Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.NC1C=CC=CC=1.[OH:26][C:27]1[CH:28]=[C:29]([C:33](=[O:43])[CH2:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH:30]=[CH:31][CH:32]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.COCCOC.CO.[Cu]I.CS(C)=O>[NH2:18][C:14]1[C:13]([C:9]2[N:10]([CH2:11][CH3:12])[C:4]3[CH:3]=[C:2]([O:26][C:27]4[CH:28]=[C:29]([C:33](=[O:43])[CH2:34][CH2:35][CH2:36][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:30]=[CH:31][CH:32]=4)[N:7]=[CH:6][C:5]=3[N:8]=2)=[N:17][O:16][N:15]=1
Reactant: O=C(CCCN1CCOCC1)c1cccc(O)c1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Br)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: Nc1ccccc1
Solvent: COCCOC
Product: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(C(=O)CCCN4CCOCC4)c3)cc21
Temperature: 170 °C
Yield: 43 %

Procedure:
Under argon, to a suspension of 4-(6-bromo-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-furazan-3-amine (prepared by the method of Example 8, Steps 3-7, substituting ethylamine for aniline in Step 3) (80 mg, 0.26 mmol) in toluene (4 mL) and DME (4 mL), was added the product of Step 4 (78 mg, 0.31 mmol), CuI (50 mg, 0.26 mmol), 1,10-phenanthroline (94 mg, 0.52 mmol), and Cs2CO3 (170 mg, 0.52 mmol). This mixture was then heated to 170° C. by microwave for 15 min. The reaction mixture was added DMSO (1.5 mL), diluted with EtOAC/MeOH, sonicated for 10 min, then filtered and concentrated. The residue was purified with reverse phase HPLC (10% MeCN/H2O→80% MeCN/H2O, containing 0.1% TFA), to afford the title compound as a pale yellow solid (66 mg, 43%). MS (ES+) m/e 478 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][CH3:30])[C:26]([C:31]([F:34])([F:33])[F:32])=[CH:25][N:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[CH3:9][O:8][C:7]1[C:2]([NH:1][C:23]2[N:28]=[C:27]([NH:29][CH3:30])[C:26]([C:31]([F:34])([F:32])[F:33])=[CH:25][N:24]=2)=[CH:3][C:4]([C:18]([F:21])([F:20])[F:19])=[C:5]([C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])[CH:6]=1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: COc1cc(C(=O)N2CCOCC2)c(C(F)(F)F)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1nc(Nc2cc(C(F)(F)F)c(C(=O)N3CCOCC3)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 74.7 %

Procedure:
A mixture of (4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (94 mg, 0.31 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (66 mg, 0.31 mmol) and para-toluene sulfonic acid (59 mg, 0.31 mmol) in dioxane (4 mL) was heated to 100° C. for 2 h. Saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was purified by reversed phase HPLC to give (5-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-(trifluoromethyl)phenyl)(morpholino)methanone (111 mg, 75%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=480 at 3.32 min. 1H NMR (400 MHz, CDCl3): δ 9.13 (s, 1H), 8.19 (s, 1H), 7.82 (s, 1H), 6.77 (s, 1H), 5.34 (q, J=4.7 Hz, 1H), 3.97 (s, 3H), 3.95-3.88 (m, 1H), 3.83-3.68 (m, 3H), 3.65-3.55 (m, 2H), 3.27-3.21 (m, 2H), 3.13 (d, J=4.7 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14](O)[CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[OH:18])[CH:6]=[C:7]([I:13])[C:8]=1[O:9][CH2:10][CH2:11][OH:12].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:15][CH2:16][C@H:17]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[O:18]2)[CH:6]=[C:7]([I:13])[C:8]=1[O:9][CH2:10][CH2:11][OH:12]
Reactant: COc1cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc(I)c1OCCO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(I)c1OCCO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 1-(3-methoxy-4-hydroxyethoxy-5-iodophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanediol (11.8 g, 21.5 mmol) in chloroform (100 mL) at 0° C. was added dropwise trifluoroacetic acid (9.82 g, 86.1 mmol) in chloroform (100 mL) over 30 minutes. The solution was stirred at 0° C. for 2 hours and then at room temperature for 1 hour. The reaction mixture was quenched with 1N NaOH and chloroform (100 mL) was added. The organic layer was washed with 1N NaOH solution, water and saturated NaCl solution, and then dried over MgSO4, filtered and evaporated in vacuo to an oil which was a cis and trans mixture. The trans isomer was isolated by column chromatography (silica, 1:1 hexane/ethyl acetate) (4.7 g, 41.4%) as the faster eluting isomer. 1H NMR (CDCl3): 1.99 (m, 2H); 2.47 (m, 2H): 3.83 (t, 2H); 3.84 (s, 3H); 3.87 (s, 3H); 3.89 (s, 6H); 4.16 (t, 2H); 5.18 (m, 2H); 6.62 (s, 2H); 6.96 (d, 1H); 7.39 (d, 1H).
