Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Cl[CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].C([O-])(O)=O.[Na+]>CCCCCC.C1COCC1>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]#[C:8][CH:9]1[CH2:11][CH2:10]1)[CH2:22][CH2:23][CH3:24]
Reactant: C#CCCCCl
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](C#CC1CC1)(CCCC)CCCC
Reaction time: 3 h

Procedure:
To n-butyllithium (7.28 mL of a 2.5 M solution in hexane, 18.2 mmol) at −5° C. was added dry THF (80 mL) dropwise, maintaining the temperature below 5° C. 5-Chloro-1-pentyne (7.75 mL , 73.1 mmol) was added at 5° C., and the solution was stirred for 3 hours. The reaction was quenched by the addition of tri-n-butyltin chloride (21.0 mL, 77.4 mmol), and was allowed to stir for an additional 10 min. The solution was poured into saturated aqueous NaHCO3 (500 mL) and hexane (500 mL). The hexane layer was washed with H2O (200 mL), then brine (200 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to provide the titled product as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(COC(=O)c2c(N)ncnc2Cl)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1ccc(COC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1
Temperature: 80 °C
Yield: 323.5 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (515 mg, 0.27 mmol), 4-methoxybenzyl 4-amino-6-chloropyrimidine-5-carboxylate (691 mg, 1.86 mmol), DIEA (1.77 ml, 10.16 mmol) and cesium fluoride (770 mg, 5.07 mmol) were suspended in tert-butanol (50 ml) and the mixture was heated at 80° C. in a sealed tube for 24 h. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by flash chromatography (0 to 50%, hexane-ethyl acetate) using SP1® Purification System to give 459 mg (51% yield) of the title compound as a solid. Purity 99%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]I)=[CH:24][CH:23]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:8][O:9]3)=[CH:4][CH:3]=2)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Reactant: O=[N+]([O-])c1ccc(CI)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1c(-c2ccccc2)coc2cc(OCc3ccc([N+](=O)[O-])cc3)ccc12

Procedure:
10.5 g of 7-hydroxy-isoflavone in 200 ml of anhydrous acetone are boiled for 2 hours with 11.8 g of p-nitrobenzyl iodide in the presence of 5.7 g of anhydrous potassium carbonate under reflux condenser. On distilling off about half of the volume of acetone, the residue is poured onto 1000 ml of water. The precipitating crude product is subjected to suction and recrystallized from glacial acetic acid, affording light yellow plates of 7-p-nitrobenzyloxy-isoflavone, m.p. 225°-226° C.
Reaction SMILES: [C:1]([C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][CH:6]=1)([O:3]C)=[O:2].[Al+3].[Cl-].[Cl-].[Cl-].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O=S(Cl)Cl>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:11]([C:10]2[CH:9]=[N:8][CH:7]=[CH:6][C:5]=2[C:1]([OH:3])=[O:2])=[O:13])=[CH:21][CH:20]=1
Reactant: Fc1ccccc1
Reactant: COC(=O)c1ccncc1C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: O=C(O)c1ccncc1C(=O)c1ccc(F)cc1

Procedure:
A mixture of 4-carbomethoxynicotinic acid (2.0 g, 11.04 mmol) in 20 mL of SOCl2 is heated to reflux for 4 hours, then allowed to cool. Evaporation of excess SOCl2 results in 4-carbomethoxynicotinoyl chloride HCl which is suspended in fluorobenzene (15 ml) and treated with AlCl3 (4.04 g, 30.3 mmol). After heating at reflux for 2 hours, the reaction is quenched with ice and neutralized with aqueous NaOH to generate a precipitate which is filtered. The aqueous fraction of the biphasic filtrate is separated, washed with several portions of EtOAc and acidified to pH 3.5 with 5% aqueous HCl to generate a white solid. The solid is collected by filtration, washed with H2O, and dried by suction to generate 3-(4-fluorobenzoyl)pyridine-4-carboxylic acid.
Reaction SMILES: [S:1]([Cl:3])Cl.N1C=CC=CC=1.[CH2:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:11][CH3:12]>ClCCl>[CH2:10]([N:13]([CH2:14][CH2:15][CH3:16])[S:1][Cl:3])[CH2:11][CH3:12]
Reactant: ClSCl
Reactant: CCCNCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN(CCC)SCl
Reaction time: 0.25 h

