Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[F-].[Cs+].[F:14][C:15]([F:37])([F:36])[C:16]([N:18]([C@@H:27]1[CH2:29][C@H:28]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:17].FC(F)(F)C([O-])=O>CN(C)C(=O)C.O>[F:37][C:15]([F:14])([F:36])[C:16]([N:18]([CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:23][CH2:22]1)[C@@H:27]1[CH2:29][C@H:28]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:17]
Reactant: O=C(N(CCC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: COC(=O)c1ccc(Br)nc1
Agent: O=C([O-])C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(N2CCC(CCN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)nc1
Temperature: 100 °C
Yield: 27.3 %

Procedure:
Methyl 6-bromonicotinate, 13 (0.476 g, 2.206 mmol) and CsF (2.68 g, 17.64 mmol) were added to a stirred solution of 2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)-N-(2-(piperidin-4-yl)ethyl)acetamide, trifluoroacetate (1 g, 2.206 mmol) in N,N-dimethylacetamide (10 mL) in a Microwave vial. The reaction vessel was sealed and heated in CEM Discover to 100° C. for 45 min under microwave conditions. Reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layer was washed with water (2×30 mL), brine (1×50 mL), filtered and dried over Na2SO4 and concentrated under reduced pressure to afford crude product The crude product was purified by column chromatography using 100-200 mesh silica gel, by eluting with 30% ethyl acetate in pet-ether to afford methyl 6-(4-(2-(2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)ethyl)piperidin-1-yl)nicotinate (500 mg, 27.3% yield) as yellow gum. LCMS (ES) m/e 476.14 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[N:18]#[C:19][NH2:20].OS(C(F)(F)F)(=O)=O>C1COCC1>[C:19](=[NH:18])([O:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[CH:14][CH:13]=1)[NH2:20]
Reactant: N#CN
Reactant: Cc1cccc(Oc2ccc(CCO)cc2)n1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cccc(Oc2ccc(CCOC(=N)N)cc2)n1
Temperature: 55 °C
Yield: 49.1 %

Procedure:
To a solution of 2-{4-[(6-methyl-2-pyridinyl)oxy]phenyl}ethanol (1.7 g, 7.41 mmol) and cyanamide (0.405 g, 9.64 mmol) in dry THF (20 mL) under nitrogen was added triflic acid (0.856 mL, 9.64 mmol). The mixture was heated at 55° C. for 4 h. Purification via reverse phase flash chromatography afforded the title compound (1.4 g, 3.64 mmol, 49.1% yield) as a colorless oil. LCMS: rt=1.87 min, [M+H+]=272
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[NH:13][CH:14]=[CH:15][C:16]=1[C:17]#[N:18].[C:19](Cl)(=[O:21])[CH3:20]>C1(C)C=CC=CC=1.CCOC(C)=O.[Zn]>[C:19]([C:14]1[NH:13][C:12]([C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[Cl:1])=[C:16]([C:17]#[N:18])[CH:15]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: N#Cc1cc[nH]c1-c1cc(C(F)(F)F)ccc1Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(C#N)c(-c2cc(C(F)(F)F)ccc2Cl)[nH]1
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
To a mixture of 2-[2-chloro-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbonitrile (450 mg, 1.66 mmol) in toluene (3 mL) was added acetyl chloride (0.176 mL, 2.49 mmol) at room temperature, under nitrogen, and zinc (217 mg, 3.32 mmol). The mixture was allowed to stir for 3 h at 80° C. The mixture was cooled to room temperature, diluted with EtOAc and washed with water. The aqueous layer was separated and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was chromatographed on silica gel (0 to 10% EtOAc/hexane) to afford the title compound (386 mg, 74%).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH2:8]([S:12](Cl)(=[O:14])=[O:13])[CH:9]([CH3:11])[CH3:10]>C1C=CC=CC=1>[CH2:1]([N:4]([CH2:5][CH:6]=[CH2:7])[S:12]([CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCNCC=C
Reactant: CC(C)CS(=O)(=O)Cl
Solvent: c1ccccc1
Product: C=CCN(CC=C)S(=O)(=O)CC(C)C

Procedure:
A solution was formed containing 19.4 g. of diallylamine in 100 ml. of benzene. Then, 1.57 g. of isobutylsulfonyl chloride was added at such a rate that the temperature did not exceed 45° C. The mixture was stirred and refluxed for 10 minutes, cooled, washed with 100 ml. of dilute hydrochloric acid and then with H2O. It was then dried over magnesium sulfate, filtered and evaporated to give 20.1 g. (02% of theory) of the product, a liquid, nD30 = 1.4697.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.O.[NH2:10][NH2:11]>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:10][NH2:11])=[CH:6][CH:7]=1
Reactant: NN
Reactant: Clc1ccc(Cl)nn1
Solvent: CCO
Solvent: O
Product: NNc1ccc(Cl)nn1

