Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][N:23]([CH:30]1[CH2:33][NH:32][CH:31]1[CH3:34])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26].C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:32]4[CH2:33][C@@H:30]([N:23]([CH3:22])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[C@@H:31]4[CH3:34])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1NCC1N(C)C(=O)C(F)(F)F
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: C[C@H]1[C@H](N(C)C(=O)C(F)(F)F)CN1c1c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c2c1F
Yield: 53.2 %

Procedure:
A mixture of 2.6 g (9.2 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 2.57 g (11 mmol) of 3-[N-(methyl)trifluoroacetamido]-2-methylazetidine hydrochloride and 3 g (30 mmol) of triethylamine in 30 ml of pyridine is heated to reflux for 2 hours. The mixture is evaporated under vacuum, the residue is diluted with ice-cold water, the resulting mixture is filtered and the product is washed with water. 2.5 g are obtained. The product is recrystallized from acetonitrile. 2.25 g of 1-cyclopropyl-6,8-difluoro-7-{trans-3-[N-(methyl)trifluoroacetamido]-2-methyl-1-azetidinyl}-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point 246°-9° C., are obtained. 1H NMR, δ,J=Hz[DMSO]; 14.1, (s, 1H); 8.6 (s, 1H); 7.75 (d, 1H, J=13 Hz); 4.5 (m, 5H); 3.2 (s, 3H). IR(KBr).-1730, 1704, 1627, 1466 cm-1.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:21][O:22][C:23]1[C:24](=[O:47])[C:25]([CH3:46])=[C:26]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:42][C:43](=[O:45])[CH3:44])=[C:37]([CH:41]=2)[C:38](O)=[O:39])[C:27](=[O:31])[C:28]=1[O:29][CH3:30]>C(Cl)Cl>[CH:1]1([NH:4][C:38](=[O:39])[C:37]2[CH:41]=[C:33]([CH2:32][C:26]3[C:27](=[O:31])[C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[C:24](=[O:47])[C:25]=3[CH3:46])[CH:34]=[CH:35][C:36]=2[O:42][C:43](=[O:45])[CH3:44])[CH2:3][CH2:2]1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: NC1CC1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)NC3CC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.2 %

Procedure:
Cyclopropylamine (0.0916 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.089 g, 0.215 mmol, 40%).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][NH:33][CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:33]([CH3:32])[CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CNCCS(C)(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN(C)CCS(C)(=O)=O)c4)cc23)CC1
Yield: 31 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (42.0 mg, 0.096 mmol), N-methyl-2-(methylsulfonyl)ethanamine (12.0 mg, 0.087 mmol) and NaBH(OAc)3 (58.0 mg, 0.261 mmol) were reacted to give the title compound (15.1 mg, 28.0%).
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:21])[C:12]([OH:20])=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=[C:3]21.[CH3:22][N:23]([CH3:29])[C:24](=[O:28])[C:25](O)=[O:26].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:22][N:23]([C:24](=[O:28])[C:25]([NH:1][C:2]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH2:5][N:4]1[C:11](=[O:21])[C:12]([OH:20])=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=[C:3]21)=[O:26])[CH3:29]
Reactant: CN(C)C(=O)C(=O)O
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of ethyl 10-amino-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (250 mg, 0.895 mmol) and 2-(dimethylamino)-2-oxoacetic acid (157 mg, 1.343 mmol) in DMF (6 mL) was added diisopropyl-ethylamine (0.498 mL, 2.86 mmol), 4-(dimethylamino)pyridine (DMAP) (21.87 mg, 0.179 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (511 mg, 1.343 mmol) and the resulting mixture stirred at room temperature for 5 hr. Solvent was removed under reduced pressure. The crude material was diluted with ethyl acetate (50 mL) and washed with 1N HCl (20 mL), dried (Na2SO4) and concentrated to yield the title compound.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:18][C:19](=[O:41])[CH2:20][C@H:21]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:16][OH:17])=O)C1C=CC=CC=1.C(N(CC)CC)C.C(O)C.[H][H]>[Pd].ClCCl.CO.C(N(CC)CC)C>[NH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:18][C:19](=[O:41])[CH2:20][C@H:21]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:16][OH:17]
Reactant: [H][H]
Reactant: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)CCCNC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)CCCN)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a three neck-flask, 150 mg of 20% palladium/carbon were added to the solution of (2R)-5-(Benzyloxycarbonylamino)-2-[(R)-3-benzyloxytetradecanoylamino]pentan-1-ol (3.0 g, i.e. 5.27 mmol) and 6 ml of triethylamine in 300 ml of HPLC-grade ethanol, Air was discharged under vacuum then the flask was loaded with hydrogen. The reaction mixture was stirred at room temperature for 2 hours then the catalyst was filtered off by membrane filtration and the filtrate was concentrated to provide a homogenous white solid as shown by TLC, to be used as such in the next step with no further purifcation, Rf=0.2, dichlormethane-methanol-triethylamine 5:10.5, m.p.=47–48° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2.[N+:18]([O-])([O-:20])=[O:19].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:14])([F:15])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2
Reactant: O=c1[nH]c2cc(Br)c(C(F)(F)F)cc2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(C(F)(F)F)c(Br)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 25 °C
Reaction time: 30 h
Yield: 73.9 %

