Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]2[C:6](=[O:16])[CH:7]3[CH2:14][CH2:13][C:12](=O)[N:8]3[CH2:9][C:10]=2[CH:11]=1.Cl.[NH2:19][OH:20].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]2[C:6](=[O:16])[CH:7]3[CH2:14][CH2:13][C:12](=[N:19][OH:20])[N:8]3[CH2:9][C:10]=2[CH:11]=1
Reactant: NO
Reactant: O=C1c2cc(Cl)c(Cl)cc2CN2C(=O)CCC12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1c2cc(Cl)c(Cl)cc2CN2C(=NO)CCC12
Yield: 78.7 %

Procedure:
A stirred suspension of 6.37 g of 7,8-dichloro-1,10a-dihydropyrrolo[1,2-b]isoquinoline-3,10[2H,5H]-dione in 95% ethanol (40 ml) was treated with a premixed solution of 3.28 g of hydroxylamine hydrochloride in water (25 ml) and 6.42 g of sodium acetate trihydrate in water (25 ml). The solution was heated at reflux for 2.5 hours. The solution was then cooled with an ice-water bath as a precipitate began to separate from the reaction mixture. The solid was collected by vacuum filtration and recrystallized from 95% ethanol (250 ml) to afford 5.29 g of crystals, m.p. 245°-246° C.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[N:13][CH:14]=2)[N:7]=[N:6][N:5]=1>O.C1COCC1>[CH3:3][C:4]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[N:13][CH:14]=2)[N:7]=[N:6][N:5]=1
Reactant: CCOC(=O)Cc1ccc(-n2nnnc2C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnnn1-c1ccc(CC(=O)O)nc1
Temperature: 25 °C

Procedure:
Lithium hydroxide (161 mg, 3.84 mmol) dissolved in water (3 mL) was added to ethyl 2-(5-(5-methyl-1H-tetrazol-1-yl)pyridin-2-yl)acetate (776 mg, 3.14 mmol) in THF (10 ml) and stirred at room temperature. The reaction was followed by TLC. Evaporated off the organics without heating and cooled in ice bath then acidified with 1N HCL (3.84 ml, pH ˜3). Extracted with EtOAc/THF (2×), washed with brine (1×), dried over Na2SO4, filtered and concentrated to yield 2-(5-(5-methyl-1H-tetrazol-1-yl)pyridin-2-yl)acetic acid: 1H-NMR (500 MHz, CD3OD) δ ppm 8.79 (d, J=2.4 Hz, 1H), 8.098 (dd, J=8.0, 2.5 Hz, 1H), 7.710 (d, J=8.3 Hz, 1H), 3.978 (s, 2H), 2.649 (s, 3H)
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[N+:6]([O:9][CH2:10][CH2:11][CH2:12][OH:13])([O-:8])=[O:7].C(N(CC)CC)C>>[C:1]([O:13][CH2:12][CH2:11][CH2:10][O:9][N+:6]([O-:8])=[O:7])(=[O:4])[CH2:2][CH3:3]
Reactant: O=[N+]([O-])OCCCO
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCC(=O)OCCCO[N+](=O)[O-]
Temperature: 3 °C
Reaction time: 2 h

Procedure:
9.1 mmol Propionyl chloride were dissolved in 10 ml TMBE and cooled to 3° C. 8.25 mmol 3-Nitrooxypropanol and 9.1 mmol triethylamine in 5 ml TMBE were dropped over a period of 5 min at 3 to 6° C. After 2 hours and 30 minutes stirring without cooling the reaction mixture were extracted with 1N HCl, twice with water, washed with brine, dried over Na2SO4 and the solvent was removed in vacuo leaving 1.35 g.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:28])=[C:11]([CH3:27])[C:12]3[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13]=3[C:25]=2[CH3:26])=O)=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:8][C:9]2[C:10]([CH3:28])=[C:11]([CH3:27])[C:12]3[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13]=3[C:25]=2[CH3:26])=[CH:29][CH:30]=1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccccc1)C(C)(C)O2
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1NCc1ccc(F)cc1)C(c1ccccc1)C(C)(C)O2
Yield: 60 %

