Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[CH2:23](I)[CH3:24]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:23][CH3:24]
Reactant: CCI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Solvent: CN(C)C=O
Product: CCn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 67.1 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 200 mg, 0.65 mmol) and ethyl iodide (262 μL, 3.3 mmol) in dimethylformamide (2 mL) was heated at 100° C. over the weekend. The solvent was evaporated and ethyl acetate was added. The solution was washed twice with saturated aqueous sodium thiosulfate, and three times with water. The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 75% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2,4-difluoro-phenyl)-1-ethyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (145 mg, 67%) as a white solid. IR 1667 cm−1.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[Cl:13][C:14]1[N:15]=[CH:16][C:17]([C:2]2[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=2)=[CH:18][CH:19]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CCOC(=O)c1sc(Br)nc1C
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(Cl)nc2)nc1C
Yield: 69.1 %

Procedure:
Ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (1 g, 1.3 eq, 4 mmol) is added to a mixture of 2-chloro-5-pyridine boronic acid (0.48 g, 1 eq, 3.07 mmol), tetrakis(triphenylphosphine)palladium (0.18 g, 0.05 eq, 0.15 mmol) and an aqueous solution of 2 M potassium carbonate (3 ml, 2 eq, 6.14 mmol) in toluene/ethanol (18 ml, 2:1 v/v). The mixture is refluxed overnight and the solvent is evaporated, then taken up in ethyl acetate, and washed two times with an aqueous solution of sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography over silicagel (eluent: dichloromethane 100%) affords 0.6 g of ethyl 2-(6-chloropyridin-3-yl)-4-methyl-1,3-thiazole-5-carboxylate i97.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl.N1C=CC=CC=1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C[C@@H]1CN(c2ccc(OCc3ccccc3)c(N)c2)C[C@H](C)N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H]1CN(c2ccc(OCc3ccccc3)c(NS(=O)(=O)c3ccc(Br)cc3)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-[(phenylmethyl)oxy]aniline (D39) (500 mg, 1.61 mmol) in dichloromethane (8 ml) and pyridine (8 ml) was added 4-bromobenzenesulfonyl chloride (820 mg, 3.21 mmol) and the resulting mixture stirred at room temperature, under an atmosphere of argon for 2 hours. The mixture was then reduced in vacuo, azeotroped with methanol and the residue partitioned between dichloromethane (75 ml) and saturated aqueous sodium hydrogen carbonate (75 ml). The layers were separated, the aqueous re-extracted with dichloromethane (50 ml) and the combined organic layers washed with brine (125 ml), dried over anhydrous magnesium sulphate, filtered and reduced in vacuo. The residue was purified by chromatography on silica gel (gradient: dichloromethane:methanol 25:1 to 10:1) to afford the title compound (D40). MS (ES+) m/e 530/532 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.O.O.C([O-])(=O)C.[Na+]>O.C(O)C>[C:10]1([N:16]([C:6]2[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]=2)[NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: NNc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NN(c1ccccc1)c1cc(Cl)nc(Cl)n1
Reaction time: 72 h

Procedure:
A mixture of 2,4,6-trichloropyrimidine (50ml.) and phenylhydrazine (45ml.) was added to a solution of sodium acetate trihydrate (100g.) in water (270ml.) and ethanol (720ml.). The resulting mixture was kept at room temperature for 3 days. The resulting crystalline precipitate was collected by filtration, washed with ethanol (100ml.) and dried at 60° C. to give N-phenyl-N-(2,6-dichloropyrimidin-4-yl)hydrazine, m.p. 114°-116° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:11][C:12]2[S:16][C:15]([Cl:17])=[N:14][CH:13]=2)[CH2:9][CH3:10])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[CH2:21]([O-:24])[CH:22]=[CH2:23].[Na+]>CN(C=O)C>[CH2:21]([O:24][C:2]1[N:7]=[C:6]([N:8]([CH2:11][C:12]2[S:16][C:15]([Cl:17])=[N:14][CH:13]=2)[CH2:9][CH3:10])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1)[CH:22]=[CH2:23]
Reactant: CCN(Cc1cnc(Cl)s1)c1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C=CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc([N+](=O)[O-])c(N(CC)Cc2cnc(Cl)s2)n1
Temperature: 7.5 °C
Yield: 21.3 %

