Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH:24]2[CH2:29][CH2:28][CH:27](C)[CH2:26][CH2:25]2)[C:13]([NH:15][C:16]2[S:17][C:18]([S:21][C:22]#N)=[CH:19][N:20]=2)=[O:14])[CH2:8][CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4].SC[C@@H]([C@@H](CS)O)O.CI>>[C:1]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[S:17][C:18]([S:21][CH3:22])=[CH:19][N:20]=2)=[O:14])[CH2:10][CH2:11]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)C2CCC(C)CC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Solvent: CI
Product: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(SC)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (H) and (I) using 1-(1-butyryl-piperidin-4-yl)-1-(4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and methyliodide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.[C:26]1([CH2:32][CH2:33][CH2:34][CH2:35]O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:35][CH2:34][CH2:33][CH2:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCCc1ccccc1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)OCCCCc2ccccc2)=C(C)N1

Procedure:
259 mg (0.718 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 0.122 ml (0.79 mmol) of 4-phenylbutyl alcohol, 193 mg (1.01 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 17.5 mg (0.144 mmol) of 4-dimethylaminopyridine were stirred together in 7.2 ml of dichloromethane at room temperature overnight. Water was added to the reaction liquid. After the extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/1) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1)=[O:5])[CH3:2].[C:16]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])[CH:17]=[CH2:18]>O.C1(C)C=CC=CC=1>[CH2:21]([O:20][C:16]([CH2:17][CH2:18][N:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1CNc2ccccc2O1
Reactant: C=CC(=O)OCc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CN(CCC(=O)OCc2ccccc2)c2ccccc2O1

Procedure:
2.3 mmol (0.9 ml) of 40% Triton B in water are added at 0° C. to 22.6 mmol (5 g) of 2-ethoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazine (described in J. Heterocyclic Chem., 1985, 22, 177) and 79 mmol (12.8 g) of benzyl acrylate in 17 ml of toluene. The reaction mixture is refluxed overnight, the solvent is evaporated off and the reaction mixture is heated again for 24 hours. After cooling, hydrolysis and extraction with ethyl acetate, the organic phase is concentrated and purified by chromatography on silica gel using an ethyl acetate/petroleum ether mixture (3/7) as eluant to yield the expected compound.
Reaction SMILES: [SH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13].Cl>C(O)(=O)C>[C:12]([S:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:14])[CH3:13]
Reactant: Cc1cccc(C(=O)O)c1S
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Sc1c(C)cccc1C(=O)O

Procedure:
2-Mercapto-3-methylbenzoic acid (9.0 g, 54 mmol), acetic anhydride (6.5 g, 63 mmol) and glacial acetic acid (25 ml) were refluxed 1 hour, then poured into dilute hydrochloric acid. The product was filtered and recrystallized from toluene.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]2[C:11]([O:13][C:14](=[O:15])[C:2]=12)=[O:12].[NH2:16][C:17]([CH3:24])([CH:21]([CH3:23])[CH3:22])[C:18]([NH2:20])=[O:19]>O1CCCC1>[C:18]([C:17]([NH:16][C:14]([C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:15])([CH3:24])[CH:21]([CH3:23])[CH3:22])(=[O:19])[NH2:20]
Reactant: O=C1OC(=O)c2nc3ccccc3cc21
Reactant: CC(C)C(C)(N)C(N)=O
Solvent: C1CCOC1
Product: CC(C)C(C)(NC(=O)c1nc2ccccc2cc1C(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,3-quinolinedicarboxylic anhydride (0.037 mol) in tetrahydrofuran (THF, 250 mL) is stirred at 5° C. under a drying tube, and a solution of 2-amino-2,3-dimethylbutyramide (0.037 mol) in THF (50 mL) added thereto, in small increments, over a 15 minute period. The reaction mixture is allowed to warm slowly to room temperature for an extended period of time, i.e. about 17 hours. The solvent is evaporated in vacuo to afford a gummy residue, which is triturated with hot ethyl acetate (400 mL) and then filtered to afford the desired 2-[(1-carbamoyl-1,2-dimethylpropyl)-carbamoyl]-3-quinolinecarboxylic acid, mp 172.5°-173.5° C.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][OH:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].O[C:27]1[CH:31]=[CH:30][O:29][N:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:25][C:27]1[CH:31]=[CH:30][O:29][N:28]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Oc1ccon1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccon1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.3 %

