Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][O:10][BH:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(O)CO)C=CC=CC=1.CSC.B.I[C:27]1[CH:32]=[CH:31][C:30]2[O:33][CH2:34][O:35][C:29]=2[CH:28]=1>O1CCOCC1.C(N(CC)CC)C.C(Cl)Cl>[C:1]1([CH:7]2[CH2:11][O:10][B:9]([C:27]3[CH:32]=[CH:31][C:30]4[O:33][CH2:34][O:35][C:29]=4[CH:28]=3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Ic1ccc2c(c1)OCO2
Reactant: B1OCC(c2ccccc2)O1
Agent: B
Agent: OCC(O)c1ccccc1
Solvent: CSC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(C2COB(c3ccc4c(c3)OCO4)O2)cc1
Temperature: 80 °C

Procedure:
The 4-phenyl-1,3,2-dioxaborolane was first prepared by reaction of 236 mg phenyl-1,2-ethanediol (1.7 mmol) with borane dimethylsulfide adduct (0.15 ml, 1.5 mmol) in 2 ml of dioxane. A stock solution of the catalyst in dioxane was made by heating 250 mg PdCl2[dppf].CH2Cl2 with triethylamine (4.5 ml) at 80° C. for 20 h in 40 ml dioxane. To this solution was added 2.48 g (10 mmol) of 1-iodo-3,4-methylenedioxybenzene. 4.8 ml of this reaction solution was then placed in the reaction tube containing the borane ester. The mixture was heated for 20 h at 80° C. and then an aliquot was removed, dissolved in some ethyl acetate containing a little of the diol and shaken with 10% brine solution. After drying with MgSO4, the gc was measured. One major peak, of retention time 15.7 mins was found. This was shown by gc/ms to be the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-])=O.[H][H]>[Ni].O1CCCC1>[NH2:16][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:2]=1[NH2:1])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)c2ccccc2)cc1N
Yield: 100 %

Procedure:
Fifty grams of 4-amino-3-nitrobenzophenone was hydrogenated at room temperature in 945 ml. of tetrahydrofuran with 15 g. of Raney nickel at 40 psi. After 4 hours three equivalents of hydrogen were absorbed. The catalyst was filtered and the filtrate was evaporated in vacuo to a solid residue. The residue was chromatographed over silica gel using ethyl acetate as eluant. Fractions 5-9 were combined to yield 43.6 g. (100 percent yield) of 3,4-diaminobenzophenone.
Reaction SMILES: O=C1CCCN1CC(O)=O.S(Cl)(Cl)=O.NC1C=CC([C:22]2[NH:23][C:24](=[O:31])[C:25](=[CH:29][CH:30]=2)[C:26]([OH:28])=[O:27])=CC=1.Cl[Si](C)(C)C>C(N(CC)CC)C.ClCCl.CN(C)C=O>[O:31]=[C:24]1[NH:23][CH:22]=[CH:30][CH:29]=[C:25]1[C:26]([OH:28])=[O:27]
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: C[Si](C)(C)Cl
Agent: O=C(O)CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)c1ccc[nH]c1=O
Temperature: 25 °C

Procedure:
A suspension of 4.29 g (30 mM) of 2-oxo-1-pyrrolidineacetic acid, 2.20 ml (30 mM) of thionyl chloride, 2.32 ml (30 mM) of dimethylformamide, and 75 ml of dichloromethane was stirred with ice bath cooling for 11/4 hrs. A mixture of 4.60 g (20 mM) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 140 ml of dichloromethane, 8.4 ml (60 mM) of triethylamine, and 7.6 ml (60 mM) of chlorotrimethylsilane was stirred at room temperature for 1 hr. The silylated pyridone solution was cooled with an ice bath and the cold solution of the acid chloride was added. The reaction mixture was stirred for 4 hrs with cooling and at room temperature for 18 hrs. The reaction mixture was evaporated to a wet solid. Ethanol was added, and the mixture was evaporated. The residue was treated with water and the solid filtered. The solid was washed with water, ethanol, and ether and dried to give 6.49 g of 6-[4-[2-oxo-1-pyrrolidinyl)acetylamino]-phenyl]-1,2-dihydro-2-oxonicotinic acid; mp <320°.
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[NH2:15][C:16]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N(CC)CC)C>[O:29]([C:27]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[C:16]([NH:15][C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:28]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)COc1ccccc1
Reaction time: 2 h

