Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([F:28])([F:27])[F:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:7]=1.[NH2:29][CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33]>>[OH:34][C@@H:31]([CH2:32][OH:33])[CH2:30][NH:29][C:22]([C:21]1[CH:20]=[N:19][N:16]2[CH:17]=[CH:18][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[C:25]([F:27])([F:28])[F:26])=[N:14][C:15]=12)=[O:24]
Reactant: NC[C@@H](O)CO
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)(F)F)nc12
Product: O=C(NC[C@@H](O)CO)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)(F)F)nc12
Yield: 73 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation M) and (R)-3-aminopropane-1,2-diol. The crude material was purified by reverse phase HPLC (0-60% acetonitrile/water) to provide the title compound (34 mg, 73% yield). MS (apci) m/z=468.1 (M+H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[OH:6][C:7]1[N:8]=[C:9]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[S:21][CH:22]=[C:23]([CH:25]([CH3:27])[CH3:26])[N:24]=3)[CH:15]=[CH:14][N:10]2[C:11](=[O:13])[CH:12]=1.[C:28](=O)([O-])[OH:29].[Na+]>CN(C)C=O>[OH:6][C:7]1[N:8]=[C:9]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[S:21][CH:22]=[C:23]([CH:25]([CH3:27])[CH3:26])[N:24]=3)[CH:15]=[CH:14][N:10]2[C:11](=[O:13])[C:12]=1[CH:28]=[O:29]
Reactant: CC(C)c1csc(COc2ccn3c(=O)cc(O)nc3c2)n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)c1csc(COc2ccn3c(=O)c(C=O)c(O)nc3c2)n1
Reaction time: 1 h
Yield: 14 %

Procedure:
Dimethylformamide (3 ml) was added with phosphorus oxychloride (130 μl, 1.42 mmol) under ice cooling, and further added dropwise with 2-hydroxy-8-[(4-isopropyl-1,3-thiazol-2-yl)methoxy]-4H-pyrido[1,2-a]pyrimidin-4-one (300 mg, 0.945 mmol) dissolved in dimethylformamide (6 ml) under ice cooling. Then, the reaction solution was returned to room temperature and stirred for 1 hour. The reaction was stopped with saturated aqueous sodium hydrogencarbonate, and the reaction solution was extracted with chloroform. The resulting organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=50:1→30:1→10:1) to obtain 45 mg (14%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:41])[C:13](=O)[CH:14](Br)[CH:15]([CH3:38])[CH:16]2[CH:19]([CH:20]([O:22][Si](C(C)(C)C)(C)C)[CH3:21])[C:18](=[O:30])[N:17]2[Si](C(C)(C)C)(C)C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[SH:42][CH:43]1[CH2:47][O:46][CH:45]([CH2:48][OH:49])[CH2:44]1.O1CCCC1>C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]([C:13]2[N:17]3[CH:16]([CH:15]([CH3:38])[C:14]=2[S:42][CH:43]2[CH2:44][CH:45]([CH2:48][OH:49])[O:46][CH2:47]2)[CH:19]([CH:20]([OH:22])[CH3:21])[C:18]3=[O:30])=[O:41])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OCC1CC(S)CO1
Reactant: CC(O[Si](C)(C)C(C)(C)C)C1C(=O)N([Si](C)(C)C(C)(C)C)C1C(C)C(Br)C(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CO)C3)C(C)C12

Procedure:
The title compound is prepared by the procedure of Example 104 using 0.166 g of product from Example 103, 0.0396 g of product from Example 77, 2.3 ml of dry tetrahydrofuran and 0.0413 ml of triethylamine to obtain the crude β-lactam. The subsequent cyclization uses the above product, 1.48 ml of 1M solution in methylene chloride of titanium tetrachloride and 1.6 ml of dry tetrahydrofuran to give 0.053 g of the desired product as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.CCN(CC)CC>COCCOC>[C:1]([NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: NC1CCc2ccccc21
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCCC(=O)NC1CCc2ccccc21
Yield: 58 %

