Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=[O:2].[CH2:14]([N:16]([CH2:31][CH3:32])[CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH:29]=O)=[CH:23]2)[CH3:15].N1CCCCC1.Cl>C(O)C>[O:13]=[C:8]1[C:7](=[CH:29][C:24]2[NH:25][C:26]3[C:22]([CH:23]=2)=[CH:21][C:20]([CH2:19][CH2:18][CH2:17][N:16]2[CH2:31][CH2:32][CH2:15][CH2:14]2)=[CH:28][CH:27]=3)[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[NH:9]1
Reactant: CCN(CC)CCCc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(C(=O)O)cc2C1=Cc1cc2cc(CCCN3CCCC3)ccc2[nH]1
Temperature: 80 °C

Procedure:
A mixture of 5-carboxy-2-oxindole (35 mg, 0.2 mmol), 5-(3-diethylamino-propyl)-1H-indole-2-carbaldehyde (51 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 80° C. for 6 hours. The reaction was acidified with 1N HCl and the precipitate was collected by vacuum filtration, washed with 1N HCl, water and ethanol, dried to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:11][O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:11][O:12][C:13](=[O:18])[C:14]([O:8][C:5]1[C:4]([CH:9]=[O:10])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)([CH3:16])[CH3:15]
Reactant: O=Cc1cc(Cl)cnc1O
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Oc1ncc(Cl)cc1C=O
Temperature: 126 °C
Yield: 47.2 %

Procedure:
A mixture of 5-chloro-2-hydroxy-pyridine-3-carbaldehyde (8 g, 51 mmol), 2-bromo-2-methyl-propionic acid methyl ester (27.6 g, 153 mol), Cs2CO3 (28 g, 86.7 mol) in DMF (80 mL) was heated at 126° C. for 3 h. After cooled to room temperature, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried and concentrated. The residue was purified by flash column to give the title compound (6.2 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH:24](N1CCOCC1)=[O:25].[Cl-].[NH4+]>O1CCCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[O:14][C:15]3[C:7]([CH:24]=[O:25])=[CH:8][CH:9]=[CH:10][C:11]=3[CH:12]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2cc3cccc(Br)c3o2)cc1
Reactant: O=CN1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3cccc(C=O)c3o2)cc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
83 ml of butyllithium were added at -70° C. to a mixture of 36.4 g of the product of Step B and 100 ml of tetrahydrofuran and the mixture was stirred for one hour at -60° C., 24.2 ml of N-formyl morpholine in 50 ml of tetrahydrofuran were added and the reaction mixture was stirred for 16 hours at -60° C. Ammonium chloride was added and the two phases were decanted. Extraction was carried out with ethyl acetate, followed by drying and concentrating to obtain 35.12 g of product which was purified by chromatography on silica, eluting with a hexane - ethyl acetate mixture (9-1) to obtain 13.8 g of the desired product.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].[BrH:15].Br.[NH+]1C=CC=CC=1.O>C(O)(=O)C>[NH2:9][C:7]1[S:8][C:4]([C:1](=[O:3])[CH2:2][Br:15])=[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:6]=1
Reactant: Br
Reactant: CCOC(=O)c1nc(N)sc1C(C)=O
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(N)sc1C(=O)CBr
Reaction time: 1 h

Procedure:
To a solution of ethyl 5-acetyl-2-amino-4-thiazolecarboxylate (12.9 g) in a mixture of 30% solution of hydrogen bromide in acetic acid (50 ml) and acetic acid (50 ml) was added pyridinium hydrobromide perbromide (21.1 g) at ambient temperature and stirred for one hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was washed with diisopropyl ether to give ethyl 2-amino-5-(2-bromoacetyl)-4-thiazolecarboxylate (14.86 g). mp 164°-166° C. (dec.).
Reaction SMILES: Cl[CH:2]([C:10]1[CH:22]=[C:21]2[C:13]([CH:14]=[CH:15][C:16]3[O:17][C:18](=[O:25])[C:19](C)(C)[C:20]=32)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:22]=[C:21]3[C:13]([CH:14]=[CH:15][C:16]4[O:17][C:18](=[O:25])[CH2:19][C:20]=43)=[CH:12][CH:11]=2)[N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)=[CH:4][CH:5]=1
Reactant: c1nc[nH]n1
Reactant: CC1(C)C(=O)Oc2ccc3ccc(C(Cl)c4ccc(Cl)cc4)cc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1Cc2c(ccc3ccc(C(c4ccc(Cl)cc4)n4cncn4)cc23)O1