Procedure:
By using 4-fluoro-N-(2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)benzamide, the title compound was synthesized according to Example 2b. Yield: 60%. Melting point: 93-95° C. (Methanol)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]2[C:16]=1/[C:17](=[CH:28]/[C:29]1[NH:30][CH:31]=[CH:32][C:33]=1[O:34][CH3:35])/[C:18](=[O:27])[NH:19]2.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([C:15]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]3[C:16]=2/[C:17](=[CH:28]/[C:29]2[NH:30][CH:31]=[CH:32][C:33]=2[O:34][CH3:35])/[C:18](=[O:27])[NH:19]3)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2c([N+](=O)[O-])ccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1
Yield: 71.4 %

Procedure:
Using Method S above, 4-methoxycarbonyl-phenyl boronic acid (29.6 mg, 0.164 mmol) (from Step A above) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (50 mg, 0.137 mmol) (Starting Material 6) using DPPFPdCl2 (5.6 mg) (Aldrich) as catalyst in aqueous 2M Na2CO3 (0.14 mL, 0.28 mmol) and DME (5 mL) at reflux for 18 h to give (Z)-4-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2-oxo-1H-indol-4-yl]-benzoic acid methyl ester (yield: 41 mg, 71%).
Reaction SMILES: CC1(C)[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([CH:14]=[CH2:15])[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C([O-])(O)=O.[Na+]>[OH:3][CH2:4][C@@H:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:14]=[CH2:15]
Reactant: C=C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To a solution of tert-butyl (4S)-2,2-dimethyl-4-vinyl-1,3-oxazolidine-3-carboxylate (1.90 g, 8.36 mmol) in methanol (83 mL) was added p-toluenesulfonic acid monohydrate (0.80 g, 4.2 mmol) at 0° C. The mixture was slowly warmed to room temperature overnight. The reaction mixture was diluted with saturated NaHCO3 solution, concentrated, and then diluted with ethyl acetate. The organic layer was washed with sat. NaHCO3 (2×) and brine, dried over Na2SO4, filtered and concentrated to give the desired product as colorless oil (1.187 g, 76%). 1H NMR (400 MHz, CDCl3) δ 5.81 (1H, m), 5.25 (2H, m), 4.90 (1H, m), 4.25 (1H, br s), 3.67 (2H, m), 1.45 (9H, s) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(N(CC)CC)C.C(NC1C=CC(S([N:36]=[N+:37]=[N-])(=O)=O)=CC=1)(=O)C>C(#N)C>[N+:36](=[C:9]([C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-:37]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1ccccc1F
Temperature: 0 °C

Procedure:
Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (1.00 g, 4.76 mmol) was dissolved in acetonitrile (14 mL) and treated with triethylamine (0.760 ml, 5.47 mmol, 1.15 equiv). The mixture was cooled to 0° C., treated with 4-acetamidobenzenesulfonylazide (1.26 g, 5.23 mmol, 1.1 equiv) and warmed to ambient temperature over 1.5 hours. The mixture was partially concentrated in vacuo, cooled to 0° C., treated with sodium hydroxide (50 mL, 1 N aqueous) and extracted with chloroform (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 85:15; hexanes:ethyl acetate) providing the titled compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[S:21])[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Solvent: c1ccncc1
Solvent: O
Product: S=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Yield: 98.8 %

Procedure:
A suspension of 7-benzyloxy-3,4-dihydroquinazolin-4-one (7 g, 28 mmol), (prepared as described for the starting material in Example 6), in pyridine (350 ml) containing phosphorus pentasulphide (12.5 g, 33 mmol) was heated at reflux for 8 hours. After cooling, the mixture was poured into water (1 liter). The precipitate was collected by filtration, and washed with water. The solid was dissolved in 6M sodium hydroxide and the solution was filtered. The filtrate was acidified to pH2 with 6M hydrochloric acid. The precipitate was collected by filtration, washed with water, and dried under vacuum at 60° C. to give 7-benzyloxy-3,4-dihydroquinazolin-4-thione (7.42 g, 99%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[C:6]1([Sn:12](Cl)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(OCC)C>[CH2:2]([Sn:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Cl[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCBr
Solvent: CCOCC
Solvent: O
Product: CCCC[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 84.5 %

