Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH2:14][C:7]3=[CH:6][C:5]=2[CH:4]=1.OP(O)(O)=O.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.[OH-].[NH4+]>CC(O)=O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH2:14][C:7]3=[C:6]([C:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH:23]=3)[C:5]=2[CH:4]=1
Reactant: CN1CCC(=O)CC1
Reactant: COc1ccc2c(c1)cc1n2CCC1
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c(C1=CCN(C)CC1)c1n2CCC1
Temperature: 60 °C
Yield: 98.9 %

Procedure:
To a solution of 7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole (718 mg, 3.83 mmol) (Clark, R. D.; Muchowski, J. M.; Fisher, L. E.; Flippen, L. A.; Repke, D. B.; Souchet, M. Synthesis 10,871-878(1991); Ishikura, M.; Terashima, M. Tetrahedron Lett. 33, 6849-6852(1992)) in glacial AcOH (20 mL) at 60° C. was added H3PO4 (5.0 mL, 10 mmol, 2.0 N) and 1-methyl-4-piperidone (1.2 mL, 11.5 mmol). The reaction was heated for 1 h at 60° C., cooled to room temperature and poured into a mixture of ammonium hydroxide in ice water. This reaction mixture was extracted with ethyl acetate and washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure yielded 1.07 g (99%) of the title compound as a brown oil: MS (ES+): m/e 283.0 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(Nc2ccc3[nH]ccc3c2)ncn1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 37.5 %

Procedure:
4,6-Dichloropyrimidine (5.89 g, 40 mmol), 5-aminoindole (6.27 g, 47 mmol) and N,N-diisopropylethylamine (20.6 ml, 0.12 mol) were dissolved in N-methylpyrrolidone (80 ml), and the reaction mixture was stirred at 50° C. for 2.5 hours. The reaction mixture was partitioned between ethyl acetate and water; the aqueous layer was subjected to re-extraction with ethyl acetate; and the combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure; a small amount of ethyl acetate was added to the residue to crystallize; and the crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (3.70 g, 15 mmol, 38%) as white crystals.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[H-].[Na+].[CH3:18]N(C)C=O.CI>O>[CH3:18][N:8]1[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[NH:5][C:4]2=[CH:3][S:2][CH:1]=[C:10]2[C:9]1=[O:11]
Reactant: O=C1Nc2ccccc2Nc2cscc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN1C(=O)c2cscc2Nc2ccccc21
Reaction time: 2.5 h

Procedure:
To a stirred mixture of 0.84 g. of 4,9-dihydro-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and 0.18 g. of 55% sodium hydride-mineral oil dispersion in 25 ml. of dimethylformamide is added 0.3 ml. of methyl iodide. The reaction mixture is stirred for 2.5 hours, cooled, diluted with water and filtered. The solid product is recrystallized from methanol-water to give pale yellow crystals, m.p. 195°-198°C.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[C:11]([O:14][CH3:15])=[CH:10][N:9]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][C:17]=2[F:27])[N:8]=1)=O.Cl.[F:30][C:31]([F:42])([F:41])[O:32][C:33]1[CH:34]=[C:35]([NH:39][NH2:40])[CH:36]=[CH:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(O)C>[F:27][C:17]1[CH:18]=[C:19]([N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)[CH:20]=[CH:21][C:16]=1[N:9]1[CH:10]=[C:11]([O:14][CH3:15])[C:12](=[O:13])[C:7]([C:5]2[N:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([O:32][C:31]([F:41])([F:42])[F:30])[CH:34]=3)[N:40]=[CH:3][CH:4]=2)=[N:8]1
Reactant: NNc1cccc(OC(F)(F)F)c1
Reactant: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(=O)C=CN(C)C)c1=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(-c2ccnn2-c2cccc(OC(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.9 %

