Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:13][C@H:12]([O:14][C:15]2[C:16]3[C:30]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)=[CH:29][N:28](COCC[Si](C)(C)C)[C:17]=3[N:18]=[C:19]([NH:21][C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)[N:20]=2)[CH2:11]1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O.O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO>[CH3:1][NH:2][C@H:10]1[CH2:13][C@H:12]([O:14][C:15]2[C:16]3[C:30]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)=[CH:29][NH:28][C:17]=3[N:18]=[C:19]([NH:21][C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)[N:20]=2)[CH2:11]1
Reactant: Cn1cc(Nc2nc(O[C@H]3C[C@H](N(C)C(=O)OC(C)(C)C)C3)c3c(-c4cccnc4)cn(COCC[Si](C)(C)C)c3n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H]1C[C@H](Oc2nc(Nc3cnn(C)c3)nc3[nH]cc(-c4cccnc4)c23)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl methyl{trans-3-[(2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(pyridin-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}carbamate (250 mg, 0.4 mmol) in DCM (10 mL) was added TFA (0.33 mL). The reaction solution was stirred at ambient temperature for 20 hrs. The volatiles were removed in vacuo to give a residue, which was dissolved in methanol (8 mL). Water (4 mL) and solid K2CO3 (223 mg) were added, and the mixture was stirred at ambient temperature for 2 hrs. The volatiles were then removed in vacuo to give the title compound that was used as crude in the next step.
Reaction SMILES: COC1N=C(SC2C=CC=C(Cl)C=2C([O-])=O)N=C(OC)C=1.[Na+].CO[C:25]1[N:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34](OC3N=C(OC)C=C(OC)N=3)[C:33]=2[C:49]([O-:51])=[O:50])[N:28]=[C:27](OC)[CH:26]=1.[Na+].C/C(/C1C=CC=C(OC2N=C(OC)C=C(OC)N=2)C=1C(OC)=O)=N/OC.COC1N=C(OC2C=CC=C(OC3N=C(OC)C=C(OC)N=3)C=2C(ON=C(C2C=CC=CC=2)C2C=CC=CC=2)=O)N=C(OC)C=1.CC1OC(=O)C2C(SC3N=C(OC)C=C(OC)N=3)=CC=CC1=2.COCC1C=CC=C(C(O)C2N=C(OC)C=C(OC)N=2)C=1NS(C(F)F)(=O)=O>>[N:28]1[CH:27]=[CH:26][CH:25]=[N:30][C:29]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:49]([OH:51])=[O:50]
Reactant: COc1cc(OC)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)[O-])n1
Agent: CO/N=C(/C)c1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OC
Agent: COCc1cccc(C(O)c2nc(OC)cc(OC)n2)c1NS(=O)(=O)C(F)F
Agent: COc1cc(OC)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)ON=C(c2ccccc2)c2ccccc2)n1
Product: O=C(O)c1ccccc1Oc1ncccn1

Procedure:
such as pyrithiobac-sodium, bispyribac-sodium, pyriminobac-methyl, pyribenzoxim, pyriftalid, and pyrimisulfan;
Reaction SMILES: C(P(CCCC)CCCC)CCC.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30](/[C:33](/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:34]/[CH2:35]O)=[CH:29][CH:28]=1>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:35]/[CH:34]=[C:33](/[C:30]2[CH:29]=[CH:28][C:27]([Br:26])=[CH:32][CH:31]=2)\[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:20][CH:19]=1
Reactant: OC/C=C(\c1ccccc1)c1ccc(Br)cc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC/C=C(\c2ccccc2)c2ccc(Br)cc2)cc1
Reaction time: 1 h
Yield: 81.2 %

