Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]O.C(N(S(F)(F)[F:17])CC)C.C(=O)(O)[O-].[Na+].CCOCC>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][F:17]
Reactant: CCN(CC)S(F)(F)F
Reactant: OCCCCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: FCCCCCCCCBr
Temperature: -78 °C
Yield: 61.3 %

Procedure:
A solution of 8-bromooctan-1-ol (Hendry et al., J. Chem. Ecol., 1, 317, 1975), (2.50 g, 11.9 mmol) in methylene chloride (about 3 ml) is slowly added to a stirred solution of diethylaminosulfur trifluoride (DAST) (Middleton, J. Org. Chem, 40, 574, 1975) (1.5 mL, 11.9 mmol) in methylene chloride (10 mL), cooled to -78° C. After the addition is completed, the reaction mixture is warmed to 25° C. and saturated aqueous sodium bicarbonate (about 5 mL) is added, followed by dilution with ether (about 200 mL). The organic layer is then separated, and washed with water (20 mL), saturated sodium bicarbonate (20 mL) and then dried (MgSO4). The volatiles are removed in vacuo and the crude product is purified by flash chromatography using hexane/ethyl acetate, (95.5, v/v) to afford 8-bromo-fluoro-octane (1.54 g, 61%) as a clear colorless liquid: Rf=0.70, hexane/ethyl acetate (7:3, v/v); IR (film) ν2850-3000 (alkane CH) and 1H-NMR (CDCl3) δ1.15-2.0 (m, 12H), 3.39 (t, J=6 Hz, 2H), 4.42 (dt, J=48 Hz, 6 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:12](I)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([Cl:14])[CH:3]=1.[C:15]([OH:20])(=[O:19])[C:16]([CH3:18])=O.N12CCN(CC1)CC2>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:14][C:4]1[CH:3]=[C:2]2[C:12]([CH:18]=[C:16]([C:15]([OH:20])=[O:19])[NH:1]2)=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc(I)c(N)cc1Cl
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)O)[nH]c2cc1Cl
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 129 %

Procedure:
A solution of ethyl 4-amino-2-chloro-5-iodobenzoate (1.82 g, 5.59 mmol) in N,N-dimethylformamide (18 ml) under argon was admixed with pyruvic acid (1.27 ml, 18.2 mmol) and 1,4-diazabicyclo[2.2.2]octane, evacuated and flushed with argon. Then argon was passed through the solution for 5 min and then palladium(II) acetate (68 mg, 0.30 mmol) was added and the mixture was heated to 100° C. for 2 h. The cooled solution was filterd through Celite and the filtercake was rinsed with ethyl acetate (100 ml). The filtrate (suspension) was washed with hydrochloric acid (2 M; 2×25 ml) and with water (2×25 ml), dried over sodium sulphate and filtered. The filtrate was concentrated to dryness under reduced pressure and gave a red-brown solid (1.93 g, approx. 51% product), which was used for the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[CH:14]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])[C:15](=C)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)=[O:35]>C(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])=[C:15]([OH:35])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S=O
Reactant: C=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12

Procedure:
Following the ozonization procedures described in Example 9, a solution of 350 mg. of p-nitrobenzyl 7-phenylacetamido-3-methylenecepham-4-carboxylate in 250 ml. of methylene chloride was cooled to -78° C. and was ozonized. The intermediate ozonide was decomposed in situ with sulfur dioxide and the reaction product was recovered and obtained crystalline by extraction with ethyl acetate.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[CH:12][CH:11]=2)=[CH:6][N:5]=[C:4]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[CH:18]1([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]3[O:21][C:2]4[CH:3]=[C:4]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[N:5]=[CH:6][C:7]=4[N:8]=3)=[CH:11][CH:12]=2)[CH2:20][CH2:19]1
Reactant: C[C@@H](COc1cc(Cl)c(NC(=O)c2ccc(OCC3CC3)cc2)cn1)NC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COc1cc2oc(-c3ccc(OCC4CC4)cc3)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
A suspension of tert-butyl ((2S)-1-((4-chloro-5-((4-(cyclopropylmethoxy)benzoyl)amino)pyridin-2-yl)oxy)propan-2-yl)carbamate (500 mg), potassium carbonate (290 mg) and copper(I) iodide (20.0 mg) in DMF (10 mL) was stirred at 160° C. for 5 hr and 30 min under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained solid was washed with ethyl acetate/hexane to give the title compound (162 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:26]([C:25]3[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccc(F)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 54.2 %

