Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:21][C:20]([C:22]([O:24]CC)=O)=[N:19][CH:18]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9].ClC(OCC(C)C)=O.Cl.[CH3:36][O:37][C:38](=[O:44])[C@H:39]([CH:41]([CH3:43])[CH3:42])[NH2:40]>C1COCC1.CCN(CC)CC>[CH3:42][CH:41]([CH3:43])[CH:39]([NH:40][C:22]([C:20]1[S:21][C:17]([C:14]2[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=2)=[CH:18][N:19]=1)=[O:24])[C:38]([O:37][CH3:36])=[O:44]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: CCOC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
N-methyl morpholine (1.01 ml) was added to a solution of 5-(4-nitrophenyl)thiazole-2-carboxylic acid (Intermediate 2, step B, 2.3 g) in THF (72 ml). The reaction mixture was stirred for 10 minutes at RT, cooled to −20° C. Isobutyl chloroformate (1.19 ml) was added and the mixture was stirred for 15-20 minutes at −20 to −30° C. This was followed by the addition of L-valine methyl ester hydrochloride (2.15 g) previously neutralized with Et3N (1.8 ml). The reaction mixture was stirred at −20 to −30° C. for 5 minutes and was then allowed to gradually warm to RT. The solvent was removed under reduced pressure and the crude material was chromatographed on silica gel in 15:85 EtOAc:CHCl3 to get pale yellow colored solid which was crystallized in EtOAc/Pet ether to yield 2.25 g (67%) of the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 8.95 (d, 1H), 8.7 (s, 1H), 8.34 (d, 2H), 8.09 (d, 2H), 4.33 (m, 1H), 3.68 (s, 3H), 2.27 (m, 1H), 0.95 (t, 6H); MS (ES+): m/z 364 (M+1).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]([NH2:11])=[S:10])[CH:6]=[CH:7][N:8]=1.Cl[CH2:13][C:14](=O)[CH2:15][C:16]([O:18][CH3:19])=[O:17]>CO>[CH2:2]([C:3]1[CH:4]=[C:5]([C:9]2[S:10][CH:13]=[C:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:11]=2)[CH:6]=[CH:7][N:8]=1)[CH3:1]
Reactant: COC(=O)CC(=O)CCl
Reactant: CCc1cc(C(N)=S)ccn1
Solvent: CO
Product: CCc1cc(-c2nc(CC(=O)OC)cs2)ccn1

Procedure:
A mixture of ethionamide (Aldrich) (1.65 g, 10.0 mmol) and methyl 4-chloroacetoacetate (Fluka) (1.41 g, 10.0 mmol) in 50 mL of anhydrous MeOH was heated at reflux for 18 h. The solvent was evaporated to give an oily residue that was purified by chromatography (gradient elution: 10-50% EtOAc in hexanes) to afford the title compound as a light brown oil. MS m/z: 263 (M+1). Calc'd for C13H14N2O2S: 262.08.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[C:11]2[N:12]([CH3:17])[O:13][C:14](=[O:16])[N:15]=2)[N:6]=1.N1C=CC=CC=1.[O:30]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][CH2:32][CH:31]1[C:40](Cl)=[O:41]>ClCCl>[CH3:17][N:12]1[C:11](/[C:10](=[N:9]\[O:8][CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:40]([CH:31]3[O:30][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[O:33][CH2:32]3)=[O:41])[S:3][CH:4]=2)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14](=[O:16])[O:13]1
Reactant: O=C(Cl)C1COc2ccccc2O1
Reactant: Cn1oc(=O)nc1/C(=N\OCc1csc(N)n1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1oc(=O)nc1/C(=N\OCc1csc(NC(=O)C2COc3ccccc3O2)n1)c1ccccc1
Reaction time: 8 h
Yield: 106.4 %

Procedure:
To a solution of 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (120 mg, 0.362 mmol, 1 eq.) and pyridine (0.044 ml, 0.543 mmol, 1.5 eq) in dry dichloromethane (2.0 ml) at room temperature was added 2,3-dihydro-1,4-benzodioxine-2-carbonyl chloride (108 mg, 0.543 mmol, 1.5 eq) and stirring was allowed overnight. The reaction was quenched by addition of water and concentrated to dryness. The residue was taken in EtOAc and 0.5 ml of 1N NaOH was added. The solution was filtered through a chemelut pad and washed with EtOAc. After concentration, the residue was purified by chromatography on silica gel to give N-{4-[({[(Z)-(2-methyl-5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-yl}-2,3-dihydro-1,4-benzodioxine-2-carboxamide (190 mg, 99% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>C(#N)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CCNCC
Reactant: O=C(O)c1cc(Br)cnc1F
Solvent: CC#N
Product: CCN(CC)c1ncc(Br)cc1C(=O)O
Temperature: 80 °C