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH2:15][OH:16])[CH:11]=[C:12]([CH3:14])[CH:13]=1.Cl.C(=O)(O)[O-:19].[Na+]>O.CC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[C:15]([OH:19])=[O:16]
Reactant: Cc1cc(Br)cc(CO)c1
Reactant: O=C([O-])O
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(Br)cc(C(=O)O)c1
Temperature: 25 °C

Procedure:
A solution of KMnO4 (39.3 g, 249 mmol) in water (600 mL) was added slowly to a solution of (3-bromo-5-methylphenyl)methanol (25.0 g, 124 mmol) in acetone (500 mL). The mixture was kept at reflux for 60 mins. After cooling to room temperature, the mixture was acidified with HCl (2N, 100 mL). A brown precipitate formed and was dissolved by adding a solution of saturated sodium bicarbonate (100 mL); then acetone was evaporated in vacuum. Ammonia (150 mL) was added. The mixture was filtered over Celite and the filtrate acidified with concentrated HCl. The product was extracted with diethyl ether (3×150 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuum to obtain 16.0 g of the acid, 3-bromo-5-methylbenzoic acid, as white crystals (yield: 60%). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.85-7.84 (m, 1H), 7.58 (s, 1H), 2.40 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:6]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][Cl:30])=[CH:23][CH:24]=2)[N:19]=[CH:18][N:17]=1>C(O)(C)C.C(OCC)C>[Cl:30][CH2:29][CH2:28][CH2:27][O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([NH:1][C:2]3[CH:3]=[N:4][N:5]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:6]=3)=[N:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(N)cn1
Reactant: ClCCCOc1ccc2c(Cl)ncnc2c1
Solvent: CC(C)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1
Temperature: 90 °C

Procedure:
A mixture of tert-butyl (4-amino-1H-pyrazol-1-yl)acetate (0.305 g, 1.55 mmol) and 4-chloro-7-(3-chloropropoxy)quinazoline (0.398 g, 1.55 mmol) in isopropanol (8 ml) was heated at 90° C. for 5 minutes and then allowed to cool to room temperature. The mixture was diluted with diethyl ether and then filtered to give tert-butyl (4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)acetate as the hydrochloride salt (0.674 g, 96% yield):
Reaction SMILES: Br[C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1.C(=NO)C1C(=CC=CC=1)O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH:15]1[CH:19]=[CH:18][C:17]([C:2]2[C:10]3[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[O:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[N:16]1
Reactant: Brc1cccc2oc3ccccc3c12
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)oc1cccc(-c3cc[nH]n3)c12
Yield: 78 %

Procedure:
Under nitrogen current, a mixture containing 12.35 g (50 mmol) of bromodibenzofuran (Compound 16-1), 5.11 g (75 mmol) of pyrazole, 358 mg (2.5 mmol) of cuprous oxide (I), 1.37 g (10 mmol) of salicylaldoxime, 32.6 g (100 mmol) of cesium carbonate, and 100 ml of DMF is reacted under reflux with heating for 6 hours. DMF is distilled off from the resulting mixture by heating under reduced pressure. Ethyl acetate is added to the residue and the mixture is filtered with Celite, and a 1M sodium hydroxide aqueous solution is added to the obtained liquid. Organic layers extracted from the obtained mixture with ethyl acetate are dried with sodium sulfate. The organic layers are concentrated and refined by silica gel column chromatography to obtain 9.12 g (39 mmol) of Compound 17-1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)/[C:8]([OH:10])=[O:9])[N:6]=1.N12CCN(CC1)CC2.