Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH3:16])=[CH:11][C:10]=1[NH:17][C:18](=[O:26])OC1C=CC=CC=1)(C(C)(C)C)(C)C.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[OH:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH3:16])=[CH:11][C:10]=1[NH:17][C:18]([N:40]1[CH2:39][CH2:38][N:37]([C:31]2[CH:30]=[C:29]([O:28][CH3:27])[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=2)[CH2:42][CH2:41]1)=[O:26]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: Cc1cc(NC(=O)Oc2ccccc2)c(O[Si](C)(C)C(C)(C)C)cc1C
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C)c(C)cc3O)CC2)c1
Reaction time: 2 h
Yield: 87 %

Procedure:
Phenyl N-[2-(t-butyldimethylsilyloxy)-4,5-dimethylphenyl]carbamate (0.17 g, 0.5 mmole) and 1-(3,5-dimethoxyphenyl)piperazine(0.13 g, 0.6 mmole) were dissolved in tetrahydrofuran(10 ml), and thereto with stirring DBU(0.09 g, 0.6 mmole) was added, and the resulting mixture was stirred for 2 hours, concentrated and chromatographed to obtain the titled compound.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2.C(N(CC)CC)C.[N:25]([C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)=[C:26]=[O:27]>O1CCCC1>[CH3:2][N:3]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2)[C:26]([NH:25][C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)=[O:27]
Reactant: CNc1cccc2cc(-c3nccs3)[nH]c12
Reactant: O=C=Nc1ccsc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)Nc1ccsc1)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 111 %

Procedure:
To a solution of N-methyl-2-(1,3-thiazol-2-yl)-1H-indole-7-amine hydrochloride (50 mg) and triethylamine (35 mL) in tetrahydrofuran (3 mL) was added 3-isocyanatothiophene (26 mg). The reaction mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (74 mg, yield 99%) as yellow crystals. melting point 266° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=1)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCOC(C)=O>[CH3:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]([NH:9][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=2)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH:8]=[CH:7][CH:6]=1)=[O:18]
Reactant: C#Cc1cccc(NC(=O)c2ccccc2C)c1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
In a 4 mL vial, N-(3-ethynylphenyl)-2-methylbenzamide (0.104 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (0.100 g, 0.295 mmol) were added and dissolved into EtOAc (2 mL) The mixture was then degassed for ˜20 min after which NEt3 (0.141 mL, 1.035 mmol) was added followed by Pd(PPh3)2Cl2 (21.0 mg, 0.030 mmol) and CuI (2.9 mg, 0.016 mmol). The reaction mixture was allowed to stir at 50° C. for 4 hours after which the reaction mixture was partitioned between EtOAc (4 mL) and water (4 mL) The organic extracts were combined, dried over anhydrous Na2SO4 and concentrared. The residue as purified by chromatography (silica gel, gradient elution 25% EtOAc/Hexanes EtOAc). The product containing fractions were concentrated to give the title compound as a solid (121 mg, 83%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:14][C:6]2=[C:7]([CH3:13])[N:8]=[CH:9][C:10]([CH2:11][NH2:12])=[C:5]2[CH2:4][O:3]1.[C:16]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(Cl)CCl.C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.ClCCl>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:12][CH2:11][C:10]2[CH:9]=[N:8][C:7]([CH3:13])=[C:6]3[O:14][C:2]([CH3:15])([CH3:1])[O:3][CH2:4][C:5]=23)=[O:25])=[CH:27][CH:28]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: Cc1ncc(CN)c2c1OC(C)(C)OC2
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ncc(CNC(=O)c2ccc(C(C)(C)C)cc2)c2c1OC(C)(C)OC2
Yield: 86.3 %

