Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.[CH3:35][S:36]([NH:39][C:40]1[CH:41]=[CH:42][C:43]2[O:48][CH2:47][CH:46]([CH2:49][NH2:50])[O:45][C:44]=2[CH:51]=1)(=[O:38])=[O:37]>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][NH:50][CH2:49][CH:46]2[CH2:47][O:48][C:43]3[CH:42]=[CH:41][C:40]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:51][C:44]=3[O:45]2)=[CH:2]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OC(CN)CO2
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Nc1ccc2c(c1)OC(CNCCCc1c[nH]c3ccccc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
3-Indolepropionic acid (0.77 g, 4.1 mmole), 1-hydroxybenzotriazole hydrate (0.66 g, 4.9 mmole) and 1,3-diisopropylcarbodiimide (0.77 ml, 4.9 mmole) were combined in 75 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methylsulfonylamino-2,3-dihydro-1,4-benzodioxin-2-methanamine (1.0 g, 4.1 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using 10% hexane in ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.1 g (61%) of the desired product, (S)-(7-methylsulfonyl-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-propanamide, as a white solid.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[K+].[Br-].[O:11]=[C:12]([CH2:20][CH3:21])[CH2:13][S+:14]1[CH2:19][CH2:18][CH2:17][CH2:16]C1>C(#N)C>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[O:11]=[C:12]([CH2:20][CH3:21])[CH2:13][S+:14]1[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCC(=O)C[S+]1CCCCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Product: CCC(=O)C[S+]1CCCC1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
In a 300 ml three-necked flask, 2 g of 2-oxobutyl-thiacyclohexanium bromide obtained in Example 1 was dissolved in 10 ml of acetonitrile. To the solution, a solution prepared by dissolving 1.6 g of a potassium trifluoromethanesulfonate salt in 100 ml of acetonitrile was added dropwise. After stirring for three hours, the deposited potassium bromide was removed by filtration and acetonitrile was distilled off under reduced pressure by an evaporator. The residue was dissolved in chloroform and the insoluble matter was removed by filtration. Chloroform in the filtrate was distilled off under reduced pressure and the residue (transparent viscous liquid) was cooled in a refrigerator at −20° C. for three hours. The residue was converted into a white crystal by cooling. The white crystal was recrystallized from ethyl acetate and then dried under reduced pressure at 30 ° C. for six hours to obtain 1.7 g of 2-oxobutyl-thiacyclopentanium trifluoromethanesulfonate (yield: 65.8%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[N:9]=[C:10]([CH2:13][O:14][C:15]2[C:16]([F:25])=[C:17]([C:21]([F:24])=[CH:22][CH:23]=2)[C:18]([NH2:20])=O)[S:11][CH:12]=1.C(N(CC)CC)C>CN(C=O)C>[Br:7][C:8]1[N:9]=[C:10]([CH2:13][O:14][C:15]2[C:16]([F:25])=[C:17]([C:21]([F:24])=[CH:22][CH:23]=2)[C:18]#[N:20])[S:11][CH:12]=1
Reactant: NC(=O)c1c(F)ccc(OCc2nc(Br)cs2)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1c(F)ccc(OCc2nc(Br)cs2)c1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 70.2 %

Procedure:
To an ice cold solution of DMF (0.20 ml) and acetonotrile (5 ml) was added oxalyl chloride (45 μL, 0.52 mmol) dropwise while maintaining the temperature to 0° C. The reaction mixture was stirred at 0° C. for 40 min followed by addition of a solution of 3-((4-bromothiazol-2-yl)methoxy)-2,6-difluorobenzamide (0.15 g, 0.43 mmol) in DMF (2 ml). The resulting reaction mixture was stirred at 0° C. 40 min and then allowed to come to room temperature. After completion of reaction (10 min, TLC monitoring), triethyl amine (100 μL, 0.86 mmol) was added dropwise. The reaction mass was concentrated in vaccuo followed by addition of water (50 ml) and extraction with ethyl acetate (3×75 ml). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 20% EtOAc-Hexane) to get the desired product (0.10 g, 71%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1([F:15])[CH2:11][CH:10]([C:12](O)=[O:13])[CH2:9]1.[CH3:16][N:17](C=O)[CH3:18].N(C)C>C(Cl)Cl.C1COCC1>[F:7][C:8]1([F:15])[CH2:11][CH:10]([C:12]([N:17]([CH3:18])[CH3:16])=[O:13])[CH2:9]1