Procedure:
Azodicarboxylic dipiperidide (0.756 g, 3.0 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (0.94 ml, 786 mg, 3.0 mmol), methyl 4-hydroxyphenylacetate (332 mg, 2.0 mmol) and (E)-3-(4-bromo-phenyl)-3-phenyl-prop-2-en-1-ol (578 mg, 2.0 mmol) in dry THF (25 ml), the mixture was stirred for 1 h. The mixture was filtered and concentrated I vacuo. The residue was purified by flash chromatography on silica gel (toluene as eluent) to give 710 mg (81%) of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:8]
Reactant: C1COCCN1
Reactant: O=C(Cl)Cc1cccs1
Solvent: ClCCl
Product: O=C(Cc1cccs1)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(2-Thienyl)acetyl chloride (16 g) was added slowly to a stirred mixture of morpholine (17.5 ml) and methylene chloride (150 ml). A further portion (5 ml) of morpholine was added and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was washed in turn with 2M aqueous hydrochloric acid, a saturated aqueous sodium bicarbonate solution and brine. The organic phase was dried and evaporated. The residue was triturated under a mixture of hexane and diethyl ether to give N-[2-(2-thienyl)acetyl]morpholine (20.9 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11](C2C=C(F)C=CC=2F)[C@H](C)CCCBr)(=[O:10])=[O:9])=[CH:4][CH:3]=1>CCOCC>[C:5]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: C[C@H](CCCBr)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CCOCC
Product: NS(=O)(=O)c1ccccc1
Temperature: 22 °C
Reaction time: 96 h
Yield: 50 %

Procedure:
To a solution of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-4-bromobutyl]benzenesulfonamide (0.194 g, 0.427 mmol) in ether (4 mL) was added AgNO2 (0.395 g, 2.56 mmol) at 22° C. The resulting mixture was allowed to stir at 22° C. for 4 days. The mixture was filtered and concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) of the concentrate afforded 0.0913 g of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-4-nitrobutyl]]-benzenesulfonamide as a light brown oil in 50% yield. MS (ESI) 419.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[C:14](Cl)(=[O:16])[CH3:15]>C(Cl)Cl>[C:14]([O:13][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([F:1])[CH:3]=1)[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: O=C1CCc2cc(O)cc(F)c2N1
Solvent: ClCCl
Product: CC(=O)Oc1cc(F)c2c(c1)CCC(=O)N2
Yield: 54 %

Procedure:
Crude 8-fluoro-6-hydroxy-3,4-dihydroquinolin-2(1H)-one (0.574 g) was treated with acetyl chloride (330 mg) and TEA (0.68 mL) in DCM (8 mL) over 3 h. After aqueous work-up with EtOAc/water, the crude product was purified with a flash column chromatography to afford the desired product (382 mg) as colorless solids.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:42]1[CH2:46][CH2:45][C@@H:44]([OH:47])[CH2:43]1>ClCCl>[O:24]1[C:23]2[CH:27]=[CH:28][C:20]([C:17]3([C:15]([NH:14][C:12]4[S:13][C:9]([CH:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[N:42]5[CH2:46][CH2:45][C@@H:44]([OH:47])[CH2:43]5)=[CH:10][N:11]=4)=[O:16])[CH2:18][CH2:19]3)=[CH:21][C:22]=2[O:26][CH2:25]1
Reactant: O=C(Nc1ncc(C(O)c2ccccc2Cl)s1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: O[C@@H]1CCNC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ncc(C(c2ccccc2Cl)N2CC[C@@H](O)C2)s1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33333.3 %