Procedure:
A mixture of C-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)-methylamine (1.77 g, 8.49 mmol), 4-tert-butylbenzoic acid (5.6 g, 31 mmol), EDC (5.7 g, 29 mmol), and DMAP (4.53 g, 35.6 mmol) was stirred in dichloromethane (200 mL) for 24 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the dichloromethane layer was separated. The aqueous layer was then extracted with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The crude mixture was purified by column chromatography on silica gel using a gradient mixture of dichloromethane:acetone (1:0 to 7:3) as eluant to give 4-tert-butyl-N-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl-methyl)-benzamide (74) (2.7 g, 85%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].C1C[O:20]CC1.O>>[CH3:1][O:2][C:3]([C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:20])=[O:14])=[CH:9][CH:8]=1)([CH3:6])[CH3:5])=[O:16]
Reactant: C1CCOC1
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: O
Product: COC(=O)C(C)(C)c1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The product obtained from Example 193, Step C (240.0 mg, 1.0 mmol) was treated with THF/H2O (1:1, 10 ml). The mixture was stirred at 60° C. for 2 hr. The reaction mixture was extracted with EtOAc, washed with 1N HCl, H2O and brine. Reverse phase HPLC purification provided 4-(1-methoxycarbonyl-1-methyl-ethyl)-benzoic acid as white solid. MS found: (M+1)+=223.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][Si:14]([CH3:18])([CH3:17])[CH2:13][CH2:12]1.C([O-])(O)=O.[Na+].[C:24](Cl)([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O1CCCC1>[CH3:17][Si:14]1([CH3:18])[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[CH:5][C:6]([NH:8][C:24](=[O:25])[O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:7][C:2]=2[F:1])[CH2:12][CH2:13]1
Reactant: C[Si]1(C)CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si]1(C)CCN(c2ccc(NC(=O)OCc3ccccc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.2 %

Procedure:
To a solution of 9 (610 mg, 2.28 mmol) in Tetrahydrofuran (THF) Pd/C is added for hydrogenation under a pressure of 35 psi in a par hydrogenator. The reaction mixture is filtered through celite. To the filtrate, saturated NaHCO3 (420 mg, 5.01 mmol), CBzCl (427 mg, 2.5 mmol) are added and stirred at 25° C. for 5 h. The solvent is removed, 10 mL water is added and the aqueous layer is extracted with EtOAc. The crude mixture is then subjected to column chromatography on silica gel using hexane-DCM mixtures to afford the product 10 as a viscous liquid (690 mg) in 82% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:12][C:13]#[N:14])[C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=O.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]#[N:14])=[C:16]3[CH2:17][CH2:18][CH2:19][N:15]3[C:9]2=[O:10])=[CH:6][CH:7]=1
Reactant: N#CCN(C(=O)Cl)c1ccc(Cl)cc1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c2n(c(=O)n1-c1ccc(Cl)cc1)CCC2
Temperature: 25 °C

Procedure:
N-(4-chlorophenyl)-N-cyanomethylcarbamoyl chloride, prepared as described in Example 53, (2.7 g, 0.012 mol) was dissolved in 10 mL of dimethylformamide and added dropwise to a cold solution (0° C.) of 2-pyrrolidinone (1.0 g, 0.012 mol) and sodium hydride (0.96 g, 0.024 mol) in 20 mL of DMF. The solution was allowed to warm to ambient temperature over two hours, then it was poured onto ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over magnesium sulfate, and concentrated to yield an oil. Elution of this oil through a silica gel column using 1:2 ethyl acetate:hexane furnished 0.4 g of 2-(4-chlorophenyl)-2,3,6,7-tetrahydro-3-oxo-5H-pyrrolo-[l,2-c]imidazol-1-carbonitrile, as a solid (m.p. 154°-6° C.).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][C:8](N)=[CH:9][C:4]=2[CH2:3][O:2]1.N([O-])=[O:12].[Na+].NC(N)=O>O.OS(O)(=O)=O>[CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:12])=[CH:9][C:4]=2[CH2:3][O:2]1
Reactant: O=N[O-]
Reactant: Nc1ccc2c(c1)COC2
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc2c(c1)COC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
1,3-Dihydro-2-benzofuran-5-amine (prepared according to U.S. Pat. No. 4,000,286) (2.7 g, 20 mmol) was dissolved in a mixture of water (300 mL) and conc. H2SO4 (21 mL), cooled to 0° C. and NaNO2 (1.43 g, 20.7 mmol) in water (10 mL) was added over 15 min. After stirring at 0° C. for 1 h the mixture was allowed to stir at 10° C. for 30 min and urea was added until a negative test with starch/KI paper was observed. The solution was then poured over 2 min into a mixture of water (180 mL) and conc. H2SO4 (12.6 mL) at 90° C. and stirred at this temperature for 1.5 h. The hot mixture was filtered then allowed to cool to room temperature. The aqueous mixture was extracted with EtOAc (2×100 mL) and the combined organic layers were dried (MgSO4) and evaporated to give the title phenol (974 mg, 36%) as a cream solid; δH (CDCl3, 400 MHz) 5.03 (4H, s), 6.71 (2H, m), 7.08 (1H, d).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:13]([C:14]([O:16]C)=[O:15])[C:12]([OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:27]1[CH2:32][CH2:31][O:30][C:28]1=[O:29]>CC(C)=O>[C:14]([C:13]1[CH:18]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=[CH:11][C:12]=1[O:19][CH:27]1[CH2:32][CH2:31][O:30][C:28]1=[O:29])([OH:16])=[O:15]
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: O=C1OCCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1cc(OCc2ccccc2)ccc1OC1CCOC1=O

