Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:4][S:5][N:6]=1.[CH2:20]([OH:23])[CH2:21][OH:22]>N1C=CC=CC=1.CCOC(C)=O>[OH:22][CH2:21][CH2:20][O:23][C:2]1[C:3]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:4][S:5][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Reactant: OCCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2OCCO)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
K-t-BuO (1.24 g, 1 mmol) was added to a mixture of the product obtained in Step 1 (198 g, 6.5 mmol) and ethylene glycol (2.54 ml, 45.5 mmol) in pyridine (15 ml). The reaction mixture was stirred at 100° C. for 6 h and at room temperature overnight. The solution was then poured into ice-water and diluted with EtOAc. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The residue %% as purified by chromatography on silica gel eluting hexane/EtOAc (1:1) to give 1.71 g (65%) of title product as an orange oil. MS m/z 331 (M+H)+.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[CH2:19]([NH2:23])[C:20]#[C:21][CH3:22]>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:23][CH2:19][C:20]#[C:21][CH3:22])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Reactant: CC#CCN
Solvent: CC#N
Product: CC#CCNC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Reaction time: 15 h
Yield: 80 %

Procedure:
A mixture of 1-nitro-2-methylthio-2-{2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamino}ethylene (2.25 g, 7.8 mmole) and 2-butyn-1-amine (2.16 g, 31.2 mmole) in acetonitrile (35 ml) was stirred under a positive pressure of nitrogen at reflux temperature for 7 hours and at room temperature for 15 hours. The solvent was removed by evaporation under reduced pressure, and the residue placed on silica gel and chromatographed by gradient elution using methylene chloride-methanol. The appropriate fractions yielded 1.93 g (80%) of the title product from acetonitrile. Recrystallization from isopropyl alcohol gave the product with mp 147.5°-151°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(OCC)(=O)C>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)Nc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
5.08 g (30 mmol) of 2-aminobiphenyl, 50 ml of ethyl acetate, and 3.1 g (30 mmol) of triethylamine were placed in a flask, to which 4.1 g (30 mmol) of ethyl chloroglyoxylate was added dropwise under ice cooling. The reaction mixture was stirred at room temperature for three hours, and then 50 ml of ethyl acetate was added thereto. The organic layer was washed with 30 ml of 1N hydrochloric acid and 30 ml of brine one by one, and then was dried with anhydrous sodium sulfate. The solvent was removed by evaporation to obtain 6.8 g (24 mmol, yield 85%) of ethyl N-biphenyl-2-yloxamate as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:19])=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:10]=2)[CH:7]=1.[H-].[Na+].Cl[S:23]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:14]([O:13][C:12]([N:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]2[C:8]=1[CH3:19])[S:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=1)(=[O:25])=[O:24])=[O:18])([CH3:15])([CH3:16])[CH3:17]
Reactant: Cc1c(NC(=O)OC(C)(C)C)nc2ccc(F)cn12
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3ccc(F)cn3c2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of compound 6-C (0.70 g, 2.64 mmol) in DMF (20 mL) was cooled in an ice bath and treated with a 60% dispersion of NaH in mineral oil (0.126 g, 3.17 mmol) and stirred at ambient temp for 30 min. The solution was cooled on an ice bath and treated with methyl 4-(chlorosulfonyl)benzoate (1.24 g, added in portions). The resultant solution was stirred at ambient temperature for 18 hours. The solution was poured into ice water, and the resultant suspension was made basic with careful addition of a saturated aqueous solution of NaHCO3. The solid was collected by filtration, washed with water and air dried. The solid was pre-absorbed onto silica gel and purified by flash chromatography, using a gradient of EtOAc (10-60%) in heptanes as the eluant to afford compound 6-D as a colorless solid (1.1 g, 90%). MS: m/z 464.1 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[O:25]1[CH2:30][CH2:29][CH:28]([Mg]Br)[CH2:27][CH2:26]1>C1COCC1.CN1C(=O)CCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[O:25]1[CH2:30][CH2:29][CH:28]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[S:17][C:18]5[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=5[N:20]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:27][CH2:26]1
Reactant: Br[Mg]C1CCOCC1
Reactant: Clc1nccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: c1ccc2sc(Nc3ccc(Oc4nccnc4C4CCOCC4)cc3)nc2c1

