Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:23]([C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[CH:26]=1)#[CH:24].C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1.[Cu]I.O>[NH2:1][C:2]1[C:3]2[C:10]([C:24]#[C:23][C:25]3[CH:26]=[C:27]([O:33][CH3:34])[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=3)=[CH:9][N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C#Cc1cc(OC)cc(OC)c1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(I)c3c(N)ncnc32)C1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(C#Cc2cn(C3CN(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
PdCl2(dppf)CH2Cl2 (122 mg) was added to a mixture of tert-butyl 3-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate (639 mg) obtained in Step 2 above, 1-ethynyl-3,5-dimethoxybenzene (374 mg), copper (I) iodide (44 mg), and triethylamine (2.0 ml) in THF (15 ml). After nitrogen purging, the resulting mixture was stirred at 80° C. for 3.5 hours. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, amorphous substance (704 mg). Physical properties: m/z [M+H]+ 450.1
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-:21][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[CH2:28]([O:30][C:31]([C:33]1[CH:37]=[CH:36][N:35]([CH:38]([CH3:40])[CH3:39])[C:34]=1[CH3:41])=[O:32])[CH3:29]>CC#N.O>[CH2:28]([O:30][C:31]([C:33]1[CH:37]=[CH:36][N:35]([CH:38]([CH3:40])[CH3:39])[C:34]=1[CH:41]=[O:21])=[O:32])[CH3:29]
Reactant: CCOC(=O)c1ccn(C(C)C)c1C
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccn(C(C)C)c1C=O
Reaction time: 0.17 h

Procedure:
CAN (979 mmol) was added to a mixture of 1-isopropyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester [224180-70-5] (218 mmol) in CH3CN (1800 mL) and water (360 mL) at 15° C. After 10 min, the reaction mixture was quenched with ice and extracted with MTBE. The organic phase was successively washed with a saturated aqueous solution of NaHCO3 (2×) and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a yellow oil. tR: 4.43 min (HPLC 1); ESI-MS: tR=1.06 min, [M+H]+ 210 (LC-MS 1); TLC: Rf=0.21 (1:9 EtOAc/heptanes).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([F:27])=[CH:25][C:24]([CH:28]=[O:29])=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[C:26]([F:27])=[CH:25][C:24]([CH2:28][OH:29])=[CH:23][N:22]=3)[CH2:19][CH2:20]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc(C=O)cc3F)CC2)CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc(CO)cc3F)CC2)CC1
Reaction time: 2 h
Yield: 44 %

Procedure:
The crude 53b was taken up with methanol (10 mL), cooled in an ice bath and treated with NaBH4 (0.52 g, 13.7 mmol). The mixture was stirred for 2 h and treated with aqueous NaHCO3 (10 mL). The mixture was extracted with 40 mL of ethyl acetate, washed with brine (3×30 mL) and concentrated under vacuum. The residue was purified by flash chromatography (eluent: 20 to 70% ethyl acetate+0.1% triethylamine in hexane) to afford 296 mg (44% yield) of 53-1: LC-MS 409.2 (MH+), tR=5.59 (Method 2). EC50: 224 nM.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:12][Br:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(Br)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(Br)c1CBr
Yield: 96 %