Procedure:
880 mg (4.00 mmol) of 5-bromo-2-fluoronicotinic acid was dissolved in 3 ml of acetonitrile. 1.0 ml (9.7 mmol) of diethylamine was added and the resulting mixture heated to 80° C. for 18 h. The mixture was evaporated and the resulting brown oil used without further purification. MS: m/z 273 [MH+].
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15][NH:16]C(OC(C)(C)C)=O)[O:12][N:11]=1>C(Cl)Cl>[NH3:11].[OH:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[O:12][N:11]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(CO)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N
Product: NCc1cc(CO)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 195.4 %

Procedure:
Trifluoroacetic acid (4 ml, 54 mmol) was added to a solution of 3-hydroxymethyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole (Method 75; 1.25 g, 5.4 mmol) in DCM (40 ml). The mixture was stirred at ambient temperature for 18 hours then the volatiles removed by evaporation. The residue was purified by chromatography on a SCX-2 column (50 g) eluting with methanol then 7N ammonia in methanol to give the title compound (676 mg, 96%). NMR (DMSO): 1.97 (br s, 2H), 3.76 (s, 2H), 4.44 (s, 2H), 5.38 (s, 1H), 6.26 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([CH:9]1[O:11][CH2:10]1)[Cl:8]>C(O)C>[Cl:8][CH2:7][CH:9]([OH:11])[CH2:10][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: ClCC1CO1
Solvent: CCO
Product: OC(CCl)CN1CCOCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A mixture of morpholine (2.6 mL, 30 mmol) and epichlorohydrin (2.35 ml, 30 mmol) in ethanol (50 mL) was stirred at 70° C. overnight. After removing the solvent, the residue was diluted with methylene chloride (50 mL). The clear solid precipitated was collected by vacuum filtration to give 1-chloro-3-morpholin-4-yl-propan-2-ol (2.0 g, 37%). 1H NMR (DMSO-d6) δ 3.49 (t, J=4.8 Hz, 2H), 3.60 (t, J=4.6 Hz, 2H), 3.75 (m, 4H, 2×CH2), 4.20 (dd, J=5.2, 12 Hz, 2H), 4.54 (m, 2H), 4.62 (m, 1H, CH), 6.64 (d, J=6.4 Hz, 1H, OH). MS (m/z) 180.2 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F-].[K+].CN(C=O)C.[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH:22]=[CH:23][C:24]=1[OH:25]>O>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[O:31])[N:28]([CH3:29])[CH3:30])[CH:22]=[CH:23][C:24]=1[O:25][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)Nc1ccc(O)c(Cl)c1
Reactant: O=C(CCl)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Nc1ccc(OCC(=O)c2ccccc2)c(Cl)c1
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
A mixture of α-chloroacetophenone (4.64 g; 0.03 mol), anhydrous potassium fluoride and DMF (200 ml) is stirred for 15 minutes. Next, 3-(3-chloro-4-hydroxyphenyl)-1,1-dimethylurea (6.44 g; 0.03 mol) is added and the mixture stirred for 20 hours at room temperature and then for 24 hours at 80° C. The mixture is then drowned in water, and extracted with methylene chloride. The organic layer is separated, washed with water and filtered through a 5 cm pad of neutral alumina. The pad is washed with acetonitrile, filtrate and washings are combined and evaporated under vacuum to give a brown-yellow oil (7.0 g, 70.1%). This oil is purified by chromatographing on silica gel (eluent: methylene chloride) to afford the title compound: 6.75 g of a cream colored solid, m.p. 148°-150° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl-:15]>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=[O:14])[CH2:13][Cl:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=NOCCCl)C(C)=O
Reactant: [Cl-]
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCCCl)C(=O)CCl
Yield: 70.4 %

Procedure:
Ethyl 2-(2-chloroethoxyimino)-3-oxobutyrate (syn isomer, 83.6 g.), sulfury chloride (52.4 g.) and acetic acid (83.6 ml.) were treated in a similar manner to that of Example F-(2) to give Ethyl 2-(2-chloroethoxyimino)-3-oxo-4-chlorobutyrate (syn isomer, 68 g.), oil.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH3:7][S:8][C:9]1(C([O-])=O)OC[N:11]=[N:10]1.[K+]>C1C=CC=CC=1.[Hg]>[CH3:7][S:8][C:9]1[O:3][C:2]([C:1]([Cl:6])=[O:5])=[N:11][N:10]=1
Reactant: CSC1(C(=O)[O-])N=NCO1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Hg]
Agent: [K+]
Solvent: c1ccccc1
Product: CSc1nnc(C(=O)Cl)o1