Procedure:
In a similar fashion to compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (100.00 mg, 0.29568 mmol), 4-Fluorobenzaldehyde (40.4 mg, 0.325 mmol), and Ammonium acetate (45.6 mg, 0.591 mmol) were reacted to yield 70.9 mg (54%) of the title compound. (300 MHz, DMSO-d6) 13.42 (s, 1H), 8.06 (s, 1H), 7.99 (d, J=8 Hz, 1H), 7.90 (d, J=11 Hz, 1H), 7.76 (s, 1H), 7.61 (m, 1H), 7.33 (m, 1H), 7.24 (m, 2H) 6.39 (s, 2H), 5.21 (t, J=17 Hz, 8.5 Hz, 1H), 2.89 (s, 1H), 2.78 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS=444 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:13][C@@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.O>[CH3:19][C:16]1([CH3:20])[O:15][C@H:14]([CH2:13][O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:18][O:17]1
Reactant: COC(=O)c1cccc(O)c1
Reactant: CC1(C)OC[C@@H](CCl)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OC[C@@H]2COC(C)(C)O2)c1
Temperature: 160 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
A mixture of methyl 3-hydroxybenzoate (10.0 g, 65.8 mmol), (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (13.0 g, 98.7 mmol) and K2CO3 (18.0 g, 132 mmol) in DMF (100 ml) was stirred for 18 h at 160° C. The mixture was diluted with water (150 mL) and adjusted to pH=6 by the addition of 3N HCl. The mixture was extracted with ethyl acetate (200 ml×3) and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (10% Ethyl acetate in petroleum ether) to give (R)-methyl 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoate as a brown oil, (8.5 g, 49% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].[CH3:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:4]2[C:5](=[O:14])[C:6]3[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:15])=[CH:20][CH:19]=1
Reactant: COc1ccc(OCCCCCCBr)cc1
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Product: CCCn1cnc2c1c(=O)n(CCCCCCOc1ccc(OC)cc1)c(=O)n2C
Yield: 47 %

Procedure:
3-Methyl-7-propylxanthine and 6-(4-methoxyphenoxy)hexyl bromide were reacted and treated in substantially the same manner as described in Example 9 (a) to give 1-[6-(4-methoxyphenoxy)hexyl]-3-methyl-7-propylxanthine (47%).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][N:9]1[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[N:10]1.F[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1>O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([O:15][CH2:14][C:13]2[N:9]([CH3:8])[N:10]=[CH:11][CH:12]=2)=[N:18][CH:19]=1
Reactant: Fc1ccc(F)nc1
Reactant: Cn1nccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nccc1COc1ccc(F)cn1
Reaction time: 2 h
Yield: 58.4 %

Procedure:
60% Sodium hydride (390 mg) was added to a dimethylformamide (9.0 mL) solution of (1-methyl-1H-pyrazol-5-yl)methanol (1.00 g) at a room temperature, and the obtained solution was then stirred for 2 hours. Thereafter, 2,5-difluoropyridine (1.17 g) was added to the reaction solution, and the mixed solution was then stirred for 16 hours. Subsequently, water was added to the reaction solution, and the obtained mixture was then extracted with hexane/ethyl acetate (1/2). The organic layer was concentrated under a reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=95:5 to 60:40), so as to obtain the title compound (1.08 g) in the form of a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH:14]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1OC)[C:19]([NH2:21])=[O:20])=O>>[F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:14]/[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH2:21])=[O:20]
Reactant: Fc1cc(C(F)(F)F)ccc1CBr
Reactant: COc1ccc(C(N)=O)cc1C=O
Product: NC(=O)c1cccc(/C=C/c2ccc(C(F)(F)F)cc2F)c1

