Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[CH3:28][O:29][CH2:30][CH2:31][NH2:32].CC(O)=O.O>CCO>[CH3:28][O:29][CH2:30][CH2:31][NH:32][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Reactant: COCCN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COCCNC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A mixture of 7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (15 mg, 0.041 mmol) and 2-methoxyethylamine (0.012 mL, 0.14 mmol) in EtOH (2 mL) was refluxed for 16 h. After cooling the mixture to r.t., AcOH (0.1 mL) and water (2 mL) were added. The resulting precipitate was isolated by filtration, washed with cold MeOH/H2O (5 mL, 1:1), and dried under vacuum to give 9 mg of the title compound. MS: (+) m/z 414.36 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].CC1C=C(C)[N:30]=[C:29](C)C=1.CC1C([IH+])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F.C([Cu])#N.Cl>C(Cl)Cl.O.CN(C=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Reactant: Cc1cc(C)nc(C)c1
Agent: N#C[Cu]
Agent: Cc1cc(C)c([IH+])c(C)n1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1nc(C#N)c2cc(Sc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
A mixture of 4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (300 mg, 0.85 mmol) (prepared according to WO 2004108681) and bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (1.09 g, 2.12 mmol) in CH2Cl2 (10 mL) was stirred at r.t. for 16 h, then diluted with CH2Cl2 (50 mL). The resulting mixture was washed with 5% sodium thiosulfate and 1 M HCl. The organic layer was dried over MgSO4 and concentrated. To the residue were added CuCN (152 mg, 1.70 mmol) and anhydrous DMF (10 mL), and the resulting mixture was refluxed for 20 min. The reaction mixture was poured into a mixture of CH2Cl2 and water. 4 M HCl was added with vigorous stirring until no solid was observed. The aqueous layer was extracted with additional CH2Cl2, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-30% EtOAc/hexanes) to give 274 mg of the title compound as a white solid. MS: (+) m/z 379.09 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:57]([S:59][CH2:60][CH2:61][NH2:62])[CH3:58]>CN(C=O)C>[CH2:57]([S:59][CH2:60][CH2:61][NH:62][C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:31])[CH3:58]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: CCSCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCSCCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c1C
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol), HOBt (32 mg, 1.2 eq.), EDAC.HCl (45 mg, 1.2 eq.), TEA (0.138 mL, 5 eq.) and 2-ethylsulfanyl-ethylamine hydrochloride salt (69 mg, 2.5 eq.) in DMF (2 mL) was stirred at rt for 7 days. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, dried, concentrated and purified on a silica gel column to give the titled compound as a yellow waxy solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:11]OC(F)(F)F.CC(NC1C=CC(F)=CC=1)=O.CC(NC1C=CC(F)=CC=1F)=O.CC(NC1C(F)=CC=CC=1F)=O>C(Cl)(Cl)Cl>[F:11][CH2:2][C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3]
Reactant: CC(=O)Nc1ccccc1
Reactant: FOC(F)(F)F
Agent: CC(=O)Nc1c(F)cccc1F
Agent: CC(=O)Nc1ccc(F)cc1
Agent: CC(=O)Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Product: O=C(CF)Nc1ccccc1
Yield: 37 %

Procedure:
A solution of 67.5 parts of acetanilide in 22,200 parts of chloroform was cooled to 0° C. and maintained at that temperature for 2.5 hours while fluoroxytrifluoromethane was bubbled into the solution at a rate of 46 parts per hour. Analysis of the reaction product by gas chromatographic technique indicated a 91 percent conversion with a yield of 37% 2-fluoroacetanilide, 16% 4-fluoroacetanilide, 10% 2,4-difluoroacetanilide, 3% 2,6-difluoroacetanilide and about 25% higher molecular weight material.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:28]>C(OCC)(=O)C>[ClH:28].[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:27])=[CH:19][CH:20]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)C(=O)N1CCC(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from 2-(4-benzyl-piperidin-1-yl)-N-(4-nitrophenyl)-2-oxo-acetamide (Example 70) according to the method described in Example 11. The residue is treated with 2.5 N hydrochloric acid in ethyl acetate to yield the title compound. Melting Point: >260° C. (ethyl acetate)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])=[C:7]([NH:17][CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:6]=1)=[O:4].[OH-].[Na+].C(O)(=O)C>CO>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])=[C:7]([NH:17][CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:6]=1)([OH:4])=[O:2]
Reactant: CCC(CC)Nc1cc(C(=O)OC)ccc1N1CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCC(CC)Nc1cc(C(=O)O)ccc1N1CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
A solution of the above ester (0.150 g, 0.49 mmol) in 1 mL of methanol was treated with 1N sodium hydroxide (2 mL) and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was acidified with glacial acetic acid and a solid precipitated. The solid was collected by filtration, washed with water and dried to give 0.125 g (87%) of the title compound, mp 178-180° C.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([O:38][CH2:39][C:40]([OH:42])=O)[C:35]3[C:30](=[CH:31][C:32]([CH3:43])=[CH:33][CH:34]=3)[CH:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(Cl)CCl.FC1C(O)=C(F)C(F)=C(F)C=1F.Cl.[CH:62]1([NH:66][C:67]([C@@H:69]2[CH2:73][CH2:72][CH2:71][NH:70]2)=[O:68])[CH2:65][CH2:64][CH2:63]1>C(Cl)Cl.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:44])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([O:38][CH2:39][C:40]([N:70]3[CH2:71][CH2:72][CH2:73][C@H:69]3[C:67](=[O:68])[NH:66][CH:62]3[CH2:63][CH2:64][CH2:65]3)=[O:42])[C:35]3[C:30](=[CH:31][C:32]([CH3:43])=[CH:33][CH:34]=3)[CH:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)c3ccc(C)cc3c2)CC1
Reactant: O=C(NC1CCC1)[C@@H]1CCCN1
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3c2)CC1
Reaction time: 2 h