Procedure:
To a solution of 6-bromo-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (40 mg, 0.13 mmol) in concentrated H2SO4 (0.5 mL) at 25° C. was added KNO3 (16 mg, 0.15 mmol, Baker). The mixture was stirred at 25° C. for 30 h and poured into ice water (2 g). The yellow precipitate was collected by filtration and the solid was dissolved in 1N KOH (10 mL). It was filtered and the filtrate was acidified to pH=5 with 4N HCl (2.5 mL) to give a yellow precipitate. The precipitate was collected and dried in the air at 50° C. for 4 h, affording the title compound (34 mg, 74%) as a yellow powder. Recrystallization from DMSO/H2O gave 18 mg (40%) of the title compound as yellow needles. Mp: 333°-5° C. (dec.); IR (KBr, cm-1): 3428, 3308, 3251, 3207, 1761, 1698, 1537, 600. 1H NMR (DMSO-d6): δ12.601 (br, 1H), 12.341 (s, 1H), 7.606 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O.[CH3:33][C:34]1([CH3:45])[C:38](C)(C)OB(C=C(C)C)O1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O1CCOCC1>[F:15][C:13]1[CH:14]=[C:9]([NH:8][C:5]2[C:4]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=3)=[CH:3][C:2]([CH:33]=[C:34]([CH3:45])[CH3:38])=[CH:7][N:6]=2)[CH:10]=[N:11][C:12]=1[O:16][CH3:17]
Reactant: COc1ncc(Nc2ncc(Cl)cc2-c2nc(C)nc(N)n2)cc1F
Reactant: CC(C)=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(Nc2ncc(C=C(C)C)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 80 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To 4-(5-chloro-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.85 g, 2.350 mmol) was added dioxane (23.50 mL), potassium carbonate in water (3.52 mL, 7.05 mmol), 4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane (0.723 mL, 3.52 mmol) (Frontier Scientific), and bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Aldrich; 0.083 g, 0.117 mmol). The resulting mixture was sparged with nitrogen and then stirred at 80° C. for 16 h. The reaction mixture was subsequently diluted with 150 mL of EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 150 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc/hexanes) gave the title compound (88% yield) as a yellow solid. m/z (ESI, +ve ion) 382.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:22]([OH:24])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH2:32]([O:39][C:40](=[O:53])[CH2:41][CH2:42][NH:43][C:44](=[O:52])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([NH2:51])[CH:46]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([O:39][C:40](=[O:53])[CH2:41][CH2:42][NH:43][C:44](=[O:52])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([NH:51][C:22](=[O:24])[CH:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=2)[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:46]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N#Cc1ccc(CC(NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CC(NC(=O)OCc2ccccc2)C(=O)Nc2cccc(C(=O)NCCC(=O)OCc3ccccc3)c2)cc1

