Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:11]1[CH:17]=[C:16]([CH3:18])[C:14]([NH2:15])=[C:13]([CH3:19])[CH:12]=1)[C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=O>C(O)C.C(O)=O>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[N:15][C:14]1[C:13]([CH3:19])=[CH:12][C:11]([CH2:1][C:2]2[CH:3]=[C:4]([CH3:10])[C:5]([N:6]=[CH:26][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)=[C:7]([CH3:9])[CH:8]=2)=[CH:17][C:16]=1[CH3:18]
Reactant: Cc1cc(Cc2cc(C)c(N)c(C)c2)cc(C)c1N
Reactant: O=Cc1ccccn1
Solvent: CCO
Solvent: O=CO
Product: Cc1cc(Cc2cc(C)c(N=Cc3ccccn3)c(C)c2)cc(C)c1N=Cc1ccccn1
Temperature: 45 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To a suspension of 2a (0.50 g, 1.97 mmol) in absolute ethanol (2 ml) was added 2-pyridinecarboxaldehyde (0.56 ml, 5.91 mmol, 3 eq.) and one drop of formic acid. The mixture was stirred at 45° C. overnight. On cooling to room temperature the suspension was filtered, washed with cold ethanol and dried under reduced pressure to afford 17 as a yellow solid (0.28 g, 18%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:17]=[C:16]([C:18]([C:20]3[C:21](Cl)=[N:22][CH:23]=[CH:24][CH:25]=3)=O)[NH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.[NH2:28][NH2:29]>C(O)C>[N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:17]=[C:16]([C:18]3[C:20]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:29][N:28]=3)[NH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(c1cc(S(=O)(=O)NCCN2CCOCC2)c[nH]1)c1cccnc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=S(=O)(NCCN1CCOCC1)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 80 °C

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-sulfonic acid (2-morpholin-4-yl-ethyl)-amide (100 mg) and hydrazine hydrate (excess) in ethanol (5 mL) was heated at 80° C. for 48 hours. The reaction was concentrated, diluted with water, acidified to pH 2 with 1N HCl and extracted with DCM. The aqueous layer was adjusted to pH 7 with NaHCO3, the precipitate was collected by vacuum filtration, washed with water to give the titled compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:6]=[CH:7][CH:8]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:43])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:43])[NH:13]3)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)O
Reactant: FC(F)(F)c1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To the suspension of 4-(3-trifluoromethyl-phenyl)-1H-indole (3.37 g, 12.90 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (155 mL) was added pyridinium tribromide (12.38 g, 38.70 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (63 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (2.07 g, 58%) as a tan solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[NH2:18].[C:20](OC(OCC)OCC)(=O)C.[OH-].[Na+]>O>[CH3:1][CH:2]([CH3:19])[CH2:3][N:4]1[C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]3[N:15]=[N:16][N:17]=[C:7]3[C:6]=2[N:18]=[CH:20]1
Reactant: CCOC(OCC)OC(C)=O
Reactant: CC(C)CNc1c(N)c2nnnn2c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)Cn1cnc2c1c1ccccc1n1nnnc21

Procedure:
N5 -(2-Methylpropyl)tetrazolo[1,5-a]quinoline-4,5-diamine (0.2 g, 0.78 mmole, Example 16) was combined with diethoxymethyl acetate (2 mL) and heated on a steam bath for 3 hours. Water (10 mL) and 10% sodium hydroxide (2 mL) were added and the reaction mixture was heated on a steam bath for 1 hour. A solid was isolated by filtration then recrystallized from methanol/ethyl acetate to provide 0.16 g of 6-(2-methylpropyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a white crystalline solid, m.p. 210-212° C. Analysis: Calculated for C14H14N6 : %C, 63.14; %H, 5.30; %N, 31.56; Found: %C, 63.12; %H, 5.32; %N, 31.61.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:41][C:38]3[C:39]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc2[nH]c(-c3cccc(F)c3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8])=[O:2].[CH2:14](O)[CH3:15].OS(O)(=O)=O.C1(C)C=CC=CC=1>O>[CH2:14]([O:8][C:7]([CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[CH:1]=[O:2])=[O:9])[CH3:15]
Reactant: O=Cc1ccccc1OCC(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccccc1C=O
Yield: 87.4 %