Procedure:
The captioned compound was synthesized from 2-fluoro-4-trifluoromethylbenzyl bromide and 3-formyl-4-methoxybenzamide by the same procedure as in the manufacturing method described in Example 2-3-6.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[C:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:13]=[C:12]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:8]=2[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+:32].C(C(C)=O)C(C)C>O>[CH:22]1([C:12]2[CH:13]=[C:14]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH:15]=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]=2[C:9]([O-:11])=[O:10])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[Na+:32]
Reactant: O=C(O)c1c(C2CCCCC2)cc(C2CCCCC2)cc1C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C([O-])c1c(C2CCCCC2)cc(C2CCCCC2)cc1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A 300-mL eggplant shaped flask was charged with 2.0 g of 2,4,6-tricyclohexylbenzoic acid (prepared in Synthesis Example 1-5), 0.5 g of sodium hydrogencarbonate, 10 g of methyl isobutyl ketone, and 10 g of water, which were stirred at room temperature. At the end of stirring, the reaction solution was concentrated, followed by twice of azeotropic dehydration with 30 g of methyl isobutyl ketone. To the solid precipitate, 30 g of acetonitrile was added, whereupon solid-liquid washing was conducted for 30 minutes. The solid was filtered and dried, obtaining the target compound, sodium 2,4,6-tricyclohexylbenzoate as white crystal. Amount 2.0 g, yield 90%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]3[C:13](=[O:14])C(=O)[NH:11][C:10]=13)[NH:7][N:6]=[CH:5]2.[OH:16]O.Cl>[OH-].[Na+]>[NH2:11][C:10]1[C:9]([C:13]([OH:14])=[O:16])=[C:8]2[C:4]([CH:5]=[N:6][NH:7]2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc2cn[nH]c2c2c1NC(=O)C2=O
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc2cn[nH]c2c(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-methyl-1,6-dihydro-pyrrolo[2,3-g]indazole-7,8-dione (23 g, 114.3 mmol) in 4N aqueous sodium hydroxide solution (160 ml) at ambient temperature, was added dropwise 30% aqueous hydrogen peroxide solution (27 ml) maintaining the temperature <30° C. with external cooling. The resulting reaction mixture was stirred at ambient temperature for 2 hours. According to TLC, the reaction was complete after 2 hours. The pH was adjusted to pH 3.5 by addition of concentrated hydrochloric acid. The resulting brown suspension was filtered and the filtercake washed with cold water and dried in vacuo at 50° C. to afford the desired product as brown solid. LC/MS: 192 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH2:11][NH:10][C:9]2=[O:20])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].O.C[N:29]([CH:31]=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:5]4[N:8]=[N:29][CH:31]=[CH:3][CH:4]=4)[CH:14]=3)[CH2:11][NH:10][C:9]2=[O:20])=[CH:6][CH:7]=1
Reactant: O=C1NC[C@H](c2cccc(O)c2)N1c1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: O=C1NC[C@H](c2cccc(Oc3cccnn3)c2)N1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-1-(4-chlorophenyl)-5-(3-hydroxyphenyl)imidazolidin-2-one (210 mg, 0.73 mmol, prepared by using a similar procedure as described in Example 460) and 3-chloropyradazine (167 mg, 1.46 mmol) in DMF (2 mL) is added Cs2CO3 (354 mg, 1.09 mmol). The mixture is stirred at 80° C. for 14 h and is then cooled to room temperature. The reaction mixture is then treated with water (20 mL) and extracted with EtOAc (3×15 ml). The combined organic layers are washed with brine and dried (MgSO4). After removing the drying agent, the solution is concentrated and purified by flash column chromatography (silica gel, 0%˜10% MeOH/CH2Cl2) to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.95 (dd, J=4.4, 1.2 Hz, 1H), 7.49 (dd, J=8.8, 4.4 Hz, 1H), 7.32-7.40 (m, 3H), 7.10-7.20 (m, 6H), 5.28 (dd, J=8.0, 4.8 Hz, 1H), 4.70 (br s, 1H), 3.97 (t, J=8.8 Hz, 1H), 3.41 (dd, J=8.8, 6.0 Hz, 1H); HPLC-MS calculated for C19H15ClN4O2 (M+H+) 367.1, found 367.1.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]=2[C:4](O)=[N:3][CH:2]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>C[Si](C)(C)N[Si](C)(C)C>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][NH:24][C:4]2[C:5]3[CH:10]=[N:9][CH:8]=[CH:7][C:6]=3[N:1]=[CH:2][N:3]=2)=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(CCN)cc1
Reactant: Oc1ncnc2ccncc12
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: CC(C)(C)c1ccc(CCNc2ncnc3ccncc23)cc1