Procedure:
To a round bottomed flask was added N-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (0.3000 g, 0.846 mmol) dissolved in a mixture of THF (1.353 mL) and NMP (0.338 mL). Iron(III)acetylacetonate (0.015 g, 0.042 mmol) was added and the temperature was brought to 0° C. (Tetrahydro-2H-pyran-4-yl)magnesium bromide (3.70 mL, 2.96 mmol) was added dropwise to the reaction. The reaction was quenched with sat. ammonium chloride. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated. LC showed formation of N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine and N-(4-(pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 1% to 5% MeOH in DCM, to provide N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine. MS (ESI, pos. ion) m/z: 405.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: C(OC(Cl)=O)C.[C:7]([OH:15])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:16]([N:18](CC)[CH2:19]C)C.CNC>O1CCCC1.C(O)C>[CH3:16][N:18]([CH3:19])[C:7](=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCC(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CNC
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ethylchloroformate (18.3 ml) was added slowly to a solution of heptanoic acid (20.0 g) and triethylamine (26.7 ml) in tetrahydrofuran (250 ml), maintained at -10°. The resulting mixture was stirred at 10° for 0.75 hour, cooled to 5° and a 33% solution of dimethylamine in ethanol (41.6 ml) added dropwise. This mixture was then allowed to warm to room temperature and stirred for 4 hours. The mixture was filtered and the filtrate evaporated to dryness. The residue was dissolved in chloroform (250 ml) and washed with 1% aqueous sodium carbonate solution (200 ml) and water, then dried and evaporated. The residual oil was chromatographed on silica gel to give N,N-dimethylheptanamide (14.1 g) as a colourless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][N+:3]=1[O-:12].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH2:24].CCN(C(C)C)C(C)C>C(O)CCC>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH:24][C:2]1[N+:3]([O-:12])=[CH:4][C:5]([CH3:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Cc1c[n+]([O-])c(Cl)cc1[N+](=O)[O-]
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(CNc2cc([N+](=O)[O-])c(C)c[n+]2[O-])c(OC)c1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
A mixture of 2-chloro-5-methyl-4-nitropyridine 1-oxide (1.1 g, 5.8 mmol), 1-(2,4-dimethoxyphenyl)methanamine (1.1 mL, 7.0 mmol), DIEA (2.0 mL, 11.6 mmol), and 1-butanol (9 mL) was subjected to microwave irradiation at 120° C. for 8 h. The reaction mixture was allowed to cool to rt and was filtered. The resulting solid was washed with water (20 mL) and dried to give N-(2,4-dimethoxybenzyl)-5-methyl-4-nitropyridin-2-amine 1-oxide (1.2 g, 67%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.O.[C:24]1([S:30]([OH:33])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[C:4]=2[CH:3]=1.[S:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O-:33])(=[O:32])=[O:31]
Reactant: O=S(=O)(O)c1ccccc1
Agent: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Solvent: O
Solvent: CC(C)=O
Product: O=S(=O)([O-])c1ccccc1

Procedure:
To a solution of 5.0 g of olanzapine in 150 ml acetone was slowly added a solution of 2.8 g benzenesulfonic acid monohydrate in 50 ml acetone at room temperature under stirring. The mixture was stirred 1 hour at room temperature and then at 4° C. overnight. Crystals were isolated by filtration, washed with 20 ml of acetone and 20 ml of ether and dried at 40° C. under vacuum overnight. Yield: 5.98 g (79%).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[C:27]([CH3:28])=[C:26]([C:29](O)=[O:30])[C:25](=[O:32])[N:24]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[OH:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:20]=[CH:21][C:2]([NH:1][C:29]([C:26]4[C:25](=[O:32])[N:24]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:23]([CH3:22])[C:27]=4[CH3:28])=[O:30])=[CH:3][CH:4]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: COc1cc2c(Oc3ccc(N)cc3)ccnc2cc1O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1O
Temperature: 60 °C
Reaction time: 10 h
Yield: 93.6 %

