Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]#[N:18].CS(C)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCOc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A mixture of 64.25 g of 4-chlorophenol, 98 g of anhydrous potassium carbonate, 40 g of chloroacetonitrile and 100 ml of dimethyl sulfoxide was heated with stirring in a 500 ml round-bottomed three-necked flask at 70°-80° C. for 3.0 hours. The reaction mixture was then poured into ice and water. After the ice melted, the mixture was filtered and the product washed well with water which gave 77.5 g of 4-chlorophenoxyacetonitrile.
Reaction SMILES: [C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26](OCC)=[O:27])[C:8]1=[O:31])(=[O:3])[CH3:2].[CH2:33]([CH2:35][NH2:36])[OH:34]>>[C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26]([NH:36][CH2:35][CH2:33][OH:34])=[O:27])[C:8]1=[O:31])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(C)=O)c1=O
Reactant: NCCO
Product: CC(=O)N(C)CCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-{2-[acetyl(methyl)amino]ethyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine using methods similar to Example 574: step 2 to provide an off-white solid: 1H NMR (400 MHz, DMSO-d690° C.) δ ppm 1.85 (s, 3 H), 2.95 (s, 2 H), 3.49 (q, J=5.58 Hz, 3 H), 3.53 (d, J=13.58 Hz, 2 H), 3.58-3.66 (m, 2 H), 4.18 (s, 2 H), 4.36 (d, J=6.04 Hz, 2 H), 4.62-4.65 (m, 1 H), 7.12 (t, J=8.92 Hz, 2 H), 7.37-7.43 (m, 2 H), 8.07 (s, 1 H), 8.55 (s, 1 H), 10.32 (s, 1 H), 17.08 (s, 1 H); ES+ MS: 457 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:22]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[Cl:14])=[O:23])=[C:3]([OH:13])[C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: O=C=Nc1ccccc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Cl)c1O
Yield: 44.3 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (40mg, 0.18mmol) and 2-chlorophenylisocyanate (33 mg, 0.22 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70, v/v), followed by recrystallization from acetone and hexane, gave the desired product (30 mg, 44%). EI-MS (m/z) 374.3, 376.1 (M−).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:23])([F:22])[C:7]1[CH:8]=[C:9]([C:13]2([CH2:16][C:17](=[O:21])[C:18]([OH:20])=O)[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[C:33](=[O:34])[O:32][N:31]=[C:30]([CH3:35])[C:29]=2[CH:36]=1>CC(N(C)C)=O>[F:22][C:6]([F:5])([F:23])[C:7]1[CH:8]=[C:9]([C:13]2([CH2:16][C:17](=[O:21])[C:18]([NH:24][C:25]3[CH:26]=[CH:27][C:28]4[C:33](=[O:34])[O:32][N:31]=[C:30]([CH3:35])[C:29]=4[CH:36]=3)=[O:20])[CH2:14][CH2:15]2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)C(=O)CC1(c2cccc(C(F)(F)F)c2)CC1
Reactant: Cc1noc(=O)c2ccc(N)cc12
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: Cc1noc(=O)c2ccc(NC(=O)C(=O)CC3(c4cccc(C(F)(F)F)c4)CC3)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.8 ml Thionylchloride are added at −10° C. to 6.0 g of 3-[1-(3-trifluoromethylphenyl)-cyclopropyl]-2-oxo-propionic acid (prepared as described in WO 98/54159) in 60 ml of dimethyl acetamide. The mixture is stirred for 30 min. at −10° C. and for 1 hour at 0° C. and then admixed to 5 g of 6-amino-4-methyl-2,3-benzoxazin-1-one. After 16 hours at ambient temperature, the phases are separated between water and ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and concentrated. After chromatography on silica gel using hexane and ethyl acetate (10-20%) as a liquid phase, 6.78 g of 6-{3-[1-(3-trifluoromethylphenyl)-cyclopropyl]-2-oxo-propionylamino}-4-methyl-2,3-benzoxazin-1-one are obtained (m.p. 136-139° C.).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=O)(=[O:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:24]1[C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][NH:26]/[C:25]/1=[N:34]\[C:35]([C:37]1[C:42]([NH2:43])=[N:41][C:40]([NH2:44])=[C:39]([Cl:45])[N:38]=1)=[O:36]>>[C:1]([O:5][C:6](=[O:7])[CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17]([N:31]2[CH2:32][CH2:33][C:28]3([NH:24]/[C:25](=[N:34]/[C:35]([C:37]4[C:42]([NH2:43])=[N:41][C:40]([NH2:44])=[C:39]([Cl:45])[N:38]=4)=[O:36])/[NH:26][CH2:27]3)[CH2:29][CH2:30]2)=[O:19])[CH:15]=1)(=[O:12])=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCNS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Agent: Cl
Product: CC(C)(C)OC(=O)CCNS(=O)(=O)c1cccc(C(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)c1