Procedure:
22.7 g of sulphur dichloride in 100 ml of dichloromethane was cooled to -5° C. and a solution of 17.4 g of pyridine in 50 ml of dichloromethane was added, over 30 minutes, while the temperature was maintained between -5° and 0° C. The resulting solution was stirred for 15 minutes and a solution of 20.2 g of di(n-propyl)amine dissolved in 50 ml of dichloromethane was added, over 30 minutes, while the temperature was maintained between -5° and 0° C. The resulting solution was stirred for 2 hours, while the temperature was allowed to rise to ambient. The solution was filtered and the solvent was evaporated. 150 ml of diethyl ether was added, the resulting solution was filtered, and the filtrate evaporated. Distillation of the residue gave di(n-propyl)aminosulphenyl chloride (38B), b.p.: 94°-5° C. at 15 Torr.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13]C#N)=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH2:13][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: N#CC[C@@H]1CCCN1c1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)CC1CCCN1c1ccc(Br)cc1
Reaction time: 1 h
Yield: 105 %

Procedure:
(S)-2-(1-(4-bromophenyl)pyrrolidin-2-yl)acetonitrile: To a solution of 20A (2 g, 7.81 mmol) in methylene chloride (16 mL) at 0° C. was added TEA (2.177 mL, 15.62 mmol), and methanesulfonyl chloride (0.913 mL, 11.71 mmol). After 1 h, the reaction mixture was diluted with water and methylene chloride. The layers were extracted, and the organic layer was dried and concentrated to give 2.6 g of 1-(4-bromophenyl)-2-(methylsulfonylmethyl)pyrrolidine (8.17 mmol, 105% yield) as a brown oil that was used directly in the next step. To a solution of 1-(4-bromophenyl)-2-(methylsulfonylmethyl)pyrrolidine (2.6 g, 8.17 mmol) in DMSO (16 mL) was added NaCN (1.531 g, 31.2 mmol) and the resultant mixture was stirred at 50° C. overnight. The reaction mixture was diluted with EtOAc and water. The layers were extracted, and the organic layer was washed successively with water and brine. The organic layer was dried and concentrated, and the resulting material was purified via silica gel chromatography to give 20B (brown oil, 2.1 g, 7.92 mmol, 101% yield). Anal Calc'd for C12H13BrN2 264.03. found [M+H]=264.9, 266.9.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C@@H:16]([CH3:19])[CH2:17][OH:18])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].BrN1C(=O)CCC1=O.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[CH3:2][CH:1]1[C:3]2=[N:15][C:6]3[CH:7]=[N:8][C:9]4[C:14]([C:5]=3[N:4]2[C@@H:16]([CH3:19])[CH2:17][O:18]1)=[CH:13][CH:12]=[CH:11][CH:10]=4
Reactant: CCc1nc2cnc3ccccc3c2n1[C@@H](C)CO
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1OC[C@H](C)n2c1nc1cnc3ccccc3c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 16.1 %