Reactant: O=C(O)C1CC(F)(F)C1
Reactant: CN(C)C=O
Agent: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)C1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Oxalyl chloride (21.74 mL, 248 mmol) was added dropwise to a stirred solution of 3,3-difluorocyclobutanecarboxylic acid (26 g, 191 mmol; prepared as described in Syn. Comm., 35:657 (2005) (Elend, D. et al.) in CH2Cl2 (500 mL) and DMF (0.5 mL) at 0° C. The reaction mixture was allowed to come to RT and stirred at RT for 1 h prior to being concentrated at RT using a rotary evaporator at ca. 50 mm Hg vacuum. After adding THF (300 mL) to the resulting residue, the stirred solution was cooled 0° C. prior to addition of a 2M solution of Me2NH (478 mL, 955 mmol) in THF. After stirring the reaction mixture at RT for 0.5 h, the mixture was partitioned between ether and 5% aq. Na2CO3. The organic layer was dried over MgSO4 and concentrated in vacuo at RT. After portioning the residue between CH2Cl2 and water, the organic layer was dried over MgSO4 and concentrated in vacuo at RT to give 3,3-difluoro-N,N-dimethylcyclobutanecarboxamide (24 g, 147 mmol, 77% yield) as a brown semi solid, used as such in the next step. 1H NMR (400 MHz, CDCl3) δ 2.82-3.13 (9H, m), 2.62-2.79 (2H, m).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:12]OC(OC)N(C)C>>[N:1]12[CH:12]3[N:4]([CH2:5][CH2:6][CH2:7][N:8]3[CH2:9][CH2:10][CH2:11]1)[CH2:3][CH2:2]2
Reactant: COC(OC)N(C)C
Reactant: C1CNCCCNCCNC1
Product: C1CN2CCCN3CCN(C1)C23
Yield: 81.8 %

Procedure:
In a manner similar to that of Example 1 (C), 5.28 g (33.6 mmol) of 1,4,8-triazacycloundecane and 4.00 g of dimethylformamide dimethyl acetal were reacted to give 4.59 g of 1,4,8-triazatricyclo[6.3.1.04,12 ]dodecane as a clear, colorless liquid, bp 80°-82° (three fractions) (1.2 mm), nD24 = 1.5182. A fraction boiling at 82° was analyzed.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCC)cc2)CCCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCC)cc2)CCCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]thio]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (0.70 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloro-perbenzoic acid (70%, 0.39 g) in dichloromethane (10 ml) and the mixture was stirred at −78° C. for 1 hour. To a reaction system was added an aqueous sodium thiosulfate solution, and the mixture was stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, the organic layer was washed with aqueous sodium bicarbonate solution and saturated brine, and was dried with magnesium sulfate. The resultant was concentrated under reduced pressure, after which the residue was separated and purified with column chromatography (basic silica gel, ethyl acetate→ethanol:ethyl acetate 1:19), followed by recrystallization (ethyl acetate-diisopropyl ether) to give 8-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (579.7 mg) as yellow crystals (Compound 51).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([CH2:14][CH2:15][O:16][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC1=CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2=CCN(Cc3ccccc3)CC2)cc1
Reaction time: 3 h

Procedure:
To a solution of 2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)ethanol (0.822 g, 4.09 mmol) (J. Med. Chem. 1990, 33, 3133) in dichloromethane was added p-toluene sulfonyl chloride (1.71 g, 9.00 mmol) and triethyl amine (2.3 mL, 16.4 mmol) and DMAP (0.050 g, 0.41 mmol) at room temperature and stirring continued at rt for 3 h. The reaction mixture was diluted with dichloromethane and washed with aq NaHCO3 (10% W/V) solution, followed by saturated NaCl solution. The organic layer was dried (Na2SO4), filtered and solvent was evaporated to dryness. The product was flash chromatographed over silica gel using gradient of 0-10% methanol in dichloromethane. 1H NMR (CDCl3) δ 7.77 (d, 8.4 Hz, 2H), 7.34-7.30 (m, 5H), 7.26 (m, 1H), 5.36 (m, 1H), 4.09 (t, J=6.8 Hz, 2H), 3.54 (s, 2H), 2.92-2.88 (m, 2H), 2.50 (t, J=5.6 Hz, 2H), 2.44 (s, 3H), 2.31 (brt, J=6.8 Hz, 2H), 2.20-1.84 (m, 2H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8]Cl)[CH:2]=[CH2:3].[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH:2]=[CH2:3]