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid [5-[(2-chloro-phenyl)-hydroxy-methyl]-thiazol-2-yl]-amide (0.500 g, 1.17 mmol) was placed in 10 mL of anhydrous dichloromethane containing triethylamine (984 μL, 7.02 mmol). The mixture was cooled to 0° C. and methanesulfonyl chloride (364 μL, 4.68 mmol) was added, immediately followed by (R)-pyrrolidin-3-ol (945 μL, 11.7 mmol) and the solution was allowed to stir for 10 minutes at room temperature. The crude product was washed three times with an equal volume of a saturated aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium chloride. The organic layer was then dried over sodium sulfate and evaporated to dryness. The crude mixture was purified by column chromatography (20-90% ethyl acetate in hexanes on silica gel) to yield the product as a white solid (194.2 mg, 0.390 mol, 33.3%). 1H NMR (400 MHz, DMSO-d6) δ 1.09-1.15 (m, 2H), 1.41-1.44 (m, 2H), 1.54-1.63 (m, 1H), 1.93-2.77 (m, 5H), 4.20 (s, 1H), 4.72-4.77 (m, 1H), 4.96 (d, J=7.0 Hz, 1H), 6.00 (s, 2H), 6.85 (d, J=0.9 Hz, 2H), 6.95 (s, 1H), 7.24-7.29 (m, 1H), 7.37-7.43 (m, 3H), 7.76-7.80 (m, 1H), 11.03 (s, 1H). ESI-MS m/z calc. 497.1. found; 498.1 (M+1)+; Retention time 2.36 minutes.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]([NH:12][CH2:13][C:14]([C:16]3[CH:17]=[C:18]([Cl:21])[S:19][CH:20]=3)=[O:15])=[O:11])[CH:8]=[CH:9][C:2]1=2.[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]([NH:12][CH:13]([C:14]([C:16]3[CH:17]=[C:18]([Cl:21])[S:19][CH:20]=3)=[O:15])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:11])[CH:8]=[CH:9][C:2]1=2
Reactant: CCOC(=O)CBr
Reactant: O=C(CNC(=O)c1ccc2occc2c1)c1csc(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(NC(=O)c1ccc2occc2c1)C(=O)c1csc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-[(5-benzo[b]furoyl)aminoacetyl]-2-chlorothiophene (543 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (71.3 mg, 60% mineral oil) under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. After ice-cooling, ethyl bromoacetate (0.21 ml) was added dropwise to the mixture, and the resulting mixture was stirred at room temperature for 40 minutes. After cooling, 5% aqueous citric acid solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product of ethyl 3-[(5-benzo[b]furoyl)amino]-4-(5-chlorothiophen-3-yl)-4-oxobutyrate (896 mg).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=1.[OH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:20]([O:19][C:17](=[O:18])[C:16]1[CH:22]=[CH:23][C:13]([O:12][CH2:2][C:3]2[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=2)=[CH:14][CH:15]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: Cc1nc(C)c(CBr)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2nc(C)c(C)nc2C)cc1
Temperature: 85 °C
Yield: 63.3 %

Procedure:
Adding 2-bromomethyl-3,5,6-trimethylpyrazine (0.86 g, 0.0040 mol), ethyl p-hydroxybenzoate (0.948 g, 0.0057 mol), anhydrous potassium carbonate (1.38 g, 0.0103 mol), and DMF (60 mL) into a 100 mL three-necked bottle in turn, heating to 85° C. with oil bath, stirring to react for 12 hours, TLC [V(cyclohexane):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.5, Rf of product=0.4), and the reaction solution appears yellow, filtering to obtain yellow filtrate, adding 30 mL water, extracting with chloroform (3×30 mL), incorporating the chloroform layer and wishing with water (2×20 mL), drying with anhydrous sodium sulfate, recycling chloroform under reduced pressure to obtain a light yellow oily matter, separating with a silica column, wherein eluant is V(cyclohexane):V(ethyl acetate)=3:1, collecting product, rotating distilling to obtain light yellow solid, recrystallizing with anhydrous alcohol to obtain 0.76 g 4-((3,5,6-trimethylpyrazine-2-yl)methoxyl)benzoic acid ethyl ester, a yield is 63.3%, m.p. 75.0-75.7° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([C:11]3[N:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=3)[C:6]=2[CH:18]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].[C:54]([Si:58]([O:61][CH2:62][C:63]([CH3:67])([CH3:66])[C:64]#[CH:65])([CH3:60])[CH3:59])([CH3:57])([CH3:56])[CH3:55]>CN(C)C=O.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[C:54]([Si:58]([CH3:59])([CH3:60])[O:61][CH2:62][C:63]([CH3:67])([CH3:66])[C:64]#[C:65][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([C:11]3[N:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=3)[C:6]=2[CH:18]=1)([CH3:56])([CH3:57])[CH3:55]
Reactant: Cc1nc2ccc(Br)cc2n1-c1ncnc(N)n1
Reactant: C#CC(C)(C)CO[Si](C)(C)C(C)(C)C
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C#CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc2n1-c1ncnc(N)n1
Yield: 64.1 %

