Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][O:8][C:7]3[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:6]=3[C:5]=2[N:16]=1.O1CCCC1.[Br:22][C:23]([CH3:30])([CH3:29])[C:24]([N:26]=[C:27]=[O:28])=[O:25]>>[Br:22][C:23]([CH3:30])([CH3:29])[C:24]([NH:26][C:27](=[O:28])[NH:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][O:8][C:7]3[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:6]=3[C:5]=2[N:16]=1)=[O:25]
Reactant: CC(C)(Br)C(=O)N=C=O
Reactant: Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)NC(=O)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reaction time: 20 h

Procedure:
A mixture of 1250 mg (4.20 mmol) of 2-amino-8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine in tetrahydrofuran (6.75 mL, 83.2 mmol) was mixed with 1.25 g (6.00 mmol, 1.42 eq.) of crude 2-bromo-2-methylpropanoyl isocyanate and stirred for 20 hours. The precipitate was filtered off, washed with ethyl ether and dried on air to give 2-Bromo-2-methyl-N-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)carbamoylpropanamide. Weight 2.21 g (75%). MS (ESI+): 488.0
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7](I)=[C:6]([O:11][CH2:12][C:13]([CH3:15])=[CH2:14])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH:23](B(O)O)=[CH:24][CH2:25][CH2:26][CH3:27]>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[C:13]([CH2:15]/[CH:23]=[CH:24]/[CH2:25][CH2:26][CH3:27])([CH3:14])[CH2:12][O:11][C:6]=2[CH:5]=1)=[O:16]
Reactant: C=C(C)COc1cc(C(=O)OC)ccc1I
Reactant: CCCC=CB(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCC/C=C/CC1(C)COc2cc(C(=O)OC)ccc21
Temperature: 160 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-Iodo-3-(2-methyl-allyloxy)-benzoic acid methyl ester (65 mg, 0.2 mmol) in DMF (2 mL) were added Potassium carbonate (54 mg, 0.39 mmol), Tetrabutylammonium chloride (54 mg, 0.2 mmol), Palladium acetate (3.5 mg, 0.02 mmol) in DMF (5 mL) and 1-Penten-1-ylboronic acid, (26 mg, 0.23 mmol). The resulting mixture was stirred under microwave irradiation (160° C., 15 min), cooled to room temperature, filtered over silica, washed with water, dried over MgSO4 and concentrated. Column chromatography (silica gel, heptane/CH2Cl2: 4/6) afforded title compound as a slightly colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:38]([C:35]2[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:37][CH:36]=2)(=[O:40])=[O:39])[N:13]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(S(=O)(=O)NCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Yield: 55.6 %

Procedure:
The operation is carried out as in Stage 1 of Example 10 starting from 280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methylene chloride, 0.2 ml of triethylamine and 248 mg of 4-methoxy-benzenesulphonic acid chloride in place of the 4-methyl-benzenesulphonic acid chloride then agitation is carried out at ambient temperature for approximately one night. Then 2 ml of water is added, followed by extracting with 3×5 ml of methylene chloride, washing with 5 ml of saturated sodium chloride, drying, evaporating, impasting in 5 ml of ether then in 5 ml of pentane, separating, and drying. After chromatography on silica eluting with methylene chloride/CH3CN in a proportion of 70/30, 250 mg of expected product is thus obtained in the form of a beige solid.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:12])[CH2:5][C@@H:6]([NH3+:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([F:21])=[CH:16][N:15]=1.C(N(CC)CC)C.O>O1CCCC1.CCO.ClCCl>[Cl:13][C:14]1[N:19]=[C:18]([NH:11][C@@H:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[CH2:5][C:4]([O:3][CH3:2])=[O:12])[C:17]([F:21])=[CH:16][N:15]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COC(=O)C[C@@H]([NH3+])C(C)(C)C
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)C[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Temperature: 55 °C

