Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH3:18][C:19]1([CH3:26])[CH2:22][CH:21]([C:23](Cl)=[O:24])[CH2:20]1>O1CCCC1.Cl.[Cu](I)I>[CH3:18][C:19]1([CH3:26])[CH2:22][CH:21]([C:23]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[O:24])[CH2:20]1
Reactant: CC1(C)CC(C(=O)Cl)C1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: I[Cu]I
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C2CC(C)(C)C2)cc1
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 74.2 %

Procedure:
In a 3-neck flask at −30° C. (monitored with thermalcouple) containing ethyl 4-iodobenzoate (25.0 g, 89.0 mmol) in anhydrous tetrahydrofuran (148 mL) was added isopropylmagnesium chloride (51.0 mL, 20.4 mmol) dropwise over 30 min. and then stirred at the same temperature for another 105 min. Copper iodide (5.07 g, 26.6 mmol) was then added quickly in one portion. The mixture was brought to −20° C. for 25 min. to ensure the solid has dissolved. The reaction is then brought back to −40° C. 3,3-dimethylcyclobutane carbonyl chloride (15.6 g, 106 mmol) was then added over 5 min. the reaction was then warmed to 0° C. over 4 h. The mixture was then diluted with 1 N HCl and extracted three times with ethyl acetate. The combined organic layers were then washed two times with brine and then dried over sodium sulfate, filtered, and concentrated to provide 26.6 g of crude brown oil. Purification by silica gel flash chromatography twice (0-5% ethyl acetate in heptane) afforded ethyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate (17.2 g, 74% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.2 Hz, 2H), 7.93 (d, J=8.2 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 3.89 (quin, J=8.8 Hz, 1H), 2.27-2.14 (m, 2H), 2.12-2.02 (m, 2H), 1.41 (t, J=7.1 Hz, 3H), 1.27 (s, 3H), 1.08 (s, 3H). MS (M+1): 261.2.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:33])[C@H:16]([CH2:28][CH2:29][C:30](=[O:32])[NH2:31])[NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[OH:26])[CH2:11][CH2:10]1)C1C=CC=CC=1>[C].[Pd]>[ClH:1].[OH:26][C:20]1[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C@H:16]([C:15]([N:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)=[O:33])[CH2:28][CH2:29][C:30](=[O:32])[NH2:31])=[O:27]
Reactant: NC(=O)CC[C@H](NC(=O)c1ccc(O)cc1O)C(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Product: NC(=O)CC[C@H](NC(=O)c1ccc(O)cc1O)C(=O)N1CCNCC1
Yield: 81.8 %

Procedure:
10% Palladium-carbon (150 mg) was added to an ethanolic solution (15 ml) of 1-benzyl-4-(2,4-dihydroxybenzoyl-L-glutaminyl)piperazine.hydrochloride (276 mg) obtained in Example 8 (ii) and catalytic reduction was carried out in the same manner as in Example 6 to obtain colorless powder 1-(2,4-dihydroxybenzoyl-L-glutaminyl)piperazine.hydrochloride (183 mg).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13](=[O:37])[C@H:14]([CH2:33][CH2:34][S:35][CH3:36])[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].C(N(CC)CC)C>C(Cl)Cl.CCOCC>[CH3:11][O:12][C:13](=[O:37])[C@H:14]([CH2:33][CH2:34][S:35][CH3:36])[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][C:18]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CO)cc1-c1ccccc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
To a mechanically stirred solution at −78° C. under N2 of anhydrous DMSO (16.9 mL, 1.08 mol) in CH2Cl2 (750 mL) was added dropwise via addition funnel oxalyl chloride (44.8 mL, 513 mmol) such that temperature was maintained below −65° C. The reaction was stirred 15 minutes, and a solution of N-[4-Hydroxymethyl-2-(2-methylphenyl)benzoyl]methionine methyl ester (110 g, 285 mmol), prepared as in example 1075F, in CH2Cl2 (100 mL) was added dropwise via addition funnel such that temperature was again maintained below −65° C. After one hour, triethylamine (159 mL, 1.14 mol) was added, and the reaction was warmed to ambient temperature over one hour. The reaction was poured into ether (1.5 L) and washed with brine (2×1.5 L). The organic layer was dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (30% EtOAC/Hexanes) to give the desired product as a pale yellow solid (66 g, 60%). 1H(300 MHz, CDCl3) δ 11.00 (1H, s), 8.07 (1H, m), 7.97 (1H, dd, J=8, 2 Hz), 7.75 (1H, bs), 7.40-7.20 (4H, bs), 6.01 (1H, m), 4.63 (1H, m), 3.68 (3H, s), 2.20-2.00 (8H, m), 1.87 (1H, m), 1.63 (1H, m). m/e (ESI) 384 (MH−).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2)#[N:2].Cl.C(N(CC)CC)C.[N-:27]=[N+:28]=[N-:29].[Na+]>COCCOC>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([C:1]4[NH:29][N:28]=[N:27][N:2]=4)=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)=[CH:13][CH:14]=1
Reactant: N#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Fc1ccc(-n2ccc3cc(-c4nnn[nH]4)ccc32)cc1