Procedure:
A mixture of 2-formylphenoxyacetic acid (9.01 g, 0.05 mol), ethanol (4.6 g), concentrated H2SO4 (0.4 ml) and toluene (40 ml) was heated to reflux with azeotropic removal of water for 1 hour. The reaction mixture was poured into 10% KHCO3 (100 ml), the layers were separated and the aqueous layer was extracted with ether (2×75 ml). The organic layers were combined, and concentrated in vacuo to afford 9.1 g (95%) of 2-(ethoxycarbonylmethoxy)benzaldehyde.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:12]([O:16][C:17](=[O:21])[CH:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[CH:18]([CH3:20])[NH:19][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)COC(=O)C(C)N
Agent: Cl
Product: CC(C)COC(=O)C(C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure BA above and using phenylacetyl chloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:19](=O)[CH2:20][CH3:21].O1CCOCC1.C([O-])(=O)C.[Na+]>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=1)=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: CCC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)OC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (1.0 g), 2-(4-methanesulfonylbenzyl)-3-oxopentanoic acid methyl ester (1.4 g), polyphosphoric acid (5 mL) and dioxane (20 mL) was heated at 130° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and the pH adjusted to 4 by the addition of sodium acetate. The mixture was extracted with ethyl acetate and the combined extracts dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as a honey coloured gum, 2.3 g.
Reaction SMILES: [H-].[Na+].C(O)C.[C:6]([CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17])([O:8][CH2:9][CH3:10])=[O:7].[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br)([O-:20])=[O:19]>O>[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][C:11]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCOC(=O)C1CCCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(Cc2ccccc2[N+](=O)[O-])CCCNC1=O
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
Sodium hydride (60% dispersion in oil, 2.45 g) was added to ethanol (100 ml), to which was added 3-carboethoxy-2-piperidone (10.0 g). The reaction mixture was stirred for 15 minutes, to which was added 2-nitrobenzyl bromide (13.2 g) at room temperature. The reaction mixture was stirred at 60° C. for 3 hours. Water was added to the reaction mixture, which was concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the entitled compound (14.6 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([O:17][C:18]1[C:19]2[N:20]([CH:24]=[C:25]([CH2:27][CH2:28][C:29]#[CH:30])[N:26]=2)[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[C:19]2[N:20]([CH:24]=[C:25]([CH2:27][CH2:28][C:29]#[C:30][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:26]=2)[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C#CCCc1cn2cccc(OCc3ccccc3)c2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCc2cn3cccc(OCc4ccccc4)c3n2)n1
Yield: 6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (82 mg, 0.43 mmol) and 8-(benzyloxy)-2-(but-3-ynyl)-imidazo[1,2-a]pyridine (119 mg, 0.43 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: from 100/0 to 60/40 as eluent) to afford 10 mg of 8-(benzyloxy)-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 6%) beige solid (Mp=92-94° C.)
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].Cl[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=1.O>CS(C)=O>[CH3:1][C:2]1[N:3]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2ccnc2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
In DMSO (5 mL) was dissolved 2-methyl-1H-imidazole (575 mg, 7.00 mmol). To the solution 60% sodium hydride (in oil) (323 mg, 8.08 mmol) was added at 0° C. and the mixture was stirred at room temperature for 30 minutes. Ethyl 6-chloronicotinate (1.00 g, 5.39 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=97/3) to give ethyl 6-(2-methyl-1H-imidazol-1-yl)nicotinate (455 mg, 37% yield).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1.[CH3:55][S:56][CH2:57][CH2:58][CH2:59][CH2:60]O>C(Cl)Cl.O>[CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:60][CH2:59][CH2:58][CH2:57][S:56][CH3:55])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: COc1cc2c(NC(C)C)ncnc2cc1O
Reactant: CSCCCCO
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(NC(C)C)ncnc2cc1OCCCCSC
Temperature: 25 °C
Reaction time: 20 h
Yield: 43 %