Procedure:
To a solution of 670 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-carboxymethoxy-7-methyl-naphthalene-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 10 ml of DCM, 418 mg of EDC, 402 mg of pentafluorophenol was added and the reaction mixture was stirred for 2 h. Then, 329 mg of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide hydrochloride and 251 mg of NEM in 1.5 ml of DCM was added. After 16 h the reaction mixture was diluted with water. After filtration through a chem Elut® cartridge by eluting with ethyl acetate the solvents were removed under reduced pressure. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 1.5 g
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.C([Sn](=O)CCCC)CCC.[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]([C:43]3[C:51]4[C:46](=[CH:47][C:48]([C:52]#[N:53])=[CH:49][CH:50]=4)[N:45]([CH3:54])[CH:44]=3)[C:28]([NH:30][S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=3)(=[O:33])=[O:32])=[O:29])=[CH:26][C:21]=2[O:20][CH2:19]1>C1(C)C=CC=CC=1>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]([C:43]3[C:51]4[C:46](=[CH:47][C:48]([C:52]5[N:5]=[N:6][NH:7][N:53]=5)=[CH:49][CH:50]=4)[N:45]([CH3:54])[CH:44]=3)[C:28]([NH:30][S:31]([C:34]3[CH:35]=[CH:36][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:39]=3)(=[O:32])=[O:33])=[O:29])=[CH:26][C:21]=2[O:20][CH2:19]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C#N)ccc23)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(-c4nn[nH]n4)ccc23)cc1

Procedure:
Trimethylsilylazide (0.23 ml, 1.74 mmol) and dibutyl tin oxide (52 mg, 0.2 mmol) were added to a solution of 3-{1-(1,3-benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-6-cyano-1-methyl-1H-indole (the product of Example 51, 300 mg, 0.58 mmol) in toluene (10 ml) and the solution was heated at reflux under an atmosphere of nitrogen for 14 h. Tlc analysis showed incomplete reaction. Further aliquots of trimethylsilylazide (0.23 ml, 1.74 mmol) and dibutyl tin oxide (52 mg, 0.2 mmol) were added and heating was continued at reflux for a further 24 h. The reaction was cooled and concentrated. The crude product was purified by flash column chromatography (gradient elution from 95% dichloromethane/5% methanol to 90% dichloromethane/10% methanol) giving a pale pink solid (100 mg).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[SH:16][CH2:17][CH2:18][OH:19].C([O-])([O-])=O.[K+].[K+].Cl>CCOCC.O.CC(CC)=O>[OH:19][CH2:18][CH2:17][S:16][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Reactant: OCCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccc(SCCO)cc1

Procedure:
11.2 g (0.05 mol) of 4-chlorobenzophenone, 4.3 g (0.055 mol) of 2-mercaptoethanol, 13.8 g (0.1 mol) of calcined K2CO3 and 15 ml of ethyl methyl ketone are warmed (under reflux) for 16 hours under nitrogen. 50 ml of water are poured over the cooled reaction mixture and the resulting mixture is acidified with HCl. The product is taken up in ether. The ether layer is washed with water, dried over Na2SO4 and concentrated. The product, which in this case also is obtained as an oil, crystallises on standing. It is boiled up in hexane as described in (a). Yield: 10.0 g (77%). Melting point 49°-51°.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[CH:23][CH:22]=1
Reactant: OCc1ccc(Br)cc1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2cc(-n3ccc(OCc4ccc(Br)cc4)cc3=O)ccc2nn1C
Reaction time: 17 h
Yield: 39.3 %