Procedure:
In a three-necked flask, a solution of 1-bromobutane (34.25 g, 250 mmol) in diethyl oxide was added on magnesium (7.3 g, 300 mmol) covered with dry diethyl oxide. When the addition was completed, the mixture was refluxed during one hour. This solution was then added to triphenyltin chloride (42.6 g, 110 mmol) in 150 mL of diethyl oxide and refluxed for 3 hours. The mixture was hydrolysed with a minimum of water, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated. Crystallization of the crude product in methanol gave a white solid (32.3 g, 93 mmol).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([CH3:15])[CH:6]=1)=O.[CH3:16][C:17]([CH3:20])([O-:19])[CH3:18].[Na+]>C1(C)C=CC=CC=1>[Br:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([C:3]([O:19][C:17]([CH3:20])([CH3:18])[CH3:16])=[O:2])=[CH:6][N:7]2[CH3:15])=[CH:12][CH:11]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1cn(C)c2cc(Br)ccc12
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)OC(C)(C)C)c2ccc(Br)cc21
Temperature: 106.5 °C
Yield: 66.1 %

Procedure:
Dissolve 6-bromo-1-methyl-1H-indole-3-carboxylic acid methyl ester (17.16 Kg, 63.98 mol) in toluene (134.5 Kg) under nitrogen atmosphere. Stir at least 15 minutes. Add magnesium sulfate to dry and charcoal to de-colorize the solution and stir at least 30 minutes. Filter the mixture. Dissolve sodium tert-butoxide (21.5 Kg, 223.70 mol) in toluene (43.7 kg) under a nitrogen atmosphere. Add the starting material solution mixture to the sodium tert-butoxide solution and heat the reaction mixture slowly over approximately 2-3 hours to a temperature of 105-108° C. and maintain temperature for 30-60 minutes. Follow by TLC until no starting material is observed. Cool the reaction to room temperature and quench the mixture into water (177.2 Kg) cooled to 0-10° C. Stir the reaction mixture for at least 30 minutes and separate the aqueous layer and emulsion. Wash the organic mixture with brine (2×47.7 Kg) maintaining the emulsion with the aqueous brine wash. Extract the combined aqueous layer with toluene (2×29.9 Kg). Filter organic layer and any emulsion through diatomaceous earth. Wash the filter cake with toluene (6.1 Kg). Wash the combined organic layers with brine (2×47.7 Kg). Add magnesium sulfate (7 Kg) and charcoal (850 g) and stir for 30 minutes. Filter the mixture and concentrate the filtrate at 50-55° C. to the lowest stirrable volume. Discontinue heating and add heptane (47.3 Kg) to the mixture. Cool the suspension to 0-5° C. for at least 2 hours and collect the solids by filtration. Rinse the solids with heptane cooled to 0-5° C. Dry solids at 30-35° C. for 12-72 hours under vacuum to give 13.110 Kg (66%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]1>C1COCC1.[H][H].[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH:14]([CH3:17])[CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: CC1CCN(CCOc2ccc([N+](=O)[O-])cc2Cl)CC1
Agent: [Ni]
Solvent: C1CCOC1
Product: CC1CCN(CCOc2ccc(N)cc2Cl)CC1