Procedure:
1.10 g of 6-chloro-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridine-2-amine, prepared according to the example 1, in 30 mL of DMF was added into a 100 mL three-necked flask equipped with a magnetic stirrer, a condenser and a drying tube, under stirring at 5-10° C., 1.02 g of sodium prop-2-en-1-olate (the content of 30.7%) in 20 mL of DMF was added dropwise, and the reaction was complete after further stirred for 4 to 6 hours. The reaction mixture was treated by the method according to the example 1 to obtain 0.25 g of 6-allyloxy-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-nitropyridine-2-amine, having the content of 91%, as a brown sticky solid in a yield of 19.4%. GC-MS (M+) (EI, 70 eV, m/z) calc: 354. found: 354. 1H NMR (CDCl3/TMS, 300 MHz) δ (ppm) 1.221 (t, J=7.2 Hz, 3H, CH3), 3.291 (q, J=7.2 Hz, 2H, CH2), 4.817 (s, 2H, CH2), 4.869 (d J=2.7 Hz, 2H, CH2), 5.464-5.267 (m, 2H, CH2), 6.086-5.957 (m, 1H, CH), 6.231 (d, J=8.7 Hz, 1H, Py H), 7.473 (s, 1H, Thiazole-H), 8.171 (d, J=8.7 Hz, 1H, Py H).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH3:8])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:18]=[C:16]1[C:15]2[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13](=[O:23])[N:17]1[CH2:2][C:3]1[N:7]([CH3:8])[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CO)n1C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
590 mg of methyl 5-(hydroxymethyl)-1-methyl-1H-pyrrole-2-carboxylate, 770 mg of phthalimide, and 1.83 g of triphenylphosphine were dissolved in 10.0 mL of THF, and 2.75 mL of diethyl azodicarboxylate was added thereto under ice-cooling, followed by stirring at room temperature overnight. The reaction liquid was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) to obtain 650 mg of methyl 5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrrole-2-carboxylate.
Reaction SMILES: [C:1]1([C:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19]O)[CH2:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:21]([N:23](CC)CC)C.CS(Cl)(=O)=O.CN>C(Cl)(Cl)Cl.C(#N)C>[CH3:21][NH:23][CH2:19][CH2:18][CH2:17][N:14]1[CH2:15][CH:16]=[C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:13]1
Reactant: CCN(CC)CC
Reactant: OCCCN1CC=C(c2cccc3ccccc23)CC1
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CNCCCN1CC=C(c2cccc3ccccc23)CC1
Temperature: 0 °C
Yield: 95.3 %

Procedure:
3,6-Dihydro-4-(1-naphthalenyl)-1(2H)-pyridinepropanol (Ex. 4: 1.20 g, 4.49 mmol) was dissolved in chloroform (50 mL) followed by the addition of triethylamine (0.94 mL, 6.73 mmol) and cooled to 0° C. Methanesulfonyl chloride (0.42 mL, 5.39 mmol) was added dropwise and the reaction was allowed to stir for thirty minutes while warming to room temperature. Solvent was then removed in vacuo yielding a crude solid (IV). This material was then dissolved in a solution of acetonitrile (60 mL) containing 40 wt. % aqueous methylamine (60 mL) and heated at reflux for three hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude residue was diluted with chloroform (500 mL) and washed with aqueous 10% potassium carbonate (200 mL) followed by saturated aqueous sodium chloride (200 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated yielding 1.20 g (98%) of the title compound as a viscous golden oil: 1H NMR (CDCl3): δ 1.80 (m, 2H), 2.05 (br s, 1H), 2.43 (s, 3H), 2.57 (m, 2H), 2.70 (t, J=Hz, 2H), 2.79 (t, J=Hz, 2H), 3.20 (m, 2H), 5.73 (m, 1H), 7.25 (d, J=1.58, 1H), 7.39-7.48 (m, 3H), 7.75 (d, J=8.19, 1H), 7.83 (m, 1H), 7.96 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH:19][C:20]2[N:25]=[C:24]([C:26](N)=[O:27])[CH:23]=[CH:22][N:21]=2)[CH2:13][CH2:12]1.[CH3:29][OH:30].Cl>C1CCCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][NH:19][C:20]2[N:25]=[C:24]([C:26]([O:30][CH3:29])=[O:27])[CH:23]=[CH:22][N:21]=2)[CH2:15][CH2:16]1
Reactant: COc1ccc(OC)c(N2CCN(CCNc3nccc(C(N)=O)n3)CC2)c1
Reactant: CO
Agent: Cl
Solvent: C1CCCCC1
Product: COC(=O)c1ccnc(NCCN2CCN(c3cc(OC)ccc3OC)CC2)n1