Procedure:
In a solution of 4-(6-bromo-2-methyl-benzoimidazol-1-yl)-[1,3,5]triazin-2-ylamine (0.15 g, 0.5 mmol) in N,N-dimethyl-formamide (3 ml) were added 1,3-bis(diphenylphosphino)propane (40 mg, 0.1 mmol), Pd(OAc)2 (10 mg, 0.05 mmol), K2CO3 (207 mg, 1.5 mmol), tert-butyl-(2,2-dimethyl-but-3-ynyloxy)-dimethyl-silane (150 mg, 1 mmol) and CuI (5 mg, 0.025 mmol). Then the solution bubbled N2 for 5 min and was microwaved for 1 h at 120° C. under nitrogen. The reaction mixture was filtrated and the filtrate was purified by column to afford 4-{6-[4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-1-ynyl]2-methyl-benzoimidazol-1-yl}-[1,3,5]triazin-2-ylamine (140 mg, 66%): LCMS m/z=+437.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[N+:18]([O-])([OH:20])=[O:19].Cl.N([O-])=O.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[C:5]([OH:17])=[C:6]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: O=C(O)c1cccc(-c2cc(Cl)ccc2O)n1
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cccc(-c2cc(Cl)cc([N+](=O)[O-])c2O)n1
Temperature: 5 °C
Yield: 29 %

Procedure:
To the solution of 6-(5-chloro-2-hydroxyphenyl)-pyridine-2-carboxylic acid; (2.3 g, 10.1 mmol) in 100 ml acetic acid; was added 1 ml fuming nitric acid; and stirred at 35° C. to 40° C. for half an hour. The reaction mixture was diluted with water and adjusted pH to 2.5. The resulting preciptation was collected, washed and dried to give solid (2.74 g; 78%, three steps). MS(ES) m/z 295 [M+H]. d) 3-Aza-3′-{N′-[1-(4-tert-butylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-5-carboxylic acid; Following the procedure of Example 1c), except substituting the compound of 4c) for the compound of 1b), the crude product was isolated. A suspension of the crude product (0.0015 mol.) in 1M aqu. hydrochloric acid; (25.0 mL) was cooled to 5° C. then treated dropwise with a solution of sodium nitrite (0.11 g; 0.0015 mol.) in water (5.0 mL). The yellow mixture was stirred at 5° C. for a further 10 min. then treated in one portion with the compound from Example 3a) (0.34 g, 0.0015 mol.) followed by the portion-wise addition of sodium hydrogen carbonate and ethanol ensuring the final pH of the reaction mixture is approximately 7-8. The red solution was then stirred at room temperature for 24 h. The mixture was filtered to give a red solid which was slurried in water (50.0 mL) and then acid;ified with concentrated hydrochloric acid;. Filtration afforded the title compound (0.2 g; 29%) as a powder. 1H NMR (300 MHz, d6-DMSO) δ 13.8 (br, 2H), 9.9 (s, 1H), 9.08 (s, 1H), 8.9 (s, 1H), 8.4 (s, 1H), 7.82 (d, J=7.7 Hz, 2H), 7.75 (d, J=7.9 Hz, 1H), 7.50 (d, J=7.0 Hz, 2H), 7.20 (m, 2H), 2.34 (s, 3H), 1.32(s, 9H) MS(ES) m/z 472 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[Cl:14][C:15]1[C:16]([O:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=2)=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1>C(OCC)C>[Cl:14][C:15]1[C:16]([O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]3[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=3[F:13])=[O:34])=[CH:28][CH:27]=2)=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1
Reactant: O=C=Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: CCOC(=N)c1c(F)cccc1F
Solvent: CCOCC
Product: CCOC(=NC(=O)Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)c1c(F)cccc1F
Temperature: 20 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
A mixture of ethyl 2,6-difluorobenzimidate (0.14 g), 3-chloro-5-trifluoromethyl-2-(4-isocyanatophenoxy)pyridine (0.24 g), and diethyl ether (10 ml) was stirred at 20° C. for 18 hours, after which the solvent was removed by evaporation and the residual solid recrystallised from petroleum ether (boiling range 60°-80° C.) to yield ethyl N-[4-(3-chloro-5-trifluoromethylpyrid-2-yloxy)phenylcarbamoyl]-2,6-difluorobenzimidate as a white solid (0.29 g), m.p. 127°-130° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CCCCC1>CN(C=O)C>[CH:48]1([NH:47][C:30](=[O:32])[C:29]2[CH:33]=[CH:34][C:35]([CH3:36])=[C:27]([C:10]3[C:11]4[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]5[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=5[F:25])[C:12]=4[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:37][CH3:38])[CH2:1][CH3:2])[N:9]=3)[CH:28]=2)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC3CCCCC3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and cyclohexanamine (11.5 uL, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9 mg, 30%). LC-MS m/z 603 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:15]=[CH:14][C:10]([CH2:11][C:12]#[N:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCCC1>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([C:11](=[C:20]([OH:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[C:17]([F:16])([F:27])[F:28])[C:12]#[N:13])=[CH:14][CH:15]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(C#N)=C(O)c2ccccc2C(F)(F)F)cc1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A mixture comprising 5.8 g of 63% sodium hydride and 137 ml of tetrahydrofuran was heated, and a mixture comprising 13.5 g of 4-tert-butylbenzyl cyanide, 15.0 g of 2-trifluoromethylbenzoyl chloride and 50 ml of tetrahydrofuran, was dropwise added thereto over a period of 2 hours under reflux. After completion of the dropwise addition, the reaction was carried out at the same temperature for 2 hours. Tetrahydrofuran in the reaction mixture was distilled off, and 250 ml of water was poured into the residue. Then, 80 ml of n-hexane was added thereto, and the mixture was stirred and washed for 10 minutes and then left to stand for 30 minutes. Then, the aqueous layer was separated. To the aqueous layer, 8.3 g of concentrated hydrochloric acid was gradually dropwise added with stirring, followed by further stirring for 30 minutes. Precipitated crystals were collected by filtration and washed with 100 ml of water and then dried at 55° C. for 24 hours to obtain 23.7 g of the desired product. The NMR spectrum data of this product were as follows.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[NH:14][N:13]=[N:12]1.[C:17](=O)([O-])[O-].[K+].[K+].CN(C)C=O.S(OC)(OC)(=O)=O>O>[CH3:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]1
Reactant: O=C([O-])[O-]
Reactant: CCOc1cccc(-n2nn[nH]c2=O)c1C
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cccc(-n2nnn(C)c2=O)c1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.1 %