Procedure:
(2S)-2-(2-Ethyl-1H-imidazo[4,5-c]quinolin-1-yl)propan-1-ol (0.50 g, 1.96 mmol) was suspended in 20 mL of CCl4 under an atmosphere of N2. The mixture was treated with N-bromosuccinimide (0.35 g, 1.96 mmol), heated to reflux, and irradiated with a sunlamp. After ˜20 hours the reaction was allowed to cool to ambient temperature, then it was partitioned between CH2Cl2 and saturated NaHCO3 solution. The layers were separated; the organic layer was washed sequentially with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a brown foam. Chromatography (AFC, SiO2, 0-15% CMA/CHCl3) gave (11S)-8,11-dimethyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (80 mg) as a light yellow solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([C@H:27]1[C@@H:32]([NH:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:31]2[CH2:39][C@@H:28]1[CH2:29][CH2:30]2)=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([C@H:27]1[C@@H:32]([N:33]([C:17](=[O:19])[CH2:16][C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=3[S:13](=[O:14])(=[O:15])[N:12]=2)[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:31]2[CH2:39][C@@H:28]1[CH2:29][CH2:30]2)=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 0.216 g, 0.649 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). (1S,2R,3S,4R)-3-(3-Methyl-butylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.164 g, 0.649 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g, 0.681 mmol). Then N-methylmorpholine (0.138 g, 1.36 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 4 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-[[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a light yellow oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C25H36N4O7S2 568.2, found 569.5 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([CH3:34])=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH2:23][N:22]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH2:21][CH2:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([CH3:34])=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH2:23][N:22]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:21][CH2:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCN1CCc2c(ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCN(CCC(=O)O)C2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of ethyl 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate (Preparation 20; 90 mg; 0.186 mmol) in ethanol (2 ml) and THF (2 ml) at room temperature was added 2N sodium hydroxide (0.186 ml; 0.372 mmol), and the resulting mixture was stirred at room temperature for ca. 2.5 h. Removal of most of the solvents, dilution with ca. 1 ml of water, followed by addition of acetic acid (ca. 300 μl) gave a precipitate. The mixture was extracted with dichloromethane to give, after removal of the solvent and trituration with diethyl ether, the title compound as a white solid (40 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:25]([C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)=[CH:24][N:23]=[C:22]([NH:31][CH2:32][CH2:33][NH:34]C2C=CC([N+]([O-])=O)=CN=2)[N:21]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:25]([C:26]2[NH:30][CH:29]=[CH:28][N:27]=2)=[CH:24][N:23]=[C:22]([NH:31][CH2:32][CH2:33][NH:34][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[N:21]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: FC(F)(F)c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl](2-{[5-(trifluoromethyl)(2-pyridyl)]amino}ethyl)amine (71480) was prepared from 2-chloro-5-(trifluoro-methyl)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[F:5][C:6]1[CH:7]=[C:8]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[CH:9]=[CH:10][N+:11]([O-:13])=[O:12].C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[F:5][C:6]1[CH:7]=[C:8]([CH:9]2[CH:10]([N+:11]([O-:13])=[O:12])[CH2:4][CH:3]=[CH:2][CH2:1]2)[CH:14]=[C:15]([F:18])[C:16]=1[F:17]
Reactant: C=CC=C
Reactant: O=[N+]([O-])C=Cc1cc(F)c(F)c(F)c1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])C1CC=CCC1c1cc(F)c(F)c(F)c1

Procedure:
3.24 g (60 mmol) of butadiene were condensed at −78° C. into an autoclave under a nitrogen atmosphere. 2.03 g (10 mmol) of 3,4,5-trifluoro-β-nitrostyrene from example 2.2 dissolved in 6 ml of toluene and 30 mg of hydroquinone were added. A nitrogen atmosphere was applied (120 bar) and the suspension was heated for 12 h to 130° C. The reaction mixture was expanded and all volatiles were evaporated in vacuo. Column chromatography (SiO2, cyclohexane/ethylacetate 9:1) yielded 2.4 g (9.4 mmol, 94% of theory) of the title compound as yellowish crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[P:12]([O-:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[OH:9])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CCOP([O-])OCC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 78.3 %