Procedure:
To a mixture of 32 g of methyl 5-benzyloxysalicylate, 17 g of anhydrous potassium carbonate and 500 ml of acetone was added 30.7 g of α-bromo-γ-butyrolactone under cooling with ice and, then, the mixture was refluxed for 15 hours. After cooling, the acetone was distilled off and 10% methanolic sodium hydroxide was added to the residue for hydrolysis. The reaction mixture was made acidic with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was dissolved in dioxane (300 ml)-benzene (200 ml) and the solution was refluxed in the presence of p-toluenesulfonic acid (30 g), with the resultant water being continuously distilled off. The solvent was distilled off and the residue was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to remove the solvent. The residue was recrystallized from ethyl acetate. By the above procedure there was obtained α-[(2-carboxy-4-benzyloxyphenyl)oxy]-γ-butyrolactone as colorless needles, m.p. 120°-122° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]1[C:20]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]3[CH3:27])=[N:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:28]([O:30]C)=[O:29])[CH:17]=3)[N:12]=1)=[CH:6][CH:5]=2.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]1[C:20]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]3[CH3:27])=[N:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:28]([OH:30])=[O:29])[CH:17]=3)[N:12]=1)=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N3CCCC[C@@H]3C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2cc(-c3nc4ccc(C(=O)O)cc4nc3N3CCCC[C@@H]3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
To a solution of (S)-methyl 2-(2-methyl-1H-indol-5-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate (142.1 mg, 0.34 mmol) in methanol (30 ml) was added NaOH (55 mg, 1.38 mmol) and water (2 ml). The resulting solution was stirred overnight at room temperature and concentrated under vacuum to give a residue, which was dissolved in water (20 ml), and the pH adjusted to 4 with HCl (3N). The solids were collected by filtration to afford (S)-2-(2-methyl-1H-indol-5-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (11.9 mg, 9%).
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:4]=[CH:3]1.[CH2:17]([O:25][C:26](=[O:30])[CH2:27][C:28]#[N:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(OC(=O)C)(=O)C>>[CH2:17]([O:25][C:26]([C:27]([C:28]#[N:29])=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:4]=[CH:3]1)=[O:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)c1ccc(-n2ccc(=O)cc2)cc1
Reactant: CCCCCCCCOC(=O)CC#N
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCOC(=O)C(C#N)=C1C=CN(c2ccc(C(=O)O)cc2)C=C1
Temperature: 130 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of 4-(4-oxo-4H-pyridin-1-yl)benzoic acid (814 mg, 3.5 mmol), octylcyanoacetate (3.44 g, 17.5 mmol) and acetic anhydride (45 ml) was heated at 130° C. for 3 hours. More octylcyanoacetate (3.44 g, 17.5 mmol) was added and the mixture heated for 3 hours more. The mixture was then filtered hot, and the filtrate was diluted with acetic acid (15 ml) and water (15 ml). Upon standing overnight in the refrigerator the product crystallized out and was isolated by suction filtration as a yellow solid (1.16 g, 85%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]=[C:7]=[O:8])[CH3:2].[F:9][C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[NH:14][CH:15]=1>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]([N:14]1[CH:15]=[C:10]([F:9])[C:11](=[O:17])[NH:12][C:13]1=[O:16])=[O:8])[CH3:2]
Reactant: CCOCCN=C=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
To the above solution of 2-ethoxyethyl isocyanate was added a solution of 5-fluorouracil (2.60 g.) in N,N-dimethylacetamide (20 ml.) at 80° and stirred for further 3 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (200 ml.), washed with saturated sodium chloride aqueous solution (each 30 ml., 2 times), dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 1-[N-(2-ethoxyethyl)carbamoyl]-5-fluorouracil (1.82 g.).
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])#[N:2].C1(N=C=NC2CCCCC2)CCCCC1.[Cl:28][C:29]1[C:34](O)=[C:33]([Cl:36])[C:32]([Cl:37])=[C:31]([Cl:38])[C:30]=1[Cl:39]>ClCCl>[Cl:28][C:29]1[C:34]([O:5][C:4](=[O:6])[CH:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])=[C:33]([Cl:36])[C:32]([Cl:37])=[C:31]([Cl:38])[C:30]=1[Cl:39]
Reactant: N#CC(C(=O)O)c1ccccc1
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#CC(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
8 g. (0.05 moles) of α-cyano-phenylacetic acid are dissolved in 80 ml. of dichloromethane. 10.3 g. (0.05 moles) of dicyclohexylcarbodiimide and 13 g. (0.05 moles) of pentachlorophenol are added dropwise dissolved in 50 ml. of dichloromethane. The mixture is stirred for 4 hours, cooled to 0° C. and the precipitated dicyclohexylurea is filtered. The filtered substance is washed twice on the filter with 15 ml. of dichloromethane. The combined organic layers are distilled off and the precipitated ester is taken up with 20 ml. of diisopropyl ether and the crystals are filtered, washed twice with diisopropyl ether and dried.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CCN(CC)CC.[C:16](Cl)(=[O:18])[CH3:17]>C(Cl)Cl>[CH2:2]([NH:1][C:16](=[O:18])[CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCN
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCNC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5.0 gms of 1-aminoheptane in 150 ml of CH2Cl2, is added 10.9 ml of Et3N followed by 2.79 ml of acetyl chloride. The reaction mixture is stirred at room temperature for 18 hours and then concentrated under vacuum. The residue obtained is partitioned between ethyl acetate and an aqueous 2N HCl solution; and after separating, the organic layer is washed with aqueous saturated NaHCO3, then brine, and dried over Na2SO4. After filtration and concentration, N-heptylacetamide is obtained as a clear liquid.
Reaction SMILES: FC(F)(F)C(O)=O.[N-:8]=[N+:9]=[N-:10].[Na+].[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:13].Cl>N1C(C)=CC=CC=1C>[CH2:17]([O:16][C:14]([C:12]1[NH:13][N:10]=[N:9][N:8]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nnn[nH]1
Temperature: 0 °C
Reaction time: 6 h
Yield: 52.6 %

