Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C@H:3]([NH:8][C:9](N1C2CCN(C)CC=2C(C2C=C(F)C(F)=CC=2F)=N1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([F:55])=[C:37]([C:39]2[C:43]3[N:44]([C:48](OC(C)(C)C)=O)[CH2:45][CH2:46][CH2:47][C:42]=3[NH:41][N:40]=2)[CH:38]=1.N[C@@H](C(C)(C)C)[C:58](NCCO)=[O:59]>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([F:55])=[C:37]([C:39]2[C:43]3[N:44]([CH3:48])[CH2:45][CH2:46][CH2:47][C:42]=3[N:41]([C:9]([NH:8][C@@H:3]([C:2]([CH3:1])([CH3:30])[CH3:31])[C:4]([NH:6][CH2:7][CH2:58][OH:59])=[O:5])=[O:10])[N:40]=2)[CH:38]=1
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Reactant: CC(C)(C)[C@H](N)C(=O)NCCO
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]nc(-c3cc(Cl)ccc3F)c21
Product: CN1CCCc2c1c(-c1cc(Cl)ccc1F)nn2C(=O)N[C@H](C(=O)NCCO)C(C)(C)C

Procedure:
Compound 94 was prepared according to the procedure for the synthesis of compound 37 by replacing intermediate 19 with intermediate 20D, and replacing tert-leucine methylamide with intermediate 23. LCMS (+ESI) m/z=466.3 [M+H]+. 1H NMR (CDCl3) δ 7.80 (d, J=8.9 Hz, 1H), 7.62-7.65 (m, 1H), 7.32-7.37 (m, 1H), 7.10 (t, J=9.0 Hz, 1H), 4.14 (d, J=8.9 Hz, 1H), 3.71 (br, 2H), 3.42-3.46 (m, 2H), 3.02-3.06 (m, 2H), 2.96 (br, 2H), 2.41 (s, 3H), 1.92 (br, 2H), 1.06 (s, 9H). Purity: 99%.
Reaction SMILES: CN(C)C=O.[CH2:6]([O:10][C:11]1[C:16]([F:17])=[C:15](Cl)[N:14]=[CH:13][N:12]=1)[C:7]#[C:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH3:25][C:26]1([CH3:31])[CH2:30][CH2:29][NH:28][CH2:27]1>C(OCC)(=O)C>[CH2:6]([O:10][C:11]1[C:16]([F:17])=[C:15]([N:28]2[CH2:29][CH2:30][C:26]([CH3:31])([CH3:25])[CH2:27]2)[N:14]=[CH:13][N:12]=1)[C:7]#[C:8][CH3:9]
Reactant: CC#CCOc1ncnc(Cl)c1F
Reactant: CC1(C)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1ncnc(N2CCC(C)(C)C2)c1F
Temperature: 80 °C
Reaction time: 6 h
Yield: 31.7 %

Procedure:
Into 4 ml of N,N-dimethylformamide was resolved 0.36 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine, 0.62 g of potassium carbonate and 0.25 g of 3,3-dimethylpyrrolidine was added therein, and the mixture was stirred for 6 hours at 80° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.15 g of 4-(2-butynyloxy)-5-fluoro-6-(3,3-dimethylpyrrolidin-1-yl)pyrimidine (hereinafter, referred to as Compound (28)).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:9]([OH:11])=O)=[C:6]([CH3:8])[N:7]=1)[CH3:2].CN(C)C(=O)C.C(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[S:4][C:5]([C:9]([Cl:20])=[O:11])=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C)c(C(=O)O)s1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CCc1nc(C)c(C(=O)Cl)s1

Procedure:
In a similar apparatus to Example 1, 15.0 g (0.09 mole) of 2-ethyl-4-methylthiazole-5-carboxylic acid were suspended in 150 ml of toluene, followed by the addition of 0.1 g of N,N-dimethylacetamide. Under heating and reflux, phosgene was blown at a rate of 1.5 l/hr for 3.5 hours (0.23 mole). After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 16.1 g of 2-ethyl-4-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 98.2% and 96.9%, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(CCl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccc(F)cc1
Yield: 7.6 %