Procedure:
Diisopropyl azodicarboxylate (1.1 ml, 5.5 mmol) was added dropwise to a solution of 2-(t-butoxycarbonylamino)ethanol (850 μl, 5.5 mmol), 3-hydroxyisoxazole (Method 75; 425 mg, 5 mmol) and triphenylphosphine (1.44 g, 5.5 mmol) in THF (20 ml) and the mixture was stirred at ambient temperature for 18 hours. The solvent was evaporated and the residue purified by flash chromatography on silica gel eluting with iso-hexane:EtOAc (100:0 increasing in polarity to 4:1) to give the title compound (506 mg, 44%) as a white solid. NMR 1.43 (s, 9H), 3.56 (m, 2H), 4.32 (m, 2H), 4.90 (s, 1H), 5.98 (s, 1H), 8.16 (s, 1H); m/z 229.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[C-:29]#[N:30].[Na+]>C1(C)C=CC=CC=1.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>[C:29]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1)#[N:30]
Reactant: CCN1c2ncc(CCc3ccncc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: [C-]#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN1c2ncc(CCc3ccncc3)cc2C(=O)N(C)c2ccc(C#N)nc21
Yield: 15 %

Procedure:
A solution of 2-chloro-5,11-dihydro-11-ethyl-8-[2-(4-pyridyl)ethyl]-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (78 mg, 0.2 mmol), Sodium cyanide impregnated alumina (2 g/4 g, 0.44 g, 4.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.04 mmol) in 5 mL of toluene was heated at 100° C. under argon for 8 hours. The reaction mixture was filtered, and the collected solid was washed with ethyl acetate. The filtrate was concentrated to give a yellow oil, which was purified by flash chromatography (elution with isopropannol-hexanes) and recrystallization (ethyl acetate-hexanes) to afford 11.5 mg (15%) of the title compound, m.p. 149°-150° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)C(C)C)(C)C.[CH3:21][C@H:22]1[N:27]([C:28]2[C:29]3[CH:36]=[CH:35][S:34][C:30]=3[N:31]=[CH:32][N:33]=2)[C@@H:26]([CH3:37])[CH2:25][N:24]([CH2:38][C:39](O)=[O:40])[CH2:23]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>O1CCOCC1.CN(C)C1C=CN=CC=1>[CH3:21][C@H:22]1[N:27]([C:28]2[C:29]3[CH:36]=[CH:35][S:34][C:30]=3[N:31]=[CH:32][N:33]=2)[C@@H:26]([CH3:37])[CH2:25][N:24]([CH2:38][C:39]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])=[O:40])[CH2:23]1
Reactant: C[C@@H]1CN(CC(=O)O)C[C@H](C)N1c1ncnc2sccc12
Reactant: Nc1ccccc1C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(CC(=O)Nc2ccccc2C(F)(F)F)C[C@H](C)N1c1ncnc2sccc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of the product from step (i) (0.2 g), 2-trifluoromethylaniline (0.11 g) and N,N-diisopropylethylamine in 1,4-dioxane (5 ml) was heated at 80° C. for 18 hours. LC mass spectrum analysis showed cis-(3,5-dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl]acetic acid present. PyBroP (0.18 g) and 4-dimethylaminopyridine (0.05 g) were added and the mixture further stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the residue purified by high pressure liquid chromatography (acetonitrile/0.1% aqueous ammonium acetate, gradient elution 25% to 75% organic phase) to give the title product as a white solid. Yield 0.08 g.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:35][C:19]3=[N:20][CH:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=4[CH3:34])[C:27]([O:29][CH3:30])=[O:28])[CH:23]=[C:18]3[CH:17]=2)=[CH:12][CH:11]=1>[Al].ClCCCl.CCOC(C)=O>[Br:8][C:17]1[C:18]2[C:19](=[N:20][CH:21]=[C:22]([C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:27]([O:29][CH3:30])=[O:28])[CH:23]=2)[O:35][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reaction time: 8 h