Procedure:
A solution of oxalyl chloride (2.57 ml., 0.03 mole) in benzene (15 ml.) was added dropwise to a refluxing suspension of potassium 5-methylthio-1,3,4-oxadiazole-5-carboxylate (3.96 g., 0.02 mole) in benzene (50 ml.). After the addition, the mixture was stirred at reflux for one hour. Filtration and evaporation left the acid chloride; distillation gave 1.86 g. (52%); B.P. 65°-69° C. at 0.05 mm. of mercury.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CNOC.[CH:26]1C=CC2N(O)N=NC=2[CH:31]=1.C([Mg]Br)=C>CN(C=O)C.C1COCC1>[F:17][C:15]1[CH:16]=[C:11]([CH:12]=[C:13]([F:18])[CH:14]=1)[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:19](=[O:21])[CH:26]=[CH2:31]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Agent: C=C[Mg]Br
Agent: CNOC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C

Procedure:
N-(tert-butoxycarbonyl)-3,5-difluoro-L-phenylalanine (1) is coupled to N-methyl-N-methoxylamine using the carbodimide EDC in the presence of HOBT in DMF. The “Weinreb” amide product (m.p. 48° C.) is then treated with vinylmagnesium bromide in THF at 0° C. for 2 hr. Workup provided vinyl ketone 2 (m.p. 115° C.).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][CH2:27][C@@H:28]([O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:39]=1)[C:34]([OH:36])=O)[CH3:29].[CH2:48]([N:50]1[CH:54]=[CH:53][C:52]([NH2:55])=[N:51]1)[CH3:49].CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH2:48]([N:50]1[CH:54]=[CH:53][C:52]([NH:55][C:34](=[O:36])[C:33]2[CH:37]=[C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:39]=[C:31]([O:30][C@@H:28]([CH3:29])[CH2:27][O:26][CH3:25])[CH:32]=2)=[N:51]1)[CH3:49]
Reactant: CCn1ccc(N)n1
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)COC)c2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
HATU (23.5 g, 61.83 mmol) was added to 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid (16.28 g, 51.53 mmol) followed by addition of DMF (140 mL) and cooled to 0° C. 1-Ethyl-1H-pyrazol-3-amine (6.86 g, 61.8 mmol) was added followed by DIPEA (21.3 mL) and the reaction stirred under argon, at 0° C., for 3 hours. The solvent volume was reduced and the residue was dissolved in ethyl acetate (500 mL), washed with citric acid (200 mL), sodium hydrogen carbonate solution (150 mL) and saturated brine solution (2×150 mL). The organic layer was separated and dried (MgSO4), filtered and evaporated. Purification by column chromatography on silica, eluting with 10-50% ethyl acetate in hexanes, afforded the title compound as a pale yellow oil (19.1 g).
Reaction SMILES: [CH2:1]([C:4]1[C:5](Cl)=[N:6][CH:7]=[C:8]([C:10]([O:19][CH2:20][O:21][CH3:22])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])[CH:9]=1)[CH:2]=[CH2:3].[H-].[Na+].[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=1.O>CN(C)C=O>[F:12][C:11]([F:14])([F:13])[C:10]([C:8]1[CH:9]=[C:4](/[CH:1]=[CH:2]/[CH3:3])[C:5]([O:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([O:27][CH3:26])=[O:36])=[N:6][CH:7]=1)([O:19][CH2:20][O:21][CH3:22])[C:15]([F:18])([F:17])[F:16]
Reactant: C=CCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cnc1Cl
Reactant: COC(=O)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C/C=C/c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cnc1Oc1cccc(C(=O)OC)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To a solution of 3-allyl-2-chloro-5-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)pyridine (80 mg, 0.220 mmol) in N,N-dimethylformamide (2 mL), sodium hydride (14.4 mg, 0.330 mmol) and 3-hydroxybenzoic acid methyl ester (50 mg, 0.330 mmol) were added under ice-cold conditions, and the resultant mixture was stirred at 80° C. for 18 hours and further stirred at 100° C. for 3 hours. The reaction solution was added with water under room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and the title compound (81 mg, yield 76.5%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]=O.[CH2:3]([C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])[CH2:4][NH2:5].[Cl:14][C:15]1[CH:16]=[C:17]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:18][N:19]([CH3:31])[C:20](=[O:30])[CH:21]=[C:22]1[C:26](=[O:27])OC(C)(C)[O:23]1>CO>[Cl:14][C:15]1[CH:16]=[C:17]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:18][N:19]([CH3:31])[C:20]([C:21]1[CH2:1][N:5]([CH2:4][CH2:3][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])[C:26](=[O:27])[C:22]=1[OH:23])=[O:30]
Reactant: NCCC(=O)NCCC(=O)O
Reactant: C=O
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC(=O)NCCC(=O)O)C1
Temperature: 55 °C
Reaction time: 0.08 h
Yield: 15.6 %

