Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](C)=[N:9]2)=[CH:4][N:3]=1.[Se](=O)=O.[CH:16]([OH:18])=[O:17].OO>O1CCOCC1.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:16]([OH:18])=[O:17])=[N:9]2)=[CH:4][N:3]=1
Reactant: O=CO
Reactant: Cc1ccc2cnc(Br)cc2n1
Agent: O=[Se]=O
Agent: OO
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)c1ccc2cnc(Br)cc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7-Bromo-2-methyl-1,6-napthyridine (Preparation 65, 206 mg, 0.92 mmol) and selenium dioxide (102.5 mg, 0.92 mmol) were heated in dioxane (3 mL) at 80° C. for 2 hours. The reaction was diluted with DCM (6 mL) and filtered through celite. The filter cake was washed with DCM (3×9 mL) and the combined filtrates concentrated in vacuo. The residue was stirred with formic acid (1 mL) and hydrogen peroxide (35% aqueous solution, 50 uL, 0.67 mmol) was added. The reaction was stirred at 0° C. for 1 hour before the reaction was quenched by the addition of palladium on charcoal (3 mg) and stirred for a further 20 minutes. The reaction was concentrated in vacuo to afford the title compound.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[Cl:32][C:33]1[C:38]([S:39](Cl)(=[O:41])=[O:40])=[CH:37][CH:36]=[C:35]([Cl:43])[N:34]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:32][C:33]1[C:38]([S:39]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)(=[O:41])=[O:40])=[CH:37][CH:36]=[C:35]([Cl:43])[N:34]=1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)nc1Cl)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a 20-mL vial was added 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.40 g, 1.0 mmol, Example 91), CH2Cl2 (8 mL), and triethylamine (0.70 mL, 5.0 mmol). To this solution was added 2,6-dichloropyridine-3-sulfonyl chloride (0.30 g, 1.2 mmol, Organic Process Research and Development 2009, 875). After stirring overnight at room temperature, saturated aqueous sodium bicarbonate and CH2Cl2 were added to the reaction mixture. After stirring for 5 min, the solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies, Essex, UK) with the organic phase being collected and passed through a plug of Na2SO4. The collected solution was purified by silica gel chromatography (0 to 70% EtOAc in hexanes) to afford 2-(4-(4-((2,6-dichloropyridin-3-yl)sulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.43 g) as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH2:7][CH2:6][C@@H:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:4]=1)#[N:2].O1CCOCC1.Cl>ClCCl>[N:8]1([C@@H:5]2[CH2:6][CH2:7][C:3]([C:1]#[N:2])=[CH:4]2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN([C@H]2C=C(C#N)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#CC1=C[C@H](N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-tert-butyl 4-(3-cyanocyclopent-2-en-1-yl)piperazine-1-carboxylate (13 g, 46.9 mmol) in dry dichloromethane (30 ml) was added slowly hydrochloric acid 1,4 dioxane (100 ml, 4M solution) in a drop wise manner 0° C. The reaction mixture was stirred at 25° C. for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with dichloromethane (100 ml) and treated with methanolic ammonia (50 ml, 7M solution) and stirred for 30 minutes. The reaction mixture was then evaporated under reduced pressure to obtain crude product which was purified by flash column chromatography over silica gel (100-200 mesh) using 10% methanol in dichloromethane as an eluent to obtain title compound ((7 g, 84%).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:11][C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25](O)=[O:26].S(Cl)(Cl)=O.C(N(CC)CC)C>C1COCC1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:25](=[O:26])[C:24]2[CH:28]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=2[O:29][CH3:30])/[N:7]([CH2:11][C:12]2([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cn(CC2(O)CCCCC2)c(=N)s1
Reactant: COc1ccc(Cl)cc1C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CC1(O)CCCCC1
Yield: 51.4 %