Procedure:
A solution of 5-chloropyrimidin-2-one (1.309 g) and 2-chloro-4'-fluoroacetophenone (1.726 g) in triethylamine (2 ml) and ethanol (50 ml) was stirred and heated at reflux for 11/2 hours. After evaporation of solvents, the residue was triturated with water (100 ml). The resulting collected solid was crystallised from ethanol then acetone, but still required purification, by preparative thin-layer chromatography on silica developed in chloroform-ethanol (25:1 v/v), before crystallisation from propan-2-ol to give the title pyrimidinone (204 mg,); 196°-202°; λmaxEtOH 245 nm (ε 17780), 333 nm (ε 2090), λinf 236 nm (ε 15230), 280 nm (ε 980).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13](I)[CH2:12]1.Cl[C:19]1[S:23][N:22]=[C:21]([S:24][CH3:25])[N:20]=1>[Zn].O1CCCC1>[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:19]2[S:23][N:22]=[C:21]([S:24][CH3:25])[N:20]=2)[CH2:12]1
Reactant: CSc1nsc(Cl)n1
Reactant: CC1CCCC(I)C1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CSc1nsc(C2CCCC(C)C2)n1
Temperature: 65 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
1.31 g of zinc foil (99.998%) and 190 mg of 1,2-dibromoethane was added into 2 ml of tetrahydrofurane under nitrogen atmosphere and the mixture was heated in an oil bath at 65° C. for 1 minute. After cooling to room temperature, 0.1 ml of trimethylsilyl chloride, 2.14 g of 3-methylcyclohexyl iodide and 10 ml of tetrahydrofuran were added to the mixture, and the mixture was exposed to ultrasonic wave in a water bath for 4 hours. Further, 1.31 g of 5-chloro-3-methylthio-1,2,4-thiadiazole, 390 mg of {1,1′-bis(diphenylphosphino)ferrocene} dichloro palladium(II) dichloromethane complex and 10 ml of tetrahydrofuran were added in the mixture, and the reaction mixture was stirred for 3.5 days at room temperature. The reaction mixture was concentrated, and the residue subjected to silica gel column chromatography to give 790 mg of 5-(3-methylcyclohexyl)-3-methylthio-1,2,4-thiadiazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1.[O:22]1[CH2:27][CH2:26]OCC1.C([N:31]([CH2:35][CH3:36])C(C)C)(C)C>O>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][N:14]([C:12]([C:5]2[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([NH:31][C@@H:35]3[C@@H:36]4[CH2:4][C@@H:5]([CH2:6][CH2:8]4)[C@@H:26]3[CH2:27][OH:22])=[N:3][CH:4]=2)=[O:13])[CH2:15][CH2:16]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1CCS(=O)(=O)CC1
Reactant: C1COCCO1
Solvent: O
Product: O=C(c1cnc(N[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2CO)nc1C(F)(F)F)N1CCS(=O)(=O)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}thiomorpholin-1,1-dioxide (100 mg), 3-exo-hydroxymethylbicyclo[2.2.1]heptyl-2-exo-amine hydrochloride (129 mg), and 1,4-dioxane (3 mL) was added N,N-diisopropyl ethylamine (0.20 mL) at room temperature, and the mixture was stirred at 80° C. for 2 hours. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain rac-[(1R,2S,3R,4S)-3-({5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-yl}amino)bicyclo[2.2.1]hept-2-yl]methanol (72 mg) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:24])=[C:13]([F:23])[CH:14]=2)[N:9]=1.[CH3:25][NH:26][CH2:27][CH2:28][C:29]#[N:30]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]([C:17]1[C:8]([N:26]([CH3:25])[CH2:27][CH2:28][C:29]#[N:30])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([F:23])=[C:12]([F:24])[CH:11]=2)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Reactant: CNCCC#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(F)c(F)cc2nc1N(C)CCC#N
Temperature: 20 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
19.08 g of sodium carbonate are added to a solution of 16.3 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline, prepared as described in Application Example 1, and 10 g of N-methyl-N-(b-cyanoethyl)amine in 160 cm3 of toluene. The suspension obtained is heated to reflux and then stirred for 4 hours at this temperature. The reaction mixture is then cooled to approximately 20° C. and thereafter washed with 3 times 50 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 19.17 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N-(b-cyanoethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps.
Reaction SMILES: C([O:3][C:4](Cl)=[O:5])C.N[C:8]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[NH:10][C:9]1=[O:18].[OH2:27]>N1C=CC=CC=1.CCOCC>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2([O:3][C:4](=[O:5])[OH:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26].[C:11]1([NH-:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccccc1C1(N)C(=O)Nc2ccc(Cl)cc21
Reactant: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: COc1ccccc1C1(OC(=O)O)C(=O)Nc2ccc(Cl)cc21
Product: [NH-]c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.38 ml (3.1 mmol) chloroformic acid ethyl ester were added to 0.8 g (2.8 mmol) of the intermediate product 3b in 20 ml pyridine at 0° C., and then everything was stirred for 16 h at room temperature. Then the batch was poured on to icy water and extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated in a vacuum. The residue obtained in this way was dissolved in a little ether and the product was precipitated by the careful addition of n-pentane. 1.1 g were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([NH:11][C:12]([O:14]CC[Si](C)(C)C)=O)[CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1)=[O:5])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:46][C:47]1[S:51][C:50](C(O)=O)=[CH:49][CH:48]=1.CN1CCOCC1.ClC(OCC(C)C)=O>C(#N)C.C1COCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([NH:11][C:12]([C:50]2[S:51][C:47]([Cl:46])=[CH:48][CH:49]=2)=[O:14])[CH2:9][N:8]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)OCC[Si](C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN1CCOCC1
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)c1ccc(Cl)s1
Temperature: 50 °C
Reaction time: 18 h
Yield: 43.2 %