Procedure:
The reaction flask was wrapped in aluminum foil. NBS (175 mg, 0.983 mmol) was added to a stirring solution of methyl 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (289 mg, 0.800 mmol) in DCE (8 mL) at room temperature. It was allowed to stir overnight. The mixture was diluted with EtOAc and quenched with 10% sodium metabisulfate and washed with sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) the expected product consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (1H, d, J=2.01 Hz), 8.16-8.26 (2H, m), 8.06 (1H, d, J=2.26 Hz), 7.95 (1H, dd, J=8.03, 1.76 Hz), 7.87 (1H, d), 7.45-7.57 (3H, m), 3.86 (3H, s), 2.34 (3H, s). LC-MS retention time: 2.85 min; m/z (MH+):440, 442. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: Cl[CH2:2][C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)[C:4]#[N:5].[N-:21]=[N+:22]=[N-:23].[Na+]>O>[N:21]([CH2:2][C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)[C:4]#[N:5])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC(CCl)(CCOC1CCCCO1)c1ccccn1
Agent: [Na+]
Solvent: O
Product: N#CC(CCOC1CCCCO1)(CN=[N+]=[N-])c1ccccn1
Temperature: 140 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
To a solution of 8.01 g of the compound obtained in Step 2 in 200 ml of dimethylformamide(DMF) was added 8.84 g of sodium azide. The resulting mixture was stirred for 18 hours at 140° C. After the reaction was completed, water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue thus obtained was purified by a silica gel column chromatography using a mixture of ethyl acetate and n-hexane of 1:6 to obtain 6.2 g of the title compound as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[S:9]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[C:13]=2[OH:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)Cl.[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.[BH4-].[Na+]>C(O)(C)C>[Cl:19][C:14]1[C:13]([OH:20])=[C:12]([S:9]([N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([F:34])=[CH:36][CH:37]=3)=[CH:30][CH:29]=2)(=[O:11])=[O:10])[CH:17]=[C:16]([Cl:18])[CH:15]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NCc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1ccc(CNCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a solution of N-(4-(aminomethyl)benzyl)-3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxybenzenesulfonamide (235 mg, 0.50 mmol) in a mixed solvent (10 mL of CH2Cl2 and 2 mL of i-propanol) at rt was added 4-fluorobenzaldehyde (62 mg, 0.50 mmol). The reaction mixture was stirred at rt overnight. The next morning, sodium borohydride (37 mg, 1.00 mmol) was added, and the mixture was stirred at rt for 2 h. The reaction mixture was quenched by adding 3 mL of MeOH and 3 ml of saturated aq NaHCO3. The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were dried, concentrated and purified by prep HPLC to give the title compound (164 mg, 57%) as a white solid. MS (ESI): 577.0 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[N:22]([CH2:25][CH3:26])[CH:21]=[C:20]([CH3:27])[C:18]=3[N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].C(O)(=O)C>[CH2:25]([N:22]1[CH:21]=[C:20]([CH3:27])[C:18]2[N:19]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:15]=[CH:16][C:17]=2[C:23]1=[O:24])[CH3:26]
Reactant: [H][H]
Reactant: CCn1cc(C)c2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCn1cc(C)c2nc(N3CCNCC3)ncc2c1=O
Yield: 88.2 %

Procedure:
Added to 300 mg (0.83 mmol) of the 2-(4-benzylpiperazino)-6-ethyl-8-methylpyrido[4,3-d]pyrimidine-5(6H)-one obtained in Referential Example 11 were 6 ml of ethanol, 2 ml of acetic acid and 30 mg of 10% Pd-C. The resultant mixture was stirred at 45° C. for 3.5 hours in a hydrogen atmosphere. The Pd-C was removed from the reaction mixture, followed by concentration under reduced pressure. The concentrate was added with 20 ml of water, to which potassium carbonate was added until no foams were developed. The resultant mixture was extracted three times with 50 ml of chloroform. The chloroform layer was dried with sodium sulfate and then concentrated under reduced pressure, thereby obtaining 200 mg of 6-ethyl-8-methyl-2-piperazinopyrido[4,3-d]pyrimidine-5(6H)-one as colorless crystals (yield: 88%).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19](=[O:32])[CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[CH:11]([CH2:33][NH:34]C(OCC2C=CC=CC=2)=O)[CH2:10][C:9]1=[O:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:46].C(O)(=O)C>C(Cl)(Cl)Cl>[BrH:46].[NH2:34][CH2:33][CH:11]1[CH2:10][C:9](=[O:45])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]1[C:19](=[O:32])[CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]
Reactant: O=C(NCC1CC(=O)N(Cc2ccccc2)c2ccccc2N1C(=O)CN1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: NCC1CC(=O)N(Cc2ccccc2)c2ccccc2N1C(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 82 %

Procedure:
To a solution of 1-benzyl-4-(benzyloxy-carbonylamino methyl)-5-(phthalimidoacetyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.51 g, 2.5 mol) in chloroform (20 mL) was added 25% hydrogen bromide-acetic acid solution (5 mL). The mixture was stirred for 25 minutes at room temperature, which was concentrated under reduced pressure. The concentrate was crystallized from ethanol-diethyl ether, followed by recrystallization from dichloromethane-ethanol-diethyl ether to afford the object compound (1.13 g, 82%), m.p.232°-234° C.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].Br[CH2:16][CH2:17][C:18]12[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]1[C:22](=[O:28])[NH:21][C:19]2=[O:20]>>[NH2:21][CH2:19][CH2:18][N:6]1[CH2:5][CH2:4][C:3]([C:1]#[N:2])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:8][CH2:7]1.[C:1]([C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:5][N:6]([CH2:16][CH2:17][C:18]23[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]2[C:22](=[O:28])[NH:21][C:19]3=[O:20])[CH2:7][CH2:8]1)#[N:2]
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: O=C1NC(=O)C2(CCBr)C=CC=CC12
Product: N#CC1(c2ccccc2)CCN(CCC23C=CC=CC2C(=O)NC3=O)CC1
Product: N#CC1(c2ccccc2)CCN(CCN)CC1