Procedure:
Trifiuoroacetic acid (24.47 g, 0.21M) was added dropwise over 0.5 hr under nitrogen to a stirred suspension of sodium azide (12.59 g, 0.19M) in 2,6-lutidine (100 ml) at 8° to 12°. After stirring for 7 minutes ethyl cyanoformate (20.4 g, 0.20M) was added in one portion. The mixture was heated and stirred at 75° for 6 hours and then, after cooling, stirred at 20° for 16 hr. After cooling to 10° the mixture was added to ice (250 g) and 11 molar hydrochloric acid (100 ml) keeping the temperature below 20°. The product was extracted into ethyl acetate (1×250, 1×200, 2×100 ml) and the combined extracts dried over magnesium sulphate. After evaporation of the solvent under reduced pressure the oily product (38.22 g) was taken up in ether (50 ml) and hexane (25 ml) added. Storage at 4° for 2-3 days produced crystalline ethyl-1H-tetrazole-5-carboxylate that was filtered off, washed with chilled ether, and air dried, 14.12 g (52.6% yield), m.p. 88°-93°.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH3:24])[C:12](=[O:13])[CH:11]2[C:6](=[C:7]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:15]=[C:8]3[C:9](=[O:14])[CH2:10]2)[CH:5]=[N:4]1.Cl.[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][Cl:31]>>[ClH:31].[ClH:1].[CH3:2][C:3]1([CH3:24])[C:12](=[O:13])[CH:11]2[C:6](=[C:7]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:15]=[C:8]3[C:9](=[O:14])[CH:10]2[CH2:30][CH2:29][CH2:28][N:27]([CH3:32])[CH3:26])[CH:5]=[N:4]1
Reactant: CN(C)CCCCl
Reactant: CC1(C)N=CC2=C3N=C(c4ccccc4)N=C3C(=O)CC2C1=O
Agent: Cl
Product: CN(C)CCCC1C(=O)C2=NC(c3ccccc3)=NC2=C2C=NC(C)(C)C(=O)C21