Procedure:
A suspension of 5-cyano-1-(4-fluorophenyl)-1H-indole (20 g) (prepared according to the method in Perregaard et al. J. Med. Chem. 1992 (35), 1092-1101), triethylamine hydrochloride (35 g) and sodium azide (20 g) in DME (250 mL) was boiled at reflux for 16 hours. Inorganic salts were filtered off and the solvent evaporated in vacuo. The remaining solid material was dissolved in ethyl acetate (500 mL) and water (500 mL) and glacial acetic acid was added. The organic phase was worked-up according to the general procedure above yielding 19 g of crystalline title compound 8a, mp 224-225° C. (washed with diethyl ether).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=O)[C:13]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[S:25])[C:13]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCc1nc(C)c2c(=S)[nH]c(-c3ccccc3OCC)nn12
Reaction time: 0.5 h
Yield: 144.6 %

Procedure:
2-(2-ethoxy)-phenyl-5-methyl-7-n-propyl-3H-imidazolo[5,1-f][1,2,4]triazine-4-one (50 g (0.16 mol)), phosphorus pentasulfide (17.8 g (0.08 mol)), pyridine (250 ml) were added into a 500 ml three-neck flask with a mechanical stirrer, stirred, heated and refluxed for 6 hours, TLC tracing was performed until the reactants were totally disappeared. The solvent pyridine was removed by distilling under reduced pressure, concentrated ammonia water ((25-28%) 75 ml) and ethanol (300 ml) were added, heated and refluxed for 30 min. It was cooled, filtered, dried, and crude product (45 g) was obtained. The crude product was heated and solved into chloroform (150 ml), activated carbon (5 g) was added, stirring and reflux was performed for 30 min, it was filtered and the filtrate was washed with saturated brine and water consequently and dried with magnesium sulfate anhydrous, chloroform was removed by distilling, the obtained solid was re-crystallized with ethanol and dried, solid (38 g) was obtained with a yield of 72%.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.C(Br)C.II.[CH:20]([O:24][C:25](=[O:29])/[CH:26]=[CH:27]/[CH3:28])([CH2:22][CH3:23])[CH3:21].[Cl-].[NH4+]>O1CCCC1>[CH:20]([O:24][C:25](=[O:29])[CH2:26][CH:27]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)([CH2:22][CH3:23])[CH3:21]
Reactant: C/C=C/C(=O)OC(C)CC
Reactant: BrCCCCCOC1CCCCO1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCC(C)OC(=O)CC(C)CCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.4 %