Procedure:
To a solution of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (150 mg) in tetrahydrofuran (3 ml) were added (4-bromophenyl)methanol (110 mg), bis(2-methoxyethyl)azodicarboxylate (179 mg) and triphenylphosphine (200 mg) at room temperature, and the mixture was stirred at the same temperature for 17 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate to give the title compound (98 mg).
Reaction SMILES: [C:1]([C:4](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:6])(=O)[CH3:2].[NH2:26][C:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH:28][C:29]([O:31][CH2:32]C)=[O:30]>>[CH3:2][C:1]1[NH:26][C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:28]([C:29]([O:31][CH3:32])=[O:30])[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:4]=1[C:5]([NH:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:6]
Reactant: CCOC(=O)C=C(N)c1ccccc1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)NCC(=O)OC(C)(C)C
Product: COC(=O)C1=C(c2ccccc2)NC(C)=C(C(=O)NCC(=O)OC(C)(C)C)C1c1cccc([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
More specifically a mixture of 330 mg (1 mmol) of t-butyl 2-[N-[2-acetyl-3-(3-nitrophenyl)-2-propenoyl]amino]acetate and 191 mg (1 mmol) of ethyl 3-amino-3-phenyl-2-propenoate was stirred under a light-shielding condition at 110° C. overnight. After cooling to room temperature, the reaction mixture was chromatographed on a silica gel column for purification, whereby 98 mg (22%) of the captioned compound was obtained as an oily material.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[Mg+].[Br-].[CH3:22]COCC>C1COCC1>[OH:1][C@@:2]1([CH3:22])[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(NC1CCCCC1=O)OCc1ccccc1
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: C[C@]1(O)CCCC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
Benzyl 2-oxocyclohexylcarbamate (173 mg, 0.7 mmol) in THF (3 mL) was cooled to −78° C. and added MeMgBr in ether (0.7 mL, 2.1 mmol) dropwise via syringe. The ice bath was removed and the reaction was allowed to stir at rt for 3 h. The reaction was quenched with sat. aqueous NH4Cl (1 mL) and partitioned between ethyl acetate and water. The layers were separated and the organic layer washed with brine, dried (Na2SO4), filtered and concentrated. The product was subjected to flash chromatography on silica gel (10% to 70% ethyl acetate/hexanes) to afford the title compound (81 mg, 88% yield) as a single diastereomer. This material was used as is in the next transformation.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1B1OC(C)(C)C(C)(C)O1>>[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:13][CH2:14]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2F)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3[nH]2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(S(C)(=O)=O)cc4F)ccc3[nH]2)CC1
Yield: 33.8 %

Procedure:
Following the General Procedure-1, the titled compound (40 mg) was prepared from Intermediate 4 (100 mg, 0.25 mmol) and Intermediate 3 (98 mg, 0.33 mmol) as a yellow solid. M.P.: 88-92° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.39 (s, 1H), 7.89-7.81 (m, 3H), 7.69-7.58 (m, 2H), 7.40-7.32 (m, 1H), 4.01 (d, J 12.5, 2H), 3.30 (s, 3H), 3.12-3.05 (m, 1H), 3.00-2.88 (m, 2H), 2.00 (d, J 11.8, 2H), 1.76-1.55 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[N:6][CH:7]=1.[O:14]1[CH2:16][CH:15]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:13][CH2:12][N:11]([CH2:16][CH:15]([OH:14])[CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10]2)=[N:6][CH:7]=1
Reactant: O=C(Nc1ccccc1OCC1CO1)c1ccccc1
Reactant: Clc1ccc(OC2CCNC2)nc1
Product: O=C(Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)cn2)C1)c1ccccc1

Procedure:
A solution of 5-chloro-2-(3-pyrrolidinyloxy) pyridine (100 μL, 0.2M/DMSO), N-[2-(2-oxiranylmethoxy)phenyl]benzamide (100 μL, 0.2 M/DMSO) was refluxed for 3 h.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[O:10][C:3]=12.[CH3:24][C:25]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]>>[CH3:24][C:25]1[C:31]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])=[CH:13][CH:12]=4)[O:10][C:3]=23)=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(c1ccc(-c2cc3nccc(Cl)c3o2)cc1)N1CCCC1
Product: Cc1c(N)cccc1-c1ccnc2cc(-c3ccc(C(=O)N4CCCC4)cc3)oc12