Procedure:
(R)-1-methoxy-4,4-dimethyl-1-oxopentan-3-aminium chloride, 5a, (37 g, 189 mmol) was dissolved in a mixture of tetrahydrofuran (667 mL) and EtOH (74 mL). The solution was cooled in an ice bath. 2,4-dichloro-5-fluoro-pyrimidine (35 g, 208 mmol) was added, followed by the dropwise addition of triethylamine (85 mL, 606 mmol). The reaction mixture was heated at 55° C. for 17 h. The reaction mixture was then cooled to room temperature after which water (625 mL) and dichloromethane (625 mL) were added. The phases were separated and the aqueous layer was washed with dichloromethane (625 mL). The organic layers were combined and washed with brine. The solvents were removed and the residue was purified on silica gel (EtOAc/Hexanes): LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT=3.10 minutes (M+H) 291.02.
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C:10](=[O:13])[N:9]1[C:14]1[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>>[Cl:20][C:19]1[C:14]([N:9]2[C:10](=[O:13])[CH2:11][CH2:12][C@H:8]2[C:6]([OH:7])=[O:5])=[N:15][CH:16]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:18]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1c1ncc(C(F)(F)F)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CCC(=O)N1c1ncc(C(F)(F)F)cc1Cl
Reaction time: 1 h

Procedure:
(S)-1-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-5-oxo-pyrrolidine-2-carboxylic acid tert-butyl ester (760 mg, 2.1 mmol) is treated with pre-cooled trifluoroacetic acid (5 mL). The clear solution is kept at room temperature for 1 h. Trifluoroacetic acid is evaporated in vacuo and the concentrate is treated with ice/water. Precipitated white solid is filtered, washed with water to give the title compound, ESI m/z 309 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([O:25][CH3:26])[N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=1)[CH3:9])=[O:6].[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>>[CH3:26][O:25][C:23]1[CH:22]=[C:4]([CH:3]=[C:2]([NH:1][C:27](=[O:30])[CH2:28][CH3:29])[N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[CH:14][CH:15]=1)[CH3:9])=[O:6]
Reactant: COc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(N)n1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(OC)n1
Yield: 39 %

Procedure:
The title compound is prepared in 39% yield (11.2 mg) from 2-amino-6-methoxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)isonicotinamide (25 mg, 0.068 mmol, single enantiomer, Step-1) and propionyl chloride (19 mg, 0.20 mmol) by the similar manner in Step-2 of Example-8.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[Sn](Cl)(Cl)(Cl)Cl.O>ClCCl>[CH:8]1([C:11]([C:6]2[CH:5]=[C:4]([CH3:7])[S:3][C:2]=2[CH3:1])=[O:12])[CH2:10][CH2:9]1
Reactant: Cc1ccc(C)s1
Reactant: O=C(Cl)C1CC1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(=O)C2CC2)c(C)s1
Temperature: 25 °C

Procedure:
2,5 Dimethylthiophene (50 g, 0.446 mole) and cyclopropylcarbonyl chloride (54.36 g, 0.52 mole) were dissolved in dichloromethane (500 ml) and cooled in an ice bath. Tin(IV) chloride (122.44 g, 0.470 mole) in dichloromethane (150 ml) was added slowly over 1 hour with stirring to form a deep red solution. The mixture was warmed to room temperature and stirred for a further hour. The mixture was then poured into cold water (750 ml) and stirred rapidly for 30 min. The dichloromethane layer was washed with cold water and dried over magnesium sulfate. The dichloromethane solvent was removed to give the ketone, 2,5-dimethyl-3-thienyl cyclopropyl ketone, as a brown oil (73.25 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=O.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].C1(N)CCCCC1>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:7]=[C:14]([N+:11]([O-:13])=[O:12])[CH3:15])[CH:9]=1
Reactant: CC[N+](=O)[O-]
Reactant: Cc1ccc(F)cc1C=O
Solvent: NC1CCCCC1
Solvent: CC(=O)O
Product: CC(=Cc1cc(F)ccc1C)[N+](=O)[O-]
Temperature: 80 °C
Yield: 84.2 %