Procedure:
To a suspension of 3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]pyridazin-4(1H)-one (200 mg) in ethanol (2.0 mL) was added dropwise a solution of [3-(trifluoromethoxy)phenyl]hydrazine hydrochloride (139 mg) and TFA (0.2 mL) in ethanol (2.0 mL), and the mixture was so stirred at room temperature for 24 hr. To the reaction mixture was added an ethanol solution (0.3 ml) of [3-(trifluoromethoxy)phenyl]hydrazine hydrochloride (16.7 mg), and the mixture was stirred at room temperature for 24 hr. The precipitated solid was collected by filtration. The mother liquor was concentrated, and the precipitated solid was collected by filtration. The solid was combined with the previously obtained solid, and recrystallized from acetone/water to give the title compound (96.1 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1/[CH:24]=[CH:23]/[CH:11]([CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1
Reactant: Clc1ccccc1CBr
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccccc2Cl)CCc2ccc(C#N)cc2)cc1

Procedure:
A solution of 200 mg (0.49 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 10 ml of dry acetonitrile is mixed with 149.8 mg (0.73 mmol) of 2-chlorobenzyl bromide and 201 mg (1.46 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by preparative HPLC. 94 mg (0.17 mmol, 36% of theory) of a colorless foam are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C@H:9]([C:11](=[O:30])[NH:12][C@H:13]([C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[CH2:28][NH2:29])=[O:18])[CH:14]([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[N:7]([C@H:9]([C:11](=[O:30])[NH:12][C@H:13]([C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[CH2:28][NH:29][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1CNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.3 %

Procedure:
A solution of {(S)-1-[(S)-1-((S)-2-aminomethyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-2-methyl-propylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (intermediate 3) (100 mg 0.23 mmol) in DCM (4 mL) was cooled to 0-5° C. and triethylamine (0.08 mL 0.57 mmol) followed by benzoyl chloride (0.027 mL, 0.23 mmol) were added. The reaction was stirred at rt for 4 h. The reaction mixture was partitioned between water and DCM and the organic layer was then washed with water (30 mL×2) and brine (30 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by preparative-HPLC (acetonitrile and NH4OAc] to give ((S)-1-{(S)-1-[(S)-2-(benzoylamino-methyl)-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl]-2-methyl-propylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester as a white solid (35 mg), m/z=538 (M+H).
Reaction SMILES: S([CH2:11][CH2:12][CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[NH:14]1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[CH:28][C:29]=1[CH3:30].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:32][CH2:33][N:34]([CH2:11][CH2:12][CH:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14]3)[CH2:35][CH2:36]2)[CH:27]=[CH:28][C:29]=1[CH3:30]
Reactant: Cc1ccc(S(=O)(=O)CCC2NC(=O)c3ccccc32)cc1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(N2CCN(CCC3NC(=O)c4ccccc43)CC2)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.8 %

Procedure:
A solution of 1,3-dihydro-3-(2-tosylethyl)-2H-isoindol-1-one (4.2 g, 12.7 mmol), 1-(3,4-dimethylphenyl)-piperazine (2.6 g, 13.9 mmol), and K2CO3 (8.8 g, 63.3 mmol) in 150 mL of CH3CN is warmed to reflux overnight under argon. After being cooled to room temperature, the solvent is evaporated, and the remaining solid is stirred in 100 mL of H2O for 20 minutes. The solid is collected, dried, and recrystallized from CH3CN to give 2.7 g (60% yield) of 3-{2-[4-(3,4-dimethyl-phenyl)-piperazin-1-yl]-ethyl}-2,3-dihydro-isoindol-1-one; mp=167-169° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]2[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=[C:4]2[CH:3]=1.C(OCC)(=O)C.C([O-])(=O)C.[Na+]>C(O)C.[Pd]>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[CH:3][C:4]3[N:5]2[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=3)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cn2c(cc(Cl)c3ccc(OC)cc32)n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cn2c(ccc3ccc(OC)cc32)n1
Reaction time: 4 h