Procedure:
40.2 (3S,4R)-4-(2-Trimethylsilanylethoxycarbonylamino)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.4 g; 3 mmol) is dissolved in acetonitrile (15 ml) and TBAF (1.372 g; 4 mmol) is added under an argon atmosphere. The mixture is stirred for 18 h at 50° C. 5-Chlorothiophene-2-carboxylic acid (1.272 g; 8 mmol) is dissolved in THF (10 ml), N-methyl morpholine (0.86 ml; 8 mmol) followed by isobutyl chloroformate (1.03 ml; 8 mmol) is added at 0° C. to this solution. After 30 min stirring at 25° C. this solution is added to the reaction mixture above. After 18 h at 25° C. additional 0.5 equivalents of activated 5-chloro-thiophene-2-carboxylic acid is added. The whole mixture is stirred for 3 d at 25° C., evaporated to dryness, dissolved in DCM/THF and washed with 1N aq. HCl solution, 10% aq. Na2CO3 solution. The organic phase is dried over Na2SO4. Flash chromatography over silica gel using DCM/MeOH/NH3 as eluent yielded 0.522 g (37.2%) (3S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester. Light brown oil. MS 403.5 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.[C:16]([O:22][CH3:23])(=[O:21])[CH2:17][C:18]([CH3:20])=O>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:17]([C:16]([O:22][CH3:23])=[O:21])=[C:18]([CH3:20])[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: Nc1cc[nH]n1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccccc1Cl
Product: COC(=O)C1=C(C)Nc2n[nH]cc2C1c1ccccc1Cl

Procedure:
The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and methyl acetoacetate in the same manner as in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CN(C)C1C=CC=CC=1.Br[CH:20]([CH3:31])[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=O.Cl>CC1C=CC=CC=1C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[C:20]2[CH3:31]
Reactant: COc1ccc(C(=O)C(C)Br)cc1
Reactant: COc1ccc(N)cc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2[nH]c3ccc(OC)cc3c2C)cc1
Temperature: 170 °C

Procedure:
0.38 mol of p-anisidine is added to 75 ml of N,N-dimethylaniline in a 1 liter reaction flask, heated to 170° C. while being stirred and then a solution of 0.18 mol of 2-bromo-4′-methoxypropiophenone in 240 ml of o-xylene is added in drops at this temperature. The strongly foaming mixture is refluxed for another 3 hours. After the solution is cooled, it is poured onto 600 ml of 2N HCl, stirred thoroughly and extracted three times with ethyl acetate. The organic extracts are washed twice each with 2N HCl and water, dried on magnesium sulfate (MgSO4) and liberated of solvent. For purification, the crude product is chromatographed on silica gel 60 with CH2Cl2 and then recrystallized from 96% ethanol.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[C:17](=[O:23])[N:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[N:13]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:12]=1)C(=O)OC(C)(C)C.C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C.C(O)C>[ClH:39].[CH3:22][N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[N:13]([S:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH:12]=[C:11]([CH2:10][NH:2][CH3:1])[CH:15]=2)[C:17]1=[O:23]
Reactant: CN(Cc1cc(-c2cccn(C)c2=O)n(S(=O)(=O)c2ccccc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cc(-c2cccn(C)c2=O)n(S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
tert-Butyl methyl{[5-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate (9.9 mg) was dissolved in ethyl acetate (0.5 mL) and ethanol (0.5 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure. The residue was solidified with diisopropyl ether to give the title compound as a pale-gray solid (yield 5.7 mg, 78%).
Reaction SMILES: [OH-].[Na+].[C:3]1([CH2:9][SH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:11][CH2:12][CH2:13][N:14]([CH2:38][CH2:39][Cl:40])[P:15]([N:31]([CH2:35][CH2:36][Cl:37])[CH2:32][CH2:33][Cl:34])(=[O:30])[O:16][CH2:17][CH2:18]OS(C1C=CC(Br)=CC=1)(=O)=O.C1(C)C=CC=CC=1>CO>[Cl:37][CH2:36][CH2:35][N:31]([P:15]([N:14]([CH2:13][CH2:12][Cl:11])[CH2:38][CH2:39][Cl:40])([O:16][CH2:17][CH2:18][S:10][CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:30])[CH2:32][CH2:33][Cl:34]
Reactant: SCc1ccccc1
Reactant: O=P(OCCOS(=O)(=O)c1ccc(Br)cc1)(N(CCCl)CCCl)N(CCCl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=P(OCCSCc1ccccc1)(N(CCCl)CCCl)N(CCCl)CCCl
Reaction time: 0.08 h