[P:27](Cl)([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[S:28].O>CC(N(C)C)=O>[CH2:30]([O:29][P:27]([O:9][C:8](=[O:10])/[C:7](/[C:5]1[N:6]=[C:2]([NH2:1])[S:3][CH:4]=1)=[N:11]\[O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)([O:32][CH2:33][CH3:34])=[S:28])[CH3:31]
Reactant: CCOP(=S)(Cl)OCC
Reactant: Nc1nc(/C(=N/OC2CCCCO2)C(=O)O)cs1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOP(=S)(OCC)OC(=O)/C(=N\OC1CCCCO1)c1csc(N)n1
Temperature: 2 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 30 g (Z)-(RS)-(2-aminothiazol-4-yl)-[(tetrahydropyran-2-yloxyimino)]-acetic acid (80.5 mmol) and 90 mg 1,4-diazabicyclo[2.2.2]octane (DABCO) (0.80 mmol) in 300 ml dimethylacetamide was added under argon over 45 min 17 ml diethyl chlorothiophosphate (104.9 mmol). Stirring was continued at 0° C. for 1 h. The reaction was followed by HPLC. To the slightly turbid reaction mixture was added dropwise over 50 min 450 ml water. The precipitated product was filtered, washed with water and dissolved in dichloromethane. The aqueous layer was back-extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure until the product started to crystallize. To the residual solution was added dropwise over 30 min n-hexane. The resulting suspension was cooled to 2° C., stirred for 1 h and then filtered. The crystalline product was washed with n-hexane and dried to constant weight. (Z)-(RS)-(2-aminothiazol-4-yl)-[(tetrahydropyran-2-yloxyimino)]-acetic acid diethoxythio-phosphoryl ester was obtained as a white solid (28.01 g, yield=82%) and was stored under argon at -20° C. No further purification was necessary and the product was used as isolated for the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.CCCCCC>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][C:11]([F:10])([F:20])[F:21])=[CH:14][CH:15]=2)[N:3]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: FC(F)(F)Oc1ccc(Nc2nc(Cl)cc(Cl)n2)cc1

Procedure:
The title compound was prepared by reacting 2,4,6-trichloro pyrimidine (2 g, 10 mmol) with 4-trifluoromethoxy aniline (1.94 g, 10 mmol) in presence of triethylamine (5.5 g, 50 mmol) in a solvent chloroform: hexane (1:1, 20 mL) at reflux temperature for 7 hours.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>C(OCC)(=O)C>[O:18]=[C:17]1[C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][C:14](=[O:16])[O:19]1
Reactant: O=C(O)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: O=C1C[C@@H](NC(=O)OCc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
A stirred suspension of N-(benzyloxycarbonyl)-D-aspartic acid (14.7 g, 55.1 mmol) in ethyl acetate (100 mL) was treated dropwise with thionyl chloride (40 mL, 511 mmol) and the resulting homogeneous mixture was stirred at room temperature for 16 hours, and concentrated. The resulting solid was triturated in 1:1 diethyl ether/hexanes (200 mL) for 2 hours and filtered. The solid was dried to provide the desired product (13.7 g, 99%).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[CH:16]=[CH:15][C:11]2[N:12]=[CH:13][S:14][C:10]=2[CH:9]=1>C(N(CC)CC)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][Si:2]([C:5]#[C:6][C:8]1[CH:16]=[CH:15][C:11]2[N:12]=[CH:13][S:14][C:10]=2[CH:9]=1)([CH3:4])[CH3:3]