Procedure:
0.029 mL of 2-phenoxyacetyl chloride was added to 2.5 mL of methylene chloride solution containing 40 mg of tert-butyl 2-amino-4-phenoxybenzoate and 0.039 mL of triethylamine at room temperature and stirred at the same temperature for 2 hours. 0.25 g of aminomethylated polystyrene was added to the reaction mixture and after stirred at the same temperature overnight, 5 mL of 10% citric acid aqueous solution was added. The organic layer was separated and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate: acetic acid=20:5:1] to obtain tert-butyl 4-phenoxy-2-(2-phenoxyacetamido)benzoate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[S:20][CH:19]=[CH:18][C:16]=2[N:17]=1>C1COCC1.[NH4+].[Cl-].[Cl-].[Cl-].[Zn+2].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>[Cl:11][C:12]1[N:13]=[C:14]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[C:15]2[S:20][CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1nc(-c2nccs2)c2sccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
A stirred solution of thiazole (0.14 mL, 2 mmol) in dry THF (10 mL) at −78° C., under argon was treated with n-BuLi (1.6-M in hexanes, 1.3 mL, 2 mmol), stirred for 30 min, treated with a solution of ZnCl2 (1.0-M in Et2O, 2.0 mL, 2 mmol) and allowed to warm gradually to room temperature. The mixture was treated with a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (205 mg, 1 mmol) in THF (5 mL) then Pd(PPh3)4 (100 mg, 10 mol %) refluxed for 17 h, cooled, diluted with saturated NH4Cl solution and extracted with EtOAc. The organic extracts were dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isohexane:CH2Cl2 (2:1)] to give the title compound (75 mg, 26%) as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:15]=3)[NH:10][C:9](=[O:25])[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:27]([O-])([O-:29])=[O:28].[Na+]>S(=O)(=O)(O)O>[CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]([N+:27]([O-:29])=[O:28])[CH:15]=3)[NH:10][C:9](=[O:25])[C:8]2=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(=O)Nc1ccc2c(c1)[nH]c(=O)c(=O)n2C1CCCCC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(=O)Nc1cc2[nH]c(=O)c(=O)n(C3CCCCC3)c2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
48 g (0.133 mol) of ethyl N-(1-cyclohexyl-2,3(1H,4H)-quinoxalinedion-6-yl)oxamate were dissolved in 1 l of concentrated sulfuric acid and, at 0° C., 11.35 g (0.133 mol) of sodium nitrate were added a little at a time. The mixture was stirred at 0° C. for a further 2 h and poured into a large quantity of ice. The precipitate was filtered off with suction to yield 50.1 g (93%) of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:24]=4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:5]=[CH:6][CH:7]=1.NC1C=C(C2N=C3N(C=2C2C=CN=C(NC4C=CC=C(OCCCN5CCOCC5)C=4)N=2)C=CS3)C=CC=1.[N:75]([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)=[C:76]=[O:77].FC1C=CC=C(F)C=1C(Cl)=O>>[N:31]1([CH2:30][CH2:29][C:25]2[CH:24]=[C:23]([NH:22][C:18]3[N:17]=[C:16]([C:15]4[N:14]5[C:10]([S:11][CH:12]=[CH:13]5)=[N:9][C:8]=4[C:4]4[CH:3]=[C:2]([NH:1][C:76]([NH:75][C:78]5[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=5)=[O:77])[CH:7]=[CH:6][CH:5]=4)[CH:21]=[CH:20][N:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(CCN4CCOCC4)c3)n2)c1
Reactant: O=C=Nc1ccccc1
Agent: Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(OCCCN4CCOCC4)c3)n2)c1
Agent: O=C(Cl)c1c(F)cccc1F
Product: O=C(Nc1ccccc1)Nc1cccc(-c2nc3sccn3c2-c2ccnc(Nc3cccc(CCN4CCOCC4)c3)n2)c1