Reactant: C=CCOCCCCCl
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOCCCCOc1ccc(C(=O)O)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 123 %

Procedure:
A reaction mixture containing 14 g of allyl(4-chlorobutyl) ether, 14 g of 4-hydroxybenzoic acid, 14 g of potassium carbonate and 50 mL of dimethylformamide was stirred at 90° C. for 3 hours. Water was added to the reaction mixture, which was then extracted with toluene. The toluene layer was well washed with water, and then toluene was distilled off. 20 g of sodium hydroxide, 50 mL of water and 200 mL of ethanol were added to the resulting residue, followed by refluxing for 2 hours. Ethanol was distilled off, and hydrochloric acid was added to make the reaction mixture acidic. The mixture was extracted with diethyl ether and dried over anhydrous magnesium sulfate. A residue obtained by distilling the solvent was recrystallized from a mixed solvent of ethanol and water to obtain 29 g of 4-(4-allyloxybutyloxy)benzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.OC1C=CC(CC)=CC=1C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[S:33]1[CH:37]=[CH:36][CH:35]=[CH:34]1.Cl>C(=S)=S.N1C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([C:34]1[S:33][CH:37]=[CH:36][CH:35]=1)=[O:6]
Reactant: CCc1ccc(O)c(C(=O)O)c1
Reactant: c1ccsc1
Agent: CCc1ccc(O)c(C(=O)Cl)c1
Agent: Cl
Agent: [Al+3]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: S=C=S
Product: CCc1ccc(O)c(C(=O)c2cccs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.9 %

Procedure:
2-Hydroxy-5-ethylbenzoic acid (16.6g, 0.1 mol) and thionyl chloride (12.44g, 0.105 mol) were mixed together with light petroleum (bp 40°-60° C.) (75 ml) and pyridine (0.1 ml) and refluxed for 6 hours. The resulting 2-hydroxy-5-ethylbenzoyl chloride was stirred in carbon disulphide (120 ml), cooled in ice and treated with aluminium chloride for 1 to 2 minutes. The temperature of the mixture rose from 2° C. to 15° C. The temperature was allowed to return to about 2° C. and thiophene (8.4g, 7.91 ml. 0.1 mol) in carbon disulphide (25 ml) was added at a rate such that the temperature of the mixture did not rise above about 3° C. The mixture was then stirred at room temperature overnight, stirred and refluxed for 31/2 hours, cooled, poured into ice and concentrated hydrochloric acid, and extracted with ether. The ether fraction was washed firstly with a saturated solution of sodium bicarbonate and secondly with a saturated solution of sodium chloride, was dried (over Na2SO4), filtered and evaporated to yield an oil which was distilled to give the pure title product (0.67g), bp 118°-122° C./0.07 mm, nD19 1.6280.
Reaction SMILES: O.[C:2]1([CH3:13])[CH:7]=[CH:6][C:5]([S:8]([NH:11][NH2:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:15]1[C:24]2[C:19](=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][N:16]=1>C(Cl)Cl>[CH3:13][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][NH:12][C:15]2[C:24]3[C:19](=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][N:16]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)NNc2ncnc3c([N+](=O)[O-])cccc23)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
p-Toluene sulphonyl hydrazine hydrate (390 mg, 2.1 mmol) was added to a solution of 4-chloro-8-nitro-quinazoline 477 (400 mg, 1.91 mmol) in DCM at (10 ml) and the mixture was stirred at room temperature for 24 h. The mixture was concentrated in vacuo and washed with Et20 to give the title compound (650 mg, 95%).