Procedure:
A mixture of 8-(α,4-dichlorobenzyl)-1,1-dimethyl-2(1H)-naphtho[2,1-b]furanone, 1,2,4-triazole (0.3 g), potassium carbonate (0.3 g) and acetonitrile (5 ml) was heated under reflux for 18 h. The mixture was treated with water (20 ml) and extracted with ethyl acetate. The ethyl acetate extract was dried and then evaporated to dryness, and the residue was purified by flash chromatography eluting with methanol:chloroform, 1:99 v/v, to give 8-[4-chloro-α-(1H-1,2,4-triazol-1-yl)benzyl]-2(1H)-naphtho[2,1-b]furanone. Nmr in deuteriochloroform: δ8.12(2H,s); 7.94(1H,d); 7.36-7.46(4H,m); 7.15-7.25(3H,m); 6.92(1H,s); 1.62(3H,s); 1.60(3H,s).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH2:8]([SH:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>[OH-].[Na+].C1COCC1>[CH2:8]([S:24][CH:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C1C=CCCC1
Reactant: CCCCCCCCCCCCCCCCS
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCSC1CCCC(=O)C1
Yield: 70 %

Procedure:
2-Cyclohexenone (0.14 mol, 13.4 mL) was dissolved in 10 mL of 10 percent sodium hydroxide and 50 mL of THF. An equimolar amount of hexadecyl mercaptan (0.14 mol, 42.9 mL) was added to the unsaturated ketone and the mixture refluxed to produce 3-hexadecylthiocyclohexanone (70 percent yield). This product (5.23 mmol, 1.851 g) was dissolved in methanol and reduced with sodium borohydride (5.23 mmol, 0.199 g) to give a racemic mixture of 3-hexadecylthiocyclohexanol (yield 62 percent; cis:trans ratio 4:1). The phosphorylating agent was prepared by refluxing phosphorus oxychloride (0.65 mol, 60.8 mL) and 2-bromoethanol (0.38 mol, 27.0 mL) in 25 mL of trichloroethylene to produce 2-bromoethyl dichlorophosphate (yield 53 percent). The 3-hexadecylthiocyclohexanol (0.56 mmol, 0.200 g) was dissolved in diethyl ether:THF (2:1) and refluxed with the 2-bromoethyl dichlorophosphate (222 mmol, 0.3 mL) to produce 3-hexadecylthiocyclohexyl phosphoethyl bromide (yield 54 percent). The latter (0.216 mmol, 0.150 g) was dissolved in isopropyl alcohol chloroformi:DNMF (5:3.5) and heated at 65° C. with trimethylamine (0.042 mol, 2 mL) to produce the desired product, 3-hexadecylthiocyclohexyl-phosphocholine (yield 38 percent).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:8]([F:14])([F:13])[CH:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=3)[CH2:6][CH2:5][C:4]=2[C:3]=1[OH:30].[CH2:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>CCOCC>[F:14][C:8]1([F:13])[C:9]2[C:4](=[C:3]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:2]([F:1])=[C:11]([F:12])[CH:10]=2)[CH2:5][CH2:6][CH:7]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=1
Reactant: CCCCCCCCOc1ccc(C2CCc3c(cc(F)c(F)c3O)C2(F)F)cc1
Reactant: CCCCCCCCBr
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(C2CCc3c(cc(F)c(F)c3OCCCCCCCC)C2(F)F)cc1

Procedure:
From 2,3,5,5-tetrafluoro-6-(4-octyloxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-ol and 1-octyl bromide by means of the Williamson ether synthesis.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:5](=[O:6])[C:4]4[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=4[S:2][CH3:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: CSc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 64.2 %