Procedure:
A solution of methyl 3-bromo-2-methylbenzoate (1.00 g), N-bromosuccinimide (855 mg) and 2,2′-azobis(isobutyronitrile) (71.8 mg) in carbon tetrachloride (50 ml) was heated under reflux for 8 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chomatography (eluent; hexane:ethyl acetate=20:1) to give the title compound (1.29 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](F)=[C:4](F)[C:3]=1[F:14].FC1(F)C2C(=CC=CC=2)C=CC1(F)F.[NH4+].[OH-]>C1COCC1.[Zn]>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[F:14]
Reactant: Fc1c(F)c(F)c2ccccc2c1F
Agent: FC1(F)C=Cc2ccccc2C1(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Fc1ccc2ccccc2c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A solution of the tetrafluoro naphthalene, 1,1,2,2-tetrafluoro-1,2-dihydronaphthalene (5.25 g , 25.66 mmol) in THF (15 ml) was treated with 30% aqueous NH4OH (30 ml) and zinc (8.45 g, 130 mmol) (powder) and stirred under N2 for 4 hours at RT. The reaction was monitored by GC/MS for disappearance of the starting material and found to be complete. The solution was filtered, extracted with hexane (30 ml), and filtered through a short silica column (20 g). The hexane solution was evaporated in vacuo to afford an oil. This crystallized on cooling to room temperature to afford 3.99 g (95% yield) of product. MS: m/e 164 (M+).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:10]([C:13]1[S:17][C:16]([NH:18][C:19]([N:21]([CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[O:20])=[N:15][CH:14]=1)(=[O:12])=[O:11])=[O:4].C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(S(C)(=O)=O)=CC=2)CCCC1.COC([C@@H]1CCCN1S(C1SC(N)=NC=1)(=O)=O)=O>>[CH:33]1([CH2:32][N:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)[C:19](=[O:20])[NH:18][C:16]2[S:17][C:13]([S:10]([N:6]3[CH2:7][CH2:8][CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])(=[O:12])=[O:11])=[CH:14][N:15]=2)[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc(NC(=O)N(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Agent: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: CS(=O)(=O)c1ccc(NCC2CCCC2)cc1
Product: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2ncc(S(=O)(=O)N3CCC[C@H]3C(=O)O)s2)cc1

Procedure:
The title compound was prepared via (S)-1-{2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazole-5-sulfonyl}-pyrrolidine-2-carboxylic acid methyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and (S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10](=[O:14])[NH:11]2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20])(=O)C>C(O)C>[NH2:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10](=[O:14])[NH:11]2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(CC(C)C)C(=O)N2
Solvent: CCO
Product: CC(C)CC1C(=O)Nc2cc(N)c([N+](=O)[O-])cc21

Procedure:
A solution of 2.9 g. (0.01 mol) 6-acetamido-3-(2-methylpropyl)-5-nitroindolin-2-one in 50 ml. ethanol is heated under reflux for about 30 minutes with 3 ml. concentrated hydrochloric acid, evaporated and the residue purified on silica gel (elution agent: methylene chloride/ammonia-saturated methanol 20:1 v/v). Yield 1.5 g. (60% of theory).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:17])([F:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]([NH2:15])[CH3:14])=[N:11][CH:12]=1.[C:18]([C:22]1[O:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1)([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CO>[C:18]([C:22]1[O:26][N:25]=[C:24]([C:27]([NH:15][C@@H:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([F:3])([F:16])[F:17])=[CH:12][N:11]=2)[CH3:14])=[O:28])[CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: C[C@@H](N)c1ccc(OCC(F)(F)F)cn1
Reactant: CC(C)(C)c1cc(C(=O)O)no1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1cc(C(C)(C)C)on1)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
To a suspension of (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine 2HCl salt (18 mg, 0.06 mmol) and 5-tert-butylisoxazole-3-carboxylic acid (10 mg, 0.06 mmol) in dichloromethane (2 mL) were added triethylamine (19 mg, 0.18 mmol), EDC (19 mg, 0.1 mmol) and HOBT (9.4 mg, 0.06 mmol) respectively. The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated by N2-flow. The resulting residue was dissolved into ethyl acetate and water was added to the mixture. The organic layer was then washed with brine, and dried over sodium sulfate. After the filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give the residue. The residue was diluted with methanol and applied onto a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix was rinsed with methanol (6 mL). The crude mixture was eluted in a collection tube with 1 mol/L ammonia in methanol (6 mL) and concentrated in vacuo. The residue was purified by preparative LC-MS to give 17 mg, (75% yield) of the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[F:36][C:33]([F:34])([F:35])[C:32]([C:29]1[CH:30]=[N:31][C:26]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[N:27][CH:28]=1)([OH:41])[C:37]([F:40])([F:39])[F:38]
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)c3ccccc3)cc2)OC1(C)C
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc(-c2ncc(C(O)(C(F)(F)F)C(F)(F)F)cn2)cc1
Temperature: 100 °C
Yield: 71.1 %