Procedure:
As shown in FIG. 5, a mixture of 40 g (0.27 mole) of 3,6-dichloropyridazine and 40 mL of 80% hydrazine hydrate in 80 mL of ethanol was refluxed for one hour. The reaction mixture was evaporated to dryness and the residue was recrystallized from benzene to give 39 g of 1-(6-chloropyridazin-3-yl)hydrazine (compound 1003) (see Takahayashi, J. Pharm. Soc. Japan 75:778-781, 1955).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][OH:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N#N>O>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][O:22][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.0 g, 6.0 mmol) in CH2CT2 (15.0 mL) was added 2-hydroxyisoindolin-1,3-dione (978 mg, 6.0 mmol) and triphenylphosphine (2.36 g, 9.0 mmol). The resultant mixture was cooled to 0° C. and diisopropylazodicarboxylate (1.78 ml, 9.0 mmol) was slowly added drop wise under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture, H2O (100 mL) was added and extracted with CH2Cl2. The organic layers washed with brine. Dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to yield (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-((1,3-dioxoisoindolin-2-yloxy)methyl)pyrrolidine-1-carboxylate as light yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH3:10])[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[OH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1.O>C1COCC1>[CH3:37][N:34]1[CH2:35][CH2:36][CH:31]([O:30][C:2]2[N:7]=[C:6]([NH:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH3:10])[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=2)[CH2:32][CH2:33]1
Reactant: CC(Nc1nc(Cl)ccc1[N+](=O)[O-])c1ccccn1
Reactant: CN1CCC(O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(Nc1nc(OC2CCN(C)CC2)ccc1[N+](=O)[O-])c1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-chloro-3-nitro-N-[1-(pyridin-2-yl)ethyl]pyridin-2-amine E-3.8″(2 g; 7.17 mmol) is suspended in 20 ml THF and a potassium bis(trimethylsilyl)amide solution in THF (29 ml; 29 mmol) is slowly added at 25° C. After 15 min 4-hydroxy-N-methylpiperidine (3.37 g; 28.71 mmol) is added and the reaction mixture is stirred for 16 h at 25° C. The reaction mixture is diluted with ethyl acetated and water. The organic phase is separated and dried using MgSO4. The crude intermediate is purified using reversed phase chromatography (prep. HPLC1). The product containing fractions are combined and freeze-dried
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH2:21][CH2:22][NH2:23])[CH:14]=[CH:15][C:16]=3[O:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[O:24](C(C(F)(F)F)=O)[C:25]([C:27]([F:30])([F:29])[F:28])=O>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=3[O:17][CH:18]([CH3:19])[CH3:20])[CH2:21][CH2:22][NH:23][C:25](=[O:24])[C:27]([F:30])([F:29])[F:28])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)Oc1ccc(CCN)cc1C12CC3CC(CC(C3)C1)C2
Product: CC(C)Oc1ccc(CCNC(=O)C(F)(F)F)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a stirred solution of 2-(3-(1-Admantyl)-4-isopropoxyphenyl)ethanamine (0.28 g, 0.86 mmol) in a mixture of solvents (CH2Cl2:Et3N: 10:0.5 ml) (CF3CO)2O (0.157 ml) was added at 0° C. under N2. The reaction mixture was stirred for 2 h at room temperature, then the solvent was evaporated to dryness. The residue was diluted to 50 ml with EtOAc and washed with 1M HCl. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title product (0.29 g, 82.4%). 1H-NMR (CDCl3) 1.37 (d, 6H, J=6 Hz); 1.67-1.75 (m, 6H); 2.04-2.23 (m, 9H); 2.78 (tr, 2H, J=6.84 Hz); 3.53-3.59 (m, 2H); 4.57-4.63 (m, 1H); 6.77 (d, 1H, J=8.32 Hz); 6.92 (dd, 1H, J=2.21, 8.27 Hz); 6.98 (d, 1H, J=2.21 Hz).
Reaction SMILES: [F:1][CH:2]([F:49])[S:3][CH2:4][C@@H:5]1[CH2:9][C@H:8]([S:10][C:11]2[C@H:17]([CH3:18])[C@H:16]3[N:13]([C:14](=[O:22])[C@@H:15]3[C@H:19]([OH:21])[CH3:20])[C:12]=2[C:23]([O:25]CC2C=CC([N+]([O-])=O)=CC=2)=[O:24])[CH2:7][N:6]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O.P([O-])([O-])([O-])=O.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[F:49][CH:2]([F:1])[S:3][CH2:4][C@@H:5]1[CH2:9][C@H:8]([S:10][C:11]2[C@H:17]([CH3:18])[C@H:16]3[N:13]([C:14](=[O:22])[C@@H:15]3[C@H:19]([OH:21])[CH3:20])[C:12]=2[C:23]([OH:25])=[O:24])[CH2:7][NH:6]1
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CSC(F)F)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](CSC(F)F)C3)[C@H](C)[C@H]12
Yield: 58 %