Procedure:
The title compound is prepared by reacting 4-cyano-4-phenylpiperidine with 1-(2-bromoethyl)phthalimide to obtain 1-[2-(4-cyano-4-phenylpiperidin-1-yl)ethyl]phthalimide and reacting it with hydrazine.
Reaction SMILES: [CH2:1]1[O:43][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][Si](C(C)(C)C)(C)C)[N:18]=4)[C:15]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:14]([O:40][CH3:41])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:42]=[C:3]2[O:2]1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]1[O:43][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[N:18]=4)[C:15]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:14]([O:40][CH3:41])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:42]=[C:3]2[O:2]1
Reactant: COc1ccc2c(c(CCCCO[Si](C)(C)C(C)(C)C)nc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2c(c(CCCCO)nc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
After 2,3-(methylenedioxy)-6-[4-(t-butyldimethylsiloxy)butyl]-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (532 mg, 0.89 mmol) was dissolved in tetrahydrofuran (6 mL), acetic acid (102 μL, 1.78 mmol) and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 1.78 mL) were added to the solution. The mixture was stirred at room temperature. The reaction solution was concentrated in vacuo. The residue was diluted with methylene chloride (30 mL), which was then washed with water. After the organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography (eluted with 1% methanol-methylene chloride) to give 2,3-(methylenedioxy)-6-(4-hydroxybutyl)-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (372 mg, yield 87%) as light yellow needles.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>CN(C1C=CN=CC=1)C.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([N:19]([CH2:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:36](=[O:39])[CH:37]=[CH2:38])[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: Brc1cccc(Nc2ncnc3cnc(NCCCN4CCOCC4)cc23)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)N(CCCN1CCOCC1)c1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Reaction time: 1 h

Procedure:
To a stirred solution of 4-[(3-bromophenyl)amino]6-[(3-morpholinopropyl)amino]pyrido[3,4-d]pyrimidine (400 mg, 0.90 mmol), (prepared from 4-[(3-bromophenyl) amino]-6-fluoropyrido[3,4-d]pyrimidine and 3-morpholinoprop-1-ylamine) DMAP (40 mg) and Et3N (excess, 2.0 mL) at 0° C. under N2 was added acryloyl chloride (1.2 mol eq., 1.08 mmol, 89 μL). After 1 hour stirring, a further two portions of acid chloride (89 μL each) were added over the next 2 hours, and the reaction was then stirred at 20° C. for 1 hour, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure before being chromatographed on silica gel eluting with MeOH/EtOAc (1:9) to MeOH/EtOAc (1:5) to give N-[4-[(3-bromophenyl)amino]pyrido[3,4-d]pyrimidin6-yl]-N-[3-morpholinopropyl]acrylamide] (142 mg, 32%) as a cream powder, mp (CH2Cl2/hexane) 178-180° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19].[C:20](=O)([O-])[O-].[K+].[K+].[C:26](#N)[CH3:27]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:26]([CH3:27])[CH3:20])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)ccc1F
Reactant: CC#N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1

Procedure:
N-(2-Fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (VI) (9 g), n-amyl chloroacetate (8 g) and potassium carbonate (6.7 g) were dissolved in a mixture of acetonitrile (50 ml) and dimethylformamide (10 ml), and the resultant mixture was heated under reflux for 6 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The solvent was removed under reduced pressure to give 12 g of N-(2-fluoro-5-n-amyloxycarbonylmethoxyphenyl)-3,4,5,6-tetrahydrophthalimide (II: R=n-amyloxycarbonylmethyl). nD25 1.5218.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.C(O)C>O>[O:15]1[CH2:14][CH:13]1[CH2:11][NH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(N)cc1
Reactant: ClCC1CO1
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(NCC2CO2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
A mixture of 4-aminobenzylcyanide (10 g, 75.7 mmol), epichlorohydrine (7.9 ml, 9.25 g, 100 mmol), ethanol (15 ml) and water (10 ml) was heated under reflux for 2 hours. After cooling the reaction mixture was poured into 100 ml of water and extracted with ether (3×50 ml). The organic extracts were combined and stirred with 50 ml of 10N NaOH at room temperature for 3 hours. The organic layer was separated, washed with water until neutral, dried over MgSO4 and concentrated. The residue was chromatographed over a silica gel column eluting with a 3:1 mixture of benzene and ethyl acetate to afford 7.24 g of the title compound as an oil, yield: 51.0%.