Procedure:
Under an atmosphere of nitrogen, a mixture of 250 mg of magnesium, 2.8 g of 5-bromo-1-(tetrahydropyran-2-yloxy)pentane, 200 μl of ethyl bromide, a trace amount of iodine and 4 ml of tetrahydrofuran was refluxed with heating for one hour. To it were added 516 mg of crotonic acid sec-butyl ester and 14 mg of cuprous chloride at 0° C. over a period of 30 minutes, the mixture stirred at 0° C. for 15 minutes, and then at room temperature for one hour. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, the extract washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and ethyl acetate (20:1) as eluent to give 529 mg of the subtitle compound having the following physical characteristics:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.O>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][N:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)CCN(c1ccc([N+](=O)[O-])cc1)S(C)(=O)=O

Procedure:
36.00 g (0.166 mol) of N-(4-nitro-phenyl)-methanesulphonic acid amide was dissolved in 2000 mL acetone. The solution was combined with 47.8 g (0.332 mol) of 1-chloro-2-dimethylaminoethane * HCl, 68.8 g (0.498 mol) of potassium carbonate, 5.0 g (0.033 mol) of sodium iodide and 50 mL water. It was refluxed for 16 hours with stirring. After the addition of another 23.9 g (0.166 mol) of 1-chloro-2-dimethylaminoethane * HCl, 45.9 g (0.332 mol) of potassium carbonate and 5.0 g (0.033 mol) of sodiumiodide, the mixture was refluxed for 5 hours with stirring. At RT the inorganic salts were filtered off. The filtrate was evaporated down i. vac. and the residue dissolved in EtOAc. The org. phase was washed 2× with semisat. aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: Cl[O-].[Na+].[OH-].[K+].[F:6][CH:7]([F:19])[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])C)=[C:11]([CH3:18])[CH:10]=1.S(S([O-])=O)([O-])(=O)=[O:21].[Na+].[Na+].Cl>>[F:19][CH:7]([F:6])[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:21])=[C:11]([CH3:18])[CH:10]=1
Reactant: CC(=O)c1ccc(OC(F)F)cc1C
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Product: Cc1cc(OC(F)F)ccc1C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 112.8 %

Procedure:
A stirred solution of sodium hypochlorite (5.25% Aqueous, 204 mL, 143 mmol) and 2N aqueous KOH (22 mL, 44 mmol) are heated to 50° C. and 1-(4-difluoromethoxy-2-methyl-phenyl)-ethanone (A4) (5.8 g, 29 mmol) is added. After maintaining the temperature at 50-70° C. for 3 h and keeping at RT overnight, the reaction is reheated to 50° C. and sodium metabisulfite (4.5 g) is added in 3 portions. The reaction is then acidified with 12N HCl and stirred well. The precipitated white solid is filtered off, rinsed with a little water and air dried to afford 4-difluoromethoxy-2-methyl-benzoic acid (242) (5.4 g, 92%). The product is recrystallized from 1:1 mixture of ACN and water. mp: 117-119° C. Elemental Analysis: Actual C (53.23), H (3.88), F (18.66) Theoretical C (53.47), H (3.99), F (18.80).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.O1CCC[CH2:21]1.O.Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH2:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(N(C)C)cc2)cc1
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(c1ccc(OC)cc1)c1ccc(N(C)C)cc1
Reaction time: 1 h