Procedure:
The title compound was prepared from 3-(2-tert-butoxycarbonyl-ethylsulfamoyl)-benzoic acid (Int. AD) and 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide hydrochloride in an analogous method to Example 1; LC-MS Rt 0.93 mins; 636.3 [M+H]+, Method 2minLC_v003.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[OH-].[Na+].Cl[CH:14]([F:16])[F:15]>O1CCOCC1.O>[F:15][CH:14]([F:16])[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: FC(F)Cl
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccccc1OC(F)F
Temperature: 70 °C

Procedure:
A mixture of 2-nitrophenol (6.01 g, 43.2 mmol) and sodium hydroxide (8.6 g, 216 mmol) in 50 mL of dioxane and 50 mL of water was heated to 70° C. and chlorodifluoromethane gas was introduced. The mixture was diluted with water and extracted with diethyl ether. The organic phase was washed with aqueous sodium hydroxide and then brine, dried (MgSO4) and concentrated to give 1-difluoromethoxy-2-nitrobenzene (8.21 g, 43.4 mmol) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12](O)[C:13]([O:15][CH3:16])=[O:14].S(Cl)([Cl:25])=O>ClCCCl>[Cl:25][CH:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][O:4][C:3]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:2]=1[CH3:1])[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(O)c1ccccc1COc1cc(C)ccc1C
Solvent: ClCCCl
Product: COC(=O)C(Cl)c1ccccc1COc1cc(C)ccc1C
Yield: 68.6 %

Procedure:
A solution of methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxyacetate (0.50 g, 1.6 mmol) in 1,2-dichloroethane (20 ml) was stirred at room temperature. Thionyl chloride (0.61 g, 5.1 mmol) was added thereto, and the mixture was heated under reflux overnight and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=97/3) to give the desired compound methyl 2-chloro-2-[2-(2,5-dimethylphenoxymethyl)phenyl]acetate (0.35 g, 66%) as an oil.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH2:15])[CH:10]=[CH:11][CH:12]=1.CCN(CC)CC>C(Cl)Cl>[CH3:5][O:4][C:2](=[O:3])[NH:15][CH2:14][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=1
Reactant: COC(=O)Cl
Reactant: NCCc1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0, methyl chloroformate (4.6 g, 48 mmol) was added dropwise to a solution of 2-(3-chloro-phenyl)-ethylamine (5.0 g, 32 mmol) and Et3N (6.4 g, 64 mmol) in DCM (100 mL). After the addition, the mixture was stirred at room temperature for 0.5 hour. The organic layer was washed with water (3×30 mL), 1N HCl (20 mL) and brine (30 mL), dried over anhy. Na2SO4, filtered and concentrated in vacuo. After vacuum drying, the title compound was obtained (6.49 g, 95%) as a white solid. MS: 214.1 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[N:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:31][S:32]([N:23]([C:20]1[CH:21]=[N:22][C:17]([C:16]#[C:15][CH2:14][CH2:13][N:10]2[CH2:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[CH:18][CH:19]=1)[S:32]([CH3:31])(=[O:34])=[O:33])(=[O:34])=[O:33]
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-1-butynyl]-3-pyridinamine (Example 20) (0.89 g, 2.9 mmol), triethylamine (0.61 mL, 4.4 mmol) and N,N-dimethylaminopyridine (catalytic amount) in 20 mL of dichloromethane is cooled to 0° C. and methanesulfonyl chloride (0.30 mL, 3.5 mmol) is added dropwise under nitrogen. The cold bath is removed and the solution is stirred at room temperature for 18 hours. The solution is diluted with dichloromethane and washed with 30 mL of saturated aqueous sodium bicarbonate solution and 30 mL of water, and the organic layer is dried (sodium sulfate). The solvent is removed under reduced pressure and the residue is chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound as a white solid; mp 168°-169.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[S:15])[NH:13][C:12]([C:16]([OH:18])=[O:17])=[C:11]([CH3:19])[CH:10]=2)[CH:3]=1.[CH3:20][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[S:15])[NH:13][C:12]([C:16]([O:18][CH3:20])=[O:17])=[C:11]([CH3:19])[CH:10]=2)[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cc(Nc2cc(N)ncn2)c(=S)[nH]c1C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c(=S)c(Nc2cc(N)ncn2)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2-carboxylic acid (5, 0.5 g, 1.72 mmol) in tetrahydrofuran (10 mL) and methanol is added (trimethylsilyl)diazomethane (2 M in hexanes, 1.29 mL, 2.58 mmol). The reaction is stirred at room temperature for 1 h. The resulting mixture is concentrated and purified via column chromatography to afford methyl 5-(6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2-carboxylate (6).
Reaction SMILES: [Na].[N+](C(C)C)([O-])=[O:3].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[N:20]=[C:19]([CH3:21])[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:17]2)=[CH:12][CH:11]=1.CN(C)C=O>O>[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[N:20]=[C:19]([CH3:21])[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:17]2)=[CH:12][CH:11]=1)=[O:3]
Reactant: CC(C)[N+](=O)[O-]
Reactant: CCOC(=O)c1nn(-c2ccc(CBr)cc2)nc1C
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ccc(C=O)cc2)nc1C
Temperature: 18 °C