Procedure:
Under ice-cooling, to a mixture of 1-(2-methyl-3-ethoxyphenyl)-1,4-dihydrotetrazole-5-one 39.0 g, potassium carbonate 36.7 g and N,N-dimethylformamide 400 mL was added dimethyl sulfate 44.7 g and the resulting mixtures were raised to room temperature and were stirred for seven hours. Thereto was added water and the mixtures were extracted with ethyl acetate and the organic layers were washed with water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure. The resulting residues were subjected to a silica gel column chromatography to give 1-(2-methyl-3-ethoxyphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 38.2 g.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH3:7])[C:3](Br)=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=1[OH:19].C(N(CC)CC)C>ClCCl>[Br:1][CH:2]([CH2:6][CH3:7])[C:3]([O:19][C:11]1[C:12]([O:17][CH3:18])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[O:9][CH3:8])=[O:4]
Reactant: CCC(Br)C(=O)Br
Reactant: COc1cc(C)cc(OC)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(Br)C(=O)Oc1c(OC)cc(C)cc1OC
Reaction time: 1.5 h

Procedure:
2-Bromobutyryl bromide (31.1 ml) was added to a stirred solution of 2,6-dimethoxy-4-methylphenol (45 g) in dry dichloromethane (500 ml), whereupon triethylamine (37.3 ml) was added dropwise over 30 minutes, maintaining the internal temperature below 10° C. using an ice-salt bath. During the addition a white precipitate formed. After addition was complete the reaction mixture was stirred for 1.5 hours, then filtered. The solid was washed with diethyl ether (200 ml) and the filtrate washed twice with saturated sodium bicarbonate solution (100 ml). The organic phase was dried over magnesium sulphate, filtered and the solvent removed under reduced pressure to give the crude product as an oil (79.4 g). To remove any residual starting phenol, the oil was dissolved in diethyl ether and washed with sodium hydroxide solution (0.1 M; 3×100 ml), then water (4×100 ml). The organic phase was dried over magnesium sulphate, filtered and the solvent removed under reduced pressure to give the title compound as a yellow oil (72.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:27]1[CH2:28][CH2:29][CH2:30][CH:26]1[CH3:25])=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1CCCN1C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 2-methylpyrrolidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.62 minutes; C21H20Cl2N4O2 (431.32); mass spectrum: (M+H)+=431.2.