Procedure:
A mixture of paraformaldehyde (0.015 g, 0.5 mmol) and methanol (1.5 mL) was warmed to 55° C. Added to this mixture was H-β-Ala-β-ala-OH (0.08 g, 0.5 mmol) and the solution was stirred 5 min. N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo[1,3]dioxolane-4-ylidene)-N-methyl-acetamide (0.1715 g, 0.5 mmol) was added and the mixture was stirred at 55° C. for 45 min. The mixture was concentrated and the resulting residue was triturated with ethylacetate and filtered to give the desired product as a white solid (0.0358 g, 16% yield). 1H NMR (300 MHz, DMSO) δ: 2.35 (t, J=6.7 Hz, 4H), 2.96 (s, 3H), 3.32 (m, 2H), 3.57 (m, 2H), 4.02 (s, 2H), 4.57 (s, 2H), 7.23 (d, J=6.6 Hz, 1H), 7.51 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 8.05 (t, J=10.3 Hz, 1H), 10.97 (s, 1H), 12.19 (s, 1H). HRMS (M+H) calcd for C19H21N3Cl2O6: 456.07292. found: 456.0738.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([N:18]2[CH:22]=[N:21][N:20]=[CH:19]2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH3:23][Si](C=[N+]=[N-])(C)C>CO.CCCCCC>[CH3:23][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([N:18]2[CH:22]=[N:21][N:20]=[CH:19]2)[C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:5]=1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(-n2cnnc2)cc1C(=O)O
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1cc(-n2cnnc2)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A solution of 1.3 g (4.14 mmol) of 2-acetylamino-5-[1,2,4]triazol-4-yl-4-trifluoromethyl-benzoic acid in 15 ml of methanol is treated dropwise with 3.1 ml (6.21 mmol) of a 2M solution of trimethylsilyl diazomethane in hexane. The mixture is stirred for 1 hour at room temperature and another 1.5 ml (3.00 mmol) of a solution of trimethylsilyl diazomethane in hexane (2M) is added. After 1 hour, the reaction is quenched by adding glacial acetic acid until no more gas evolution is observed. The mixture is concentrated in vacuo and the residue taken up in ethyl acetate, washed with water, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, gradient 100% ethyl acetate to ethyl acetate/methanol 9:1) afforded 456 mg (34%) of 2-acetylamino-5-[1,2,4]triazol-4-yl-4-trifluoromethyl-benzoic acid methyl ester as yellow crystals, m.p. 180-184° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.Br[CH2:12][C:13](=O)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>O1CCCC1.CCOCC>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]2[CH:12]=[C:13]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[N:10]=[C:5]2[CH:4]=1
Reactant: O=C(CBr)C(=O)c1ccccc1
Reactant: COc1cc(N)nc(C)n1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc2nc(C(=O)c3ccccc3)cn2c(C)n1
Reaction time: 8 h
Yield: 66.9 %

Procedure:
A stirred solution of 2.1 g of 6-methoxy-2-methyl-4-pyrimidinamine in dry tetrahydrofuran was treated with a solution of 5.4 g of 3-bromo-1-phenyl-1,2-propanedione in 5 ml of dry ether. After stirring overnight, the mixture was chilled and the precipitated salt filtered off. A suspension of the salt in dry ethanol was refluxed for 1.5 hours, chilled, and filtered. The solid was shaken with a mixture of chloroform and aqueous sodium bicarbonate and the organic layer was evaporated to dryness under reduced pressure. The residue was chromatographed in ethyl acetate on silica to obtain 2.7 g of (7-methoxy-5-methyl-imidazo[1,2-c]pyrimidin-2-yl)-phenylmethanone as a yellow crystalline solid melting at 165°-7° C.
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=[O:3])[CH3:2].[C:16]1([C:22]([O:24]O)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)C.ClCCl.C(OCC)C>[C:1]([O:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O:11][O:24][C:22](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1ccccc1
Reactant: CC(=O)OCOc1ccccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OCOc1ccccc1C(=O)OOC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.1 %