Procedure:
4.6 g of sodium are dissolved in 330 ml of absolute alcohol, with stirring and whilst passing a vigorous stream of nitrogen over the mixture. After cooling to 18° C., 23.2 g of 2-nitropropane are added dropwise in the course of 15 minutes and the reaction mixture is stirred for a further one hour at room temperature. 64.8 g of 2-(p-bromomethylphenyl)-4-methyl-5-carboethoxy-2H-1,2,3-triazole are then introduced, 330 ml of dimethylformamide are added and the reaction mixture is stirred for 22 hours at room temperature. The reaction mixture is then discharged into 2 liters of water and the product which has crystallised out is filtered off with suction, dried in vacuo at 50° to 60° C. and recrystallised from 1 liter of hexane with the aid of bleaching earth. This gives 25.8 g of 2-(p-formyl-phenyl)-4-methyl-5-carboethoxy-2H-1,2,3-triazole with a melting point of 97° to 99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=1.C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:33])C=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N+:3]=1[O-:33]
Reactant: FC(F)(F)c1ccc2oc(-c3ccnc(Cl)c3)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(-c2nc3cc(C(F)(F)F)ccc3o2)cc1Cl
Temperature: 50 °C
Yield: 90.2 %

Procedure:
To a mixture of 0.40 g of 2-(2-chloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 4 ml of chloroform, 0.53 g of 65% m-chloroperbenzoic acid was added while ice-cooling. The reaction mixture was stirred while ice-cooling for 30 minutes, then stirred at room temperature for three hours, and then stirred while heating at 50° C. for 1.5 hours. To the mixture, 0.53 g of 65% m-chloroperbenzoic acid and 2 ml of chloroform were added and stirred while heating at 60° C. for five hours. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate, and washed with 5% aqueous solution of sodium hydroxide and a saturated sodium chloride solution, sequentially. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 0.38 g of 2-chloro-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter, referred to as “active compound 22”).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:19]Br)=[C:15]([CH:18]=1)[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCOC(C)=O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:19][O:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[C:15]([CH:18]=1)[C:16]#[N:17]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc(Br)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(Br)ccc1COc1ccc(Cl)c(Cl)c1
Temperature: 75 °C
Yield: 94.7 %