Procedure:
A solution of butyryl chloride (5.33 g, 50 mmole) in anh. DME (60 ml) was added slowly to a stirred and ice-cooled solution of 1-aminoindan (6.66 g, 50 mmole) and Et3N (10.0 g, 100 mmole) in anh. DME (75 ml), and the mixture stirred at ambient temperature for 24 hr. After removal of volatiles under reduced pressure, the residue was taken up in 1:1 water/EtOAc mixture (300 ml). The organic layer was separated, dried on Na2SO4 and evaporated to dryness. The crude product was crystallized from EtOAc, to give 5.9 g (58%) of the title compound as a white solid, m.p.: 84°-5° C.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)[CH3:16].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)C>[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:13][C:12]([C@H:9]2[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5])[CH2:11][CH2:10]2)=[O:14])=[CH:20][CH:19]=1)[CH3:16]
Reactant: C=CCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCOc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCCC[C@H]1CC[C@H](C(=O)Oc2ccc(OCC)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 520 mg of trans-4-(4-pentenyl)cyclohexanecarboxylic acid, 439.4 mg of p-ethoxyphenol, 765.5 mg of dicyclohexylcarbodiimide and 45 mg of 4-(dimethylamino)pyridine were dissolved in 80 ml of methylene chloride and the solution was stirred at room temperature for 20 hours. Subsequently, the reaction mixture was diluted with diethyl ether, the precipitated urea was filtered off and the filtrate was concentrated. The residue was taken up in hexane and the solution was washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and water. The aqueous phases were back-extracted twice with hexane. The organic phases were dried over magnesium sulphate and evaporated. Low-pressure chromatography of the resulting residue on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 0.7 g (83%) of trans-4-(4-pentenyl)cyclohexanecarboxylic acid p-ethoxyphenyl ester. After recrystallization from 3 ml of methanol there were finally obtained 455 mg of product in the form of colourless crystals; m.p. (C--N) 32.7° C., cl.p. (N--I) 57.5° C.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]([F:28])([F:27])[C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[C:15](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:14]2[CH:26]=1.O>CS(C)=O>[F:28][C:10]([F:9])([F:27])[C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]3[CH2:4][CH:20]3[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:14]2[CH:26]=1
Reactant: CCOC(=O)/C=C/c1cccc2nc(C(F)(F)F)cn12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1cccc2nc(C(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
To a suspension of 60% sodium hydride (1.24, 28.5 mmol) in dimethyl sulfoxide (50 mL) was added trimethylsulfoxonium iodide (6.26 g, 28.5 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]acrylate (6.74 g, 23.7 mmol) in dimethyl sulfoxide (100 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=33/67) to give the title compound (3.40 g, yield 48%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1.[C:22]1([CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:36]2[CH2:35][CH2:34][CH:33]([CH2:32][CH2:31][O:30][CH2:29][CH2:28][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:38][CH2:37]2)[CH:7]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1
Reactant: c1ccc(CCOCCC2CCNCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCC(CCOCCc3ccccc3)CC2)c1
Temperature: 99 °C
Yield: 57.1 %