Procedure:
5 g (24 mmol) of 2-acetoxymethoxy-benzoic acid (prepared as described in example 1-2) and 3.3 g (24 mmol) of benzenecarboperoxoic acid are dissolved in 150 mL of diethyl ether/dichloromethane mixture, 6/4. The solution is cooled to 0° C., then 4.9 g (24 mmol) of N,N′-dicyclohexylcarbodiimide dissolved in 85 ml of diethyl ether is added dropwise. After stirring for 3 hours at 0° C., the reaction mixture is filtered and then concentrated. The residue is precipitated in diethyl ether and the filtrate is concentrated under reduced pressure. 5 g of (2-acetoxymethoxy-benzoyl)benzoyl peroxide is obtained in the form of white solid at a yield of 63%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](O)=O)[CH3:2].N1CCCCC1.C=O.Cl>O.N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:2]
Reactant: CCOC(=O)C(CCCCOc1ccccc1)C(=O)O
Agent: C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: C=C(CCCCOc1ccccc1)C(=O)OCC
Yield: 74.1 %

Procedure:
66.45 g of 4-phenoxybutylmalonic acid ethyl ester, 45 ml of pyridine, 3 ml of piperidine and 9.9 g of paraformaldehyde are stirred together at 50° C. for 4 hours. After cooling, 400 ml of water are added to the reaction mixture which is then acidified with half-concentrated hydrochloric acid, while cooling with ice. The reaction mixture is then extracted 3 times with 200 ml of diethyl ether each time, the combined organic phases are concentrated and distilled in vacuo. 43.6 g 2-methylene-6-phenoxyhexanoic acid ethyl ester are obtained as a colorless liquid of b.p. 140° C. under 0.06 mm Hg (9 Pa).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH:11](=[O:15])[CH2:12][CH2:13][CH3:14].Cl>CCO>[CH:1](=[C:12]([CH2:13][CH3:14])[CH:11]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC=O
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCC(C=O)=Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
30.0 mL Benzaldehyde was dissolved in 150 mL EtOH and cooled with an ice bath. Added was 5.01 mL 45% KOH (0.2 equiv.), followed by dropwise addition of 16.5 mL butyraldehyde. The mixture was stirred for 3 days at room temperature, acidified with 1M HCl and extracted with ether. The organic layer was dried over Na2SO4, filtrated and concentrated in vacuo. Vacuum distillation yielded 20.4 g of a yellow fluid (78-82° C., 0.6 mbar) containing 70% of the desired product. This material was used in subsequent steps without further purification. Characteristic signals in 1H NMR (400 MHz, CDCl3): δ 1.15 (t, J=7.5 Hz, 3H), 2.57 (q, J=7.5 Hz, 1H), 7.22 (s, 1H), 9.56 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.C(N(CC)C(C)C)(C)C.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].CN(C1C=CC=CN=1)C.[SiH4]>C(Cl)Cl>[C:24]([Si:21]([O:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=1[O:10][CH3:11])([CH3:23])[CH3:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(F)c(F)cc1O
Agent: CN(C)c1ccccn1
Agent: [SiH4]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)c(F)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4,5-difluoro-2-methoxy-phenol (3.75 g, 23.42 mmol, Example 264) in methylene chloride (60 mL) cooled to 0° C. were added N,N-diisopropylethylamine (4.895 mL, 28.10 mmol), tert-butyldimethylsilyl chloride (4.367 g, 28.10 mmol, Aldrich), and dimethylaminopyridine (286 mg, 2.342 mmol, Aldrich). At the end of addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 90 minutes. Water (30 mL) was added and the layers were separated. The aqueous layer was extracted with methylene chloride (20 mL). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 3% ethyl acetate in hexanes) yielded tert-butyl-(4,5-difluoro-2-methoxy-phenoxy)-dimethyl. silane as a clear oil (5.22 g, 81%).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[N+:11]([C:14]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][C:15]=1[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[O:17])([O-])=O>C1COCC1>[CH:1]([NH:11][C:14]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][C:15]=1[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[O:2]
Reactant: O=CO
Reactant: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1NC=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.3 %

Procedure:
A solution of formic acid (0.02 mL, 0.56 mmol) and acetic anhydride (0.05 mL, 0.56 mmol) was heated to 50° C. for 2 hours under an argon atmosphere. The resulting mixture was diluted with THF (0.2 mL) and added dropwise to a solution of 34B (50 mg, 0.19 mmol) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The resulting solution was concentrated to dryness and purified by chromatography (SiO2, 40% EtOAc in hexane) to afford 44A (58 mg, 100%).