Procedure:
8.76 g (22.66 mmol) of 2-[[2-[4-(2,5-dimethoxyphenyl) piperazin-1-yl]ethyl]amino]pyrimidine-4-carboxamide are introduced into 650 ml of methanol in a 1 l round-bottomed flask, a stream of gaseous hydrochloric acid is passed through for a few minutes and the mixture is then heated at the reflux temperature of the methanol for 5 h. The solventis evaporated under reduced pressure, 300 ml of dichloromethane are added to the residue and the mixture is then basified with a saturated aqueous sodium hydrogencarbonate solution. The organic phase is dried over sodium sulphate, filtered and the solvent is then evaporated under reduced pressure. After purification by chromatography on a silica gel column (eluent: 100/0 to 90/10 dichloromethane/methanol mixture) and then by recrystallisation from cyclohexane, 6.93 g (17.26 mmol) of ester are isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:29]([O-:31])=[O:30])[C:5]2[C:6]([CH2:19][NH:20][C@@H:21]3[CH:26]4[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]4)[CH2:22]3)=[N:7][N:8](COCC[Si](C)(C)C)[C:9]=2[CH:10]=1.[Li+].Cl>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:29]([OH:31])=[O:30])[C:5]2[C:6]([CH2:19][NH:20][C@@H:21]3[CH:26]4[CH2:25][CH2:24][N:23]([CH2:28][CH2:27]4)[CH2:22]3)=[N:7][NH:8][C:9]=2[CH:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(CN[C@H]2CN3CCC2CC3)c2c(C(=O)[O-])cc(Br)cc21
Agent: Cl
Agent: [Li+]
Solvent: CC(C)O
Product: O=C(O)c1cc(Br)cc2[nH]nc(CN[C@H]3CN4CCC3CC4)c12
Temperature: 140 °C
Yield: 34.9 %

Procedure:
To a sealed tube containing a solution of crude lithium (R)-6-bromo-3-((quinuclidin-3-ylamino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-carboxylate 0.40 g, 0.90 mmol) in 2-propanol (40 mL) was added 6N HCl (4 mL). The reaction mixture was flushed with argon, sealed and heated to 140° C. for 30 min, cooled to ambient temperature and concentrated under reduced pressure. The residue was concentrated and purified by reverse phase semi-preparative HPLC (5-20% acetonitrile in water—both eluents contained 0.05% trifluoroacetic acid as modifier). The solvents were removed in vacuo and the desired product trifluoracetate salt was purified further by preparative TLC (6:3:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (R)-6-bromo-3-((quinuclidin-3-ylamino)methyl)-1H-indazole-4-carboxylic acid (119 mg, 40%) as an amorphous white solid: 1H NMR (500 MHz, d4-MeOH) δ, 7.74 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 4.40-4.28 (m, 2H), 3.60-3.30 (m, 3H), 3.22-3.00 (m, 5H), 2.26-2.20 (m, 1H), 2.19-2.02 (m, 1H), 2.00-1.90 (m, 1H) 1.88-1.68 (m, 2H).
Reaction SMILES: O=[C:2]([CH2:16][CH2:17][C:18]([O-:20])=[O:19])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:46]([O:53][C:54]([NH:56][C@@H:57]1[CH2:61][O:60][NH:59][C:58]1=[O:62])=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH2:46]([O:53][C:54]([NH:56][C@@H:57]1[CH2:61][O:60][N:59]([C:2]2([C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=3)=[O:4])[CH2:16][CH2:17][C:18](=[O:19])[O:20]2)[C:58]1=[O:62])=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(N[C@@H]1CONC1=O)OCc1ccccc1
Reactant: O=C([O-])CCC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C1CCC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@@H](NC(=O)OCc3ccccc3)C2=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
In 3 ml of dichloromethane were dissolved 85 mg of the Compound (1) obtained in Example 1 and 41 mg of 1-hydroxybenzotriazole (HOBT). To the solution was added 62 mg of DCC, and the mixture was stirred at room temperature for 30 minutes, to which was added 60 mg of (4R)-4-benzyloxycarbonylamino-3-isoxazolidinone, prepared by the method described in Journal of Medicinal Chemistry, 13 1013 (1970), followed by stirring at room temperature for 30 minutes. The insolubles which separated out were filtered off and washed with dichloromethane. The filtrate and the washing were combined and concentrated. The concentrate was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate and a saturated saline, successively, which was then dried (Na2SO4). The solvent was evaporated off under reduced pressure, and the residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (1:1) to give 96 mg of the subject compound (8) as colorless foamy substance.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH3:12])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:20][C:18]1[CH:17]=[CH:16][C:15]([O:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:14]([CH:19]=1)[O:13][C:10]1([CH3:12])[CH2:11][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(C)(Oc2cc(Br)ccc2OCCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(Oc2cc(Br)ccc2OCCc2ccccc2)CNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A mixture of 3-(5-bromo-2-phenethyloxy-phenoxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (20 mg) and TFA (1 mL) in CH2Cl2 (2 mL) was stirred at rt for 2 h. The reaction was concentrated in vacuo and purified by PTLC followed by additional purification using RP HPLC (Agilent) to give the title compound as an oil (12 mg, 77%). MS (ESI): mass calcd. for C18H20BrNO2, 362.3; m/z found, 362.0 [M+H]+. 1H NMR (CDCl3): 7.38-7.18 (m, 5H), 7.04 (dd, J=8.6, 2.3 Hz, 1H), 6.74 (dd, J=5.5, 3.1, 2H), 4.15 (t, J=7.2 Hz, 2H), 3.97 (d, J=8.9 Hz, 2H), 3.45 (d, J=9.2 Hz, 2H), 3.11 (t, J=7.1 Hz, 2H), 1.98 (s, 1H), 1.65 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=2)[O:3]1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:18])=[CH:13][CH:14]=2)[O:3]1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Reactant: C1COCCN1
Product: CC1(C)OB(c2ccc(CC(=O)N3CCOCC3)cc2)OC1(C)C
Yield: 34.8 %