Procedure:
The product of Example 20A (1.3 g, 3.7 mmol), 5-chloro-2-methoxybenzoic acid (0.70 g, 3.7 mmol), thionyl chloride (10 mL) and triethylamine (1.6 mL, 11 mmol) in THF (25 mL) were processed as described in Example 18B and Example 18C to provide the title compound (0.82 g, 1.9 mmol, 50% yield). MS (DCI/NH3) m/z 437 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([CH2:11]O)=[N:7][CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.CS([Cl:24])(=O)=O.O>ClCCl>[CH2:1]([O:4][C:5]1[C:6]([CH2:11][Cl:24])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOc1cccnc1CO
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOc1cccnc1CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
(3-Allyloxy-pyridin-2-yl)-methanol (34 g, 205.8 mmol) is dissolved in dichloromethane (340 mL) under nitrogen and triethylamine (34.4 mL, 247 mmol) is added at 22° C. The mixture is warmed to room temperature in a water bath and methanesulfonyl chloride (16.7 mL, 216 mmol) is added keeping the temperature below 30° C. The reaction is allowed to stir overnight at room temperature. Water (500 mL is added and the mixture stirred for 10 min. The organic portion is separated and washed with a solution of saturated NaHCO3 (100 mL). The organic portion is dried over sodium sulfate, filtered, and the solvent evaporated. The resulting residue is dried under vacuum to constant weight to afford the title compound (29 g, 79%). LC-ES/MS m/z: 184.6 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH3:33][NH:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1>>[CH3:33][N:34]([C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)[C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([C:11]2[O:12][C:8]([CH3:7])=[C:9]([CH2:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:24])=[O:25])[N:10]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Reactant: CNc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)N(C)c4cccnc4)cc3)oc2C)cc1
Yield: 73.4 %

Procedure:
Method E. Reaction of oxalyl chloride (100 λL, 1.1 mmol) and benzoic acid 4 (275 mg, 0.7 mmol) with subsequent coupling to N-methyl-N-(3-pyridinyl)amine (88 mg, 0.8 mmol) gave benzamide 7 (237 mg, 69%) as a white powder: mp (MeOH) 195-197° C.; 1H NMR δ 8.37 (d, J=2.4 Hz, 1 H, H-2′), 8.35 (dd, J=4.7, 1.5 Hz, 1 H, H-6′), 7.72 (ddd, J=8.2, 2.4, 1.5 Hz, 1 H, H-4′), 7.67 (br d, J=8.5 Hz, 2 H, H-2, H-6), 7.63 (br d, J=8.2Hz, 2 H, H-2″, H-6″), 7.37-7.42 (m, J=8.2Hz, 4 H, H-3, H-5, H-3″, H-5″), 7.34 (ddd, J=8.2, 4.7 Hz, 1 H, H-5′), 4.58 (s, 2 H, CH2SO2), 3.42 (s, 3 H, NCH3), 2.34 (s, 3 H, CH3), 2.06 (s, 3 H, CH3); 13C NMR δ 168.8, 157.8, 149.8, 148.1, 147.3, 144.4, 140.7, 137.4, 135.5, 134.2, 129.6 (2), 129.0 (2), 128.2 (2), 127.2, 125.9, 125.0 (2), 123.8, 52.9, 37.6, 21.0, 9.6; MS m/z 462.6 (MH+, 100%). Anal. calcd for C25H23N3O4S: C, 65.06; H, 5.02; N, 9.10. Found: C, 64.90; H, 4.92; N, 8.83%.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[O:2].N1C(C)=CC=CC=1C.[O:20]([Si:28](C(C)(C)C)(C)C)S(C(F)(F)F)(=O)=O>C(Cl)Cl.O>[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O:4][O:20][SiH3:28])(=[O:3])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClCCl
Solvent: O
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(S(=O)(=O)OO[SiH3])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 140 mg of the primary tosylate 26, 0.10 ml of 2,6-lutidine and 0.10 ml of t-butyldimethylsilyl triflate in 8 ml of methylene chloride was stirred at 0° C. for 1 hour. A few drops of water were added and the mixture concentrated under vacuum. The residue was diluted with diethyl ether and the solution filtered thru silica gel. The filtrate was concentrated under vacuum and chromatography of the residue over silica gel (6 hexanes: 1 EtOAc) provided the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:25])[C:23]=1[OH:24])[CH:19]=O.C([O-])([O-])=O.[K+].[K+].II>CN(C=O)C>[OH:24][C:23]1[C:22]([CH3:25])=[CH:21][C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:17][C:16]=1[CH3:15]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(O)c(C)c3)nc2c1
Temperature: 80 °C
Yield: 51.1 %