Procedure:
To a solution of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(R)-pyrrolidinyl]methoxy]pyridine (118 mg, 0.33 mmol) and 4-[2-(2-phenylethoxy)ethyl]piperidine (77 mg, 0.33 mmol) in anhydrous toluene (2 mL) were added successively sodium tert-butoxide (48 mg, 0.50 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (6.1 mg, 6.6 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 11.5 mg, 20 μmol, 0.06 equiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed to 98-100° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc, and the solution was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by CC on SiO2 with CH2Cl2/EtOAc 4:1, then 1:1. 3-[[1-(tert-Butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[4-[2-(2-phenylethoxy)ethyl]-1-piperidinyl]pyridine (96 mg, 57%) was obtained as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.[Cl-].[Na+].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:20]([O:19][C:17]([NH:16][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:29]2[CH:30]=[C:25]([Cl:24])[CH:26]=[CH:27][C:28]=2[Cl:31])=[CH:3][CH:4]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
A mixture of (R)-ethyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (1.005 g, 2.60 mmol), 2,5-dichlorophenylboronic acid (0.745 g, 3.90 mmol), Pd(PPh3)4 (0.301 g, 0.260 mmol) and 2 M aqueous Na2CO3 (2.60 ml, 5.20 mmol) in 1,2-dimethoxyethane (20 ml) is allowed to stir at 95° C. under nitrogen for 3 hours. The reaction mixture is cooled to room temperature and diluted with brine. The two phases are separated. The products are extracted twice with ethyl acetate (2×100 ml) from the aqueous layer. The combined organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 70:30) to give (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(2′,5′-dichlorobiphenyl-4-yl)butanoate (1.09 g); HPLC retention time=1.50 minutes (condition B); MS (ES+)=352.00 (m-BOC+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.1 Hz, 3H) 1.41 (s, 9H) 2.45-2.58 (m, 2H) 2.85-3.00 (m, 2H) 4.17 (t, J=7.1 Hz, 2H) 4.20 (br s, 1H) 5.06-5.08 (m, 1H) 7.23-7.28 (m, 3H) 7.31-7.40 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].O[C:12]1[CH:20]=[CH:19][C:15]([CH2:16][C:17]#[N:18])=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1.[OH-].[Na+]>[CH3:10][C:3]1([CH2:2][O:1][C:12]2[CH:20]=[CH:19][C:15]([CH2:16][C:17]#[N:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]
Reactant: N#CCc1ccc(O)cc1
Reactant: CC1(CO)CCCCC1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC1(COc2ccc(CC#N)cc2)CCCCC1=O
Temperature: 25 °C
Yield: 65 %

Procedure:
2-Hydroxymethyl-2-methylcyclohexanone [Pearson et al., J. Chem. Soc. Perkin I, 2774, 2778 (1980)] (3.7 g), 4-hydroxybenzyl cyanide (4.49 g) and triphenylphosphine (8.86 g) were dissolved in benzene (100 mL) and cooled in ice under a nitrogen atmosphere. Diethylazodicarboxylate (5.3 mL) was added dropwise and the mixture was allowed to warm to room temperature. The reaction was then refluxed overnight. After cooling to room temperature, the reaction mixture was diluted with 25% aqueous NaOH and extracted with benzene. The extracts were washed with saturated brine solution, dried over MgSO4, filtered and concentrated. The crude residue was chromatographed on SiO2, elution with dichloromethane to give 4.35 g (65% yield) of 2-methyl-2-[[4-(cyanomethyl)phenoxy]methyl]cyclohexanone as an amber oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(CCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice/water bath cooled solution of 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (11.43 g) and (2-bromo-ethyl)-benzene (20.20 mL) in DMF (100 mL) was carefully added NaH (3.88 g, 60% suspension in mineral oil). The mixture was subsequently stirred at room temperature overnight, and cooled with ice/water bath again, another 20.20 mL of (2-brom-ethyl)-benzene and 3.88 of NaH were added to the reaction, which was allowed to stir for another 5 h; then the mixture was quenched by pouring into a mixture of ammonium chloride and ice/water, extracted with EtOAc; EtOAc phase was washed with water twice, saturated NaCl solution (once) and then dried over anhydrous sodium sulfate, filtered, concentrated; the residue was purified with silica column to give the desired title product (3.30 g) with recovered starting pyrrole (6.31 g). The title compound, ESI MS (m/z): 258 (M+H)+.
Reaction SMILES: [Li]CCCC.Cl.C(N(CC)CC)C.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1.[N:22]1[C:29]([Cl:30])=[N:28][C:26](Cl)=[N:25][C:23]=1[Cl:24]>C1CCCCC1.C1COCC1.C(Cl)Cl>[Cl:24][C:23]1[N:22]=[C:29]([Cl:30])[N:28]=[C:26]([C:16]2[C:15]([F:14])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])[N:25]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Fc1cccc(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: Fc1cccc(F)c1-c1nc(Cl)nc(Cl)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 8.9 %