Procedure:
5 g of ethyl 5-chloro-8-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate were suspended in 75 ml of ethanol and 75 ml of ethyl acetate and then 2.5 g of anhydrous sodium acetate and 250 mg of 5% palladium on charcoal were added. The mixture was hydrogenated at 50° C. under atmospheric pressure for 4 hours and the catalyst was filtered off. Then, the solvent was removed under vacuum and the residue was partitioned between chloroform and 2 N sodium carbonate solution. The organic solution was dried over magnesium sulfate and was reduced in volume under vacuum and ether was added to obtain pale cream crystals of ethyl 8-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate melting at 152°-153° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:32][CH2:33]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:3][CH2:4]1
Reactant: CCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)nc(C)nc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f57) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1[N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2ccc(C)nc2n(CC)c1=O
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCCC2)c2ccc(C)nc2n(CC)c1=O

Procedure:
A stirred mixture of 5.9 g. (0.02 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 1.4 g. (0.02 mole) of pyrrolidine and 2.12 g. (0.02 mole) of sodium carbonate was heated under reflux in 50 ml. of ethanol for 3 hours. The mixture was filtered and the filtrate was diluted with water to the cloudy point. The precipitate which formed was collected, air dried and was recrystallized from heptane to give 3.3 g. of the title compound, m.p. 113°-115° C.
Reaction SMILES: [CH2:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)(C(OCC)=O)[C:4]([O:6]CC)=[O:5])[CH3:2].[OH-].[Na+]>C(O)C.O>[N+:20]([C:17]1[CH:16]=[CH:15][C:14]([CH:3]([CH2:1][CH3:2])[C:4]([OH:6])=[O:5])=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: CCOC(=O)C(CC)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Yield: 69.2 %

Procedure:
In 150 ml of ethanol was dissolved 37.18 g (0.12 mole) of diethyl 2-ethyl-2-(4-nitrophenyl)malonate and a solution of 30.41 g (0.76 mole) of sodium hydroxide in 100 ml of water was added and then heated under reflux for 3 hours on an oil bath. After the solvent was distilled off in vacuo, the residue was dissolved in 200 ml of water and then extracted with 300 ml of ether. The ether layer was removed and the water layer was acidified with conc. hydrochloric acid and extracted again with ether. The ether layer was separated, washed with saturated sodium chloride solution and dried over magnesium sulfate. The ether was distilled off in vacuo to give 17.25 g (0.083 mole, 69% yield) of 2-(4-nitrophenyl)-n-butyric acid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21](N2CCCC2)=[O:22])[CH2:17][CH2:16]1>CC(OC)(C)C>[Br:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)=[O:22])[N:8]=1
Reactant: Brc1cccc(Br)n1
Reactant: CN1CCC(C(=O)N2CCCC2)CC1
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: CN1CCC(C(=O)c2cccc(Br)n2)CC1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 85.3 %

Procedure:
Add a solution of n-butyllithium (1.9M in n-hexane, 4 ml, 7.6 mmol) to a solution of 2,6-dibromopyridine (1.81 g, 7.64 mmol) in MTBE (20 mL) dropwise under nitrogen, over 20 min., maintaining the temperature between −72 and −67° C. Stir the yellow heterogeneous solution at −70° C. for 20 min. to provide a green homogeneous solution. Add a solution of 1-methyl-4-(pyrrolidin-1-yl-carbonyl)piperidine (1 g, 5.09 mmol) in 10 mL MTBE dropwise over 20 min., maintaining the temperature below 69° C. Stir the yellow mixture at −75° C. for 1 hr. Quench the reaction mixture with a saturated solution of ammonium chloride (5 mL) between 0 and 10° C. Acidify the mixture to pH 2 with fuming HCl (2 mL). Extract the organic layer. Wash the aqueous phase with MTBE (50 mL), make the aqueous layer basic with a solution of 30% NaOH, and extract with ethyl acetate (2×50 mL). Combine the organic layers, dry over MgSO4, and concentrate under reduced pressure at 40° C. to provide the title intermediate as an oil (1.23 g, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[C:4]([CH3:17])[CH:3]=1.C(N(CC)CC)C.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:25]2=[O:26])=[C:4]([CH3:17])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(Cl)ccc1NNC(=O)c1ccco1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1-n1nc(-c2ccco2)oc1=O
Yield: 60 %