Procedure:
A mixture of 3,4-dichlorophenol (267.1 mg, 1.639 mmol), 5-bromo-2-(bromomethyl)benzonitrile (447.3 mg, 1.627 mmol), and potassium carbonate (674.1 mg, 4.877 mmol) in acetone (20 mL) was heated to 75° C. under nitrogen for 18 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL) and filtered through arbocel. The arbocel was then washed with EtOAc (2×20 mL), and the combined organics were washed with brine (3×20 mL), dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound as a white solid (549.9 mg, 95%).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:51])[CH2:40][CH:41]2[C:46](=[O:47])[O:45][C:44]([CH3:49])([CH3:48])[O:43][C:42]2=[O:50])=[CH:35][CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.C(OCC)C>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:33]2[CH:38]=[CH:37][C:36]([C:39](=[O:51])[CH2:40][CH:41]3[C:46](=[O:47])[O:45][C:44]([CH3:49])([CH3:48])[O:43][C:42]3=[O:50])=[CH:35][CH:34]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(CC(=O)c2ccc(Br)cc2)C(=O)O1
Reactant: CC1(C)OB(c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC1(C)OC(=O)C(CC(=O)c2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2)C(=O)O1
Temperature: 80 °C
Yield: 75.6 %

Procedure:
A solution of 2-benzyl-3-[4′-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]-benzofuran (500 mg, 1.22 mmol) in anhydrous DMSO (5 mL) was added to a stirred suspension of 5-[2-(4-bromophenyl)-2-oxoethyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione (436 mg, 1.22 mmol) and tripotassium phosphate (1.04 g, 4.88 mmol) in anhydrous DMSO (5 mL). [1,1′-bis-(Diphenylphosphino)ferrocene]dichloropalladium(II)-DCM complex (100 mg, 0.12 mmol) was added as a solid, and the resulting suspension was heated to 80° C. for 2 hrs. The reaction mixture was cooled to room temperature, diluted with diethyl ether (150 mL), washed with water (2×50 mL), brine (3×50 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 50-60% ethyl acetate/heptane as eluent, afforded the title compound as an off-white solid (502 mg): 1H-NMR (DMSO-d6, 300 MHz): δ 8.12 (2H, d, J=8 Hz, Ar-H), 7.92 (4H, d, J=6 Hz, Ar-H), 7.53-7.69 (4H, m, Ar-H), 7.26 (7H, m, Ar-H), 4.82 (1H, s, CH), 4.26 (2H, s, PhCH2), 3.86 (2H, CH2CO), 1.84 (3H, s, Me), 1.74 (3H, s, Me).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:22])[C:9](=[O:21])[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH:3]=1.CN(C)C=O.Cl[C:36]([F:43])([F:42])C(OCC)=O>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:22])[C:9](=[O:21])[C:10]([C:13]2[CH:18]=[C:17]([O:19][CH:36]([F:43])[F:42])[CH:16]=[C:15]([Cl:20])[CH:14]=2)([CH3:11])[CH3:12])=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH:3]=1
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: CN(C(=O)C(C)(C)c1cc(O)cc(Cl)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)C(C)(C)c1cc(Cl)cc(OC(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Temperature: 65 °C
Yield: 48.7 %

Procedure:
To a solution of 0.700 g (1.56 mmol) N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-chloro-5-hydroxy-phenyl)-N-methyl-isobutyramide in 10 ml N,N-Dimethylformamide 0.215 g (1.56 mmol) K2CO3 and 0.2 ml (1.56 mmol) ethyl chlordifluoroacetate was added and the resulting suspension heated at 65° C. for 15 h. After cooling to ambient temperature, the reaction mixture was poured into 75 ml water and extracted three times with 80 ml CH2Cl2. The combined organic solvents were dried (Na2SO4), filtered and evaporated. The residue was purified by flash-chromatography (SiO2, CH2Cl2/ethyl acetate 4:1) to give 0.38 g (49%) of the title compound as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=[O:14])[CH2:9][CH2:8]1)=[O:2].C(O)([C:25]([F:28])([F:27])[F:26])=O>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:13]([N:10]1[CH2:11][CH2:12][CH:7]([O:6][C:5]2[CH:4]=[C:3]([CH:22]=[CH:21][CH:20]=2)[CH:1]=[O:2])[CH2:8][CH2:9]1)=[O:14]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C=O)c2)CC1
Solvent: ClCCl
Product: O=Cc1cccc(OC2CCN(C(=O)C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-butyl 4-(3-formylphenoxy)piperidine-1-carboxylate (61) (5.55 mmol) was taken in DCM and cooled to 0° C. when TFA (5 ml) was added drop wise and then stirred at rt for 16 h when TLC confirmed completion of reaction. The reaction mixture was concentrated and used directly for the next step. White solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([O:22]C(C)C)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[OH-].Cl>C1COCC1.O>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(C)OC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.8 %