Procedure:
Using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylacetic acid (786 mg, 3.0 mmol) and morpholine (1.3 mL, 15.0 mmol), the desired title compound (346 mg, yield 35%) was obtained by the same method as the amidation step in Example 4 (4b).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH2:11][CH:12]([CH:20]([OH:27])[CH:21]([OH:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[N:28]1([S:34]([NH:37][C@H:38]([C:46]([NH:48][C@H:49]([C:57](O)=[O:58])[CH2:50][C:51]2[N:52]=[C:53]([NH2:56])[S:54][CH:55]=2)=[O:47])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:36])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.C(N(CC)CC)C>[N:28]1([S:34]([NH:37][C@H:38]([C:46]([NH:48][C@H:49]([C:57]([NH:11][CH:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:20]([OH:27])[CH:21]([OH:26])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:58])[CH2:50][C:51]2[N:52]=[C:53]([NH2:56])[S:54][CH:55]=2)=[O:47])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:35])=[O:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CC(C)CC(O)C(O)C(N)CC1CCCCC1
Reactant: Nc1nc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)N2CCOCC2)C(=O)O)cs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)CC(O)C(O)C(CC1CCCCC1)NC(=O)[C@H](Cc1csc(N)n1)NC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)N1CCOCC1
Temperature: 25 °C