Procedure:
Separately, a solution was prepared by mixing 18.2 g of 4-methoxy-4'-dimethylaminobenzophenone (melting at 126°-127° C.) and 100 ml of tetrahydrofurane, and the solution was slowly added to the liquid reaction mixture and the whole matter was stirred for one hour at a temperature of 40° to 50° C. Then the whole matter was mixed with 400 ml of water and 300 ml of toluene and after making the mixture weakly acidic by dilute hydrochloric acid, the acidified mixture was stirred for a whole at 80° C. and separated into an aqueous layer and an organic layer (toluene layer). After adding activated carbon to the toluene layer and filtering the layer while hot, toluene was distilled off from the filtrate to obtain 17.1 g of 1-(p-methoxyphenyl)-1-(p-dimethylaminophenyl)ethylene of pale yellow in color, melting at 123°-125° C.
Reaction SMILES: [CH2:1]([C:6]1[CH:12]=[CH:11][C:9](N)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].S(=O)(=O)(O)O.N([O-])=O.[Na+].[Br-:22].[Na+]>O.[Cu].O.O.O.O.O.O.O.S([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([C:6]1[CH:12]=[CH:11][C:9]([Br:22])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(N)cc1
Reactant: [Br-]
Agent: [Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
A reaction vessel was charged with 100 g of 4-pentylaniline and 600 ml of water, and 80 g of concentrated sulfuric acid was added dropwise with ice water cooling and stirring. A solution of 43 g of sodium nitrite in 80 ml of water was then added dropwise and the reaction was carried out at the same temperature for 2 hours with stirring whereby a diazonium salt solution was prepared. Another reaction vessel was charged with 38.5 g of cupric sulfate pentahydrate (CuSO4.5H2O ), 12.2g of copper powder, 70 g of sodium bromide and 600 ml of water. To the mixture were added at room temperature with stirring 18.5 g of concentrated sulfuric acid and then 4.5 g of sodium sulfite heptahydrate. The temperature of the resultant temperature was allowed to rise, and the previously prepared diazonium salt solution was added dropwise over a period of 1 hour under reflux with stirring, whereafter the mixture was subjected to reaction for a further period of 1 hour. The reaction liquid was cooled and then extracted with 1 l of hexane added. The resultant hexane solution was washed successively with water, aqueous caustic soda and water and then dried over Glauber's salt. The hexane was distilled off and the residue was distilled under reduced pressure to obtain 61.5 g (44%) of 4-pentylbromobenzene (b.p. 135°-142° C./ 15-17 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](O[C@H]2C[C@H](C(O)=O)C2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[NH:8][C:7]12[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.FC1C=CC(OCC2CC(C(O)=O)C2)=C2C=1NC(=O)NC12CCCCC1.C(C1C=CC([O:70][C@H:71]2[CH2:74][C@H:73]([C:75]([OH:77])=[O:76])[CH2:72]2)=C2C=1NC(=O)NC12CCCCC1)#N.FC1C=CC(OCC2(C(O)=O)CCC2)=C2C=1NC(=O)NC12CCCCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[NH:8][C:7]12[CH2:17][CH:16]([O:70][C@@H:71]2[CH2:74][C@H:73]([C:75]([OH:77])=[O:76])[CH2:72]2)[CH2:15][CH2:14][CH2:13]1
Reactant: O=C1Nc2c(Cl)ccc(O[C@H]3C[C@H](C(=O)O)C3)c2C2(CCCCC2)N1
Reactant: N#Cc1ccc(O[C@H]2C[C@H](C(=O)O)C2)c2c1NC(=O)NC21CCCCC1
Agent: O=C1Nc2c(F)ccc(OCC3(C(=O)O)CCC3)c2C2(CCCCC2)N1
Agent: O=C1Nc2c(F)ccc(OCC3CC(C(=O)O)C3)c2C2(CCCCC2)N1
Product: O=C1Nc2c(Cl)cccc2C2(CCCC(O[C@H]3C[C@@H](C(=O)O)C3)C2)N1