Procedure:
Sodium hydroxide, 6.4 g (161 mmol), was dissolved in 100 mL methanol under nitrogen at room temperature, and α-toluenethiol, 9.52 mL (10 g, 80.5 mmol), was added. After the resulting mixture was stirred for 5 minutes, 2-(4-bromobenzenesulfonyloxy)ethyl tetrakis(2-chloroethyl)phosphorodiamidate, 80.5 mL of 1 M solution in toluene (80.5 mmol), was added with stirring. A precipitate formed within 1 minute of the addition, and stirring was continued. Analysis of the reaction after 2 hours showed that the reaction was nearly complete, and stirring was continued overnight at room temperature. Analysis then showed that the reaction was complete, and stirring was stopped and the reaction mixture allowed to stand and then filtered to remove the precipitated sodium 4-bromobenzenesulfonate. The methanol was removed from the filtrate by evaporation and the residue was dissolved in 250 mL isopropyl acetate. The isopropyl acetate solution was washed with aqueous sodium hydroxide (100 mL of 1 M), water (100 mL), and brine (100 mL), and was then dried over anhydrous sodium sulfate and filtered. The isopropyl acetate was removed by vacuum evaporation to give an oil, which was dried under vacuum at 40° C. overnight, giving 40.4 g of α-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]toluene as an orange oil containing residual toluene. HPLC analysis of the product showed a purity of 96.8%. 1H NMR: δ 7.16-7.33 (m, 5H), 4.04-4.06 (m, 2H), 3.74 (s, 2H), 3.60-3.65 (m, 8H), 3.36-3.43 (m, 8H), 2.69 (t, 2H).
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])(=O)=O.[CH2:22]([C:24]([C:49]1[CH:54]=[CH:53][C:52](O)=[C:51]([CH3:56])[CH:50]=1)([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:44][CH2:45][O:46][CH3:47])([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[C:29]([CH3:48])[CH:28]=1)[CH2:25][CH3:26])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:22]([C:24]([C:49]1[CH:54]=[CH:53][C:52]([O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])=[C:51]([CH3:56])[CH:50]=1)([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:44][CH2:45][O:46][CH3:47])([C:40]([F:42])([F:43])[F:41])[C:36]([F:38])([F:39])[F:37])=[C:29]([CH3:48])[CH:28]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(/C=C/C(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(CC)(c1ccc(/C=C/C(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
Pyridine (0.513 mL, 6.36 mmol) and trifluoromethanesulfonic anhydride (0.835 mL, 5.09 mmol) were added to a solution of 4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenol (Example 26-(2); 2.14 g, 4.24 mmol) in dichloromethane (20 mL) in a nitrogen atmosphere at 0° C., and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 70:30) to give the target product as a colorless oil (2.41 g, 89%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](Br)[C:5]2OC[N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.[C:30](=[O:33])([O-])[O-].[K+].[K+]>CC(O)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>[C:11]([NH:8][CH2:7][C:6]1[CH:5]=[C:4]([C:22]2[CH:23]=[N:24][C:19]([C:18]([F:29])([F:28])[F:17])=[CH:20][CH:21]=2)[CH:3]=[C:2]([C:15]2[CH:23]=[N:24][C:19]([C:18]([F:29])([F:28])[F:17])=[CH:20][CH:21]=2)[C:30]=1[OH:33])([CH3:12])([CH3:13])[CH3:14]
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)N1COc2c(Br)cc(Br)cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)NCc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2ccc(C(F)(F)F)nc2)c1O
Temperature: 72 °C
Yield: 42.6 %