Reaction SMILES: O=S(Cl)Cl.[NH2:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1)=[O:10].[OH:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:39]=2[O:46][CH3:47])=[CH:34][C:33]=1[CH:48]=O.CO>ClCCl>[CH3:26][N:23]1[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:9]([C:8]3[CH:27]=[CH:28][C:29]4[N:30]=[C:48]([C:33]5[CH:34]=[C:35]([C:38]6[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:39]=6[O:46][CH3:47])[CH:36]=[CH:37][C:32]=5[OH:31])[NH:5][C:6]=4[CH:7]=3)=[O:10])=[CH:17][CH:16]=2)[CH2:21][CH2:22]1
Reactant: COc1ccc(OC)c(-c2ccc(O)c(C=O)c2)c1
Reactant: CN1CCN(CCc2ccc(NC(=O)c3ccc(N)c(N)c3)cc2)CC1
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(OC)c(-c2ccc(O)c(-c3nc4ccc(C(=O)Nc5ccc(CCN6CCN(C)CC6)cc5)cc4[nH]3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a suspension of silica gel (0.8 g) in dichloromethane (3 mL) was added SOCl2 (0.6 mL) and the mixture was stirred at the room temperature for 1 h (gas was released from the reaction mixture). 3,4-Diamino-N-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenyl}-benzamide (178.2 mg, 0.5 mmol), 4-hydroxy-2′,5′-dimethoxy-biphenyl-3-carbaldehyde (129.1 mg, 0.5 mmol) and 2 mL dichloromethane were added, and the resulting reaction mixture was stirred at the room temperature for 4 h. After methanol (5 mL) was added, the reaction mixture was stirred at room temperature for another 1 h and was evaporated under reduced pressure. The residue on silica gel was purified by chromatography (250:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (217 mg, 84%). 1H NMR (MeOH-d4) δ 2.26 (s, 3H), 2.37-2.72 (12H), 3.73 (s, 3H), 3.77 (s, 3H), 6.80 (m, 1H), 6.94 (s, 1H), 6.95 (m, 1H), 7.03 (d, J=9 Hz, 1H), 7.13 (d, J=9 Hz, 2H), 7.49-7.64 (4H), 7.80 (d, J=9 Hz, 1H), 8.10 (s, 1H), 8.17 (s, 1H). ESI-MS m/z 592 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]([CH3:27])[C:15]([C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)([CH3:20])[CH3:19])=[N:16][N:17]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:20][C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)([C:15]1[N:14]([CH3:27])[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:17][N:16]=1)[CH3:19]
Reactant: C1CCNC1
Reactant: Cn1c(-c2ccccc2Br)nnc1C(C)(C)c1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(-c2ccccc2N2CCCC2)nnc1C(C)(C)c1ccccn1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A toluene solution (3.0 ml) of pyrrolidine (0.100 ml) was added to a mixture of 2-{1-[5-(2-bromophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methylethyl}pyridine (360 mg), sodium tert-butoxide (136 mg), bis(dibenzylideneacetone)dipalladium (23.1 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (31.4 mg) under a nitrogen condition, followed by stirring at 100° C. for 18 hours. The reaction solution was diluted with water (15 ml) and then extracted with ethyl acetate (15 ml). The organic layer washed with brine, dried over anhydrous magnesium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by flash column chromatography (chloroform:methanol=90:10) and further purified by preparative thin layer chromatography (hexane:acetone=1:1) to obtain 81.4 mg of 2-(1-methyl-1-{4-methyl-5-[2-(1-pyrrolidinyl)phenyl]-4H-1,2,4-triazol-3-yl]ethyl}pyridine (pale yellow crystals).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:7]([C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N+:11]([O-:13])=[O:12])=[O:9])=[N:16][CH:17]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Br)cn1)c1cc(F)ccc1[N+](=O)[O-]
Yield: 68.1 %

Procedure:
A solution of 5-fluoro-2-nitrobenzoic acid (10.0 g, 54 mmol, 1.0 equiv), 2-amino-5-bromopyridine (12.2 g, 1.3 equiv), in 80 mL of pyridine was treated with phosphorous oxychloride (25.3 g, 3.0 equiv) for 30 min. The volatile was evaporated and the residue was redissolved into EtOAc, washed with 1N HCl, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, and evaporated. The volatile was evaporated, and the product was triturated with diethyl ether to give N-(5-bromo-2-pyridinyl)-(2-nitro)-5-fluorophenylcarboxamide (12.5 g, 68%). MS found for C12H7BrFN3O3 (M+H)+: 340, 342. Step 2: A solution of N-(5-bromo-2-pyridinyl)-(2-nitro)-5-flurophenylcarboxamide (2.0 g, 5.88 mmol, 1.0 equiv) in 30 mL of EtOAc was treated with SnCl2H2O (5.90 g, 4 equiv) at reflux for 4 h. The volatile was evaporated and the residue was redissolved in EtOAc, washed with saturated aqueous NaHCO3 and 1N NaOH. The organic layer was dried over MgSO4, filtered and evaporated to N-(5-bromo-2-pyridinyl)-(2-amino)-5-fluorophenylcarboxamide (1.79 g, 98%). MS found for C12H9BrFN3O (M+H)+: 310, 312. Step 3: A mixture of N-(5-bromo-2-pyridinyl)-(2-amino)-5-fluorophenylcarboxamide (0.310 g, 1 mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoyl chloride (0.430 g, 1.3 equiv), pyridine (2 mL) in 10 mL of dichloromethane was stirred at rt overnight. The volatile was evaporated and the residue was redissolved into EtOAc, washed with 1N HCl, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, and evaporated. The intermediate was reacted into 5 mL of trifluoroacetic acid at rt overnight. TFA was then evaporated and the product was triturated with diethyl ether, and then with chloroform to give N-(5-bromo-2-pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)-5-fluorophenylcarboxamide (120 mg, 21%). MS found for C25H18BrFN4O4S (M+H)+: 569, 571.
Reaction SMILES: [N-]=C=O.[O:4]=[C:5]1[CH:10]=[N:9][C:8]2[N:11]=[CH:12][CH:13]=[C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])OC(C)(C)C)=[CH:18][CH:17]=3)[C:7]=2[NH:6]1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=C=O)=[CH:33][C:32]=1[C:40]([F:43])([F:42])[F:41]>FC(F)(F)C(O)=O>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:23]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:14]3[C:7]4[NH:6][C:5](=[O:4])[CH:10]=[N:9][C:8]=4[N:11]=[CH:12][CH:13]=3)=[CH:17][CH:18]=2)=[O:29])=[CH:33][C:32]=1[C:40]([F:41])([F:42])[F:43]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3ncc(=O)[nH]c23)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: [N-]=C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc3ncc(=O)[nH]c23)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.7 %

Procedure:
Method F1 (one pot deprotection of Boc and coupling with isocyanate): Tert-butyl 4-(2-oxo-1,2-dihydropyrido[2,3-b]pyrazin-8-yloxy)phenylcarbamate (0.240 g, 0.67 mmol) is dissolved in trifluoroacetic acid (2 ml) and the solution is stirred at room temperature under Argon atmosphere for 2 h. The solvent is evaporated under reduced pressure and the resulting dark oil is dissolved in THF (3 ml) and triethylamine (1 ml). 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (0.180 g, 0.80 mmol) is added in one portion, and the solution was stirred overnight at 45 C under Ar atmosphere. The solution is then cooled and evaporated and the crude was crystallised from dichloromethane and diethyl ether to afford the title compound (15 mg, 5% yield) as a brown solid.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([C:8]1[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH3:17])=[CH:10][C:9]=1[F:18])[O:6][CH3:7])C.[Li+].[OH-].Cl>C1COCC1.CO>[CH2:16]([O:15][C:11]1[CH:10]=[C:9]([F:18])[C:8]([CH:5]([O:6][CH3:7])[C:4]([OH:19])=[O:3])=[C:13]([F:14])[CH:12]=1)[CH3:17]
Reactant: CCOC(=O)C(OC)c1c(F)cc(OCC)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(F)c(C(OC)C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
To (4-ethoxy-2,6-difluoro-phenyl)-methoxy-acetic acid ethyl ester (4.0 g, 14.58 mmol, 1.0 equiv), dissolved in THF (75 mL) and methanol (15 mL), was added a solution of 1 M LiOH (17.5 mL) and the reaction mixture stirred at rt for 4 h. A solution of 1 M HCl (25 mL) was added, the organic solvents removed by evaporation under reduced pressure and the residue extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated by evaporation under reduced pressure yielding 3.5 g (98%) of the title compound.