Procedure:
trans-3-[(8′-Chloro-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-quina-zolin]-5′-yl)oxy]cyclobutanecarboxylic acid; 3-[(8′-fluoro-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-quinazolin]-5′-yl)oxymethyl]cyclobutanecarboxylic acid; trans-3-[(8′-cyano-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-quinaz-olin]-5′-yl)oxy]cyclobutanecarboxylic acid; 1-[(8′-fluoro-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-quinazolin]-5′-yl)oxymethyl]cyclobutanecarboxylic acid; trans-3-[(8′-chloro-2′-oxo-2′,3′-dihydro-1′H-spiro[cycloheptyl-1,4′-quina-zolin]-5′-yl)oxy]cyclobutanecarboxylic acid; and trans-3-[(8′-chloro-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclopentyl-1,4′-quinazolin]-5′-yl)oxy]cyclobutanecarboxylic acid; or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH2:12][C@H:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:18]([O:23][CH3:24])(=[O:22])[C@H:19]([CH3:21])O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:24][O:23][C:18]([C@@H:19]([O:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH2:12][C@H:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[CH:6][CH:5]=1)=[O:3])[CH3:21])=[O:22]
Reactant: CC(C)[C@H]1COC(c2ccc(C(=O)O)cc2)=N1
Reactant: COC(=O)[C@H](C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](C)OC(=O)c1ccc(C2=N[C@@H](C(C)C)CO2)cc1

Procedure:
(S)-2-(4-Carboxyphenyl)-4-isopropyl-2-oxazoline (2.0 g), 0.5 g of methyl (S)-lactate and 0.1 g of 4-(dimethylamino)pyridine are dissolved in 50 ml of dichloromethane and the solution is treated portionwise with 1.4 g of N,N'-dicyclohexylcarbodiimide within 10 minutes while stirring. The mixture is stirred at room temperature overnight and then filtered. The filtrate is diluted with dichloromethane, washed twice with 50 ml of saturated sodium carbonate solution each time and then with water, dried over magnesium sulphate and concentrated. The crude product obtained is purified by chromatography on silica gel with toluene. The (S)-2-[4-([(S)-1-(methoxycarbonyl)-1-ethoxy]carbonyl)phenyl]-4-isopropyl-2-oxazoline obtained is recrystallized from ethanol;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][O:12][C:11](=[O:14])[N:10]1[C:15]1[CH:20]=[CH:19][N:18]2[N:21]=[CH:22][C:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[N:34]=[CH:33][N:32](COCC[Si](C)(C)C)[N:31]=4)=[C:26]([F:43])[CH:25]=3)=[C:17]2[N:16]=1.FC1C=C(F)C=CC=1[C@@H]1COC(=O)N1C1C=CN2N=CC(C3C=CC(C4N(COCC[Si](C)(C)C)N=CN=4)=C(F)C=3)=C2N=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][O:12][C:11](=[O:14])[N:10]1[C:15]1[CH:20]=[CH:19][N:18]2[N:21]=[CH:22][C:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[N:34]=[CH:33][NH:32][N:31]=4)=[C:26]([F:43])[CH:25]=3)=[C:17]2[N:16]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@H]5c5ccc(F)cc5F)nc34)cc2F)n1
Agent: C[Si](C)(C)CCOCn1ncnc1-c1ccc(-c2cnn3ccc(N4C(=O)OC[C@H]4c4ccc(F)cc4F)nc23)cc1F
Product: O=C1OC[C@@H](c2ccc(F)cc2F)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Yield: 81 %

Procedure:
(R)-4-(2,4-difluorophenyl)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (16 mg, 81%) was prepared by the procedure described in Example 1, Step 9, using a mixture of (R)-4-(2,4-difluorophenyl)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one and (R)-4-(2,4-difluorophenyl)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one. LCMS (APCI+) m/z 478.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[CH2:16])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24]>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16][S:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH2:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccccc1S
Solvent: CCO
Product: Nc1ccccc1SC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 49.4 %

Procedure:
23 g of α-benzyloxycarbonylaminoacrylic acid and 30 g of 2-aminobenzenethiol were dissolved in 20 ml of ethanol, and the resulting mixture was stirred at room temperature for an hour. After the solvent was distilled off, ether was added to the residue so as to cause crystallization. The precipitated crystals were separated by filtration and washed with ether to obtain 17.8 g of the desired compound. Its melting point was 150°-151° C.
Reaction SMILES: C1CCCCC1.[Li]CCCC.[N+:12]([CH3:14])#[C-:13].C[O:16][S:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=O.[NH4+].[Cl-]>C1COCC1>[N+:12]([CH2:14][S:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:16])#[C-:13]
Reactant: [C-]#[N+]C
Reactant: COS(=O)c1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: [C-]#[N+]CS(=O)c1ccccn1
Yield: 64.7 %