Procedure:
A mixture consisting of 0.45 g of pyrido[4,3-d]pyrimidine-4-ol, 0.53 g of 2-[4-(t-butyl)phenyl]ethylamine, about 40 mg of (NH4)2SO4 in 4 mL of hexamethyldisilazane was refluxed for about five hours. The mixture was then cooled and excess disilazane was removed in vacuo. The residue was dissolved in CH2Cl2, and the solution was washed with water and filtered through phase separating paper. Evaporated the CH2Cl2 and adsorbed the residue onto silica gel, which was applied to a thin silica pad and eluted with CH2Cl2 →50% EtOAc/50% CH2Cl2 →EtOAc. Fractions containing the major product were combined and the product which crystallized was recrystallized from hexane/EtOAc. Yield 0.2 g. M.P. 157°-158° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.[N:29]1(OC(N(C)C)=[N+](C)C)[C:33]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN>CN(C=O)C>[CH3:33][NH:29][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and methylamine (1 M solution in MeOH, 354 μL, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (40 mg, 33%) as an off white solid. MS: m/e=324.4 [M+H]+.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:11]=2[CH:12]([CH3:14])[CH3:13])[C:3]1=[O:22].[CH3:23][C:24]1[NH:28][N:27]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([N:28]4[C:24]([CH3:23])=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[N:27]4)[C:3]3=[O:22])[CH:8]=[N:9]2)=[CH:16][CH:17]=1
Reactant: CC(C)c1c(N2CCC(Br)C2=O)cnn1-c1ccc(F)cc1
Reactant: Cc1cc(C(F)(F)F)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1C1CCN(c2cnn(-c3ccc(F)cc3)c2C(C)C)C1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A mixture of 3-bromo-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.023 g, 0.063 mmol), 5-methyl-3-(trifluoromethyl)-1H-pyrazole (0.040 g, 0.27 mmol) and K2CO3 (0.060 g, 0.43 mmol) in DMF (1 mL) was stirred at 60° C. for 1 hr. It was then cooled to room temperature, quenched with water (30 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (SiO2, 0˜100% EtOAc/hexanes gradient elution) to give the title compound (0.022 g, 80%). 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.37 (dd, J=9.2, 4.8 Hz, 2H), 7.17 (dd, J=8.6, 8.6 Hz, 2H), 6.32 (s, 1H), 5.05 (dd, J=9.2, 5.6 Hz, 1H), 4.07 (m, 1H), 3.80 (m, 1H), 2.84-3.02 (m, 2H), 2.74 (m, 1H), 2.45 (s, 3H), 1.21 (d, J=7.6 Hz, 3H), 1.11 (d, J=6.8 Hz, 3H); MS: (ES) m/z calculated for C21H21F4N5O [M+H]+ 436.1. found 436.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]([CH3:19])([CH3:18])[CH2:16]O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]1[O:6][CH2:16][C:15]([CH3:19])([CH3:18])[N:14]=1
Reactant: CC(C)(N)CO
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(C2=NC(C)(C)CO2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A solution of 27.4 g of 2,4-dimethoxybenzoyl chloride in 30 ml of methylene chloride was added dropwise to a solution of 26.2 g of 2-amino-2-methyl-1-propanol in methylene chloride at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was filtered and the filtrate washed twice with 1N hydrochloric acid, once with water, dried, and concentrated in vacuo. Excess thionyl chloride was added to the oily residue. After stirring one hour the mixture was poured into diethyl ether. The resulting solid was recovered by filtration and washed with diethyl ether. The solid was added to 1N sodium hydroxide and stirred. The aqueous mixture was extracted with ethyl acetate and the organic layer separated, dried, and concentrated in vacuo. Distillation of the resulting yellow oil at 165°-170° C. at 0.02 mm pressure provided 17.8 g of the desired subtitled intermediate.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].Br[CH2:14][CH2:15][O:16][CH3:17]>O1CCCC1>[CH3:17][O:16][CH2:15][CH2:14][O:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9]
Reactant: COCCBr
Reactant: N#Cc1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (55% in mineral oil, 1.76 g, 40.5 mmol) was suspended in 100 mL tetrahydrofurane. 3-(Hydroxymethyl)benzonitrile (5.0 g, 36.5 mmol), dissolved in 200 mL tetrahydrofuran was added drop wise. The reaction mixture was stirred at room temperature for 1 h. 2-Bromoethylmethylether (7.0 mL, 76 mmol) was added and the reaction mixture was refluxed overnight. The reaction mixture was quenched with 3 mL 2N sodium carbonate solution and the solvent was evaporated. The residue was taken up in 100 mL water and extracted three times with ethyl acetate (100 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). 3-(2-Methoxy-ethoxymethyl)-benzonitrile was obtained as a yellow liquid (2.63 g, 38%).
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[CH:16]=[C:17]([C:25]#[N:26])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.C(=O)([O-])[O-].[Cs+].[Cs+].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>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:16]=[C:17]([C:25]#[N:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=2)=[CH:7][CH:6]=1
Reactant: N#Cc1cc(Br)cc2ccccc12
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(C#N)c3ccccc3c2)cc1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 40.4 %

Procedure:
4-Methoxycarbonylphenylboronic acid (0.039 g), 3-bromonaphthalene-1-carbonitrile (0.05 g), tetrakis(triphenylphosphine)palladium (0.012 g) and cesium carbonate (0.11 g) were suspended in a mixed solvent of N,N-dimethylformamide (3 mL) and water (1 mL), and the resulting mixture was stirred at 150° C. for 40 minutes using microwave reactor (Biotage). The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=100/0-66/34) to give 4-(4-cyanonaphthalene-2-yl)benzoic acid methyl ester (0.025 g).