Procedure:
Prepared analogous to Example 23 from 3.4 gm of 7,7-dimethyl-2-phenyl-5H,7H-imidazo(4,5-h]isoquinoline-4,6-dione hydrochloride and 1.7gm of 3-dimethylamino-propyl chloride hydrochloride (reaction temperature: 50°-60° C.; reaction time: 18 hous).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:11][C:12]([CH3:14])=O>>[CH3:11][C:12]1([CH3:14])[NH:10][C:1](=[O:9])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4]1
Reactant: CC(C)=O
Reactant: NC(=O)c1ccccc1O
Product: CC1(C)NC(=O)c2ccccc2O1
Yield: 47 %

Procedure:
A solution of salicylamide (4.14 g, 30.2 mmol) and conc. sulfuric a-id (3 drops) in acetone (40 mL) was refluxed for 5 h. The reaction was concentrated and the residue taken up in ethyl acetate. The organic solution was washed with 1 N NaOH (2×), 1 N HCl (2×), H2O, then sat. aq. NaCl, dried (MgSO4) and concentrated to afford 2,2-dimethyl-4-keto-1,3-benzoxazine (2.50 g, 47%) as a white solid: 1H NMR (CDCl3, 300 MHz, ppm) 7.92 (d, 1H), 7.60 (bs, 1H), 7.47 (m, 1H), 7.06 (m, 1H), 6.92 (d, 1H), 1.65 (s, 6H).
Reaction SMILES: [CH:1]1[C:10]2[CH:11]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13][CH:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1[C:10]2[CH:11]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][CH:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC2c3cccc4c3N(CCC4)C2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2c3c(c1)C1CCNCCC1N3CCC2
Temperature: 20 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a solution of tert-butyl (±)-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-10-carboxylate in CH2Cl2 (2.4 mL) was added TFA (0.6 mL). This was stirred at 20° C. for 3 h. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4 and concentrated in vacuo to afford the title compound as a yellow oil (87 mg, 59%). 1H NMR (CDCl3, 300 MHz) δ1.77-2.13 (m, 7H), 2.56-2.79 (m, 5H), 2.83-2.93 (m, 1H), 3.00-3.16 (m, 2H), 3.33-3.41 (td, 1H, J=3.7, 9.2 Hz), 3.60 (td, 1H, J=4.4, 9.1 Hz), 6.50 (t, 1H, J=7.3 Hz), 6.76 (t, 2H, 8.0 Hz) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]2=[N:4][N:3]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>ClC(Cl)C>[N:15]1([C:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]3=[N:4][N:3]=[C:2]([NH:1][C:37](=[O:39])[CH3:38])[N:6]3[N:7]=2)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: CC(=O)Cl
Reactant: Nc1nnc2c3c(c(N4CCOCC4)nn12)CCCC3
Agent: CN(C)c1ccccn1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nnc2c3c(c(N4CCOCC4)nn12)CCCC3

Procedure:
A 5.80 gm (0.0211 mole) quantity of the compound of Example 15 was dissolved in 100 ml of dichloroethane, and 380 mg (0.003 mole) of dimethylaminopyridine and 3.1 gm (0.03 mole) of triethylamine were added, followed by 2.38 gm (0.030 mole) of acetyl chloride. This mixture was refluxed overnight and evaporated. The resulting mixture was partioned between dilute aqueous NaHCO3 and CH2Cl2. The organic layer was dried and evaporated. The residue was triturated with ether and the resulting solid was collected to give 4.40 g of N-(7,8,9,10-tetrahydro-6-(4-morpholinyl)-1, 2,4-triazolo[3,4-a]phthalazin-3yl)acetamide; mp 147-149° C. (toluene-hexane).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[N:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].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.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)[CH:14]=[N:15][CH:16]=1
Reactant: Cc1oc(Br)cc1C=O
Reactant: OB(O)c1cncc(Cl)c1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1oc(-c2cncc(Cl)c2)cc1C=O
Reaction time: 8 h
Yield: 49.4 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 5-chloropyridine-3-boronic acid (1.9 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.1 g, 49%) as a yellow solid.