O:18][CH3:19])=[C:5]([O:20][CH3:21])[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=32)[C:12]1=[O:16])[CH3:23]
Reactant: CCI
Reactant: CCc1cc(OC)c(OC)c2c1C1C(=O)NC(=O)C1CC2
Product: CCc1cc(OC)c(OC)c2c1C1C(=O)N(CC)C(=O)C1CC2

Procedure:
Using the procedure as in example 64, but starting with 9-ethyl-3a,4,5,9b-tetrahydro-6,7-dimethoxy-1H-benz[e]isoindole-1,3-(2H)-dione, and ethyl iodide in place of methyl iodide afforded the desired compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:17]2=[C:18]3[C:10]([C:11]4[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:9][CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1.[NH2:19][C:20]([CH3:25])([CH2:23][OH:24])[CH2:21][OH:22].C([O-])([O-])=O.[K+].[K+].CCO>O.Cl>[ClH:1].[C:3]1([CH2:2][NH:19][C:20]([CH3:25])([CH2:23][OH:24])[CH2:21][OH:22])[C:17]2=[C:18]3[C:10]([C:11]4[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:9][CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1
Reactant: ClCc1ccc2cccc3c2c1-c1ccccc1-3
Reactant: CC(N)(CO)CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(CO)(CO)NCc1ccc2cccc3c2c1-c1ccccc1-3
Yield: 43.8 %

Procedure:
To a RB flask equipped with magnetic stirring bar, condenser and N2 inlet line with bubbler was added crude 1-chloromethylfluoranthene (3C, 13.01 g, 52 mmol), 2-amino-2-methyl-1,3-propanediol (Aldrich, 5.46 g, 52 mmol), K2CO3 (MCB, 14.37 g, 0.104 mol) and abs. EtOH (300 mL). The reaction was stirred at reflux overnight, filtered hot, and the solvent removed by rotary evaporation to give a crude dark oil. This was acidified with 1N HCl and dissolved in H2O, filtered, basified with 5N NaOH solution and filtered to give a crude white solide. The material was dissolved in ethanolic HCl solution, filtered and precipitated with Et2O. Filtration followed by crystallization (abs. EtOH/Et2O, 1:4) gave after filtration and drying a 43.8% yield of 2-[(1-fluorantheneylmethyl)amino]-2-methyl-1,3-propanediol hydrochloride 0.3 H2O, mp 185-188 (dec), (C,H,N,Cl).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[C:20](=[O:27])[N:21]([CH3:26])[N:22]=[C:23]([Cl:25])[CH:24]=1>CN(C)C=O>[Cl:25][C:23]1[CH:24]=[C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:20](=[O:27])[N:21]([CH3:26])[N:22]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cn1
Reactant: Cn1nc(Cl)cc(Cl)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(Cl)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
(6-Amino-pyridin-3-yl)-morpholin-4-yl-methanone (2.921 g, 14.11 mmol) was suspended in 50 mL dimethylformamide and cooled to 0° C. Sodium hydride 60% suspension in mineral oil (847 mg, 21.2 mmol) was added. This was stirred at room temperature for 30 minutes and was cooled to 0° C. 4,6-Dichloro-2-methyl-2H-pyridazin-3-one (1.256 g, 7.056 mmol) was added. After 2 hours, this was partitioned between saturated aqueous ammonium chloride solution and ethylacetate. The ethylacetate layer was dried over anhydrous MgSO4, concentrated in vacuo, and purified by flash chromatography (2% MeOH/CH2Cl2) to yield 6-Chloro-2-methyl-4-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-2H-pyridazin-3-one (732 mg, 2.09 mmol). MS (ESI) 350.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CS(C)=O>[CH2:17]([N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCCCCCCCC=CCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCC=CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 34.1 %

Procedure:
Sodium hydride (95%, 84 mg, 3.5 mmol) was added to a solution of theobromine (0.595 g, 3.2 mmol) in dimethylsulfoxide (15 ml). After 20 minutes of stirring, 1-bromo-9-octadecene (0.995 g, 3 mmol), prepared above, was added. After 6 hours of stirring at room temperature, the reaction mixture was warmed to 60° C. over 3 hours and then poured into a separatory funnel containing 50 ml of water. The reaction mixture was extracted with five 40 ml aliquots of dichloromethane. The organic extracts were combined, washed with water (50 ml) and brine (50 ml) and dried over anhydrous magnesium sulfate. Removing the solvent under reduced pressure resulted in a crude product further purified by flash chromatography over silica gel using a 30% acetone/petroleum ether eluant, yielding 0.44 g of 1-(9-octadecenyl)-3,7-dimethylxanthine (34% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[CH3:10][C@@H:11](O)[CH2:12][CH:13]=[CH2:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][C@H:13]([CH2:12][CH:11]=[CH2:10])[CH3:14]
Reactant: C=CC[C@@H](C)O
Reactant: Oc1cc(Cl)ccc1Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC[C@H](C)Oc1cc(Cl)ccc1Br
Reaction time: 20 h
Yield: 92.1 %

