Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CO[C:4](=[NH:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH:15]([NH:17][NH2:18])=O>N1C=CC=CC=1>[N+:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]2[NH:18][N:17]=[CH:15][N:14]=2)=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: NNC=O
Reactant: COC(=N)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(-c2ncn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Nitro-benzimidic acid methyl ester hydrochloride (635 mg, 2.93 mmol) was suspended in pyridine (7 mL) and formic hydrazide (Aldrich, 178 mg, 2.95 mmol) was added and the mixture was stirred at rt for 1 hr. The solvent was removed and the residue was dissolved in toluene (10 mL) and the mixture was stirred at reflux for 1.5 hrs. the mixture was cooled and water was added. The organic layer was separated and dried over sodium sulfate. The solvent was removed and the residue was suspended in 25% EtOAc/Hexanes and the solid was filtered to give a solid. 510 mg.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[C:10]([I:30])=[C:11]([C:17]([I:29])=[C:18]([NH:21][C:22](=[O:28])[CH2:23][O:24]C(=O)C)[C:19]=1[I:20])[CH2:12]CC([O-])=O)=[O:7])(=O)C.C[OH:32]>[OH-].[Na+]>[OH:4][CH2:5][C:6]([NH:8][C:9]1[C:10]([I:30])=[C:11]([C:17]([I:29])=[C:18]([NH:21][C:22](=[O:28])[CH2:23][OH:24])[C:19]=1[I:20])[CH2:12][OH:32])=[O:7]
Reactant: CO
Reactant: CC(=O)OCC(=O)Nc1c(I)c(CCC(=O)[O-])c(I)c(NC(=O)COC(C)=O)c1I
Agent: [Na+]
Agent: [OH-]
Product: O=C(CO)Nc1c(I)c(CO)c(I)c(NC(=O)CO)c1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3,5-Bis(acetoxyacetylamino)-2,4,6-triiodobenzylacetate (152 mg, 0.2 mmol) was dissolved in a mixture of methanol (6 ml) and 1 M aqueous NaOH (2 ml) and the solution was stirred for 2 h at room temperature. After neutralization with 1 M HCl, the solvents were removed by evaporation and the product was purified by preparative HPLC. Yield: 105 mg (83%).
Reaction SMILES: [CH2:1]([O:4][C:5](OCCC)=[N:6][NH:7][C:8]([O:10]C)=O)[CH2:2][CH3:3].[CH3:16][NH2:17]>CO.C(O)C>[CH2:1]([O:4][C:5]1[N:17]([CH3:16])[C:8](=[O:10])[NH:7][N:6]=1)[CH2:2][CH3:3]
Reactant: CN
Reactant: CCCOC(=NNC(=O)OC)OCCC
Solvent: CO
Solvent: CCO
Product: CCCOc1n[nH]c(=O)n1C
Temperature: 100 °C

Procedure:
693.6 g (94.4%) of methyl N′-dipropoxymethylenehydrazinecarboxylate (3 mol) were dissolved in 1752 g of methanol and admixed with 564.7 g (6 mol) of methylamine, dissolved in ethanol, and the mixture was heated in an autoclave at 100° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, the residue was taken up in water (880 ml) the mixture was extracted with methylene chloride and the extract was concentrated under reduced pressure. The crystals which precipitated out on cooling were filtered off and dried. This gave 383 g (71.2%, content 87.6%) of 5-propoxy-4-methyl-2,4-dihydro-1,2,4-triazol-3-one in the form of a solid. Melting point: 72.5-73.5° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH2:9][C:8](=[O:10])[NH:7][C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.O>[CH2:19]([N:7]1[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]1=[O:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CC(C(F)(F)F)=Nc2ccccc2N1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(Cc2ccccc2)C(C(F)(F)F)=Nc2ccccc2N1Cc1ccccc1
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
To a solution of 4-trifluoromethyl-1,3-dihydro-1,5-benzodiazepin-2(2H)-one(3.0 g, 13.1 mmol) in N,N-dimethylformamide(20 mL) was added sodium hydride (content 60%, 1.1 g, 27.5 mmol), and the mixture was stirred for 15 minutes. To the mixture was added benzyl bromide (4.7 g, 27.5 mmol), which was stirred for further 30 minutes. The reaction mixture was diluted with water, which was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The concentrate was crystallized from ethyl acetate-hexane to give 3.3 g of the titled compound. Yield 61%. m.p. 150°-151° C.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)=[CH:20][C:21]=1[CH2:22][CH3:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:22]([C:21]1[CH:20]=[C:19]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)[S:18][C:17]=1[C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])[C:3]([OH:37])=[O:2])=[O:16])[CH3:23]
Reactant: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (S)-2-({3-Ethyl-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (28.0 mg, 0.052 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (22 mg, 2.0 mmol) in water (5 mL). The mixture was then stirred at room temperature 2 d. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 19.2 mg (70%). MS m/e 525.9 (M+H+).
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[N:5]1.[H][H]>[Pd].C(O)C>[NH2:9][C:6]1[CH:7]=[CH:8][N:4]([CH2:3][C:2]([CH3:12])([OH:13])[CH3:1])[N:5]=1
Reactant: [H][H]
Reactant: CC(C)(O)Cn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(O)Cn1ccc(N)n1
Yield: 93.1 %