Procedure:
A mixture of 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(difluoromethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.58 g), 20% palladium hydroxide on carbon (0.5 g), 0.05M phosphate buffer (pH 6.3, 18 ml) and tetrahydrofuran (18 ml) was stirred at ambient temperature for 4 hours under atmospheric pressure of hydrogen. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to remove the organic solvent. The resulting aqueous residue was washed with ethyl acetate (10 ml×2) and the aqueous layer was concentrated under reduced pressure to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (20 ml) eluting in turn with water (80 ml) and 6% aqueous acetone (80 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(difluoromethyl)thiomethylpyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.19 g).
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:6][N:5]=1)([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]([C:4]1[S:8][C:7]([N:9]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=2)(=[O:11])=[O:12])=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(=O)Oc1ccc(S(=O)(=O)Nc2nnc(C(C)C)s2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Oc1ccc(S(=O)(=O)N(COCC[Si](C)(C)C)c2nnc(C(C)C)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
3.3 g Acetic acid 4-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl ester were dissolved in 12 ml dichloromethane. 2.69 ml N,N-diisopropylethylamine, 78 mg 4-dimethylaminopyridine and 2.1 g 2-(trimethylsilyl)ethoxymethyl chloride were added. The reaction mixture was stirred at room temperature for one hour. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel with the eluents n-heptane:ethyl acetate=1:1=>1:3 to obtain 2.7 g acetic acid 4-[(5-isopropyl-[1,3,4]thiadiazol-2-yl)-(2-trimethylsilanyl-ethoxymethyl)-sulfamoyl]-phenyl ester.
Reaction SMILES: O.[CH:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([C:14]=2[C:16]([OH:18])=O)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[CH:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([C:14]=2[C:16]([Cl:21])=[O:18])=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1c2ccccc2nc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: O
Product: O=C(Cl)c1c2ccccc2nc2ccccc12

Procedure:
A mixture of 9-acridinecarboxylic acid hydrate (7.3 g, 30 mmole), and thionyl chloride (50 ml, 0.685 mole) was heated at reflux in a round bottom flask equipped with a reflux condenser, a drying tube, and a stirring bar. The reaction mixture was heated further for one hour after the dissolution occurred, then cooled and evaporated to remove any excess thionyl chloride. The residue was directly utilized in the subsequent reaction without further purification.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C=O)C>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][O:21][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
N6-benzoyl-2′-deoxyadenosine (20.95 g ) was dissolved in 200 ml of DMF. Imidazole (15.7 g) was dissolved to the resultant solution by addition. Then, 20.8 g of tert-butyldimethylsilyl chloride was added. DMF (100 ml) was further added and the solution was stirred at room temperature. After 8 hours, extraction using chloroform was carried out and the organic layer was washed by a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. After concentration of the extract, the target compound was purified by column chromatography (methanol/chloroform) to obtain 16.1 g of the titled compound (yield; 61%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:12][O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([NH:24][CH2:25][CH2:26][NH2:27])=[N:16][CH:15]=1.O>CN(C)C=O>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:27][CH2:26][CH2:25][NH:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([O:13][CH3:12])=[CH:15][N:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: COc1cnc(NCCN)c2ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc(NCCNCC(O)COc2ccccc2)c2ccccc12
Reaction time: 72 h

Procedure:
5.2 g. Phenyl glycidyl ether and 15 g. 4-methoxy-1-(2-aminoethylamino)-isoquinoline are dissolved in dimethylformamide and left to stand for 72 hours at ambient temperature. The reaction mixture is then poured into water, extracted with methylene chloride, dried and purified chromatographically on a silica gel column using, as elution agent, methylene chloride-methanol-triethylamine (8:1:0.05 v/v/v). By evaporation of the pure fractions, there are obtained 5.5 g. (44% of theory) of an oil. By the addition of 1.7 g. fumaric acid to a solution of this oil in ethyl acetate-ethanol, a hydrogen fumarate is precipitated out and this is then recrystallized from isopropyl alcohol. The desired product is obtained in the form of colorless cyrstals; m.p. 152°-153° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([OH:17])[CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[H-].[Na+].I[CH2:31][CH3:32]>CN(C=O)C>[CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([O:17][CH2:31][CH3:32])[CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCI
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)cnc1CC
Reaction time: 0.25 h
Yield: 77 %