Procedure:
A 3-neck round-bottom flask was charged with a solution of (Z)-isopropyl 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate (3) (130 g, 1.0 eq.) in THF (1.3 L) and treated with a solution of LiOH (69.3 g, 5 eq) in water (1.3 L). The reaction mixture was stirred at ambient temperature for 3-4 h before being diluted with 400 mL water, acidified (pH=2-3) with dilute aqueous HCl and extracted with EtOAc (3×1 L). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 110 g (94% yield) of desired compound (4); Z/E ratio=90.0/8.2 by LCMS.
Reaction SMILES: [C:1]([N:5]1[C:13](=[O:14])[NH:12][C:11]2[C:6]1=[N:7][C:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)=[N:9][C:10]=2[C:15]([O-])=[O:16])([CH3:4])([CH3:3])[CH3:2].[NH2:25]C1C(C([O-])=O)=NC(C2C=CC=C(O)C=2)=NC=1NC(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>>[C:1]([N:5]1[C:13](=[O:14])[NH:12][C:11]2[C:6]1=[N:7][C:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)=[N:9][C:10]=2[C:15]([NH2:25])=[O:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)Nc1nc(-c2cccc(O)c2)nc(C(=O)[O-])c1N
Reactant: CC(C)(C)n1c(=O)[nH]c2c(C(=O)[O-])nc(-c3cccc(O)c3)nc21
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)(C)n1c(=O)[nH]c2c(C(N)=O)nc(-c3cccc(O)c3)nc21
Yield: 46 %

Procedure:
9-tert-Butyl-2-(3-hydroxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. 5-Amino-6-tert-butylamino-2-(3-hydroxy-phenyl)-pyrimidine-4-carboxylate (0.26 g, 0.79 mmol) and 1,1′-carbonyldiimidazole (0.64 g, 4.0 mmol) were reacted according to General Procedure F. The crude residue was purified using Biotage silica gel chromatography (0-50% ethyl acetate in hexanes) to afford the title compound (0.13 g, 0.36 mmol, 46% yield). MS (ESI) m/z 357.4 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:13]([CH2:16][CH2:17][CH3:18])([O-:15])=[O:14].C([O-])(=O)C.[NH4+].O>C(O)CC>[CH3:11][N:10]([CH3:12])[C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[C:16]([N+:13]([O-:15])=[O:14])[CH2:17][CH3:18])=[C:2]([Cl:1])[CH:9]=1
Reactant: CCC[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCCO
Product: CCC(=Cc1ccc(N(C)C)cc1Cl)[N+](=O)[O-]

Procedure:
A solution of 36.8 g of 2-chloro-4-dimethylaminobenzaldehyde, 25 ml of 1-nitropropane and 20 g of ammonium acetate in 150 ml of 1-propanol is refluxed for 15 hours. The mixture is then poured into 1.5 l of water whereupon the compound separates as a viscous red oil. Recrystallization twice from aqueous acetic acid yields 5.0 g of the compound, melting at 90°-91°.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C([Li])CCC.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16]1>C1COCC1.CCCCCC>[OH:24][C:21]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)[CH2:22][CH2:23][C:18]2([O:17][CH2:16][CH2:15][O:25]2)[CH2:19][CH2:20]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: N#Cc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(O)CCC3(CC2)OCCO3)nc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
A solution of 6-bromonicotinonitrile (2 g, 0.011 mol) in 50 mL of dry THF and 15 mL of dry hexane under argon was cooled to −100° C. in a liquid nitrogen-Et2O bath. n-Butyllithium (7.5 mL, 0.011 mol, 1.6 M solution in hexane) was added rapidly dropwise so that the internal temperature did not exceed −95° C. The orange solution was stirred for an additional 10 min at −100° C. to −95° C. and then treated dropwise over 10 min with a solution of 1,4-cyclohexanedione monoethylene ketal (1.8 g, 0.011 mol) in 55 mL of dry THF, again carefully maintaining the temperature below −95° C. The reaction mixture was stirred for 10 min at −100° C. to −95° C., allowed to warm to 20° C. and poured into ice water (400 mL). The organic layer was separated, and the aqueous layer was extracted twice with Et2O (200 mL). The combined organic extracts were dried over MgSO4 and evaporated to give 2.8 g of white crystalline solid. Trituration with Et2O afforted 1.9 g (67% yield) of white crystals: MS: 261 (M+1)+.