Procedure:
In a Parr shaker bottle was placed 2-methyl-1-(3-nitro-pyrazol-1-yl)-propan-2-ol (prepared in example 74, 100 mg, 0.54 mmol), 10% palladium on activated carbon (10 mg) and ethanol (5 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 1 h. The reaction was then filtered through a pad of celite and washed with ethanol and concentration in vacuo afforded l-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (78 mg, 94%) and taken on to the next step without characterization.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:22]([P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[CH2:23]>CC#N>[CH2:26]([O:25][P:24]([CH2:22][CH2:23][N:18]1[CH2:19][CH2:20][O:21][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)[CH2:17]1)(=[O:31])[O:28][CH2:29][CH3:30])[CH3:27]
Reactant: CCCCCCCCOc1ccc(C2CNCCO2)cc1
Reactant: C=CP(=O)(OCC)OCC
Solvent: CC#N
Product: CCCCCCCCOc1ccc(C2CN(CCP(=O)(OCC)OCC)CCO2)cc1
Temperature: 25 °C
Yield: 31.8 %

Procedure:
A mixture of 2-(4-octyloxy-phenyl)-morpholine (0.83 g; 2.9 mmol) and diethyl vinylphosphonate (0.53 ml; 3.4 mmol) in CH3CN (10 mL) was heated under reflux for 3 days. After cooling to RT the mixture was concentrated in vacuo and the residue was purified by column chromatography (SiO2, EtOAc: MeOH 90:10) to afford {2-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-ethyl}-phosphonic acid diethyl ester (0.42 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[C:27]1([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:33]([NH:35][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([F:23])[CH:18]=1)=[S:37])(=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (64 mg, yield 85%).
Reaction SMILES: [Na+:1].[Na+].[Na+].[NH2:4][C:5]1[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:10]2.O.O.O.C([O-])(=O)C.[Na+].[N+](C1C=CC(C([O:44][C:45](=O)[C:46]2[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][C:47]=2[S:55]([OH:58])(=[O:57])=[O:56])=O)=C(S(O)(=O)=O)C=1)([O-])=O>O>[Na+:1].[Na+:1].[Na+:1].[Na+:1].[N+:52]([C:49]1[CH:50]=[CH:51][C:46]([C:45]([NH:4][C:5]2[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]3[C:14]=2[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:10]3)=[O:44])=[C:47]([S:55]([OH:58])(=[O:56])=[O:57])[CH:48]=1)([O-:54])=[O:53]
Reactant: O=C(OC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reactant: Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reaction time: 0.17 h

Procedure:
To an ice-bath cooled solution (5° C.) of 8-amino-1,3,6-naphthalenetrisulfonic acid trisodium salt and 6.7 g of sodium acetate trihydrate in 100 ml of water is added 8.8 g of 4-nitro-2-sulfobenzoic acid anhydride. The mixture is stirred vigorously for 10 minutes and is filtered. The filtrate is cooled in an ice bath and diluted with 500 ml of cold ethyl alcohol. The mixture is filtered and the product is washed with ethyl alcohol and ether and then is dried. The product is dissolved in 50 ml of warm water and is stirred for 10 minutes after the addition of one ml of acetone. The mixture is treated with activated charcoal, filtered through diatomaceous earth and is washed with 20 ml of water. The filtrate is cooled in an ice bath and acidified with 1.5 ml of concentrated hydrochloric acid. The solution is diluted with 500 ml of cold ethyl alcohol, and the precipitated material is filtered, washed with ethanol followed by ether and dried. The above purification process is repeated without acidification. The product obtained is dried overnight at 110° C. to give 18.5 g of 8-(4-nitro-2-sulfobenzamido)-1,3,6-naphthalenetrisulfonic acid tetrasodium salt.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CN(C=O)C>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[CH2:9][CH2:10][C:11](=[O:17])[NH:12]4)[CH2:2][CH2:3]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Agent: CN(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCN(c3cccc4c3CCC(=O)N4)CC2)cc1
Temperature: 25 °C
Yield: 48 %