Procedure:
To a stirred solution of 0.364 g of 2-(methylthio)benzoyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0 ° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give a solid which is crystallized from ethyl alcohol to give 0.480 g of the desired product as a white solid, m.p. 171°-174° C.
Reaction SMILES: C(OC([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15](OC(=O)C(F)(F)F)[C:16]2[C:17]([O:23][CH3:24])=[N:18][CH:19]=[CH:20][C:21]=2[I:22])=[C:10]([N+:32]([O-:34])=[O:33])[C:9]=1N)=O)(C)(C)C.[OH2:36]>C1COCC1>[C:11]([O:36][C:17](=[O:23])[NH:18][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]2[C:17]([O:23][CH3:24])=[N:18][CH:19]=[CH:20][C:21]=2[I:22])=[C:10]([N+:32]([O-:34])=[O:33])[CH:9]=1)([CH3:14])([CH3:12])[CH3:10]
Reactant: COc1nccc(I)c1C(Cc1ccc(C(=O)OC(C)(C)C)c(N)c1[N+](=O)[O-])OC(=O)C(F)(F)F
Reactant: O
Solvent: C1CCOC1
Product: COc1nccc(I)c1/C=C/c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A solution of crude trifluoro-acetic acid 2-(4-tert-butoxycarbonyl-amino-2-nitro-phenyl)-1-(4-iodo-2-methoxy-pyridin-3-yl)-ethyl ester (crude 1.88 g, 3.08 mmol) in THF (10 mL) was added 8-diazabicyclo[5.4.0]undec-7-ene (1.33 g, 8.74 mmol) at 25° C. The reaction was allowed to stir at 70° C. for 3 hours. The reaction mixture was cooled to 25° C., and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded {4-[(E)-2-(4-iodo-2-methoxy-pyridin-3-yl)-vinyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester (850 mg, 55%) as an oil. MH+ 497.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH:10]=[CH:11][N:12]([CH3:14])C.N[C:17]1[C:21]([C:22]#[N:23])=C[NH:19][N:18]=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:19]2[N:18]=[CH:17][C:21]([C:22]#[N:23])=[C:14]2[N:12]=[CH:11][CH:10]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1cc(Cl)ccc1Cl
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cnn2c(-c3cc(Cl)ccc3Cl)ccnc12
Yield: 92.5 %

Procedure:
A mixture of 98.3 g of 2',5'-dichloro-3-dimethylaminoacrylophenone and 43.5 g of 3-aminopyrazole-4-carbonitrile in one liter of glacial acetic acid was heated at reflux for 63/4 hours. The reaction mixture was cooled and diluted with water to provide a precipitate which was collected, washed with water and dried in vacuo to give 107.6 g of 7-(2,5-dichlorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile as pale yellow crystals, mp 202°-204° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].[I-:6].O[CH2:8][CH2:9][N:10]([CH2:18][CH3:19])[CH2:11][CH2:12][CH2:13][N+:14]([CH3:17])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[ClH:3].[I-:6].[Cl:5][CH2:8][CH2:9][N:10]([CH2:18][CH3:19])[CH2:11][CH2:12][CH2:13][N+:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: CCN(CCO)CCC[N+](C)(C)C
Agent: Cl
Agent: [I-]
Solvent: Cc1ccccc1
Product: CCN(CCCl)CCC[N+](C)(C)C
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
A total of 28 ml of thionyl chloride was added dropwise, with stirring, to 27.35 g of 3-[(2-hydroxyethyl)ethylamino]-N,N,N-trimethyl-1-propanaminium iodide hydrochloride in 200 ml of toluene at 50° C. Upon completion of the addition the mixture was stirred at 50° for 15 minutes, and then heated at 80° C. for 3 hours. The reaction mixture was steam distilled to remove toluene. Organic chloride analysis on the resulting aqueous solution showed the corresponding alkyl chloride was obtained in 88% yield.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH2:18]C(O)=O)([C:15]([OH:17])=[O:16])=[O:14].[OH-].[K+].Cl>>[C:1]1([CH2:7][C:8]([OH:12])([C:9]([OH:11])=[O:10])[CH2:18][C:13](=[O:14])[C:15]([OH:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(=O)C(=O)O
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C(=O)CC(O)(Cc1ccccc1)C(=O)O
Yield: 37 %

Procedure:
Phenyl pyruvic acid (5.0 g, 30.5 mmol) and 12.1 g (91.4 mmol) of oxaloacetic acid were added to 25 mL of aqueous solution in which 13.8 g of potassium hydroxide (purity 85%) had been dissolved, and reacted at room temperature for 72 hours. A pH value of the reaction mixture was adjusted to 2.2 using concentrated hydrochloric acid, and the reaction mixture was extracted with ethyl acetate. An organic layer was washed with saturated aqueous NaCl solution, dried on magnesium sulfate anhydrate, and then concentrated to yield residue. The residue was recrystallized from ethyl acetate and toluene to yield 2.8 g (11.3 mmol) of 4-phenylmethyl-4-hydroxy-2-ketoglutaric acid as crystal.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:2]1.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>CCOCC.C([Li])CCC.O1CCCC1>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[S:1][CH:5]=[CH:4][C:3]=1[CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1cc(C2OCCO2)cs1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1sccc1C1OCCO1
Temperature: -78 °C