Procedure:
To a solution of 4-(4-aminophenoxy)-6-methoxyquinolin-7-ol (3.61 g, 12.8 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (2.85 g, 12.27 mmol) in DMF (50 mL) was added EDCI (2.81 g, 14.66 mmol) and HOAT (0.33 g, 2.4 mmol). The reaction was stirred at 60° C. for 10 hours, cooled to room temperature and diluted with H2O (200 mL). The solid was collected by filtration and dried in vacuo at 60° C. overnight to give the title compound as a white solid (5.7 g, 89.9%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]>CN(C=O)C>[N:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[N+:2]=[N-:3]
Reactant: OCCCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCCO
Temperature: 80 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
NaN3 (390 mg, 6.0 mmol) was added to a solution of 7-bromoheptanol (880 μL, 5.7 mmol) in DMF (5 mL). The mixture was stirred for 24 at r.t. and additional 3 h at 80° C. to complete the reaction. The mixture was concentrated under reduced pressure, the residue was dissolved in water/Et2O (10/20 mL), the organic layer was separated, dried over Na2SO4 and filtered. Concentration under reduced pressure yielded 7-azidoheptanol (710 mg, 78%) as an colourless oil which was pure enough for further reactions.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:20]2[CH2:22][O:21]2)[CH:19]=1>C(O)(C)(C)C>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:20]2[CH2:22][CH2:7][O:21]2)[CH:19]=1
Reactant: CC(C)(C)[O-]
Reactant: Brc1cncc(C2CO2)c1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Brc1cncc(C2CCO2)c1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a suspension of trimethylsulfoxonium iodide (CAS#1774-47-6, 6.38 g, 29.0 mmol) in tert-butanol (20 mL), was added potassium tert-butoxide (3.25 g, 29.0 mmol). The reaction was heated to 50° C. and permitted to stir for 15 min. A solution of 3-bromo-5-oxiranyl-pyridine (2.9 g, 14.50 mmol) in tert-butanol (20 mL) was then added slowly to the reaction. The reaction was permitted to stir at 50° C. for 16 hr. The reaction mixture was cooled to 0° C., quenched with brine, and diluted with diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether two additional times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 0 to 60%) to afford 3-bromo-5-oxetan-2-yl-pyridine; MS: (ES+) m/z 214.3 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH:10]([CH:11]([O:22][C:23](=[O:25])[CH3:24])[CH:12]([O:18][C:19](=[O:21])[CH3:20])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:9][C:8]([C:26]([O:28][CH3:29])=[O:27])=[CH:7][CH:6]1[NH2:30])(=[O:3])[CH3:2].[N:31]#[C:32]F.N#CCl.N#CBr.N#CI>>[C:1]([NH:4][CH:5]1[CH:10]([CH:11]([O:22][C:23](=[O:25])[CH3:24])[CH:12]([O:18][C:19](=[O:21])[CH3:20])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:9][C:8]([C:26]([O:28][CH3:29])=[O:27])=[CH:7][CH:6]1[NH:30][C:32]#[N:31])(=[O:3])[CH3:2]
Reactant: N#CF
Reactant: COC(=O)C1=CC(N)C(NC(C)=O)C(C(OC(C)=O)C(COC(C)=O)OC(C)=O)O1
Agent: N#CBr
Agent: N#CCl
Agent: N#CI
Product: COC(=O)C1=CC(NC#N)C(NC(C)=O)C(C(OC(C)=O)C(COC(C)=O)OC(C)=O)O1

Procedure:
A] treating a compound of formula (V) with a cyanogen halide which may be selected from cyanogen fluoride, cyanogen chloride, cyanogen bromide or cyanogen iodide to obtain methyl 5-acetamido-4-cyanamido-6-(1,2,3-triacetoxypropyl)-5,6-dihydro-4H-pyran-2-carboxylate (VIII); B] deacetylating the intermediate (VIII) to obtain methyl 5-acetamido-4-cyanamido-6-(1,2,3-trihydroxypropyl)-5,6-dihydro-4H-pyran-2-carboxylate (IX). The reaction may be carried out in the presence of a deacetylating agent which may be selected from the group consisting of methanol/iodine, methanol/water, sodium t-butoxide, potassium carbonate, sodium hydroxide, or sodium methoxide; C] hydrolyzing the compound (IX) in a basic medium to obtain 5-acetamido-4-cyanamido-6-(1,2,3-trihydroxypropyl)-5,6-dihydro-4H-pyran-2-carboxylic acid of formula (VII). The base used in the reaction may be organic or inorganic. The organic base may be selected from the group consisting of pyridine, dimethylamine, trimethylamine and sodium ethoxide. The inorganic base may be selected from the group consisting of sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate; and D] reacting the compound (VII) with ammonium formate in the presence of ammonia which may be in the form of gaseous ammonia, liquid ammonia or aqueous ammonia and at a high temperature, for example ranging from 80° C. to 100° C., to obtain zanamivir (I).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[C:9]([C:11]1[CH:12]=[C:13](I)[CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][N:17]([C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:24]([O:26][CH3:27])=[O:25])[C:16]2=[O:32])#[N:10]>>[C:9]([C:11]1[CH:12]=[C:13]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)[CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][N:17]([C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:24]([O:26][CH3:27])=[O:25])[C:16]2=[O:32])#[N:10]
Reactant: CCN1CCNCC1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3c(C#N)cc(I)cc3c2=O)c1
Product: CCN1CCN(c2cc(C#N)c3ncn(-c4cc(C(=O)OC)ccc4C)c(=O)c3c2)CC1