Procedure:
For the preparation of the ester starting material, MS: 756 (15, M+H), N-(benzyloxycarbonyl)-3-(p-cyanophenyl)-DL-alanine and N-(m-aminobenzoyl)-β-alanine benzyl ester trifluoroacetate are coupled to give N-[m-[[N-(benzyloxycarbonyl)-3-(p-cyanophenyl)-DL-alanyl]amino]benzoyl]-β-alanine benzyl ester, MS: 605 (15, M+H), and this is converted with hydrogen sulphide and triethylamine in pyridine into N-[m-[[N-(benzyloxycarbonyl)-3-[p-(thiocarbamoyl)phenyl]-DL-alanyl]amino]benzoyl]-β-alanine benzyl ester, m.p. 145°-146° C. (from ethyl acetate). The latter is then reacted with methyl iodide in acetone and subsequently with ammonium acetate in methanol and treated with benzyl chloroformate and triethylamine in THF.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[CH:6]=[CH:7][C:8](=[N:10][OH:11])[NH2:9])([O-:3])=[O:2].[CH:16]([O-])([O-])OCC>B(F)(F)F.CCOCC>[N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1/[CH:6]=[CH:7]/[C:8]1[N:9]=[CH:16][O:11][N:10]=1)([O-:3])=[O:2]
Reactant: NC(C=Cc1ccccc1[N+](=O)[O-])=NO
Reactant: CCOC([O-])[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: O=[N+]([O-])c1ccccc1/C=C/c1ncon1
Reaction time: 8 h
Yield: 64 %

Procedure:
o-Nitrocinnamamidoxime (1.84 g.) was refluxed for 1 hr. in ethyl orthoformate (15 ml.) containing boron trifluoride etherate (4 drops). The mixture was refrigerated overnight and filtered to give trans-3-o-nitrostyryl-1,2,4-oxadiazole (1.24 g., 64%), m.p. 128°. Evaporation of the filtrate gave an additional 0.51 g. (26%) of the title compound. A sample recrystallised from aqueous acetone has m.p. 120°- 121°, λmax. 247 nm, ε 18900 (Found: C, 55.2; H, 3.3; N, 19.4. C10H7N3O3 requires C, 55.3; H, 3.25; N, 19.35%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@H:7](Br)[C@@H:6]1[NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])(=[O:3])[CH3:2].[OH2:32]>CC(C)=O.C(=O)([O-])[O-].[Ag+2]>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@@H:7]([OH:32])[C@@H:6]1[NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](NC(=O)OCc2ccccc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](O)[C@H](NC(=O)OCc2ccccc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
700 mg of 3,4,6-tri-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-α-D-glucopyranosyl bromide [Bull, Chem. Soc. Japn., 34, 183 (1963)] was dissolved in 2 ml of acetone, and with the solution cooled to 0° C, 290 mg of silver carbonate and 20 ml of water were added. The mixture was stirred for 1 hour at this temperature and filtered. The filtrate was concentrated to obtain 580 mg of 3,4,6-tri-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-β-D-glucopyranose
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](C)[CH:13]=1)=[C:5]2[CH2:20][C:21]([OH:23])=[O:22].BrC1C=C([Cl:31])C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:31])[CH:13]=1)=[C:5]2[CH2:20][C:21]([OH:23])=[O:22]
Reactant: Cc1cccc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)O)c1
Reactant: Clc1cccc(Br)c1
Product: O=C(O)Cc1c(C(=O)c2cccc(Cl)c2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 7 from 5-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 18, step 1) and 3-bromochlorobenzene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.[OH:16][CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1.Cl>C(O)C>[OH:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[O:9])[CH:5]=[N:4][CH:3]=2)[CH2:18]1
Reactant: OC1CCCNC1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1nnn[nH]1)c1cncc(N2CCCC(O)C2)n1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 20 ml of ethanol, 1.52 g of 3-hydroxypiperidine was added, and the mixture was refluxed for 6 hours. The reaction mixture was adjusted with ethanolic hydrogen chloride to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 0.93 g of the desired compound as yellow crystals, m.p. 257°-259° C. (decomp.).
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[O:4][C:5]([CH2:11][CH3:12])([CH2:9][CH3:10])[CH2:6][C:7]=1[OH:8].[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]2[N:22]=[C:23]([SH:25])[N:24]=[C:17]2[N:16]=1>>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]2[N:22]=[C:23]([S:25][C:2]3[C:3](=[O:13])[O:4][C:5]([CH2:11][CH3:12])([CH2:9][CH3:10])[CH2:6][C:7]=3[OH:8])[N:24]=[C:17]2[N:16]=1
Reactant: CCC1(CC)CC(O)=C(Cl)C(=O)O1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Product: CCC1(CC)CC(O)=C(Sc2nc3nc(C)cc(C)n3n2)C(=O)O1