Procedure:
A mixture of 5-fluoro-2-methylbenzaldehyde (50.0 g, 0.382 mol), nitroethane (54.34 g, 0.724 mol), and cyclohexylamine (35.90 g, 0.382 mol) in 300 mL of acetic acid was heated at 80° C. for 5-6 h under an argon atmosphere. After the end of the reaction was established by TLC, the reaction mixture was cooled to rt and the solvent was removed under vacuum. The residue was diluted with water, extracted with ethyl acetate three times. The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated under vacuum. Product was purified by a silica gel chromatography using ethyl acetate and hexanes (1:6 to 1:4) as eluent to afford 62.8 g (89%) of the designed compound as yellow solid. Mass (ESI, positive) m/z 217.9 [M+Na]+.
Reaction SMILES: [CH2:1]([P:11]([OH:13])[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].[O-:16][Mn](=O)(=O)=O.[K+].P(O)O.Cl.S(=O)(O)[O-].[Na+]>CC(C)=O.O>[CH2:1]([P:11](=[O:16])([OH:13])[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCCCCCCCCP(O)O
Agent: Cl
Agent: O=S([O-])O
Agent: OPO
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCP(=O)(O)O
Temperature: 25 °C

Procedure:
To a solution of n-decylphosphonous acid (1 g, 0.0048 mole) in acetone (10 ml) and water (10 ml) was added a solution of sodium hydroxide (0.19 gm, 0.0047 mole) in water (5 ml) until a pH of about 7 was reached. A solution of KMnO4 (0.46 gm, 0.0029 mole) in water (5 ml) was added solwly to the vigorously stirred solution of phosphonous acid at 20-25° C. After the addition (5 minutes), the reaction mixture was stirred for minutes at ambient temperature and acidified with concentrated HCl acid until a pH of 1 was reached. Saturated sodium bisulfite solution was added to the reaction mixture thereby resulting in formation of a precipitate.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:14]([C:15]([F:18])([F:17])[F:16])=[C:7]2[C:8]([O:10][C:11](=O)[NH:12][C:6]2=[CH:5][CH:4]=1)=[O:9].C[O-].[Na+].C(=O)=O>CO>[F:1][C:2]([F:19])([F:20])[C:3]1[C:14]([C:15]([F:18])([F:16])[F:17])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([NH2:12])=[CH:5][CH:4]=1
Reactant: O=c1[nH]c2ccc(C(F)(F)F)c(C(F)(F)F)c2c(=O)o1
Agent: C[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(N)ccc(C(F)(F)F)c1C(F)(F)F

Procedure:
The anhydride (195 g., 0.65 mol.) is suspended in 750 ml. of dry methanol and treated with sodium methoxide. The mixture is refluxed for 30 minutes until evolution of carbon dioxide stopped. The mixture is cooled, filtered, acidified with acetic acid and evaporated to yield methyl 5,6-bis(trifluoromethyl)anthranilate.
Reaction SMILES: O=[C:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH2:3]1.Cl.[NH2:19][OH:20].N1C=CC=CC=1>C(O)C>[OH:20][N:19]=[C:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH2:3]1
Reactant: NO
Reactant: O=C1Cc2ccccc2C=Cc2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1Cc2ccccc2C=Cc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 5-oxo-dibenzo[a,e]cyclooctene (1 g, Example 1, step E) in ethanol (40 ml) was added hydroxylamine hydrochloride (0.316 g) and pyridine (0.404 ml). This mixture was heated to reflux for 8hr, cooled to room temperature and evaporated to dryness. To the residue was added ethyl acetate (100 ml). water (100 ml),then sodium hydroxide (1M) until pH 10. The aqueous layer was extracted with ethyl acetate (200 ml), the combined organic layers were washed with water (100 ml), brine (100 ml) then dried and evaporated to yield the crude product. Recrystallisation from ethyl acetate-hexane gave pure 5-hydroxyimino-dibenzo[a,e]cyclooctene (0.72 g, m.p. 191°-192°C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH2:10].N1C=CC=CC=1>ClCCl>[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH:10][C:2](=[O:3])[O:4][CH2:5][CH3:6]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Yield: 98.2 %