Procedure:
A mixture of p-nitrobenzaldehyde (3.022 g, 20 mmol), diethyl phosphite (2.762 g, 20 mmol), and MgO (2.0 g, 49.6 mmol) in THF (30 mL) was stirred at room temperature for 5 days. The reaction mixture was filtered, the filtrate was concentrated, and residue was purified by silica gel chromatography (EtOAc/hexanes: 1:4) to give 4.53 g of diethyl [(4-nitrophenyl)(hydroxy)methyl]phosphonate (yield: 78%). 1H NMR (CDCl3, 400 MHz): δ=1.27 (m, 6 H), 4.08-4.18 (m, 4 H), 5.18 (d, J=12.0 Hz, 1 H), 7.67-7.70 (m, 2 H), 8.24 (dd, J=0.8, 8.8 Hz, 2 H). MS (ES+): m/z 290.07 [MH+]. HPLC: tR=1.15 min (UPLC TOF, polar—3 min). This material (4.53 g) was hydrogenated in the presence of 10% Pd/C (200 mg) in MeOH (20 mL) under 1 atmosphere for 4 h. The catalyst was filtered off, filtrate was concentrated, and the residue was purified by silica gel chromatography (2% MeOH in DCM) to afford 3.93 g of the title compound (yield: 72%). MS (ES+): m/z 242.08 [MH+—H2O]. HPLC: tR=0.8 min (UPLC TOF, polar—3 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)O
Reactant: COc1cccc(CC(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CC(=O)OC(C)(C)C)c1

Procedure:
To a solution of (3-methoxyphenyl)acetylchloride (25 g, 135 mmol), in dry dichloromethane (50 ml) was added t-butanol (14 ml) slowly with stirring. After stirring at room temperature for 5 minutes, the reaction was cooled in ice, and triethylamine (20 ml) added dropwise. After stirring a further 2 hours at room temperature, the reaction was poured into saturated aqueous sodium carbonate solution, extracted with dichloromethane, dried (MgSO4), solvents evaporated, and the residue chromatographed on silica (eluted 10% diethyl ether-petroleum ether bp 60°-80°), to give t-butyl (3-methoxyphenyl)acetate. 1H NMR (250 MHz, CDCl3) δ1.38 (9H, s), 3.42 (2H, s), 3.73 (3H, s), 6.69-6.82 (3H, m), 7.17 (1H, t, J=8.4Hz).
Reaction SMILES: C([O:3][C:4](=[O:51])[CH:5]([NH:33][S:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[CH2:39][CH2:38]1)(=[O:36])=[O:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:20][CH:19]=3)[O:15][N:14]=2)=[C:9]([F:32])[CH:8]=1)C.CC1C=CC(CN2CCNCC2)=CC=1.C(N(CC)CC)C>C(#N)C>[C:28]([O:27][C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([NH:33][S:34]([N:37]4[CH2:38][CH2:39][N:40]([CH2:43][C:44]5[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=5)[CH2:41][CH2:42]4)(=[O:35])=[O:36])[C:4]([OH:51])=[O:3])=[CH:8][C:9]=3[F:32])[N:17]=2)=[CH:19][CH:20]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCOC(=O)C(Cc1ccc(-c2noc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)c(F)c1)NS(=O)(=O)N1CCN(Cc2ccc(C)cc2)CC1
Agent: Cc1ccc(CN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(CN2CCN(S(=O)(=O)NC(Cc3ccc(-c4noc(-c5ccc(NC(=O)OC(C)(C)C)cc5)n4)c(F)c3)C(=O)O)CC2)cc1
Temperature: 85 °C
Yield: 69 %