Procedure:
The title compound was prepared from 3-Chloro-6,6-diethyl-4-hydroxy-5,6-dihydro-pyran-2-one (from Step 1) and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol using the coupling method described in Example C(4). 1H NMR (CDCl3): δ 0.97 (t, 6H, J=7.5 Hz), 1.85 (m, 2H), 1.94 (m, 2H), 2.63 (s, 3H), 2.71 (s, 3H), 2.78 (s, 2H), 6.78 (s, 1H). Anal. Calcd. For C16H20N4O3S.0.5H2O: C, 53.76; H, 5.92; N, 15.68. Found: C, 53.96; H, 5.84; N, 15.37.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=2)=[C:4]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[OH:21])[CH:3]=1.C[Sn](C)(C)[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=1.[Cl-].[Li+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH:20]([OH:21])[C:4]2[CH:3]=[C:2]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=3)[S:6][C:5]=2[C:7]2[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=2)=[CH:23][CH:24]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(Br)cc2C(O)c2ccc(Cl)cc2)n1
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2cc(C(O)c3ccc(Cl)cc3)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A mixture of [5-bromo-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-3-thienyl](4-chlorophenyl)methanol (3.07 g, 5.52 mmol)) (synthesized in an analogous way as described in Example 2), N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (1.81 g, 6.07 mmol), tetrakis(triphenylphosphine)palladium(0) (319 mg, 0.28 mmol), copper(I) iodide (315 mg, 1.65 mmol) and lithium chloride (702 mg, 16.5 mmol) in 1,4-dioxane (25.0 mL) was stirred at 100° C. for 2 hours under an atmosphere of nitrogen. The reaction was cooled to room temperature and concentrated with Celite. The crude mixture was purified by column chromatography (SiO2, eluent with methanol in dichloromethane, 0-5% gradient) to afford a yellow solid (2.48 g, 80%). LCMS: (AA) ES+ 556, 558; 1H NMR (400 MHz, CDCl3) δ: 8.48 (br s, 1H), 8.43 (br s, 1H), 8.25 (s, 1H), 8.19 (d, J=5.6 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.33-7.24 (m, 2H), 7.19 (s, 1H), 7.16 (dd, J=1.2, 5.6 Hz, 1H), 6.22 (s, 1H), 6.05 (br s, 1 H), 5.51 (s, 2H), 3.66 (t, J=8.4 Hz, 2H), 2.22 (s, 3H), 0.94 (t, J=8.4 Hz, 2H), −0.01 (s, 9H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[C:22]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:31]=[C:32]([S:36]([NH2:39])(=[O:38])=[O:37])[O:33][C:34]=2[CH3:35])=[CH:24][CH:23]=1>O1CCCC1.CN(C)C=O.CN(C1C=CN=CC=1)C>[C:1]([NH:39][S:36]([C:32]1[O:33][C:34]([CH3:35])=[C:30]([CH2:29][O:28][C:25]2[CH:26]=[CH:27][C:22]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:23][CH:24]=2)[CH:31]=1)(=[O:38])=[O:37])(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(S(N)(=O)=O)cc1COc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1oc(S(=O)(=O)NC(=O)c2ccccc2)cc1COc1ccc(-c2ccccc2)cc1