Procedure:
A mixture of N′-(4-chloro-2-methylphenyl)furan-2-carbohydrazide (0.5 mmol), triethylamine (0.1 mL, 0.75 mmol), and carbonyldiimidazole (0.24 g, 1.5 mmol) was stirred at 80° C. in 2 mL of THF overnight. The crude product obtained after removal of the solvent was then subject to chromatography (silica gel, 1:9 ethyl acetate-hexanes), followed by crystallization from hexanes to provide 83 mg (0.3 mmol, yield 60%) of 3-(4-Chloro-2-methyl-phenyl)-5-furan-2-yl-3H-[1,3,4]oxadiazol-2-one as a white solid with an HPLC purity of 98.9%. LC-MS [M+H] 277.9 (C13H9ClN2O3+H, expected 277.68). The 1H-NMR spectrum was in accordance with the chemical structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:13]([OH:19])=[C:12]([I:20])[CH:11]=2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Cl)[C:28]#[CH:29]>CN(C)C=O>[I:20][C:12]1[C:13]([O:19][CH2:29][C:28]#[CH:27])=[CH:14][C:15]([CH:16]([CH3:18])[CH3:17])=[C:10]([CH:11]=1)[O:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CC(C)c1cc(O)c(I)cc1Oc1cnc(N)nc1N
Reactant: C#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To 4-(2,4-Diamino-pyrimidin-5-yloxy)-2-iodo-5-isopropyl-phenol (200 mg, 0.43 mmol) dissolved in anhydrous N,N-dimethylformamide (2 mL) was added anhydrous potassium carbonate (414 mg, 3.00 mmol) and propargyl chloride (0.03 mL, 0.43 mmol). After stirring at room temperature overnight, the reaction was extracted with dichloromethane, water and brine. The dichloromethane layer was dried using anhydrous magnesium sulfate, concentrated, and purified via silica gel column chromatography (95/5/0.1 dichloromethane/methanol/ammonium hydroxide) to yield 5-(5-iodo-2-isopropyl-4-prop-2-ynyloxy-phenoxy)-pyrimidine-2,4-diamine as white solid (131 mg, 71%), MS (M+H)=425.
Reaction SMILES: [CH:1]1[C:5]2=[C:6]([OH:15])[C:7]3[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=3[CH:9]=[C:4]2[O:3][CH:2]=1.[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20]I.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][O:15][C:6]1[C:7]2[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=2[CH:9]=[C:4]2[O:3][CH:2]=[CH:1][C:5]=12
Reactant: O=c1ccc2c(O)c3ccoc3cc2o1
Reactant: ClCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1ccc2c(OCCCCCl)c3ccoc3cc2o1
Reaction time: 0.29 h

Procedure:
817 mg (4.041 mmol) of 5-hydroxypsoralen and 1.413 g (6.47 mmol) of 4-chlorobutyl iodide were refluxed in 80 ml of acetone in the presence of an excess of (3.0 g) anhydrous potassium carbonate for 30 hours. The progress of the reaction was monitored by thin layer chromatography. After 30 hours the reaction mixture was concentrated under reduced pressure and distilled off the solvent almost completely. The oily residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and extracted with 3×100 ml of dichloromethane. The dichloromethane layer was extracted with 1×25 ml of 1% sodium hydroxide to separate trace amounts of un-reacted 5-hydroxypsoralen. The dichloromethane layer was washed with 30 ml of 2% hydrochloric acid and further washed with water to neutral pH. The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated to dryness. The resulting residue was then suspended in petroleum ether and filtered to wash out the excess 4-chlorobutyl iodide. The resulting 5-(4-chlorobutoxy)psoralen was used for the synthesis of various derivatives without further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]3[O:18][CH2:19][O:20][C:14]=3[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]3[O:23][CH2:22][O:21][C:7]=3[CH:8]=2)[N:3]=1.[CH3:24][NH:25][CH3:26]>CO>[CH3:24][N:25]([CH3:26])[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]3[O:18][CH2:19][O:20][C:14]=3[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]3[O:23][CH2:22][O:21][C:7]=3[CH:8]=2)[N:3]=1
Reactant: Clc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Reactant: CNC
Solvent: CO
Product: CN(C)c1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3