Procedure:
3-{4-[5-(4-tert-Butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-3-fluoro-phenyl}-2-[4-(4-methyl-benzyl)-piperazine-1-sulfonylamino]-propionic acid ethyl ester. A mixture of oxazolidione from Step A (40 mg, 0.065 mmol), 1-(4-methylbenzyl)piperazine (24.7 mg, 0.13 mmol), and triethylamine (20 mg, 0.2 mmol) in acetonitrile (3 mL) was heated at 85° C. for 2.5 hrs. TLC showed the reaction was completed. The solution was concentrated. Ethyl acetate (20 mL) and 1N aq. HCl solution (10 mL) were added to the solution. The layers were separated, and the aqueous portion was extracted with ethyl acetate (20 mL). The combined organic layer was washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (32 mg, 69% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.C(N(CC)CC)C.C(O[CH:20]=[C:21]([C:27](=O)[C:28]([F:31])([F:30])[F:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([N:8]2[C:27]([C:28]([F:29])([F:30])[F:31])=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:20]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Reactant: NNc1cccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(Cl)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution 2-chloro-6-hydrazinopyridine (1.00 g, 6.97 mmol) and triethylamine (971 mL, 6.97 mmol) in acetonitrile (35 mL) was added ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (1.36 mL, 6.97 mmol). After 20 min, the reaction mixture was placed in a 60° C. oil bath. After 30 min, the reaction mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30% EtOAc in hexanes, then 30 to 100% EtOAc in hexanes) gave the title compound (PCT publication WO 2009/032249): LCMS m/z 319.9 [M+H]; 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1 H),7.88 (t, J=7.5 Hz, 1 H),7.58 (d, J=8.0 Hz, 1 H),7.47 (d, J=8.0 Hz, 1 H),4.38 (q, J=7.0 Hz, 2 H), 1.38 (t, J=7.0 Hz, 3 H).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[C:18]([O:26][C:27]1[N:32]=[C:31]([OH:33])[C:30]([C:34]#[N:35])=[CH:29][CH:28]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[C:18]([O:26][C:27]1[N:32]=[C:31]([O:33][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([Br:8])=[CH:10][CH:11]=2)[C:30]([C:34]#[N:35])=[CH:29][CH:28]=1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1ccc(OC(=O)c2ccccc2)nc1O
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#Cc1ccc(OC(=O)c2ccccc2)nc1OC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
Triethylamine (3.46 ml) and 1.82 g of 4-bromobenzoyl chloride were added to a solution of 2.00 g of 6-benzoyloxy-3-cyano-2-hydroxypyridine in 50 ml of dioxane. The mixture was stirred at room temperature for 1 hour. The salt thus produced was separated by filtration and the filtrate was concentrated. The concentrate was applied to silica gel column chromatography using, as an eluent, chloroform, giving 2.97 g of the title compound in a yield of 84%.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=2[CH3:1])[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: Cc1c(C=O)cccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1c(CN2CCN(C)CC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2-Methyl-3-nitrobenzaldehyde (J. Org. Chem. 1981, 46, 1752-1755) (1.0 g, 6.1 mmol) was dissolved in DCE and N-methylpiperazine and HOAc were added followed by sodium triacetoxyborohydride. The reaction was stirred at rt for 1 h and was then quenched with 5% K2CO3 solution. The reaction mixture was extracted (3×) with ethyl acetate, dried over magnesium sulfate, filtered, concentrated onto silica gel and flash chromatographed to give the title compound (1.6 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.69 (d, J=7.7 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.34 (t, J=7.9 Hz, 1H), 3.48 (s, 2H), 2.16-2.42 (m, 1H), 2.10 (s, 3H).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16](#[N:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.[I:24]I>O1CCCC1>[I:24][C:22]1[C:17]([C:16]#[N:23])=[CH:18][N:19]=[CH:20][CH:21]=1
Reactant: II
Reactant: N#Cc1cccnc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cnccc1I
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2,2,6,6-tetramethyl-piperidine (42.3 g, 0.3 mol) in 2 L of tetrahydrofuran was added butyllithium (120 mL, 2.5M, 0.3 mol) at −78° C. under N2 atmosphere. The mixture was stirred for 1 hour before a solution of nicotinonitrile (26 g, 0.25 mol) in 500 mL of tetrahydrofuran was slowly added, and the resulting mixture was stirred for 0.5 hour at −78° C. Then I2 (76.2 g, 0.3 mol) in 500 mL of tetrahydrofuran was added in a dropwise manner. After stirring for 2 hours, the mixture was quenched with 500 mL of ice-water. Tetrahydrofuran was removed under reduced pressure and the aqueous phase was extracted with ether. The organic phase was washed with brine, citric acid, brine, aqueous Na2S2O3 and brine again. After being dried over Na2SO4, the organic phase was concentrated and purified by using column chromatography on silica gel (petroleum ether:ethyl acetate, 10:1) to obtain the title compound.