Procedure:
6.90 g (23.1 mmol) of 3-chloro-4-[2-(4-methylpiperidin-1-yl)ethoxy]nitrobenzene (III.1.b) are dissolved in 100 mL of THF and hydrogenated for 8 hours at ambient temperature at a pressure of 20 psi with hydrogen and 3.0 g of Raney nickel as catalyst. Then the catalyst is filtered off, the solvent is eliminated, and the residue is purified through a silica gel column with a gradient of methylene chloride/methanol (33:1 to 9:1) as eluant. Yield: 3.66 g (59% of theory); Rf value: 0.50 (silica gel, methylene chloride/methanol=9:1); C14H21ClN2O; EII mass spectrum: m/z=269/271 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[Cl:13].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:18][C:19]1[C:20]([OH:34])=[C:21]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:22]=[CH:23][C:24]=1[OH:25].Cl>C(OCC)(=O)C.ClCCCl>[Cl:13][C:12]1[C:2]([Cl:1])=[CH:3][C:4]([C:9]([OH:8])=[O:10])=[C:5]([C:6]([C:23]2[CH:22]=[C:21]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:20]([OH:34])=[C:19]([Cl:18])[C:24]=2[OH:25])=[O:7])[CH:11]=1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Reactant: COC(=O)CCCCc1ccc(O)c(Cl)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)CCCCc1cc(C(=O)c2cc(Cl)c(Cl)cc2C(=O)O)c(O)c(Cl)c1O
Temperature: -20 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
In a 2 L 3-neck round-bottomed flask equipped with a stir and addition funnel was added 4,5-dichlorophthalic anhydride (7.13 g, 32.9 mmol) followed by dry 1,2-dichloroethane (120 ml). After stirring for 30 minutes AlCl3 (11.4 g, 85.54 mmol) was added and the mixture was stirred for another 30 minutes. To this mixture was added via the addition funnel a solution of 5b (8.5 g, 32.9 mmol) with stirring. The solution in the flask became slightly warm and turned dark. Hydrogen chloride gas evolved for about 10 to 20 minutes. Stirring was continued overnight (15-18 hours) at room temperature. During this time, a tarry precipitate formed. To this mixture was added ice (160 g) and concentrated HCl (80 ml) followed by ethyl acetate (900 ml). The content of the flask was stirred until all the solids have completely dissolved. The mixture was transferred to a 2-liter separatory funnel. The organic layer was washed with about 300 ml of 1 N HCl, 2×200 ml of saturated NaCl and dried over sodium sulfate. The solution was filtered and evaporated to a solid, which was then triturated in 200 ml of dichloromethane for 30 minutes, and then cooled to −20° C. for at about 2 h. The crystalline precipitate was filtered off and washed with 2:1 hexanes/dichloromethane, followed by 4:1 hexanes/dichloromethane, and dried to afford 10.8 g (69%) of the desired benzophenone 14b. 1H NMR (DMSO-d6) δ: 12.44 (s, 1H), 10.3 (br s, 1H), 8.14 (s, 1H), 7.87 (s, 1H), 6.88 (s, 1H), 3.55 (s, 3H), 2.44 (t, J=6.8 Hz, 2H), 2.25 (t, J=6.9 Hz, 2H), 1.40 (m, 4H).
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([F:22])=[C:9]([CH:21]=1)[CH2:10][N:11]([CH3:20])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])#[N:4]>CCO>[NH2:4][C:3](=[N:1][OH:2])[C:5]1[CH:6]=[CH:7][C:8]([F:22])=[C:9]([CH:21]=1)[CH2:10][N:11]([CH3:20])[CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cc(C#N)ccc1F
Reactant: NO
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1cc(C(N)=NO)ccc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Hydroxylamine (50% in water) (539.42 μL; 8.98 mmol; 5 eq.) was added to a solution of tert-butyl N-(5-cyano-2-fluorobenzyl)-N-methylglycinate, obtained in step 1 (500 mg; 1.80 mmol; 1 eq.) in EtOH (20 mL) and the resulting mixture was stirred at RT for 24 hours. Solvent was evaporated in vacuo and the resulting oily residue was freeze-dried to afford the title compound as a colourless oil (602 mg; quantitative). 1H NMR (DMSO-d6, 300 MHz) δ 9.61 (br s, 1H), 7.73 (dd, J=7.3, 2.3 Hz, 1H), 7.62-7.56 (m, 1H), 7.20-7.12 (m, 1H), 5.81 (s, 2H), 3.71 (s, 2H), 3.20 (s, 2H), 2.28 (s, 3H), 1.43 (s, 9H). LC/MS (Method B): 310.1 (M−H)−, 312.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cncc(Oc2cccnc2)n1
Temperature: 150 °C
Yield: 93.5 %

Procedure:
2,6-Dichloropyrazine (1.0 g, 6.7 mmol, 1.0 eq), 3-hydroxypyridine (638 mg, 6.71 mmol, 1.00 eq) and K2CO3 (1.11 g, 8.03 mmol, 1.20 eq) were dissolved in DMF (10 mL) and heated in a microwave for 15 minutes at 150° C. The reaction was cooled, diluted with EtOAc and washed with H2O (3×). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 1.3 g (93%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=2.3 Hz, 1H), 8.56 (d, J=4.4 Hz, 1H), 8.41 (s, 1H), 8.37 (s, 1H), 7.71 (dq, J=8.4, 1.3 Hz, 1H), 7.51 (dd, J=8.4, 4.9 Hz, 1H); ES-MS [M+1]+: 208.1.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[N:4]=1.[F:19][C:20]1[C:28]([OH:29])=[CH:27][CH:26]=[C:25]([F:30])[C:21]=1[C:22]([NH2:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:19][C:20]1[C:28]([O:29][CH2:2][C:3]2[S:7][N:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)[N:4]=2)=[CH:27][CH:26]=[C:25]([F:30])[C:21]=1[C:22]([NH2:24])=[O:23]
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: FC(F)(F)Oc1ccc(-c2nsc(CBr)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(OC(F)(F)F)cc3)ns2)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 9.4 %