Procedure:
To a solution of benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate (17.70 g, 47.8 mmole) in DMF (0.3 M) at 0° C. under N2 was added NaH portionwise (2.48 g, 1.3 eq.). After 15 minutes, iodoethane (4.93 mL, 1.3 eq.) was added dropwise. After 2 hours, the reaction mixture was quenched with brine (200 mL), extracted with ethyl acetate (2×200 mL), dried with MgSO4, filtered and concentrated. Vacuum chromatography was run on a 1 L frit funnel (20-40% ethyl acetate in heptane gradient) to give 14.64 g (77%) of benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate as an oil. IR (liq.) 2971, 2936, 2340, 1950, 1709, 1546, 1499, 1464, 1448, 1422, 1395, 1350, 1173, 1129, 1097 (s) cm−1 HRMS (ESI) calcd for C22H30N4O3+H1 399.2396. found 399.2392. [α]25D=−50° (c 0.55, 0.1N HCl).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1>CO.C(Cl)Cl>[Cl:8][C:9]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:12]([C:13]([O:15][CH3:1])=[O:14])=[CH:11][N:10]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1

Procedure:
(Trimethylsilyl)diazomethane (8.25 mL of a 2.00 M solution in hexanes, 16.5 mmol) was added in three portions to a stirred solution of 6-chloro-5-nitronicotinic acid (1.00 g, 4.95 mmol) in methanol (12.0 mL) and DCM (24.0 mL) at 0° C. The reaction mixture was quenched with TPA and concentrated in vacuo to afford the title compound i-2a. m/z (ES) 217 (MH)+. 1H NMR (500 MHz, CDCl3): δ 9.20 (d, 1H, J=2.1 Hz), 8.79 (d, 1H, J=2.1 Hz), 4.05 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[C:9](=[O:10])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3]1.[Al+3].[Cl-].[Cl-].[Cl-].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:8]1[C:4]2[CH2:3][CH:2]([CH3:1])[C:9](=[O:10])[C:5]=2[S:6][CH:7]=1
Reactant: CC1Cc2ccsc2C1=O
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC1Cc2c(Br)csc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A total of 129 g (0.85 mol) of 5-methyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one in 130 ml of CHCl3 were added to a suspension of 250 g (1.89 mol) of AlCl3 (anhydrous powder) in 350 ml of CHCl3 at 0° C. over 0.5 h. The reaction mixture was stirred for 10 min at this temperature; then a solution of 46.7 ml of Br2 (0.91 mol) in 90 ml of CHCl3 was added dropwise for 1 h. The resulting mixture was stirred for 1 h at room temperature and, then, poured over 2000 cm3 of ice. The organic layer was separated. The aqueous layer was extracted with 4×200 ml of CH2Cl2. The combined organic fractions were washed with 1000 ml of the saturated aqueous Na2CO3, dried over K2CO3, passed through a short Silica Gel 60 column (40-63 μm, d 40 mm, 1 50 mm), and evaporated to dryness. Fractional distillation gave white crystalline product, b.p. 128° C./0.8 mm Hg. Yield 185 g (94%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[S:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[S:27][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: c1cscn1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)c3nccs3)c2)c1

Procedure:
This compound is prepared by method C using compound 12g and thiazole
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)(=O)=O.[CH3:17]O>>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccc(F)cc1F
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)c1ccc(F)cc1F
Yield: 92 %

Procedure:
To a solution of 2,4-difluorobenzoic acid (50.0 g, 316.25 mmol) in methanol (500 mL) was added sulfuryl dichloride (112 g, 949.15 mmol) at 0° C. The resulting solution was heated to reflux overnight and concentrated in vacuo to afford methyl 2,4-difluorobenzoate as a colorless oil (50 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of 2-(4-aminobenzyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (139 mg) in tetrahydrofuran (5 ml) was added triethylamine (0.083 ml) and then methanesulfonyl chloride (0.028 ml) was added. The mixture was stirred at room temperature for 3 hrs. The solvent was evaporated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1→2/3) to give the title compound (90 mg, 55%).