Procedure:
A solution of n-BuLi (15 mL, 2M, 30 mmol) in cyclohexane was added dropwise to a room temperature stirred suspension of triethylamine hydrochloride (0.25 g, 1.8 mmol). When the mixture became homogeneous, the solution was cooled to −78° C. in a dry-ice/acetone bath and 20 mL of anhydrous THF was added. Neat 1,3-difluorobenzene (3 mL, 30.4 mmol) was added dropwise and the solution stirred for 15 minutes. The −78° C. solution was transferred by cannula into a −78° C. solution of cyanuric chloride (5.5 g, 30 mmol) in dry THF (25 mL). The dry-ice/acetone cold bath was removed and the mixture allowed to come to room temperature. Once at room temperature the orange-red mixture was poured into 100 mL of half saturated aqueous bicarbonate solution. The mixture was allowed to stand for 15 minutes. Hexanes (100 mL) were added and after thorough mixing the organic layer was separated from the aqueous layer. The organic layer was dried over magnesium sulfate and then filtered to remove the magnesium sulfate. The solution was concentrated on a rotary evaporator to yield an oil. The oil was dissolved in a minimal amount of methylene chloride and loaded onto 100 g of silica gel. The silica gel was eluted with 10% ethyl acetate in hexanes. The organic eluent was concentrated on a rotary evaporator and the product precipitated from methylene chloride and hexane to yield 0.7 g of 2,4-dichloro-6-(2,6-difluorophenyl)-1,3,5-triazine (XXV). ESI/MS 262.0, 263.9, 265.9 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=S)[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.C(O)CCC.O.[NH2:30][NH2:31].C(=O)([O-])[O-].[Na+].[Na+]>CC1C=CC=CC=1.O.C(O)(=O)C>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:12][CH2:11]3)=[N:30][NH:31]2)=[CH:4][CH:5]=1
Reactant: NN
Reactant: Fc1ccc(C(=S)N2CCN(Cc3ccccc3)CC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Fc1ccc2c(N3CCN(Cc4ccccc4)CC3)n[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
A mixture of 40 parts of 1-[(2,4-difluorophenyl)thioxomethyl]-4-(phenylmethyl)piperazine, 144 parts of 1-butanol, 13 parts of hydrazine monohydrate and 24 parts of acetic acid was stirred overnight at reflux temperature. After cooling, 50 parts of sodium carbonate were added and stirring was continued for 3 hours at reflux temperature. The reaction mixture was cooled until room temperature and water and methylbenzene were added. After stirring for 15 minutes, the separated organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (92:8 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 12 parts (32.2%) of 6-fluoro-3-[4-(phenylmethyl)piperazinyl]-1H-indazole; mp. 162.0° C. (int. 7).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:10]([OH:14])[C:11]([NH2:13])=[O:12])=O)(C)(C)C.O.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(OCC)C>C(#N)C>[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[NH2:8][CH:9]([CH2:15][C:16]([F:17])([F:18])[F:19])[CH:10]([OH:14])[C:11]([NH2:13])=[O:12]
Reactant: CC(C)(C)OC(=O)NC(CC(F)(F)F)C(O)C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: NC(=O)C(O)C(N)CC(F)(F)F