Procedure:
To a stirred solution of 15.6 g (0.10 mol) of 2-(3-thienyl)-1,3-dioxolane in 100 ml of anhydrous ether, n-butyl-lithium (1.48N, in hexane, 74.3 ml) is added dropwise under nitrogen at room temperature. After being refluxed for 15 minutes, the reaction mixture is cooled to -78° C. and tri-n-butyltin chloride (34.18 g, 0.105 mol) in 100 ml of dry tetrahydrofuran is added dropwise. After the addition is complete, the mixture is warmed to room temperature and the solvent evaporated. To the oily residue 100 ml of hexane is added, and the resulting precipitate (LiCl) is filtered off. The filtrate is evaporated and the residue distilled at reduced pressure, given 34.16 g (77%) of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:15][CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[C:6]=2[CH:7]=1.O1CCCC1.C([Li])CCC.[C:26](=[O:28])=[O:27]>CCCCCC>[O:9]1[CH2:10][CH2:11][O:12][C:8]21[C:6]1[CH:7]=[C:2]([C:26]([OH:28])=[O:27])[CH:3]=[CH:4][C:5]=1[S:15][CH2:14][CH2:13]2
Reactant: Brc1ccc2c(c1)C1(CCS2)OCCO1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1ccc2c(c1)C1(CCS2)OCCO1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
13.58 g (0.047 mol) of the title compound of Step C was added to 150 mL of tetrahydrofuran. The solution was cooled to about -65° C. and 23 mL (0.057 mol) of 2.5 M n-butyllithium in hexane (purchased from Aldrich Chemical Company) was added dropwise while keeping the temperature below -55° C. After stirring under nitrogen for 1 h, excess solid CO2 was added in one portion, and the mixture was stirred overnight while warming to room temperature. 100 mL of hexane was added to the mixture, and it was then filtered. To the solid residue was added 500 mL of water and 400 mL of methylene chloride. The solution was cooled to about 0° C., acidified to pH 1 with concentrated hydrochloric acid, and extracted with methylene chloride (3×400 mL). The resulting solution was dried (MgSO4), filtered, and evaporated to dryness to yield 8.58 g of the title compound of Step D as a solid melting at 186.7° C. (dec). 1H NMR (Me2SO-d6): δ2.2 (m,2H), 3.2 (m,2H), 4.1 (m,4H), 7.2-8.0 (3H), 12.8 (br s,1H).
Reaction SMILES: OO.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[N:20]=[N:19][CH:18]3[C:11]42[CH:21]([OH:22])[CH:17]3[CH:16]2[CH:13]([NH:14][NH:15]2)[CH2:12]4)=[CH:6][CH:5]=1.CO.[OH-].[Na+]>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[N:20]=[N:19][CH:18]3[C:11]42[CH:21]([OH:22])[CH:17]3[CH:16]2[CH:13]([N:14]=[N:15]2)[CH2:12]4)=[CH:6][CH:5]=1
Reactant: OC1C2C3NNC3CC13C2N=NN3c1ccc(Br)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC1C2C3N=NC3CC13C2N=NN3c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
35 parts of 30 percent strength aqueous H2O2 were added dropwise, in the course of 1 hour, to 50 parts of 8-(4-bromophenyl)-12-hydroxy-3,4,8,9,10-pentazatetracyclo[5,4,1,02,5,07,11 ]dodec-9ene (Compound No. 69) in 400 parts of methanol and 5 parts of 25 percent strength by weight aqueous NaOH, at 65° C., while stirring, and stirring was continued for 5 hours at 65° C. The mixture was cooled to 20° C., after which 1,500 parts of water were added, and the product was filtered off under suction, washed with 300 parts of water and dried at 30° C. under 1 mbar. 44 parts (88 mole %) of 8-(4-bromophenyl)-12hydroxy-3,4,8,9,10-pentazatetracyclo[5,4,1,02,5,07,11 ]-dodeca-3,9-diene of melting point 187° C. (decomposition) were obtained (Compound No. 3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>C(NCC)C.[Cu](I)I.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:28]#[C:27][CH2:26][CH2:25][OH:29])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCCO)cc2c1O
Reaction time: 8 h