Procedure:
To a solution of 2-bromo-5-chlorophenol (0.40 g, 1.93 mmol, 1 equiv), (R)-pent-4-en-2-ol (0.397 mL, 3.86 mmol, 2 equiv), and PPh3 (1.01 g, 3.86 mmol, 2 equiv) in THF (6.4 mL) was added DEAD (0.61 mL, 3.86 mmol, 2 equiv). After stirring 20 h, reaction diluted with ether and washed with 1 N NaOH. The ether layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-10% EtOAc in hexane) to provide the product as a colorless oil (0.49 g, 92%). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.3 Hz, 1H), 6.89 (d, J=2.3 Hz, 1H), 6.83 (dd, J=8.5, 2.3 Hz, 1H), 5.90 (ddt, J=17.1, 10.1, 7.2 Hz, 1H), 5.21-5.11 (m, 2H), 4.49-4.39 (m, 1H), 2.60-2.50 (m, 1H), 2.48-2.38 (m, 1H), 1.37 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]([CH3:11])[CH3:10])[C:4]=1B(O)O.[CH3:15][O:16][C:17](=[O:38])[C@H:18]([CH2:30][C:31]1[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=1)[NH:19][C:20](=[O:29])[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:28]>>[CH3:15][O:16][C:17](=[O:38])[C@H:18]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[N:9]([CH3:11])[CH3:10])=[CH:35][CH:36]=1)[NH:19][C:20](=[O:29])[C:21]1[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COc1cccc(N(C)C)c1B(O)O
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2N(C)C)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
2-Methoxy-6-(N,N-dimethylamino)benzene boronic acid was coupled with N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine methyl ester to give N-(2,6-dichlorobenzoyl)-4-[2-(N,N-dimethylamino)-6-methoxyphenyl]-L-phenylalanine methyl ester. The preparation of the boronic acid and the coupling reaction was carried out in a similar manner as described in Example 7.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[N:5]=[C:6]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[N:7]=1.[C:20]1([CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)Cl)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH:26]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[N:5]=[C:4]([CH3:19])[CH:3]=[C:2]([CH3:1])[N:7]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: ClC(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(C)nc(NS(=O)(=O)c2ccc(NC(c3ccccc3)c3ccccc3)cc2)n1
Yield: 8 %

Procedure:
Sulfamethazine (105 mg, 0.38 mmol) and diphenylchloromethane (77 μl, 0.38 mmol) were dissolved in 3 ml pyridine. Solution was stirred and refluxed overnight. The reaction mixture was evaporated to dryness and dissolved to 1 M NaOH. Product was precipitated with 1 M acetic acid. Precipitation cycle was repeated for three times to give white crystals of the title compound with a yield of 8%. MS (ESI+): m/z 467(M+Na)+, 445 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.C1(C)C=CC(S(O[CH2:19][CH:20]([CH3:35])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=2)(=O)=O)=CC=1.[OH-].[Na+]>O>[O:28]([C:24]1[CH:23]=[C:22]([CH2:21][CH:20]([CH3:35])[CH2:19][N:4]2[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]2)[CH:27]=[CH:26][CH:25]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC1CNCC(C)O1
Reactant: Cc1ccc(S(=O)(=O)OCC(C)Cc2cccc(Oc3ccccc3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(Cc1cccc(Oc2ccccc2)c1)CN1CC(C)OC(C)C1
Yield: 23.4 %