Procedure:
5-(1-Piperazinyl)-3,4-dihydrocarbostyril (1.0 g) was added to a mixture of 10 ml of DMF and 0.85 ml of trimethylamine and the mixture was stirred at room temperature while slowly adding dropwise 5 ml of DMF solution containing 1.07 g of p-toluenesulfonyl chloride. After completion of addition, the reaction mixture was stirred at the same temperature as above for 30 minutes. The reaction mixture was poured into a large amount of saturated saline solution and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from DMF to give 800 mg of 5-[4-(p-toluenesulfonyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 302°-304° C., colorless powders.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH2:5])=[NH:4].C(=O)([O-])[O-].[K+].[K+].[Cl:14][CH:15]([C:21]([CH3:23])=O)[C:16](OCC)=[O:17].O>C1CCCCC1>[Cl:14][C:15]1[C:16]([OH:17])=[N:4][C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])=[N:5][C:21]=1[CH3:23]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: N=C(N)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: O
Product: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Reaction time: 18 h
Yield: 31 %

Procedure:
A mixture of 30.0 g (0.18 mole) trichloroacetamidine, 25.2 g (0.18 mole) potassium carbonate, 30.3 g (0.18 mole) ethyl 2-chloroacetoacetate, and 300 ml water was stirred 18 hours. The aqueous solution was decanted from heavier tars and acidified with hydrochloric acid. The precipitate that was formed was filtered, washed, and dried to give 14.7 g (31% yield; mp 130°-145° C.) of crude product. An analytical sample was prepared by recrystallization from cyclohexane (mp 156°-157° C.). The structure was confirmed via infrared and elemental analysis.
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].Br[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=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[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH: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: Fc1cccc(Br)c1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)c3cccc(F)c3)c2)c1