Procedure:
To a solid of 2-chloro-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline (50 mg, 0.15 mmol) was added dimethylamine in methanol (2.0 M, 3 mL). The resulting mixture was refluxed under argon for 2 h, and the precipitate in the reaction mixture was collected by filtration. The precipitate was washed with hexane and dried to give 2-(dimethylamino)-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)-quinazoline (40 mg); mp 200-206° C. 1H NMR (DMSO-d6) 7.23 (s, 1H), 7.18 (s, 1H), 7.13 (d, J=7.14 Hz, 1H), 7.07 (d, J=7.14, 1H), 6.95 (s, 1H), 6.13 (s, 6H), 3.18 (s, 6H).
Reaction SMILES: C(OC([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH:10]([CH2:18][NH:19][CH2:20][CH2:21][CH2:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([F:32])[CH:30]=3)[NH:25][CH:24]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[O:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:8][CH2:9][CH:10]1[CH2:18][NH:19][CH2:20][CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([F:32])[CH:30]=2)[NH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC(CNCCCc2c[nH]c3ccc(F)cc23)Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc2[nH]cc(CCCNCC3CNc4ccccc4O3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
The title compound was prepared in a 19% yield by reacting {[3-(5-fluoro-1H-indol-3-yl)-propylamino]-methyl}-3,4-dihydro-benzo [1,4]oxazine-4-carboxylic acid tert-butyl ester (0.49 g, 1.1 mmol) with trifluoroacetic acid (20 mL) in methylene chloride (20 mL). The reaction mixture was stirred at room temperature for two hours and then poured into saturated sodium carbonate and extracted with methylene chlloride. The organic layer was dried over anhydrous sodium sulfate, filtered and chromatographed (5% MeOH in methylene chloride) afforded 0.06 g (19%) of product as an oil. The oxalate salt was prepared in ethanol: mp 168-170° C.
Reaction SMILES: [O:1]([CH2:19][CH:20]([CH3:30])[CH2:21][CH2:22][CH2:23][C:24]1(OCC[O:26]1)[CH3:25])[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.C(=O)(O)[O-].[Na+]>CC(C)=O>[O:1]([CH2:19][CH:20]([CH3:30])[CH2:21][CH2:22][CH2:23][C:24](=[O:26])[CH3:25])[Si:2]([C:15]([CH3:16])([CH3:17])[CH3:18])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(CCCC1(C)OCCO1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)CCCC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
1-t-Butyldiphenylsiloxy-6,6-ethylenedioxy-2-methyl-heptane (75.35 g) in acetone (2 l) is treated with 10% hydrochloric acid (75 ml) and the solution is allowed to stir at room temperature for 21/2 hours. The reaction mixture is neutralized with a saturated sodium bicarbonate solution (150 ml), the salt is removed by filtration and the solvent is removed in vacuo. The resulting residue is partitioned between ether and water, the aqueous phase is extracted with ether, and the combined ether extracts are washed with brine and dried (Na2SO4). The solvent is removed in vacuo to give the crude product which is purified via silica gel chromatography (5% EtOAc/hexane) to give 1-t-butyldiphenylsiloxy-2-methyl-6-oxo-heptane (61.95 g, 92%); ir (neat) 5.85 μ (C=O); nmr (CDCl3,δ), 0.92 (d, 3H, CH3CH<), 1.05 [s, (CH3)3 ], 2.07 (s, 3H, CH3C=O), 3.45 (d, 2H, CHCH2O), 7.2-7.8 (m, 10H, 2φ).