Procedure:
2,6-Dimethylmorpholine (1.16 g) was added to 3-(m-phenoxyphenyl)-2-methylpropyl p-toluenesulfonate (0.8 g) at room temperature, and the resultant mixture was stirred at 100° C. for 30 minutes. The reaction mixture was made basic with addition of water (100 ml) and 15% aqueous sodium hydroxide solution (10 ml) thereto and extracted with diethyl ether (50 ml×3). The ether extracts were combined together, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 4-[3-(m-phenoxyphenyl)-2-methylpropyl]-2,6-dimethylmorpholine (trans-isomer, 0.16 g; cis-isomer, 0.41 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([O:15][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: Cc1cn2c3ccc(Br)cc3c3cc(O)cc(c1=O)c32
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cn2c3ccc(Br)cc3c3cc(OCC(=O)OC(C)(C)C)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
10-bromo-2-hydroxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (250 mg) obtained in Example 49 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (210 mg) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and t-butyl bromoacetate (0.13 ml) was added to the mixture. The mixture was stirred for 2.5 hours at room temperature, and the reaction mixture was poured into ice water (50 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride containing 2% methanol), and the crude purification product was washed with ether and recovered by filtration to obtain the title compound (130 mg, 39%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][N:5]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:31].Cl.[C:33](OCC)(=[O:35])[CH3:34]>>[C:33]([O:1][CH2:2][CH2:3][NH:4][N:5]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:31])(=[O:35])[CH3:34]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1NCCO
Agent: Cl
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1NCCOC(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the compound obtained in Example 74 (210 mg) in ethyl acetate (10 ml) is added a 4M solution of hydrogen chloride in ethyl acetate (10 ml), and the mixture is stirred at room temperature for five hours. The reaction mixture is concentrated under reduced pressure, and the residue is dissolved in ethyl acetate. The solution is washed successively with a saturated aqueous sodium hydrogen carbonate solution and water, and dried. The solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=2:1), and crystallized from diethyl ether to give 2-(2-acetoxyethylamino)-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone as listed in Table 6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.Cl[CH2:10][CH:11]=O>CCO>[N:1]1[CH:10]=[CH:11][N:3]2[C:4]([NH2:8])=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: O=CCCl
Reactant: Nc1cccc(N)n1
Solvent: CCO
Product: Nc1cccc2nccn12
Temperature: 75 °C
Yield: 80 %

Procedure:
2,6-diaminopyridine (5.0 g, 46 mmol) and chloroacetaldehyde (50% wt. soln in water, 6.4 mL, 50 mmol) were dissolved in absolute EtOH (120 mL). The solution was heated at 75° C. for 1 hour. The mixture was cooled and concentrated via rotavap. The residue was taken up in saturated NaHCO3 and EtOAc. The solution was extracted with EtOAc (3 times), dried over magnesium sulfate, and concentrated to give a brown solid. 4.85 g isolated (80% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[O:10][C:3]=12.[CH3:24][C:25]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]>>[CH3:24][C:25]1[C:31]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])=[CH:13][CH:12]=4)[O:10][C:3]=23)=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]
Reactant: O=C(c1ccc(-c2cc3nccc(Cl)c3o2)cc1)N1CCCC1
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1c(N)cccc1-c1ccnc2cc(-c3ccc(C(=O)N4CCCC4)cc3)oc12

Procedure:
The compound was synthesized according to the procedure K using 7-chloro-2-[4-(pyrrolidin-1-ylcarbonyl)phenyl]furo[3,2-b]pyridine and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.
Reaction SMILES: [CH:1]1([NH:5][C@H:6]2[CH2:10][CH2:9][CH2:8][C@@H:7]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[C:31]=1[C:32](Cl)=[O:33]>C(Cl)Cl>[CH:1]1([N:5]([C@H:6]2[CH2:10][CH2:9][CH2:8][C@@H:7]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:32](=[O:33])[C:31]2[C:35]([O:39][CH3:40])=[CH:36][CH:37]=[CH:38][C:30]=2[O:29][CH3:28])[CH2:2][CH2:3][CH2:4]1
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1NC1CCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC)c1C(=O)N(C1CCC1)[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-(cyclobutylamino)cyclopentyl]carbamate (400 mg, 1.573 mmol) in dry DCM (5.3 ml) was added DIPEA (1.3 ml, 7.86 mmol) and 2,6-dimethoxybenzoyl chloride (CAS number 1989-53-3; 473 mg, 2.359 mmol). The reaction was stirred at room temperature for 1 hour and was then partitioned between DCM and water, filtered through a hydrophobic frit and concentrated in vacuo. This was then purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [C:1]12([CH:11]3[C:20]4[C:15](=[CH:16][C:17]([O:21]C)=[CH:18][CH:19]=4)[CH2:14][CH2:13][N:12]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(Cl)Cl>CO.C(Cl)Cl>[C:1]12([CH:11]3[C:20]4[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=4)[CH2:14][CH2:13][N:12]3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: COc1ccc2c(c1)CCN(c1ccccc1)C2C12CC3CC(CC(C3)C1)C2
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCN(c1ccccc1)C2C12CC3CC(CC(C3)C1)C2

Procedure:
The title compound was prepared by analogy to Example 48 except that 1-adamantan-1-yl-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline was used instead of 6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline, and neat CH2Cl2 to 10% MeOH/CH2Cl2 was used as eluent for flash chromatography purification.