Procedure:
The title compound was prepared as described in EXAMPLE 297, with the following substitutions: 4-(6-(3-aminophenyl)imidazo[2,1-b]thiazol-5-yl)-N-(3-(2-morpholinoethyl)phenyl)pyrimidin-2-amine for 4-(6-(3-aminophenyl)imidazo[2,1-b]thiazol-5-yl)-N-(3-(3-morpholinopropoxy)phenyl)pyrimidin-2-amine and isocyanatobenzene for 2,6-difluorobenzoyl chloride. (ESI(+)) m/e 617 (M+H)+; (ESI(−)) m/e 615 (M−H)−; 1H-NMR (300 MHz, DMSO-d6) □9.65 (s, 1H), 8.84 (s, 2H), 8.70 (s, 1H), 8.29 (d, 1H), 7.74 (t, 1H), 7.49-7.63 (m, 4H), 7.43-7.48 (m, 2H), 7.39 (t, 1H), 7.16-7.31 (m, 4H), 6.92-7.01 (m, 1H), 6.87 (d, 1H), 6.63 (d, 1H), 3.52-3.60 (m, 4H), 2.66-2.77 (m, 2H), 2.52-2.57 (m, 2H), 2.36-2.44 (m, 4H).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].CO.[BH4-].[Na+]>C(O)C>[C:7]([O:6][C:4]([N:11]1[CH2:16][CH2:15][CH:14]([NH:2][NH2:3])[CH2:13][CH2:12]1)=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NN)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Hydrazine hydrate (100 mL, ˜2 mol) was added to a solution of 1-Boc-4-piperidone (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 20.0 g, 100 mmol) in ethanol (180 mL) under nitrogen at room temperature and the reaction mixture was stirred at room temperature overnight. Methanol (180 mL) was added and the reaction mixture was cooled to 0-5° C. Sodium borohydride (14.2 g, 375 mmol) was added in portions and the reaction mixture was allowed to warm to room temperature and stir for 2 h. The solvents were evaporated under reduced pressure, dichloromethane was added and the mixture was washed with water, dried (sodium sulfate), filtered, and evaporated to give 4-hydrazino-piperidine-1-carboxylic acid tert-butyl ester (18.9 g, 88%) as a viscous oil, which was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:12]>ClCCl>[Br:12][CH2:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Cc1nc(Cl)ccc1CO
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Cc1nc(Cl)ccc1CBr
Temperature: 0 °C

Procedure:
(6-Chloro-2-methylpyridin-3-yl)methanol (500 mg, 3.17 mmol) was taken up in dichloromethane (9.1 mL) and cooled to 0° C. Phosphorus tribromide (0.6 mL, 6.35 mmol) was added dropwise, and the reaction was allowed to warm to room temperature overnight. The reaction was then quenched by slow addition of saturated aqueous sodium bicarbonate, followed by solid sodium carbonate to obtain pH>7. The mixture was extracted with dichloromethane two times. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was performed via silica gel chromatography (0-40% ethyl acetate in hexane) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].N[C@@H]1CCCC[C@H]1N>[Cu]I>[F:1][C:2]1[CH:8]=[C:7]([N:13]2[CH:14]=[CH:15][C:11]([CH3:10])=[N:12]2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(I)cc1F
Reactant: Cc1cc[nH]n1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Product: Cc1ccn(-c2ccc(N)c(F)c2)n1
Yield: 38.1 %

Procedure:
2-Fluoro-4-iodoaniline (3. 0 g, 12.6 mmol), 3-methylpyrazole (1.22 mL, 15.18 mmol), Cs2CO3 (8.66 g, 26.58 mmol) and CuI (0.072 g, 0.379 mmol) were placed in a flask under nitrogen. The flask was evacuated under vacuum and refilled with nitrogen (5 times). 1,4-Dioxane (15 mL) was added followed by trans-1,2-diaminocyclohexane (152 μL, 1.266 mmol). The reaction mixture was heated under reflux for 36 h. Mixture cooled and filtered. Solvents removed. Residue purified by silica gel flash chromatography eluting with a gradient of EtOAc in hexanes (0 to 30%). This purification afforded 1 as a pale brown solid (0.917 g, 38%). MS: APCI (AP+): 192.0 (M)+.
Reaction SMILES: CC(C)([O-])C.[Na+].[Cl:7][C:8]1[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=1[NH:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[OH:26].Br[CH2:28][C:29]([O:31]CC)=[O:30].[OH-].[Na+].Cl>C1COCC1>[Cl:7][C:8]1[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=1[NH:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[O:26][CH2:28][C:29]([OH:31])=[O:30]
Reactant: CS(=O)(=O)c1ccc(Nc2cc(F)ccc2O)c(Cl)c1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Nc2cc(F)ccc2OCC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium tert-butoxide (0.073 g) was added to a solution of the product from step (ii) (0.2 g) in THF (10 ml) and stirred at RT for 5 min. Ethyl bromoacetate (0.078 ml) was added, the mixture stirred for 1 h before adding 2M sodium hydroxide solution (2 ml). After 3 h, 2M hydrochloric acid was added and the mixture extracted with ethyl acetate. The organics is were washed with brine, dried and evaporated under reduced pressure. The residue was purified by RPHPLC, yield 0.11 g.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:27]=[CH:26][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][NH:21][C@@H:20]([CH:23]([CH3:25])[CH3:24])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[O:28]1CCC(C2C3=NC=CC=C3CN2C([O-])=O)[CH2:29]1>>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][NH:21][CH:20]([CH:23]4[CH2:24][CH2:29][O:28][CH2:25]4)[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:26][CH:27]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: O=C([O-])N1Cc2cccnc2C1C1CCOC1
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)cc1
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CNC3C2CCOC2)cc1