Procedure:
To a stirred solution of benzoic acid (61 mg) in a mixture of tetrahydrofuran (10 mL) and N,N-dimethylformamide (5 mL) was added 4-(N,N-dimethylamino)pyridine (3.0 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (118 mg) and 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulfonic acid amide (45) (206 mg). After 16 hours at room temperature the reaction mixture was concentrated in-vacuo, then partitioned between 0.1 M hydrochloric acid (30 mL) and ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by HPLC to give compound 46 as light beige solid (17 mg). LC/MS System C: Rt=5.69 mins, m/z (ES−)=446 (M− for C25H21NO5S).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:21])[CH2:7][CH2:8][CH2:9][NH:10]C(OCC1C=CC=CC=1)=O.[ClH:22]>CO.[Pd]>[ClH:22].[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:21])[CH2:7][CH2:8][CH2:9][NH2:10]
Reactant: COCCNC(=O)CCCNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COCCNC(=O)CCCN

Procedure:
2.95 g of 4-benzyloxycarbonylaminobutyric acid N-(2-methoxyethyl)amide are hydrogenated in the presence of 0.24 g of 10% Pd/C in 150 ml of methanol and 100 ml of 0.1N hydrochloric acid for 2 hours at room temperature and under normal pressure. The reaction mixture is filtered and concentrated by evaporation. The crude title compound is obtained: 1H NMR (CD3OD), δ(ppm)=4.92 (4H, s), 3.53-3.20 (4H, m), 3.34 (3H, s), 2.96 (2H, t, J=12 Hz), 2.37 (2H, t, J=12 Hz), 1.93 (2H, m).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[F:12][C:13]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:14]=1[C:15]([NH:17][C:18](OC1C=CC([N+]([O-])=O)=CC=1)=[O:19])=[O:16]>>[F:12][C:13]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:14]=1[C:15]([NH:17][C:18]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N:7]=1)=[O:19])=[O:16]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(NC(=O)c1c(F)cccc1F)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(C(F)(F)F)cn1

Procedure:
A portion of 5-trifluoromethyl-2-aminopyridine is dissolved in an inert organic solvent, and to the solution is added a portion of 2,6-difluorobenzamidocarboxylic acid, 4-nitrophenyl ester. The reaction mixture is stirred at elevated temperature for a period of time, after which the reaction mixture is evaporated to dryness under vacuum, and the product named in the heading above, identical to the product of Example 1, is isolated by recrystallization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:25]([O-:27])=[O:26])[CH2:13][CH2:14][C:15](=[O:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:39](O)[CH2:40][OH:41]>C1CCCCC1>[CH2:40]1[O:41][C:15]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([CH2:14][CH2:13][CH:12]([N+:25]([O-:27])=[O:26])[CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[O:24][CH2:39]1
Reactant: COc1ccc(CC(CCC(=O)CCc2ccccc2)[N+](=O)[O-])cc1OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: COc1ccc(CC(CCC2(CCc3ccccc3)OCCO2)[N+](=O)[O-])cc1OC

Procedure:
Into a 1 l r.b. flask equipped with a Dean Stark trap was placed 46.4 g (0.12 m) of 1-(3',4'-dimethoxyphenyl)-7-phenyl-2-nitro-5-heptanone, 1.5. g p-toluenesulfonic acid, 50 mL of ethylene glycol and 300 mL of cyclohexane. The mixture was allowed to reflux overnight, then concentrated in vacuo. Dil NaHCO3 solution was added to the residue and extracted with ethyl acetate. The organic layer was backwashed with water, dried over anh. MgSO4, filtered and concentrated under reduced pressure to give 45.3 g of an oil which solidified on drying at room temperature under vacuum.