Procedure:
1-N-Hydroxybenzotriazole, 190.6 g, 395.0 g of [2S-(2R*,3S*,4R*)]-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol (U.S. Pat. Nos. 4,680,284 and 4,845,079), 682.4 g (1.62 mol) of N-(4-morpholinylsulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-L-alanine and 20 L of ethyl acetate are charged into a 50 L reactor and the slurry is stirred. Triethylamine, 107.1 g with 0.5 L of ethyl acetate, is added to the mixture and stirred for 1 hour at 30° C. A solution of 300.0 g of dicyclohexylcarbodiimide dissolved in 2.5 L of ethyl acetate is added to the reaction mixture over 15 to 30 minutes. The slurry is warmed to 35° to 40° C. and stirred at that temperature for 48 hours, cooled to 25° C., and the solids removed by filtration. The filtrate is washed with 0.5N aqueous hydrochloric acid solution (4 L), saturated sodium bicarbonate solution (4×4 L), and water (2 L). The solution is concentrated to a thick slurry under vacuum, chilled to 5° C., and the crude product solid collected by filtration and dried under vacuum at 40° C. The crude product and 4 L of isopropanol are charged into a 12 L reactor and the slurry is heated to 45° C. Water, 1 L, is added and heating continued to 60° C. The solution is cooled slowly to crystallize the product and then chilled to 10° C. The slurry is filtered and the cake is washed with cold isopropanol. After drying at 40° C. under vacuum, 770 g of [1S-(1R*,2S*,3R*)]-N-(4-morpholinylsulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-N-[(1-cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-L-alaninamide is obtained as white needles of >99% purity by HPLC; mass spectrum (fast atom bombardment): 709.2 M+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]([F:47])([F:46])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[C:33]([O:39][CH3:40])=[N:34][CH:35]=[C:36]([Cl:38])[CH:37]=4)=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=3)[C@H:20]2[CH3:45])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1>C1COCC1>[F:47][C:8]([F:7])([F:46])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[C:33]([O:39][CH3:40])=[N:34][CH:35]=[C:36]([Cl:38])[CH:37]=4)=[CH:30][N:29]=[C:28]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:27]=3)[C@H:20]2[CH3:45])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1
Reactant: COc1ncc(Cl)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: COc1ncc(Cl)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Morpholine (0.217 mL, 2.488 mmol) was added to a THF (1 mL) solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Step A, 311 mg, 0.498 mmol). This was then stirred for 30 minutes at 120° C. in a microwave reactor. LCMS showed >90% conversion to product. The reaction was concentrated on rotary evaporator. The crude isolate was purified by silica gel chromatography, eluting with a 0-50% isopropyl acetate/hexanes linear gradient followed by isocratic elution with 50% isopropyl acetate/hexanes for 10 minutes to give the titled compound as a white foam. LCMS (M+H)+: 632.3. 1H NMR (CDCl3, 500 MHz): δ 8.19 (d, J=2.5 Hz, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.75 (s, 2H), 7.48 (d, J=2.5 Hz, 1H), 5.66 (d, J=8.5 Hz, 1H), 4.72 (d, J=17.1 Hz, 1H), 4.31 (m, 1H), 3.96 (s, 3H), 3.89 (m, 4H), 3.83 (m, 4H), 0.73 (d, J=6.5 Hz, 3H). SPA IC50: 671 nM.
Reaction SMILES: [CH:1]1([C@H:4]([NH:26][C:27](=[O:38])[O:28][C:29]2C=CC([N+]([O-])=O)=C[CH:30]=2)[C:5]([N:7]2[CH2:11][C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])=[CH:9][C@H:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:39][N:40](C)[CH2:41]CO>>[CH:1]1([C@H:4]([NH:26][C:27](=[O:38])[O:28][CH2:29][CH2:30][N:40]([CH3:41])[CH3:39])[C:5]([N:7]2[CH2:11][C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])=[CH:9][C@H:8]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CN(C)CCO
Reactant: O=C(N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1)Oc1ccc([N+](=O)[O-])cc1
Product: CN(C)CCOC(=O)N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1

Procedure:
A solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethylcarbamate (31-1, 50 mg, 0.096 mmol) in 2-(dimethylamino)ethanol (1 mL) was heated at 100° C. for 1 hour. The reaction mixture was cooled, then partitioned between ethyl acetate (40 mL) and brine (3×40 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (EtOAc initially, grading to 10% saturated NH3/ethanol in EtOAc) to give 2-(dimethylamino)ethyl(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethylcarbamate (31-2) as a pale yellow solid. 1H NMR (500 MHz, CDCl3) showed a 2:1 mixture of rotamers; major rotamer: δ 7.42-7.24 (m, 5H), 7.11-6.95 (m, 3H), 6.41 (br s, 1H), 5.93 (m, 1H), 5.58 (d, 1H, J=7.6 Hz), 5.04 (br d, 1H, J=13.9 Hz), 4.91 (ddd, 1H, J=14.7, 4.4, 1.7 Hz), 4.30 (t, 1H, J=7.8 Hz), 4.15 (m, 2H), 2.54 (m, 2H), 2.27 (s, 6H), 1.14 (m, 1H), 0.57-0.33 (m, 4H). LRMS nil/z (M+H) 470.5 found, 470.2 required.