Procedure:
Procedure same as that for (S)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide, using tert-butyl34(4-(ethylsulfonyl)benzyl)carbamoyl)-7-(tetrahydrofuran-3-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate as a starting material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]=1[C:5](OC)=[O:6].Cl.[NH2:17][OH:18].[OH-].[K+]>CO>[OH:18][NH:17][C:5](=[O:6])[C:4]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1C(=O)NO
Yield: 101.7 %

Procedure:
Methyl 2-methoxy-5-nitrobenzoate (10 g, 47.39 mmol) and hydroxylamine hydrochloride (13.17 g, 189.56 mmol) were taken up in MeOH (100 ml) and a solution of KOH (13.27 g, 236.95 mmol) in MeOH (55 ml) was added carefully. Note—an exothermic reaction was observed; solids initially dissolved, then a solid precipitated out of solution. TLC (run in EtOAc) of an acid washed aliquot showed a trace of the starting benzoate and a new product. H2O (100 ml) was added and any undissolved solid collected by filtration off, washed with isopropyl alcohol (IPA) and dried in vacuo to give 10.23 g (>100%) of N-hydroxy-2-methoxy-5-nitrobenzamide as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]2[O:15][CH2:16][CH2:17][NH:18][C:19]=2[N:20]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C>CCO.O=[Pt]=O>[CH2:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[O:15][CH2:16][CH2:17][NH:18][C:19]=2[N:20]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)CCC#Cc1ccc2c(n1)NCCO2
Agent: O=[Pt]=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCOC(=O)CCCCc1ccc2c(n1)NCCO2
Reaction time: 4 h

Procedure:
A mixture of 4-5 (0.0643 g, 0.223 mmol), triethylamine (0.0169 g, 0.167 mmol), and PtO2 (0.0064 g) in EtOH (3.0 mL) was stirred under a hydrogen balloon for four hours. The reaction was filtered through Celite and concentrated to yield a cloudy, colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH:24](O)([CH3:26])[CH3:25]>>[CH:24]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[CH:22][CH:23]=1)=[O:3])([CH3:26])[CH3:25]
Reactant: Cc1cc(CCCCCCCOc2ccc(C(=O)O)cc2)on1
Reactant: CC(C)O
Product: Cc1cc(CCCCCCCOc2ccc(C(=O)OC(C)C)cc2)on1

Procedure:
[I; R is CH3, n is 7, X is O, Ar is 4--(CH3)2CHOOCC6H4 ], m.p. 45°-46° C., from 5-[7-(4-carboxyphenoxy)heptyl]-3-methylisoxazole (Example 16) and isopropyl alcohol; MIC vs. rhinovirus Type 2 in vitro=0.23 μg/ml.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>>[C:13]([NH:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1ccnc(N)c1
Agent: Cl
Product: COC(=O)c1ccnc(NC(=O)C(C)(C)C)c1