Procedure:
10.7 g (98.9 mmol) of ethyl chloroformate was added dropwise to a mixture of 15.0 g (94.2 mmol) of 2-fluoro-5-nitroaniline, 8.20 g (104 mmol) of pyridine and 150 ml of dichloromethane at a temperature of not higher than 5° C. Thereafter the temperature was raised to room temperature and the reaction was continued for one night. After the dichloromethane layer was separated out by adding water to the reaction mixture, the dichloromethane layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. Thereafter the dichloromethane was distilled off to obtain the crude product (crystals). The crude product was washed with hexane, thereby obtaining 21.1 g of the objective product (yield: 98%) in the form of ocher crystals.
Reaction SMILES: C(OC([N:8]=[C:9]([NH:42]C(OC(C)(C)C)=O)[NH:10][C:11]1[CH:12]=[C:13]([CH:17]([O:22][P:23]([CH:26]([NH:30][S:31]([CH:34]=[CH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:33])=[O:32])[CH:27]([CH3:29])[CH3:28])([OH:25])=[O:24])[C:18]([O:20]C)=[O:19])[CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[Li+].[OH-]>C(Cl)Cl.CO.O>[NH:10]([C:11]1[CH:12]=[C:13]([CH:17]([O:22][P:23]([CH:26]([NH:30][S:31]([CH:34]=[CH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:32])=[O:33])[CH:27]([CH3:29])[CH3:28])([OH:25])=[O:24])[C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1)[C:9]([NH2:42])=[NH:8]
Reactant: COC(=O)C(OP(=O)(O)C(NS(=O)(=O)C=Cc1ccccc1)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)C(NS(=O)(=O)C=Cc1ccccc1)P(=O)(O)OC(C(=O)O)c1cccc(NC(=N)N)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1-(2-phenylethenylsulfonyl)amino-2-methylpropyl)(hydroxy)-phosphinoyloxy)ethanoic acid, methyl ester (220 mg) in 5 mL methylene chloride was added 1 mL TFA. The reaction mixture was stirred at ambient temperature for 4 hours, then concentrated in vacuo to get an oil. The oil was dissolved in 2.5 mL MeOH, then a solution of LiOH (100 mg) in 3 mL water was added. The reaction mixture was stirred at ambient temperature for 2 hours. The crude product was purified by HPLC directly without work up to afford 2-(3-guanidinophenyl)-2-((1-(2-phenylethenylsulfonyl)amino-2-methylpropyl)-(hydroxy)phosphinoyloxy)ethanoic acid, as a white solid (55 mg) NMR (DMSO-d6) 0.88 (m, 6), 2.10 (m, 1), 3.40 (m, 1), 5.63 (m, 1), 7.10-7.60 (m, 11), 9.80 (d, 1) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]([NH2:38])=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[C:1]([O:5][C:6]([N:8]([C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36](=[O:37])[NH2:38])=[CH:26][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2C(N)=O)cc1)C(=O)OC(C)(C)C
Yield: 74.9 %

Procedure:
A mixture of methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (1.8 g), 4'-bromomethylbiphenyl-2-carboxamide (1.8 g) and K2CO3 (0.86 g) in acetonitrile (25 ml) was heated for 6 hours under reflux. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over MgSO4. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel to afford a yellow syrup (2.3 g, 90%).
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[Cl:15][C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:16]([Cl:15])(=[O:18])[O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[Si](C)(C)CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)Cl
Reaction time: 0.25 h