Procedure:
Two moles of a cyclohexane solution of BuLi (1.218 mmol, 1 equiv.) was added to 4 mL of a tetrahydrofuran solution of isocyanomethane (50 mg, 1.218 mmol, 10 equiv.) at a temperature of −78° C. After ten minutes, 0.5 mL of a THF solution of methylpyridine-2-sulfinate (210 mg, 1.34 mmol, 11 equiv.) was added at once. After thirty minutes, 5 mL of saturated, aqueous NH4Cl was added. A crude product was extracted with CH2 Cl2 (2×15 mL), dried (NaSO4), and concentrated. The crude product was purified by radial chromatography (1 mm alumina plate, 30:70 ethylacetate/hexanes) to produce 131 mg (65% yield) of 2-((isocyanomethyl)sulfinyl)pyridine as a white solid having M.P. 91-93° C.; IR (film) 542, 776, 960, 992, 1038, 1053, 1427, 1452, 1578, 2139, 2923, 2997 cm−1; NMR: δ 4.73 (ABq, Δv=83.3 Hz, J=14.3 Hz, 2H), 7.49-7.52 (m, 1H), 8.04-8.12 (m, 2H), 8.67-8.68 (m, 1H); 13C NMR: δ 60.33, 125.65, 125.82, 138.56, 150.02, 160.58, 165.10.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[F:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C:20]2[N:21]([NH2:26])[C:22]([NH2:25])=[N:23][N:24]=2)=[CH:17][CH:16]=1>C(O)CO>[Cl:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1[C:5]([NH:6]2)=[N:25][C:22]2=[N:23][N:24]=[C:20]([CH2:19][C:18]3[CH:27]=[CH:28][C:15]([F:14])=[CH:16][CH:17]=3)[N:21]2[N:26]=1
Reactant: Nc1nnc(Cc2ccc(F)cc2)n1N
Reactant: O=C1Nc2ccc(O)c(Cl)c2C1=O
Solvent: OCCO
Product: Oc1ccc2[nH]c3nc4nnc(Cc5ccc(F)cc5)n4nc3c2c1Cl
Temperature: 125 °C
Reaction time: 16 h

Procedure:
According to a cyclization procedure for Example 30, 0.60 mmol of 4-chloro-5-hydroxy-1H-indole-2,3-dione (118.5 mg) and 0.70 mmol of (4-fluoro-benzyl)-[1,2,4]triazole-3,4-diamine (145 mg) in 2 mL of ethylene glycol was stirred at 125° C. overnight (16 hr).
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[NH2:20][C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(N(CC)C(C)C)(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>[C:33]([N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:16](=[O:18])[CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([CH:2]([F:1])[F:19])[CH:8]=4)=[CH:14][CH:13]=3)=[N:26][CH:25]=2)[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: O=C(O)Cc1ccc(-c2ccnc(C(F)F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C(F)F)c4)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)acetic acid 203-5 (30 mg, 0.11 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (28 mg, 0.13 mmol), N,N-diisopropylethylamine (99 μL, 0.57 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (65 mg, 0.17 mmol) in DMF (2 mL) was stirred at room temperature for 3 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2 N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)acetamide 201. MS m/z 418.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.61 (d, 1H), 8.25 (d, 1H), 7.91 (d, 1H), 7.80-7.72 (m, 4H), 7.49 (d, 2H), 6.79 (d, 1H), 6.73 (t, 1H), 3.70 (s, 2H), 3.66-3.58 (m, 4H), 3.52-3.47 (m, 2H), 3.45-3.40 (m, 2H), 2.09 (s, 3H).