Procedure:
A solution of 580 mg (2.03 mmol) of 3(RS)-(tert-butoxyformamido)-5,5,5-trifluoro-2(RS)-hydroxyvaleramide and 1.16 g (6.11 mmol) of 4-toluenesulphonic acid monohydrate in 10 ml of acetonitrile was stirred until the reaction had finished according to thin-layer chromatography. 10 ml of diethyl ether were added and the 3(RS)-amino-5,5,5-trifluoro-2(RS)-hydroxyvaleramide p-toluenesulphonate (1:1) which formed was removed by filtration and added to a solution of 1.06 g (1.156 mmol) of N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine (prepared as described in Example 1), 321 mg (2.79 mmol) of N-ethylmorpholine, 268 mg (1.4 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 190 mg (1.4 mmol) of 1-hydroxy-7-azabenzotriazole in 20 ml of dichloromethane. The mixture was stirred at room temperature until the reaction had finished according to thin-layer chromatography. The solution was washed with 2M hydrochloric acid and saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulphate, filtered and evaporated to dryness. The residue was triturated with diethyl ether/petroleum ether (1:1) and the solid was removed by filtration to give 0.7 g of 3(RS)-[[N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5,5,5-trifluoro-2(RS)-hydroxyvaleramide as a white solid, MS: m/e 1086.6 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:27]=[CH:26][C:19]2[C:20]([C:23](O)=[O:24])=[CH:21][O:22][C:18]=2[CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:50][C:51]1[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][CH:52]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:50][C:51]1[CH:57]=[CH:56][C:54]([NH:55][C:23]([C:20]2[C:19]3[CH:26]=[CH:27][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][CH:7]=4)=[CH:17][C:18]=3[O:22][CH:21]=2)=[O:24])=[CH:53][CH:52]=1
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)O)coc4c3)c2cc1OC
Reactant: Nc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc4c(C(=O)Nc5ccc(Cl)cc5)coc4c3)c2cc1OC
Reaction time: 48 h
Yield: 12.4 %

Procedure:
6-(6,7-Dimethoxyquinolin-4-yloxy)benzofuran-3-carboxylic acid (31 mg, 0.085 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (41 mg, 0.127 mmol) were added to a reaction tube then dissolved in DMF (0.6 mL). 4-chloroaniline (13 mg, 0.102 mmol) was added to the reaction mixture, followed by N,N-diisopropylethylamine (22 mg, 0.17 mmol) and stirring was continued for 2 days. The mixture was concentrated in vacuo. The remaining orange oil was purified by silica gel chromatography (1% to 2% methanol in dichloromethane) to afford N-(4-chlorophenyl)-6-(6,7-dimethoxyquinolin-4-yloxy)benzofuran-3-carboxamide as a yellow solid (5 mg). MS (ESI, pos. ion) m/z: 475.1 (M+1). Mass calc'd for C26H19ClN2O5: 474.89.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1)(=O)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]2)=[CH:31][C:30]=1[CH3:48].C(O)(C(F)(F)F)=O>>[CH3:48][C:30]1[CH:31]=[C:32]([CH:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH2:40]2)[CH:33]=[CH:34][C:29]=1[NH:28][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1
Reactant: COC(=O)Cc1ccccc1CCc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Reactant: Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2C)ncc1C(F)(F)F

Procedure:
A solution of methyl 2-(2-(2-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I15) (450 mg, 1.11 mmol), tert-butyl 4-(4-amino-3-methylphenyl)piperidine-1-carboxylate (I53) (390 mg, 1.34 mmol) and TFA (0.25 mL) in 2,2,2-TFE (3 mL) was heated at 120° C. under microwave irradiation for 30 minutes. The resulting mixture was adsorbed onto silica gel and chromatographed (0-50% MeOH/DCM) to give the titie compound (I54) (478 mg, 83%) as a viscous liquid; 1H NMR (400 MHz, CDCl3) δ 9.14 (bs, 1H), 8.76 (bs, 1H), 8.51 (s, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.21 (ddt, J=10.7, 7.4, 4.3 Hz, 4H), 7.15-7.06 (m, 1H), 3.65 (s, 2H), 3.60 (d, J=12.6 Hz, 2H), 3.49 (s, 3H), 3.15-3.02 (m, 6H), 2.87-2.71 (m, 1H), 2.32 (s, 3H), 2.07 (d, J=7.8 Hz, 4H). LCMS Method C: rt 5.24 min; m/z 513.2 [M+1]+.