Procedure:
A glass microwave reaction vessel was charged with 4,4,5,5-tetramethyl-2-(4-(phenylsulfonyl)phenyl)-1,3,2-dioxaborolane (196 mg, 0.57 mmol, Example 17, Step 2), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (145 mg, 0.52 mmol, Intermediate D), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (24 mg, 0.03 mmol, Strem Chemical Inc, Newburyport, Mass.), cesium carbonate (0.51 g, 1.56 mmol, Sigma-Aldrich, St. Louis, Mo.), DME (1 mL), and water (0.1 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 30 min. The reaction was diluted with EtOAc (about 10 mL) and water (about 10 mL). The organic layer was taken and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of 10% to 20% EtOAc in hexane, to provide 1,1,1,3,3,3-hexafluoro-2-(2-(4-(phenylsulfonyl)phenyl)-5-pyrimidinyl)-2-propanol (171 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.28 (s, 2H), 8.69 (d, J=8.61 Hz, 2H), 8.22 (d, J=8.61 Hz, 2H), 8.04-8.10 (m, 2H), 7.68-7.82 (m, 4H); m/z (ESI, +ve ion) 463.1 (M+H)+. GK-GKRP IC50 (Binding)=0.484 μM. GKRP EC50 (LC MS/MS-2)=0.478 μM.
Reaction SMILES: [CH:1]1([N:4]([CH3:28])[C:5]2[C:6]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([N:4]([CH3:28])[C:5]2[C:6]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=3)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ccc4c3)c(N(C)C3CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ccc2c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-[cyclopropyl(methyl)amino]-2-(1H-indol-5-yl)quinoxaline-6-carboxylate (71 mg, 0.19 mmol) in methanol (20 mL) and water (1.0 mL) was added sodium hydroxide (22.9 mg, 0.57 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (10 mL), adjusted pH to 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford 3-[cyclopropyl(methyl)amino]-2-(1H-indol-5-yl)quinoxaline-6-carboxylic acid of as a yellow solid (20.4 mg, 30%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:8]=[CH:7][CH:6]=[C:4]([NH2:5])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: Nc1cccc(I)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 95 °C
Reaction time: 17 h

Procedure:
To a solution of 3-iodoaniline in DME (40 mL) and water (20 mL), was added para-trifluoromethylphenyl boronic acid (2.6 g, 13.7 mmol) and sodium carbonate (2.5 g, 23.6 mmol). The apparatus was flushed with nitrogen prior to the addition of tetrakis (triphenylphosphine) palladium (0) (0.312 g, 0.27 mmol). The reaction mixture was stirred at 95° C. for 17 h under nitrogen, then allowed to cool to rt and the solvents removed in vacuo. The residue was partitioned between EtOAc (2×75 mL) and water (75 mL). The organic solution was dried (MgSO4) and the solvent was removed in vacuo. Purification by Biotage™ chromatography (90 g Silica column) eluted with 1:4 EtOAc:cyclohexane afforded the title compound as a white solid (1.33 g).
Reaction SMILES: C([N:10]1[CH2:29][CH2:28][C@@:17]23[C:18]4[CH:19]=[C:20]([O:25][CH2:26][CH3:27])[CH:21]=[CH:22][C:23]=4[CH2:24][C@@H:11]1[C@@H:12]2[CH2:13][CH2:14][O:15][CH2:16]3)(OC1C=CC=CC=1)=O.[OH-].[K+].CC(O)C>O>[CH2:26]([O:25][C:20]1[CH:21]=[CH:22][C:23]2[CH2:24][C@H:11]3[NH:10][CH2:29][CH2:28][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][O:15][CH2:16]4)[CH3:27]
Reactant: CCOc1ccc2c(c1)[C@]13CCN(C(=O)Oc4ccccc4)[C@H](C2)[C@@H]1CCOC3
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCOc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1CCOC3