Procedure:
4-(Isopropylamino)-6-methoxyquinazolin-7-ol (380 mg, 1.63 mmol) is dissolved in methylene chloride (10 ml) under an argon atmosphere, treated with triphenylphosphine (641 mg, 2.44 mmol), azodicarboxylic acid dipiperidide (617 mg, 2.44 mmol) and 4-(methylthio)butan-1-ol (235 mg, 1.96 mmol) and stirred at room temperature for 20 hours. The batch is diluted with methylene chloride and water, and the organic phase is separated off and concentrated. The desired product is obtained after chromatography by means of preparative HPLC in 43% yield (258 mg).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].CN(C)C=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49]2[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=2)=[CH:44][C:43]=1[O:56][CH3:57]>>[CH3:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[C:11]([NH:53][C:52]1[CH:51]=[CH:50][C:49]([O:48][C:45]2[CH:46]=[CH:47][C:42]([CH3:41])=[C:43]([O:56][CH3:57])[CH:44]=2)=[CH:55][CH:54]=1)=[O:13]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(Oc2ccc(N)cc2)ccc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cc2)ccc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a solution of N-{[(1,1-dimethylethyl)oxy]carbonyl}-D-alanine (182 mg, 0.960 mmol) in dry N,N-Dimethylformamide (DMF) (4 mL) DIPEA (0.305 mL, 1.745 mmol) and then TBTU (336 mg, 1.047 mmol) were added and the reaction mixture was stirred for 15 minutes at r.t. 4-{[4-methyl-3-(methyloxy)phenyl]oxy}aniline (Intermediate 20, 200 mg) was then added and the reaction mixture was stirred for 1 hour at the same temperature. The reaction was quenched with water (2 mL), diluted with brine (10 mL) and extracted with ethyl acetate (2 times 20 mL). Organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system, 10 g SNAP column) using as eluent a gradient cyclohexane/ethyl acetate from 100/0 to 80/20 to afford the title compound as a yellow pale solid (304 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH3:13])[CH2:11][O:10]1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.[Na].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:12]([C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:13])[CH2:11][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: c1nc[nH]n1
Reactant: CC(c1ncccn1)C1(c2ccc(F)cc2F)CO1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(c1ncccn1)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Treatment of the product of part (iii) (0.80 g) with 1H-1,2,4-triazole, sodium salt (0.82 g) in N,N-dimethylformamide according to the method of Example 12(iv), followed by chromatography of the crude product on silica gel using ethyl acetate as eluant, first gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (0.26 g), m.p. 193°-195° (from dichloromethane/ether).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([C:19]4[CH:31]=[CH:30][C:22]([CH2:23][NH:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=4)[N:15]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:41]=[C:40]([NH:42][C:43](=[O:57])[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[C:53]([F:56])([F:55])[F:54])[CH:39]=[CH:38][C:34]=1[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[F:32][C:33]1[CH:41]=[C:40]([NH:42][C:43](=[O:57])[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[C:53]([F:55])([F:56])[F:54])[CH:39]=[CH:38][C:34]=1[C:35]([N:24]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:23][C:22]1[CH:30]=[CH:31][C:19]([C:16]2[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:13][CH:12]=3)[O:18][N:17]=2)=[CH:20][CH:21]=1)=[O:36]
Reactant: COC(=O)CNCc1ccc(-c2noc(-c3ccc(-c4ccc(C)cc4)cc3)n2)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)c(F)c2)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN(Cc1ccc(-c2noc(-c3ccc(-c4ccc(C)cc4)cc3)n2)cc1)C(=O)c1ccc(NC(=O)Cc2ccc(OC)cc2C(F)(F)F)cc1F
Temperature: 25 °C
Yield: 98 %