Reactant: Brc1ccc2ncsc2c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2ncsc2c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Trimethylsilylacetylene (106 ml), copper (I) iodide (0.948 g), and bis(triphenylphosphine) palladium(II) dichloride (1.75 g) were added to 6-bromobenzothiazole (53.3 g) in triethylamine (260 ml), and the mixture was stirred for 2.5 hours at 80° C. After the solvent was evaporated, the resultant residue was loaded on a short column (silica gel; hexane:ethyl acetate=2:1) for elution. The residue from the eluate was recrystallized from a mixed solvent of hexane-ethyl acetate, and consequently, 6-trimethylsilanylethynylbenzothiazole (20.0 g) was obtained as a colorless powder (mp: 104.5-105.0° C.). By repeated subjecting the filtrate to recrystallization repeated (n-hexhane-ethyl acetate), secondary crystals (12.1 g), tertiary crystals (9.68 g), and quaternary crystals (4.61 g) were obtained as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:17][CH2:16]2)=[CH:11][C:5]=1[CH:6]=[CH:7][C:8]([OH:10])=[O:9])([O-])=O.[OH-].[Na+]>Cl.CO>[NH2:1][C:4]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:19][CH2:20]2)=[CH:11][C:5]=1[CH:6]=[CH:7][C:8]([OH:10])=[O:9]
Reactant: COc1ccc(C(=O)N2CCN(c3ccc([N+](=O)[O-])c(C=CC(=O)O)c3)CC2)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)N2CCN(c3ccc(N)c(C=CC(=O)O)c3)CC2)cc1OC
Reaction time: 2 h
Yield: 56.3 %

Procedure:
2-Nitro-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]cinnamic acid (12 g) was dissolved in 60 ml of concentrated hydrochloric acid and to the resulting solution was added dropwise a solution of 20 g of stannous chloride in 40 ml of concentrated hydrochloric acid at room temperature. After stirring for 2 hours crystals which precipitated were collected by filtration. The crystals thus-obtained was dissolved in 240 ml of methanol and the solution was neutralized with 10% aqueous sodium hydroxide solution to precipitate crystals, which then were collected by filtration. After concentrating the methanol solution, the residue was recrystallized from ethanol to give 6.3 g of 2-amino-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]cinnamic acid, m.p. 168°-170.5° C., pale yellow powders.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.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>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=1
Reactant: OB(O)c1ccccc1O
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2O)nc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 50.2 %

Procedure:
To a round bottom flask containing (2-hydroxyphenyl)boronic acid (1.37 g, 9.9 mmol) in 1,4-dioxane:water (8:1, 40 ml) was added methyl 6-chloronicotinate (1.71 g, 10.0 mmol), potassium carbonate (4.14 g, 30.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.3 g, 0.26 mmol) and the resulting mixture stirred at 80° C. for 10 h, then stood at r.t. for 72 h. The solution was acidified to pH 1 with aqueous 2 N HCl and concentrated in vacuo to a volume of approximately 5 ml. This solution was then partitioned between saturated sodium hydrogen carbonate (30 ml) and dichloromethane:methanol (95:5, 150 ml). The layers were separated and the aqueous layer extracted with dichloromethane (50 ml). The organic layers were combined and dried with anhydrous MgSO4, filtered and concentrated to afford a yellow solid. The solid was recrystallised from ethyl acetate/methanol to give the title compound as a yellow solid (1.14 g) (50%). 1H NMR (400 MHz, CDCl3) □ ppm 9.16 (1H, s), 8.46-8.40 (1H, m), 8.02-7.96 (1H, m ), 7.86-7.80 (1H, m), 7.39-7.33 (1H, m), 7.10-7.04 (1H, m), 6.96-6.90 (1H, m), 4.00 (3H, s). LRMS: AP m/z 230 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].Cl[CH2:10][C:11](=[O:13])[CH3:12].[Cl:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][CH:24]=[O:25])=[CH:17][CH:16]=1>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([N:23]([CH2:10][C:11](=[O:13])[CH3:12])[CH:24]=[O:25])=[CH:17][CH:16]=1
Reactant: CC(=O)CCl
Reactant: COc1nc(Cl)ccc1NC=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1nc(Cl)ccc1N(C=O)CC(C)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Cesium carbonate (20.5 g), potassium iodide (521 mg) and chloroacetone (5.0 mL) were added to a solution of N-(6-chloro-2-methoxypyridin-3-yl)formamide (5.85 g) in DMF (34.3 mL), and the reaction solution was stirred at 100° C. for one hour. Ice water and chloroform were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 4.71 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [N:1]1([C:7]2[C:15]([F:16])=[CH:14][C:13]([S:17]([N:20]3[CH2:25][C@H:24]([CH3:26])[CH2:23][C@H:22]([CH3:27])[CH2:21]3)(=[O:19])=[O:18])=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[CH2:6][CH2:5]C[CH2:3][CH2:2]1.N1(C2C(F)=CC(S(N3CCOCC3)(=O)=O)=CC=2C(O)=O)CCCCC1.C(N(CCCC)C1C(Cl)=CC(S(N2C[C@H](C)C[C@H](C)C2)(=O)=O)=CC=1C(O)=O)CCC.N1(C2C(Cl)=CC(S(N(CC)CC)(=O)=O)=CC=2C(O)=O)CCCCC1.N1(C2C(C)=CC(S(NC3C=CC=CC=3)(=O)=O)=CC=2C(O)=O)CCCCC1.C(N(C1C(C(F)(F)F)=CC(S(N2C[C@H](C)C[C@H](C)C2)(=O)=O)=CC=1C(O)=O)CCC)C.C(N(CC)C1C=C(F)C(S(NCCCC2C=CC(Br)=CC=2)(=O)=O)=CC=1C(O)=O)C.N1(C2C=C(Cl)C(S(NC3C=CC=C(Cl)C=3)(=O)=O)=CC=2C(O)=O)CCCCC1.C(N(C(C)C)C1C=C(C)C(S(N2CCCCC2)(=O)=O)=CC=1C(O)=O)(C)C.N1(C2C=CC(S(NC3C=CC(Cl)=C(Cl)C=3)(=O)=O)=C(F)C=2C(O)=O)CCCCC1.C(N(CC)C1C=CC(S(N2CCOCC2)(=O)=O)=C(F)C=1C(O)=O)C.N1(C2C=CC(S(N3CCC(C)(C)CC3)(=O)=O)=C(F)C=2C(O)=O)CCCCC1.C(N(CC)C1C(F)=CC(S(N(C)CCC2C=CC=CC=2Cl)(=O)=O)=CC=1C(O)=O)C.C(N(CCC)C1C=CC(S(N(CCCC)C2C=CC(Cl)=C(Cl)C=2)(=O)=O)=C(F)C=1C(O)=O)CC.N1(C2C=CC(S(N(CCCC)C3C=CC(Cl)=C(Cl)C=3)(=O)=O)=C(F)C=2C(O)=O)CCCCC1>>[CH2:6]([N:1]([CH2:2][CH3:3])[C:7]1[C:15]([F:16])=[CH:14][C:13]([S:17]([N:20]2[CH2:25][C@H:24]([CH3:26])[CH2:23][C@H:22]([CH3:27])[CH2:21]2)(=[O:18])=[O:19])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[CH3:5]
Reactant: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2cc(F)c(N3CCCCC3)c(C(=O)O)c2)C1
Agent: CC1(C)CCN(S(=O)(=O)c2ccc(N3CCCCC3)c(C(=O)O)c2F)CC1
Agent: CCCCN(CCCC)c1c(Cl)cc(S(=O)(=O)N2C[C@H](C)C[C@H](C)C2)cc1C(=O)O
Agent: CCCCN(c1ccc(Cl)c(Cl)c1)S(=O)(=O)c1ccc(N(CCC)CCC)c(C(=O)O)c1F
Product: CCN(CC)c1c(F)cc(S(=O)(=O)N2C[C@H](C)C[C@H](C)C2)cc1C(=O)O

Procedure:
2-piperidino-3-fluoro-5-(cis-3,5-dimethylpiperidinosulfonyl)benzoic acid; 2-piperidino-3-fluoro-5-morpholinosulfonylbenzoic acid; 2-hexamethyleneimino-3-fluoro-5-morpholinosulfonylbenzoic acid; 2-di-n-butylamino-3-chloro-5-(cis-3,5-dimethylpiperidinosulfonyl)benzoic acid; 2-piperidino-3-chloro-5-diethylaminosulfonylbenzoic acid; 2-piperidino-3-methyl-5-phenylaminosulfonylbenzoic acid; 2-hexamethyleneimino-3-chloro-3-piperidinosulfonylbenzoic acid; 2-(N-ethyl-N-n-propylamino)-3-trifluoromethyl-5-(cis-3,5-dimethylpiperidinosulfonyl)benzoic acid; 2-diethylamino-4-fluoro-5-(3-p-bromophenylpropylaminosulfonyl)benzoic acid; 2-piperidino-4-chloro-5-(3-chlorophenylaminosulfonyl)benzoic acid; 2-hexamethyleneimino-4-chloro-5-hexamethyleneiminosulfonylbenzoic acid; 2-di-i-propylamino-4-methyl-5-piperidinosulfonylbenzoic acid; 2-di-n-butylamino-4-methoxy-5-hexamethyleneiminosulfonylbenzoic acid; 2-piperidino-6-fluoro-5-(3,4-dichlorophenylaminosulfonyl)benzoic acid; 2-diethylamino-6-fluoro-5-morpholinosulfonylbenzoic acid; 2-piperidino-6-fluoro-5-(4,4-dimethylpiperidinosulfonyl)benzoic acid; 2-diethylamino-3-fluoro-5-(N-methyl-N-[2-chlorophenethyl]aminosulfonyl)benzoic acid; 2-piperidino-3-fluoro-5-(N-ethyl-N-[2-p-chlorophenethyl]aminosulfonyl)benzoic acid; 2-hexamethyleneimino-3-methyl-5-(N-methyl-N-phenylaminosulfonyl)benzoic acid; 2-di-n-propylamino-6-fluoro-5-(N-n-butyl-N-[3,4-dichlorophenyl]aminosulfonyl)benzoic acid; and 2-piperidino-6-fluoro-5-(N-n-butyl-N-[3,4-dichlorophenyl]aminosulfonyl)benzoic acid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[N:13][C:12]=1[CH2:24][Br:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)NCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1nc(CBr)c(C(=O)NCc2ccccc2)s1
Yield: 58.3 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-4-methylthiazole-5-carboxylic acid benzylamide (0.108 g, 0.31 mmol) in acetonitrile (10 mL) was added N-bromosuccinimide (0.071 g, 0.40 mmol). The resultant mixture was stirred at ambient temperature until the reaction was completed. The reaction mixture was concentrated in vacuo and the crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (5/95 to 100/0) to afford 2-(tert-butoxycarbonylamino)-4-bromomethylthiazole-5-carboxylic acid benzylamide (0.077 g, 58% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][CH:12](O)[CH:13]([CH3:16])[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].BrC1C(C)=CC(C)=CC=1C.CN(C)C=O>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.O>[Cl:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:11]=[C:12]([CH:13]([CH3:16])[CH2:14][CH3:15])[NH:1]2)=[CH:4][C:5]=1[O:9][CH3:10]
Reactant: CCC(C)C(O)Cc1cc(OC)c(Cl)cc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)c1cc2cc(OC)c(Cl)cc2[nH]1
Temperature: 160 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
A mixture of 1-(2-amino-4-chloro-5-methoxyphenyl)-3-methylpentan-2-ol (602 mg), tetrakis(triphenylphosphine)palladium (0) (135 mg), potassium carbonate (646 mg), 2-bromomesitylene (0.420 mL) and N,N-dimethylformamide (11.7 mL) was stirred at 160° C. for one hour under microwave irradiation. The reaction mixture was allowed to cool to ambient temperature. Water was added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (514 mg).