Procedure:
The title compound is prepared in quantitative yield (1.25 g, colorless syrup) from methyl 2-aminoisonicotinate hydrochloride (1.00 g, 5.30 mmol) and pivaloyl chloride by the similar manner in Step-1 of Carboxylic acid-1.
Reaction SMILES: [H-].[Na+].Cl.Cl[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][NH:20][C:21]2=[O:24])=[CH:16][CH:15]=1.O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][N:20]([CH2:5][C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[C:21]2=[O:24])=[CH:16][CH:15]=1
Reactant: ClCc1cccnc1
Reactant: COc1ccc2c(c1)C(=O)NCC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)N(Cc1cccnc1)CC2
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
To a suspension of 3.70 g of sodium hydride (about 60%) in 80 ml of dimethylformamide was added portionwise 5.30 g of 3-chloromethylpyridine hydrochloride under ice cooling. The mixture was stirred under ice cooling for 15 minutes, and a solution of 4.09 g of 3,4-dihydro-7-methoxy-1 (2H)-isoquinolinone in 30 ml of dimethylformamide was added dropwise in 15 minutes thereto. The mixture was stirred at 10° C. for 1 hour, mixed with water and shaken with toluene. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate to give 4.50 g of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]([F:26])([F:25])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([N:1]=[CH:23][C:21]2[O:22][C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11]([F:25])([F:10])[F:26])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)o1
Reactant: Cc1ccc(O)c(N)c1
Product: Cc1ccc(O)c(N=Cc2ccc(-c3ccccc3C(F)(F)F)o2)c1

Procedure:
Using 2-amino-4-methylphenol and 5-(2-(trifluoromethyl)phenyl)furan-2-carbaldehyde, 3.82 g of 4-methyl-2-{[5-(2-(trifluoromethyl)phenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 92%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:29][C:30]1[CH:35]=[C:34]([O:36][C:37]2[C:42]([F:43])=[CH:41][C:40]([NH:44][C:45]([C:47]3([C:50]([NH:52][C:53]4[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=4)=[O:51])[CH2:49][CH2:48]3)=[O:46])=[C:39]([F:60])[CH:38]=2)[CH:33]=[CH:32][N:31]=1>C(Cl)Cl>[CH2:1]([O:8][C@H:9]([CH3:13])[C:10]([NH:29][C:30]1[CH:35]=[C:34]([O:36][C:37]2[C:42]([F:43])=[CH:41][C:40]([NH:44][C:45]([C:47]3([C:50]([NH:52][C:53]4[CH:54]=[CH:55][C:56]([F:59])=[CH:57][CH:58]=4)=[O:51])[CH2:49][CH2:48]3)=[O:46])=[C:39]([F:60])[CH:38]=2)[CH:33]=[CH:32][N:31]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)O
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@@H](OCc1ccccc1)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a solution of (R)-2-benzyloxy-propionic acid (500 mg, 2.78 mmol) and N-methylmorpholine (416 mg, 4.16 mmol) in anhydrous CH2Cl2 was added isobutyl chloroformate (566 mg, 4.32 mmol) dropwise. The mixture was stirred at 25° C. for 1 h. N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 0.452 mmol) was added and the resulting mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated in vacuo to give (R)—N-(4-((2-(2-(benzyloxy)propanamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 71.5%). It was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13](=[S:15])[NH2:14])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.Br[CH:28]([C:37](=O)[CH3:38])[C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[S:15][C:28]([C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:30])=[C:37]([CH3:38])[N:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1cc2ccc(O)cc2oc1=O
Reactant: CC(=O)C(Br)C(=O)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc3ccc(O)cc3oc2=O)sc1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 5.8 %

Procedure:
To a stirred suspension of 7-hydroxy-2-oxo-2H-chromene-3-carbothioic acid amide (354 mg, 1.6 mmol) in anhydrous N,N-dimethylformamide (7 mL), 1,8-diazabicyclo-[5.4.0]undec-7-ene (480 μL, 490 mg, 3.2 mmol) was added followed by a solution of 2-bromo-1-morpholin-4-yl-butane-1,3-dione (750 mg, 3.0 mmol) in anhydrous N,N dimethylformamide (15 mL) and the mixture was stirred at room temperature for 15 h. The reaction mixture was poured into water (100 mL) and extracted first with chloroform (3×30 mL) then after saturation with NaCl, with tetrahydrofuran (3×50 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was dissolved in chloroform (16 mL), pyridinium p-toluenesulfonate (40.2 mg, 0.16 mmol) was added and the mixture was stirred at 60° C. for 4.5 h. The reaction mixture was washed with a mixture of brine (10 mL) and 5% NaHCO3 solution (5 mL) and then with brine (2×15 mL), dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica, eluting with a 9:1:0.1 mixture of chloroform, methanol and cc. NH4OH. The title compound (34.6 mg, 0.093 mmol, 5.8%) was obtained as a yellow solid.