Procedure:
Prepared using General Procedure 6. To a suspension of methyl 2-((4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)amino)acetate INT-77 (50 mg, 0.121 mmol) and 2-fluoro-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-78 (44.9 mg, 0.121 mmol) in DMF (2 mL) were added HATU (50.6 mg, 0.133 mmol) and TEA (42.1 μL, 0.302 mmol). The reaction mixture was stirred at room temperature. After 60 h the reaction mixture was diluted with EA (20 mL) and washed with NaHCO3 (2×20 mL) and 1 M HCl (2×20 mL). The organics were dried over MgSO4 and concentrated in vacuo to afford 91 mg (98%) of methyl 2-(2-fluoro-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-79 as a pale yellow solid. LCMS-ESI (m/z) calculated for C42H34F4N4O6: 766; found 767 [M+H]+, tR=3.27 min (Method 10).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)Cl>[CH:1]1([CH2:7][N:8]([CH2:9][CH2:10][OH:11])[C:26]([CH2:25][O:24][C:21](=[O:23])[CH3:22])=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: OCCNCC1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)N(CCO)CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
To a solution of 2-(cyclohexylmethylamino)-ethanol (600 mg, 3.8 mmol) in DCM (6 mL) at 0° C. was added DIPEA (588 mg, 4.6 mmol) and then acetoxyacetyl chloride (467 mg, 3.44 mmol) over 5 min. The resulting mixture was warmed to room temperature, stirred overnight under an atmosphere of nitrogen, diluted with DCM and washed successively with 1 N aqueous HCl, saturated NaHCO3, and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to yield the title compound (914 mg). (m/z): [M+H]+ calcd for C13H23NO4, 258.16. found, 258.0.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1>[C:1]1([C:7]2[S:11][C:10]([C:12]3[C:13]4=[N:18][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:14]4[CH:15]=[CH:16][CH:17]=3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(-c2ccccc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)s3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of 3-(5-phenylthiophen-2-yl)pyridin-2-amine (250 mg) in dehydrated THF (10 mL) was added to a mixture of sodium hydride (60%, 198 mg) and 2-chloroethanesulfonyl chloride (485 mg) in dehydrated THF (10 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was added to water, and the resulting precipitate was washed with water and diisopropyl ether to give the title compound (262 mg) as a yellow solid. The obtained solid was crystallized from acetonitrile to give a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:22])[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[CH3:10].[H-].[Na+]>N1C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:22])[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)[CH3:10]
Reactant: Clc1ccc(Br)cc1
Reactant: CCOC(=O)CSc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)CSc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4-bromo chlorobenzene (1.92 g, 10 mmol), (4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, 10 mmol), sodium hydride (460 mg, 10 mmol) and copper(u) chloride (500 mg) was refluxed in anhydrous pyridine (50 ml) for 12 hrs. The reaction mixture was carefilfly quenched with ice cold water and acidified with concentrated HCl. The product was extracted with choroform, washed well with water; dried and concentrated The product was purified by silica gel column chromatography by eluting with 30% ethyl acetate:hexane. Yield 2.5 g (77%); Colorless low melting solid; MS: 323 (M+H)+. Alternatively the title compound may be prepared from 4-(4-chloro-phenoxy)-benzenethiol and bromo ethyl acetate as described in example 83.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=1[S:24]([O:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(=[O:26])=[O:25]>C1C=CC=CC=1>[C:8]1([NH:14][N:15]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][O:27][S:24]([C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:17][CH3:16])(=[O:26])=[O:25])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NNc1ccccc1
Reactant: COc1ccccc1S(=O)(=O)OCC(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccccc1S(=O)(=O)OCC(=NNc1ccccc1)c1ccccc1

Procedure:
Into a reactor, equipped with a Dean-Stark separator, were introduced 100 ml of benzene, 1 ml of acetic anhydride, 10.8g (0.1 mol) of phenylhydrazine and 30.6 g (0.1 mol) of 3-methoxy-4-benzenesulphonyloxy-acetophenone. The reaction medium was stired and refluxed for 1 hour.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9](O)=[O:10])=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:17])=O.CN(C)C=O>ClCCl>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([Cl:17])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1ccc(OCC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc(OCC(=O)Cl)cc1
Reaction time: 2 h

Procedure:
To a suspension of commercially available 2-(4-cyanophenoxy)acetic acid (4.0 g, 22.6 mmol) in dichloromethane (80 mL) was added oxalyl dichloride (2.17 mL, 24.8 mmol). To this mixture was added N,N-dimethylformamide (30 μL) dropwise and stirred for 2 hours during which cessation of evolution of gas was observed. The resulting solution was diluted with dichloromethane (50 mL) and the solvent was removed under reduced pressure to provide the title compound as an oil which became a solid upon storing in the refrigerator.