Procedure:
The compound was synthesized according to the procedure K using 7-chloro-2-[4-(pyrrolidin-1-ylcarbonyl)phenyl]furo[3,2-b]pyridine and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:25]([O:29][C:30](=[O:35])[C:31](Br)([CH3:33])[CH3:32])([CH3:28])([CH3:27])[CH3:26].CN(C)C=O>O>[C:25]([O:29][C:30](=[O:35])[C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:7]=1)([CH3:33])[CH3:32])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CCCCCCC(=O)NCCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC(=O)NCCc1ccc(NC(C)(C)C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Yield: 58.1 %

Procedure:
1H NMR (400 MHz, CDCl3) δ6.94 (d, 2H), 6.61 (d, 2H), 5.35 (s, 1H), 3.57 (s, 2H), 3.43 (m, 2H), 2.66 (t, 3H), 2.07 (t, 2H), 1.55 (m, 3H), 1.24 (m, 5H), 0.84 (t, 3H). A mixture of heptanoic acid [2-(4-amino-phenyl)-ethyl]-amide (1.50 g, 6.04 mmol), cesium carbonate (7.87 g, 24.2 mmol), tert butyl-2-bromoisobutyrate (10.78 g, 48.3 mmol) and dimethylformamide (14.6 mL) was heated at 80° C. for 4 days. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ether (2×). The combined organics were washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash column chromatography (2:3 ethyl acetate/hexanes) to provide 1.37 g (58%) of 2-[4-(2-heptanoylamino-ethyl)-phenylamino]-2-methyl-propionic acid tert-butyl ester as a colorless oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1B1OC(C)(C)C(C)(C)O1>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: Brc1nccs1
Product: O=[N+]([O-])c1ccc(F)c(-c2nccs2)c1

Procedure:
2-Bromothiazole (2.1 ml, 22.9 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.0 g, 11.6 mmol) using the method in Example 47. Purification by chromatography on silica gel eluting with dichloromethane then recrystallisation from toluene/isohexane gave 2-(2-fluoro-5-nitrophenyl)thiazole as a brown solid: δH (360 MHz, CDCl3) 7.38 (1H, t, J 9), 7.58 (1H, d, J 3), 8.03 (1H, t, J 3), 8.26-8.31 (1H, m), 9.26 (1H, d, J 6 and 3).
Reaction SMILES: [Li].[AlH3].[CH2:3]([O:10][C:11]1[C:19](/[CH:20]=[CH:21]\[N+:22]([O-])=O)=[CH:18][CH:17]=[CH:16][C:12]=1[N:13]([CH3:15])[CH3:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[NH2:22][CH2:21][CH2:20][C:19]1[C:11]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[C:12]([CH:16]=[CH:17][CH:18]=1)[N:13]([CH3:14])[CH3:15]
Reactant: CN(C)c1cccc(/C=C\[N+](=O)[O-])c1OCc1ccccc1
Agent: [AlH3]
Agent: [Li]
Product: CN(C)c1cccc(CCN)c1OCc1ccccc1
Temperature: 5 °C

Procedure:
Into a 1000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed oxolane (150 mL). This was followed by the addition of alumane lithium (5.6 g, 165.08 mmol, 3.35 equiv) in several batches at 0° C. To the mixture was added a solution of 2-(benzyloxy)-N,N-dimethyl-3-[(Z)-2-nitroethenyl]aniline (14.7 g, 49.27 mmol, 1.00 equiv) in tetrahtdrofuran (150 mL) dropwise with stirring at 0-10° C. The resulting solution was stirred overnight at 25° C. The mixture was cooled to 0-5° C. The reaction was then quenched by the addition of 6 mL of water, 18 mL of NaOH (10%) and 6 mL of water. The resulting solution was extracted with 2×500 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (1:50-1:20). This resulted in 6.4 g (48%) of 3-(2-aminoethyl)-2-(benzyloxy)-N,N-dimethylaniline as light yellow oil. MS (ESI) m/z 271 ([M+H]+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Br:11])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[N:6]=1)=[O:4].[OH-].[Li+].O>O1CCCC1>[Br:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:14][CH:13]=1
Reactant: COC(=O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 104.1 %

Procedure:
To a solution of 6.38 g (0.016 mol) 5-bromo-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid methyl ester in 120 ml tetrahydrofuran was added at room temperature 17 ml of a 1M lithium hydroxide solution in water (0.017 mol) and the mixture was stirred at room temperature for 45 minutes. The resulting clear reaction mixture was partitioned between 10% aqueous citric acid solution and ethyl acetate. The phases were separated and the organic layer washed with water and brine, dried over magnesium sulfate and evaporated to yield 6.05 g (99% yield) of the title compound as white crystalline solid. MS (ISP) (M+H+)=363.0 and 364.9