Procedure:
To a solution of 2-trimethylsilylethanol (5.0 g, 42.3 mmol) in dichloromethane (35 mL) at 0° C. was added triethylamine (4.7 g, 46.5 mmol). To this stirred solution was added dropwise a solution of triphosgene (4.40 g, 14.8 mmol) in dichloromethane (15 mL); a white precipitant was formed immediately. The mixture was stirred at low temperature for 15 minutes, the ice bath removed, and the mixture was stirred for an additional 1 hour at room temperature. After 1 hour, the white precipitant was filtered and washed with dichloromethane (˜60 mL). The combined filtrate and washings were concentrated. The resultant oily carbonochloridate was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[N:15][C:16](=S)[C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.[CH3:22][NH2:23]>CO.C(=O)([O-])[O-].[Ag+2]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[N:15][C:16](=[N:23][CH3:22])[C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1
Reactant: CN
Reactant: FC(F)(F)C(=S)N=c1ccccn1Cc1ccc(Cl)nc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CO
Product: CN=C(N=c1ccccn1Cc1ccc(Cl)nc1)C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
150 mg (0.45 mmol) of the N-[1-((6-chloropyridin-3-yl)methyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoroethanethioamide (1-20) synthesized by the method in Synthetic Example 4 was dissolved in 5 ml of methanol, 105 μl (42 mg, 1.36 mmol) of methylamine (40% methanol solution) and 124 mg (0.45 mmol) of silver carbonate were added thereto, and the resulting mixture was stirred at 50° C. for 1 hour. After the reaction was completed, the reaction solution was returned to room temperature and subjected to suction filtration by using celite to remove insoluble materials. Ethyl acetate and water were added thereto to perform liquid separation, and the organic layer was dried over anhydrous magnesium sulfate, then concentrated under reduced pressure and purified with silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the subject material. Amount obtained 81 mg (yield 56%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1.CN(C=O)C.N#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[N:7]=3)=[O:23])=[CH:14][CH:15]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C(=O)Nc2nc3ccc(-c4ccncc4)nc3s2)cc1
Temperature: 120 °C
Yield: 50 %

Procedure:
The titled compound was prepared using a procedure analogous to that described in connection with 9 (Example 9). To a microwave vial, N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-4-tert-butylbenzamide (4A, 120 mg, 1.0 equivalent) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.2 equivalent) in dioxane (0.17 M) and DMF (0.51 M) was stirred in N2. Followed by addition of Na2CO3 (2 M aqueous solution, 8.0 equivalents) and PdCl2(dppf)/DCM adduct (0.05 equivalent). The mixture was heated at 120° C. for 10 minutes. After cooling to room temperature, the crude mixture was added saturated aqueous NaHCO3 and extracted with EtOAc twice. Combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography (SiO2, gradient of 1 to 10% MeOH/CH2Cl2) to give the titled compound 10 (50%) as a tan solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 7.61 (d, J=8.59 Hz, 2H) 8.08-8.16 (m, 4H) 8.27 (d, J=1.77 Hz, 2H) 8.72 (d, J=6.06 Hz, 2H) 13.07 (s, 1H); ESI-MS: m/z 389.0 (M+H)+.
Reaction SMILES: [Br:1]Br.ClCCl.[C:6]1([C:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][O:14][C:13]=2[C:23]([O:25][CH3:26])=[O:24])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[Br:1][C:15]1[O:14][C:13]([C:23]([O:25][CH3:26])=[O:24])=[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:16]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: BrBr
Reactant: COC(=O)c1occ(-c2ccccc2)c1-c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1oc(Br)c(-c2ccccc2)c1-c1ccccc1
Reaction time: 4 h

Procedure:
Bromine (0.18 ml) was added to a dichloromethane (10 ml) solution of methyl 3,4-diphenyl-2-furancarboxylate (1.00 g) at 0° C., and stirred at this temperature for 4 hours. The reaction solution was diluted with chloroform, and successively washed with water, saturated aqueous sodium hydrogencarbonate solution, and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure, thereby giving 1.28 g of methyl 5-bromo-3,4-diphenyl-2-furancarboxylate.
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:22]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[N:21]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:22]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[N:21]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: COC(=O)CC(c1ccc(OC)c(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3cc(C(CC(=O)O)C4CC4)ccc3OC)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-4-methoxyphenyl)propanoate (190 mg) in methanol (2.0 mL) and THF (4.0 mL) was added 1N aqueous sodium hydroxide solution (4.5 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added to the residue to adjust to pH<4. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (144 mg) as a white solid.