Procedure:
A mixture of 6,8-dibromo-3-(tert-butyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (Intermediate 6) (0.621 g, 1.79 mmol), 6-(trifluoromethyl)pyridine-3-boronic acid [purchased from Frontier Scientific] (1.025 g, 5.37 mmol), and potassium carbonate (1.979 g, 14.3 mmol) in 2-propanol (30 mL) and water (6 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium (0) (114 mg, 0.099 mmol) was added and the resulting mixture heated at 72° C. for 60 minutes then the cooled reaction mixture concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to afford a dark brown oil. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 30% ethyl acetate in hexanes to give a yellow solid. The solid was triturated with 1:1 v/v MTBE/hexane, filtered and then dried at 40° C./4-8 mm Hg to give 2-((tert-butylamino)methyl)-4,6-bis(6-(trifluoromethyl)pyridin-3-yl)phenol (0.358 g) as an off-white solid.
Reaction SMILES: [C:1]([CH2:29][NH:30][C@H:31]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([C:25]([F:28])([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].ClC([O:50][CH2:51][CH3:52])=O.[CH2:53](N(CC)CC)C>C(Cl)Cl>[C:1]([CH2:29][NH:30][C@H:31]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][C:51]([CH2:52][CH3:53])=[O:50])=[CH:37][CH:38]=1)([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([C:25]([F:26])([F:27])[F:28])([F:23])[F:24])([F:20])[F:21])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)Oc1ccc(C[C@H](NCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OC(C)(C)C)cc1
Yield: 92.2 %

Procedure:
C9F19CH2NH-Tyr-OBut (287 mg, 0.4 mmol), ethyl chloroformate (42 microL, 0.44 mmol) and triethylamine (70 μL, 0.5 mmol) were stirred in CH2Cl2 (5 mL) at room temperature for 1 hr. The mixture was diluted with CH2Cl2 (30 ml), extracted with 2×30 mL 0.1 M citric acid. The organic phase was dried and evaporated to yield 286 mg (92%) of the desired C9F19CH2NH-Tyr(OCOEt)-OBut, pure by NMR. 1H NMR (CDCl3, 300 MHz, ref. TMS=0 ppm) 1.4 (overlapping s, 9H, But and t, 3H, OCH2CH3), 2.8 (m, 2H, tyrosine CH2), 3.0-3.4 (ABX3, m, 2H, RfCF2CH2), 3.4 (t, 1H), 4.3 (q, 2H, OCH2CH3), 6.7 (d, 2H), 7.0 (d, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.C[Si]([N:32]=[C:33]=[O:34])(C)C>C(O)(C)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)[CH:22]1[CH2:27][CH2:26][N:25]([C:33]([NH2:32])=[O:34])[CH2:24][CH2:23]1
Reactant: c1cnc2c(c1)CCCC2N(Cc1nc2ccccc2[nH]1)C1CCNCC1
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(C)O
Product: NC(=O)N1CCC(N(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)CC1
Reaction time: 20 h

Procedure:
A solution of (1H-benzimidazol-2-ylmethyl)-piperidin-4-yl-(5,6,7,8-tetrahydroquinolin-8-yl)-amine (0.16 g, 0.43 mmol) in isopropanol (3 mL) was treated with trimethylsilylisocyanate (81 μL, 0.60 mmol) at room temperature. The reaction was stirred 20 hours and concentrated under reduced pressure. This afforded, after column chromatography with silica gel (5:0.5:94.5 MeOH:NH4OH:CH2Cl2), 4-[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-piperidine-1-carboxylic acid amide (112 mg, 66%). 1H NMR (CDCl3) δ 1.42 (m, 1H), 1.60-1.95 (m, 5H), 2.02 (br, 1H), 2.24 (br, 1H), 2.60-2.80 (m, 4H), 2.89 (m, 1H), 3.70 (br, 1H), 4.03 (br, 1H), 4.15 (m, 3H), 4.39 (br, 2H, NH2), 7.18 (m, 3H), 7.45 (d, 1H, J=7.5 Hz), 7.66 (br, 2H), 8.59 (d, 1H, J=4.0 Hz).