Procedure:
A mixture of XXIX (0.005 m) from Step (d) above, 6 g potassium hydroxide, 75 ml 2-propanol and 20 ml water is heated at reflux for 40 hours. The 2-propanol is removed at reduced pressure. The resultant mixture is extracted with methylene chloride. The extracts are dried (Na2SO4), filtered and concentrated to produce the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[F:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][N:27]1[CH2:28][CH2:29][CH:24]([C:20]2[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=2)[CH2:25][CH2:26]1
Reactant: Fc1cccc(OCCCCl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-(3-chloropropoxy)-3-fluorobenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 399.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH:18]=[O:19])[C:10]([CH3:17])([CH3:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1.N12CCCC1=NCCC2>C1COCC1.C(O)C.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10]([CH3:17])([CH3:16])[C:9]=2[CH:18]=[O:19])=[CH:6][CH:7]=1
Reactant: CC1(C)C=C(c2ccc(F)cc2)C(C=O)C(C)(C)C1
Agent: C1CN=C2CCCN2C1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCO
Product: CC1(C)CC(c2ccc(F)cc2)=C(C=O)C(C)(C)C1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
The aldehyde obtained in Step 5 (130 g, 50 mmoles) was dissolved in a solution of 50 ml of THF and 50 ml of ethanol. To this solution was added 0.62 ml (5 mmoles) of 1,5-diazabicyclo-[4,3,0]-non-5-ene and the reaction mixture stirred at room temperature for 50 hours. The reaction mixture then was diluted with ether and extracted with dilute HCl, saturated NaHCO3, and brine. The solvents were evaporated in vacuo and the residue purified by flash chromatography on silica gel.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:15][CH2:16][CH2:17][OH:18])([CH:12]([CH3:14])[CH3:13])[C:8]1=[O:19].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:15][CH2:16][CH:17]=[O:18])([CH:12]([CH3:13])[CH3:14])[C:8]1=[O:19]
Reactant: CC(C)C1(CCCO)CCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1=O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)C1(CCC=O)CCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3,5-bis(trifluoromethyl)benzyl)-3-(3-hydroxypropyl)-3-isopropylpyrrolidin-2-one (1.1 g, approximately 2.67 mmol) in CH2Cl2 (27 mL) was added tetra-n-propylammonium perruthenate (47 mg, 0.134 mmol), N-methylmorpholine N-oxide (0.626 g, 5.35 mmol) and 4 angstrom molecular sieves (0.31 g). After 30 minutes stirring, the solution was filtered through celite and concentrated to provide 3-(1-(3,5-bis(trifluoromethyl)benzyl)-3-isopropyl-2-oxopyrrolidin-3-yl)propanal as an impure dark oil that was used in step 3 without further purification. LC/MS [M+H]+=410.15. HPLC tR=1.96 min [Waters Sunfire C18 4.6×50 mm column, 3 min gradient from 10/90/0.1 MeOH/H2O/TFA to 90/10/0.1 MeOH/H2O/TFA at 4 mL/min flow rate].
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[CH:30][N:29]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl-].[NH4+]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:35][CH2:34][C:32]2[CH:31]=[CH:30][N:29]=[C:28]([F:27])[CH:33]=2)[CH:7]=1
Reactant: OCc1ccnc(F)c1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3ccnc(F)c3)n2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 40.6 %

Procedure:
To mixture of 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 2-fluoro-4-pyridinemethanol (102 mg; 0.781 mmol) in THF (3.5 ml) a 1 M solution of sodium bis(trimethylsilyl)amide in THF (0.391 ml) was added. The batch was stirred under argon for 6 hours at 70° C. After cooling the batch was poored into saturated aqueous ammonium chloride solution. The organic phase was separated, washed with brine, dried (sodium sulfate) and concentrated. The residue was purified by preparative HPLC to give the desired product (38 mg; 0.08 mmol).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[O:6]1[CH2:11][CH2:10][CH2:9][O:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=O)[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1>[F:29][C:28]([F:31])([F:30])[C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:25]=1)[CH2:21][O:20][CH2:19][C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:7]1[O:8][CH2:9][CH2:10][CH2:11][O:6]1)=[CH:1][CH3:2]
Reactant: [Li]CCCC
Reactant: O=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1C1OCCCO1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1C1OCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of ethyl triphenylphosphonium bromide (7.62 g, 20.5 mmol) in tetrahydrofuran (40 mL) at −78° C. was added n-butyllithium (1.6 M in hexane, 12.8 mL, 20.5 mmol). The resulting suspension was warmed to 0° C., stirred 30 min, and cooled to −78° C. The reaction was treated with 1-(2-(1,3-dioxan-2-yl)phenyl)-2-(3,5-bis(trifluoromethyl)benzyloxy)ethanone (2.80 g, 6.25 mmol) as a solid. The reaction was placed in a 0° C. bath and stirred for 30 min. The reaction was stirred at room temperature for 1 h, and quenched by addition of saturated ammonium chloride. The mixture was extracted with ether, which was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. The reaction was purified by flash chromatography (5-->20% EtOAc/Hex) to give 1.78 g (62%). Mass spec.: 483.13 (MNa)+.