Procedure:
To a mixture of the title compound of Example 5 (0.457 g), copper iodide (0.010 g) and dichlorobis(triphenylphosphine)palladium (II) (0.035 g) in 15 mL diethylamine is added 3-butyne-1-ol (0.076 mL). The reaction is allowed to stir overnight. The solvents are evaporated and the residue is chromatographed on silica, eluting with 3% MeOH/CH2Cl2 to yield 0.279 g of the desired product as a tan solid.
Reaction SMILES: N#N.[NH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C:14](=[O:16])[CH3:15].Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])(O)=O.[Na+]>C(N(CC)CC)C>[C:20]([CH2:19][CH2:18][NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C:14](=[O:16])[CH3:15])([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CCBr
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNc1cc(OC)c(OC)cc1C(C)=O
Temperature: 25 °C
Yield: 35.2 %

Procedure:
Triethylamine (3.88 g, 5.34 mL, 38.44 mM) was added at once under N2 to a stirred mixture of 2'-amino-4',5'-dimethoxyacetophenone (2.5 g, 12.8 mM) and ethyl 3-bromopropionate (17.43 mL, 96.2 mM) at room temperature. Immediately the reaction mixture solified. This was heated under N2 to 140°-150° C. (bath temp.) for a period of 4 hours during which the reaction mixture had partially liquified into a red-brown, viscous slurry. After cooling to room temperature it was treated with 5% NaHCO3 solution (50 mL) and then extracted with CH2Cl2 (3×60 mL). The combined organic extracts were washed with H2O, dried (Na2SO4) and evaporated in vacuo to remove CH2Cl2 (low vacuum) and excess 3-bromopropionate (under high vacuum at 50°-60° C.). The dark oily residue was chromatographed on a column of SilicAR CC-7 (300 g, 55.5×6 cm) packed in hexane. The sample was applied to the column in CH2Cl2 (50 mL) followed by elution with hexane and then with increasing proportions of ethyl acetate/hexane, collecting 1 L fractions. Fractions 10 and 11, afforded, upon evaporation to dryness 2'-(N-2-carbethoxyethylamino)-4',5'-dimethoxyacetophenone as a waxy crystalline solid (1.33 g, 35.2%), mp 73°-75° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.[ClH:20].[CH:21]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[ClH:1].[ClH:20].[CH:21]1([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[N:3]=3)[CH2:26][CH2:25]2)[CH2:23][CH2:22]1
Reactant: C1CN(C2CC2)CCN1
Reactant: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(-c2cc3ccccc3c(N3CCN(C4CC4)CC3)n2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
1-Chloro-3-(4-methoxyphenyl)isoquinoline (514 mg), and 1-cyclopropylpiperazine hydrochloride salt (378 mg) described in JP-A 62-129273 were dissolved in dimethyl sulfoxide (7 ml), followed by the addition of potassium carbonate (788 mg), and the resulting mixture was stirred at 100° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system). The resulting product was converted into a hydrochloride in a conventional manner, and then recrystallized from ethanol/isopropyl ether, to give the hydrochloride of the title compound as yellow crystals (136 mg, yield; 16%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2.[OH-].[Na+]>O.CC(C)=O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Oc1ccc2ncccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Clc1cc(Oc2ccc3ncccc3c2)ncn1
Reaction time: 3 h

Procedure:
A solution of 7.45 g (50 mMol) of 4,6-dichlor-pyrimidine, 7.64 g (50 mMol) of 6-hydroxy-chinolin and 2.0 g (50 mMol) NaOH dissolved in 200 ml of H2O/acetone 1:1 is stirred for 3 h. The resulting solid is filtered off, washed with H2O/acetone ans dried: m.p.: 136-137° C.; MS: [M+1]+=258.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[I:5][C:6]1[CH:15]=[CH:14][N:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][NH:11]2.[OH-].[Na+]>S(=O)(=O)(O)O>[I:5][C:6]1[C:15]([N+:1]([O-:4])=[O:2])=[CH:14][N:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][NH:11]2
Reactant: Ic1ccnc2c1CCCN2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnc2c(c1I)CCCN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
Fuming nitric acid (0.5 mL, 10 mmol) was added a mixture of 5-iodo-1,2,3,4-tetrahydro-1,8-naphthyridine (1.0 g, 3.8 mmol) in sulfuric acid (10 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 30 min. The mixture was poured into ice-water and neutralized with 3 M aq. NaOH. The resulting solid precipitate was collected by filtration, washed with water and dried to give the sub-title compound (0.50 g, 43%). LCMS calc. for C8H9IN3O2(M+H)+: m/z=306.0. Found: 306.1.