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1 which is concerned with the preparation of starting material N-ethyl piperazine was reacted with methyl 3-(8-cyano-6-iodo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate to give methyl 3-[8-cyano-6-(4-ethylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate; Mass Spectrum: M+H+ 432.
Reaction SMILES: [Br-].[C:2]([NH:10][C:11]1[CH:16]=[CH:15][N+:14]([CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[CH:13][CH:12]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)(C)C.O>[C:2]([NH:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:16]1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cc[n+](CCc2c[nH]c3ccccc23)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=C(NC1CCN(CCc2c[nH]c3ccccc23)CC1)c1ccccc1

Procedure:
A suspension of 4-benzamido-1-[2-(3-indolyl)ethyl]-pyridinium bromide (7.3 kg.) and sodium borohydride (2.5 kg.) in isopropanol (57 kg.) was stirred and refluxed for 6 hours. The reaction mixture was cooled to 25° and diluted with water. The product was separated by filtration and washed with aqueous methanol then with water and finally with methanol, and dried to give 4.45 kg. of the crude title compound. This was purified by dissolving in dimethylformamide (21 kg.) at 50°-60° and slowly adding water (22 kg.). After cooling, the product was separated by filtration, washed with water then with methanol, and dried to give 3.9 kg. of the title compound (65% yield).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:26][C@@H:25]([O:27][CH3:28])[C@H:24]([OH:29])[CH2:23]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH2:9]([C:16]1[C:21]([I:1])=[CH:20][CH:19]=[C:18]([N:22]2[CH2:26][C@@H:25]([O:27][CH3:28])[C@H:24]([OH:29])[CH2:23]2)[N:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CO[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Reaction time: 8 h
Yield: 93.4 %

Procedure:
Under stirring in an ice bath, 2.5 g of N-iodosuccinimide was added little by little to a mixture of 3.11 g of 2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine and 10 ml of N,N-dimethylformamide, followed by stirring as it was overnight. Sodium sulfite was added thereto and the mixture was extracted with ethyl acetate-water. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to silica gel column chromatography and eluted with 30% ethyl acetate/hexane, to give 4.19 g of the target compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]([N:7]1[CH2:15][CH2:14][CH:10]([C:11](Cl)=[O:12])[CH2:9][CH2:8]1)=[O:6].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1>>[F:16][C:17]1[CH:18]=[C:19]([F:23])[CH:20]=[CH:21][C:22]=1[C:11]([CH:10]1[CH2:14][CH2:15][N:7]([CH:5]=[O:6])[CH2:8][CH2:9]1)=[O:12]
Reactant: O=CN1CCC(C(=O)Cl)CC1
Reactant: Fc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Product: O=CN1CCC(C(=O)c2ccc(F)cc2F)CC1
Temperature: 0 °C
Yield: 32.3 %

Procedure:
To a slurry of 39 g of aluminum chloride and 120 ml of 1,3-difluorobenzene was added dropwise, with stirring, 30 g of N-formylisonipecotic acid chloride. The reaction mixture was stirred under reflux for two hrs and poured into 1 l of ice-water. The mixture was extracted with 4 350-ml portions of chloroform. The combined organic extracts were washed with 2 300-ml portions of water, dried, filtered and evaporated. Trituration with petroleum ether and washing with ether at 0°, yielded 14 g (32.3%) of product, mp, 75°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2].[CH:30]([Sn](CCCC)(CCCC)CCCC)=[CH2:31]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:30]=[CH2:31])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(Br)cc2)nc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(Oc2ccc(N3CCCC3(C(=O)OCC)C(=O)OCC)cn2)cc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A mixture of 1-[6-(4-bromo-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (5.8 g, 12.2 mmol), vinyltributyltin (3.9 mL, 12.3 mmol), tetrakistriphenylphosphine palladium (0) (0.60 g, 0.52 mmol) and 24 mL of toluene was heated to reflux for 1 hour. After cooling to room temperature, the mixture was concentrated in vacuo and purified by silica gel chromatography (Flash 40, 20%-50% ethyl acetate-hexanes), affording 4.8 g of 1-[6-(4-Vinyl-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester as a colorless syrup.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([C:22]([OH:24])=O)[N:16]=[N:15]2)=[CH:10][CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C1C=C[C:28]2N(O)N=[N:31][C:29]=2[CH:30]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH2:1]([NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([C:22]([NH:31][CH:29]3[CH2:30][CH2:28]3)=[O:24])[N:16]=[N:15]2)=[CH:12][CH:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.8 %

Procedure:
1-{4-[(Butylamino)carbonyl]phenyl}-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (504 mg, 1.53 mmol) obtained in Example 56b), HOBt (208 mg, 1.53 mmol, 1.0 eq.) and cyclopropylamine (0.142 ml, 1.98 mmol, 1.3 eq.) were dissolved in acetonitrile (4 ml) and DMF (4 ml), WSC (358 mg, 1.83 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (535 mg, 1.45 mmol, 94.9%).