Procedure:
To a solution of 5-bromomethyl-3-(4-trifluoromethoxyphenyl)-[1,2,4]thiadiazole (0.11 g, 0.32 mmol) in DMF (5 ml) was added 2,6-difluoro-3-hydroxybenzamide (0.056 g, 0.32 mmol) and potassium carbonate (0.16 g, 1.13 mmol). The reaction mixture was stirred at 25° C. for 12 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under vacuum, added 30 ml water and extracted with ethyl acetate (3×20 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 50% EtOAc-Hexane) to get the desired product (0.013 g, 9%).
Reaction SMILES: N(OCCC(C)C)=O.[F:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=1N.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccccc1
Reactant: Nc1ccc(F)cc1F
Agent: CC(C)CCON=O
Product: Fc1ccc(-c2ccccc2)c(F)c1

Procedure:
To a 50 liter resin pot equipped with stirrer, thermometer, nitrogen-inlet, internal steam coil and reflux condenser is charged 31.5 liters of benzene, 1.025 liters of isoamyl nitrite and 700 g. (5.43 moles) of 2,4-difluoroaniline.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:17]3[O:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1nc2ccccc2o1
Reactant: Nc1ccc(Oc2ncccc2Br)cc1
Solvent: CN1CCCC1=O
Product: Brc1cccnc1Oc1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 170 °C

Procedure:
A mixture of 4-(3-bromopyridin-2-yloxy)aniline (1.73 g, 6.53 mmol) and 2-chlorobenzoxazole (1.00 g, 6.51 mmol, TCI America) in NMP (3 mL) was sealed in a screw-cap flask and heated at 170° C. for 20 h. The reaction was cooled to rt and partitioned with water/EtOAc. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco (80 gram)) eluting with EtOAc:hexanes (0:1→1:2) a tan amorphous solid. MS (ESI, pos. ion) m/z: 382.0, 383.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10]([C:20](O)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=C=O)=[CH:27][CH:26]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10]([C:20]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:34])[F:35])=[CH:26][CH:27]=3)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1=NN(c2cccc(Cl)c2)C(c2ccccc2)CC1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)C1=NN(c2cccc(Cl)c2)C(c2ccccc2)CC1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
To 0.70 g (0.0022 mol) of the product obtained in Step B, dissolved in 10 mL toluene, was added 0.625 g (0.0030 mol) α,α,α-trifluoro-p-tolylisocyanate and 0.30 g (0.0029 mol) triethylamine. The reaction mixture was heated at reflux for 18 h, cooled to room temperature and concentrated under reduced pressure. The crude product was triturated with ether to afford 0.50 g of a white solid, mp 183°-184° C. 1H NMR (CDCl3) δ: 1.8-2.4 (m, 3H), 2.9 (d, 1H), 5.25 (bs, 1H), 6.95-7.4 (m, 9H), 7.7 (ABq, 4H), 9.02 (bs, 1H). IR (mineral oil): 3300, 1663 cm-1.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([OH:12])[CH:5]=1)[CH3:2].[C:15](OCC)(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].N1CCCCC1>C(O)C>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[C:6]2[C:7]([CH:8]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15](=[O:22])[O:12]2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2ccc(N(CC)CC)cc2oc1=O

Procedure:
--A solution of 4-diethylamino-2-hydroxy-benzaldehyde (29.8 g, 154 mmol) and diethyl malonate (23.8 ml, 157 mmol) in ethanol (185 ml) was treated with piperidine (1.37 ml, 13.9 mmol) and heated under reflux for 4 h. The solution was allowed to cools then concentrated under reduced pressure to approx. half-volume diluted with ether and washed with water, dilute aq. NaOH and water, dried and evaporated under reduced pressure. Trituration of the residue with EtOH (approx. 15 ml) gave yellow crystals which were recrystallised from EtOAc-light petroleum to give the ester 1 as bright yellow prisms (18 the m.p. 76-77° C. A sample recrystallised a second time had m.p. 77-78° C. (Found: C, 66.4; H, 6.7g N, 4.8. C16H9NO4 requires C, 66.4; H, 6.6; N, 4.8%). The discrepancy with the m.p. (87° C.) reported by Kendal et al. (GB 867,592), together with the sharp m.p. and satisfactory analytical result for the present sample suggests that the digits of the reported value may accidently have been transposed.