Procedure:
This compound is prepared by method C using compound 12g and 1-bromo-3-fluorobenzene
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:10]=[C:9]3[NH:25][N:26]=[CH:27][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].I[CH3:31].O>CC(C)=O>[CH3:31][N:26]1[CH:27]=[C:8]2[C:9]([N:10]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:25]1
Reactant: CI
Reactant: c1ccc(-c2nc3[nH]ncc3c(-c3ccccc3)c2-c2ccncc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cn1cc2c(-c3ccccc3)c(-c3ccncc3)c(-c3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
To a suspension of 4,6-diphenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.10 g, 0.3 mmol, obtained in example 2) in acetone (1 mL), KOH (21 mg, 0.4 mmol) was added under argon atmosphere. Then, a solution of iodomethane (47 mg, 0.3 mmol) in acetone (0.1 mL) was added and stirred overnight at room temperature. Water was added and extracted with CHCl3. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 47 mg of 2-methyl-4,6-diphenyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (yield: 47%) and 38 mg of 1-methyl-4,6-diphenyl-5-(4-pirridyl)pyrazolo[3,4-b]pyridine (yield: 38%).
Reaction SMILES: [OH:1]O.[N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1>CC(O)=O>[N+:3]1([O-:1])[C:11]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=2[NH:5][CH:4]=1
Reactant: OO
Reactant: c1cnc2[nH]cnc2c1
Solvent: CC(=O)O
Product: [O-][n+]1c[nH]c2ncccc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
Hydrogen peroxide (30 wt % solution in water, 38.0 ml, 372 mmol) was added to a suspension of 3H-imidazo[4,5-b]pyridine (4.93 g, 41.4 mmol) in AcOH (40 mL) at room temperature. The resulting reaction mixture was stirred at 80° C. for 3 h, cooled to RT and concentrated in vacuo to a volume ˜50 mL. Concentration to dryness was done using a stream of N2. The resulting residue was suspended in water (˜10 mL). Filtration afforded the title compound (4.61 g, 82.4% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C:11]2[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=2)[NH2:14])[CH3:10])[CH:5]=[N:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C:11]2[CH:12]=[C:13]([NH:14][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=3)[CH:15]=[CH:16][CH:17]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: C[C@@H](Oc1cncc(Cl)n1)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](Oc1cncc(Cl)n1)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
A mixture of (R)-3-(1-(6-chloropyrazin-2-yloxy)ethyl)aniline (160 mg, 0.64 mmol), 3-trifluoromethylbenzoic acid (183 mg, 0.96 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (246 mg, 1.28 mmol), 4-dimethylamino pyridine (4 mg, 0.032 mmol) and triethylamine (0.36 mL, 2.57 mmol) in dichloromethane (6 mL) was stirred at room temperature for 18 hours. After this time the mixture was diluted with dichloromethane (30 mL), washed successively with saturated aqueous sodium hydrogen carbonate (2×20 mL) and brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure to give an orange oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give (R)—N-(3-(1-(6-chloropyrazin-2-yloxy)ethyl)phenyl)-3-(trifluoromethyl)benzamide (110 mg, 30% over 2 steps) as a yellow foam.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)=[CH2:2].[Li][CH2:15]CCC.CI>C1COCC1>[CH3:15][C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:8][CH:7]=2)[N:10]=[CH:11][N:12]=1
Reactant: [Li]CCCC
Reactant: C=Cc1ccc(-n2cncn2)cc1
Solvent: C1CCOC1
Solvent: CI
Product: C=Cc1ccc(-n2ncnc2C)cc1
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]-triazole (0.5 g, 2.9 mmol) in 10 mL of THF, was added n-BuLi (0.22 g, 3.5 mmol) at −78° C. and stirred for 30 min. To this methyl iodide in THF (0.50 g, 3.5 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) afford the title compound as a pale brown liquid (250 mg, 46%): 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.55 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 2H), 6.76 (dd, J=18, 11 Hz, 1H), 5.83 (d, J=18 Hz, 1H), 5.38 (d, J=11 Hz, 1H), 2.55 (s, 3H); ESIMS m/z 186.13 ([M+H]+); IR (thin film) 1517, 1386, 1182, 847 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][N:5]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CCOc1ccc(N)cn1
Reaction time: 16 h
Yield: 97.8 %

Procedure:
A mixture of 2-ethoxy-5-nitropyridine (3.60 g) and 10% Pd/C (360 mg) in ethanol (40 mL) was placed in a Paar bottle and shaken under hydrogen (50 PSI) for 16 h. The mixture was filtered through Celite using dichloromethane and concentrated to give 2.892 g of 2-ethoxy-5-aminopyridine as a gold solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[OH:41])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:49]1([CH2:55][C:56](Cl)=[O:57])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[O:41][C:56](=[O:57])[CH2:55][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(OC(=O)Cc2ccccc2)c1
Yield: 50.1 %

Procedure:
The title compound was prepared according to the procedure in Example 17, step 1, using 4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2, 6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.500 g, 0.691 mmol), pyridine (0.335 mL, 4.15 mmol) and phenylacetylchloride (0.183 mL, 1.38 mmol). Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave 0.272 g (51%) of the title compound. 1H NMR (DMSO-d6) δ 1.51 (s, 9 H), 1.56 (s, 3 H), 2.14 (s, 6 H), 2.43 (s, 3 H), 4.04 (s, 2 H), 7.18 (s, 2H), 7.27-7.37 (m, 5 H), 7.46-7.49 (m, 2 H), 7.66 (ddd, 1 H), 8.01-8.07 (m, 2 H), 8.13-8.21 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:18]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:25][CH:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NC1CCCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCCC1)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 92.7 %

Procedure:
Dissolve 4-bromo-benzoyl chloride (2.0 g, 9.1 mmol) in DCM (20 mL). Cool the solution to 0° C. and add triethylamine (2.54 mL, 18.2 mmol) followed by cycloheptylamine (1.24 g, 10.9 mmol). Warm the mixture to room temperature over 1 h. Wash the mixture with saturated NaHCO3 (15 mL). Collect the organic layer, and extract the aqueous layer with DCM. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the residue by chromatography on silica gel (120 g) eluting with hexane/EtOAc (1:1) to obtain the title compound as a solid (2.5 g, 93%). MS (APCI+) m/z: 296 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4cccnc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and pyridine-3-boronic acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.58 min; Mass spectrum (ESI+): m/z=382 [M+H]+.