Procedure:
2-Amino-4,6-dimethoxy-benzamide (1.06 g, 5.4 mmol), 3,5-dimethyl-4-hydroxybenzaldehyde (0.810 g, 5.4 mmol), K2CO3 (0.747 g, 5.4 mmol) and I2 (1.645 g, 6.5 mmol) were mixed in DMF (20 mL) and the reaction mixture was heated at 80° C. for 12 h. It was cooled to room temperature and poured into crushed ice. The solid was collected and purified by column chromatography to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.9 g, 51%) as a white solid. Selected data: MP 291-293° C.
Reaction SMILES: [C:1]1([C:15]([O-])=[C:11]([N+:12]([O-])=O)[CH:10]=[C:6]([N+:7]([O-])=O)[CH:5]=1)[N+]([O-])=O.[CH3:17]O>>[CH3:17][N:12]1[CH2:5][CH2:1][CH2:15][C@H:11]1[CH2:10][C:6]#[N:7]
Reactant: CO
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Product: CN1CCC[C@H]1CC#N

Procedure:
To a solution of 7.0 g (0.041 mol) of (S)-1-methyl-2-chloromethylpyrrolidine.HCl in 35 ml of 80% aq. ethanol at 0° was added in portions a solution of 3.81 g (0.045 mol) of sodium bicarbonate in 50 ml of water. The mixture was stirred at 0° for 15 min., followed by the addition of a solution of 2.52 g (0.052 mol) of sodium cyanide in 65 ml of 80% aq. ethanol. This mixture was refluxed for 30 min. The resultant solution was cooled, evaporated to a small volume, and extracted with ether (2×25 ml). The combined ethereal layer was dried wtih magnesium sulfate and evaporated to a clear, brown oil. Bulb-to-bulb distillation [oven temp 40°-55° (0.25 torr)] yielded 2.62 g (51%) of the product, a clear, colorless, mobile oil: [α]D20 =-32.5°, c=2.57, methanol; picrate, mp 175° -178°.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.C([O:19]O)(C)(C)C.[CH2:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22]>[Mo](=O)(=O)=O>[CH3:22][CH:21]([O:19][N:11]1[C:2]([CH3:14])([CH3:1])[CH2:3][C:4]2([O:5][CH2:6][CH2:7][O:8]2)[CH2:9][C:10]1([CH3:13])[CH3:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OO
Reactant: CCc1ccccc1
Reactant: CC1(C)CC2(CC(C)(C)N1)OCCO2
Agent: O=[Mo](=O)=O
Product: CC(ON1C(C)(C)CC2(CC1(C)C)OCCO2)c1ccccc1

Procedure:
A mixture of 38.1 g (191 mmol) of 7,7,9,9-tetramethyl-8-aza-1,4-dioxaspiro[4.5]decane, 73.8 g (574 mmol) of 70% aq. t-butyl hydroperoxide, 2.0 g of molybdenum trioxide, and 130 ml of ethylbenzene is refluxed for 6 hours. Water is collected in a Dean-Stark trap. The catalyst is filtered and the filtrate is concentrated at reduced pressure. The residue is dissolved in heptane and passed through silica gel. A Kugelrohr distillation (120° C., 0.1 mm Hg) is used to remove volatile by-products. The title compound crystallizes on standing.
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([NH:14][C:15]1([C:21](O)=[O:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[BH4-].[Na+]>C1COCC1.O>[C:7]([O:11][C:12](=[O:13])[NH:14][C:15]1([CH2:21][OH:22])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOCC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(CO)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl chloroformate (0.234 mL, 0.00245 mol) was added to a solution of 4-[(tert-butoxycarbonyl)amino]tetrahydro-2H-pyran-4-carboxylic acid (0.5 g, 2.0 mmol) and triethylamine (0.341 mL, 2.45 mmol) in THF (6.8 mL) at −10° C. The mixture was stirred at RT for 30 min., filtered, and washed with THF. Sodium tetrahydroborate (0.15 g, 4.1 mmol) in water (1.0 mL) was added to the filtrate at 0° C., and then stirred at RT for 2 h. The reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc. The extract was washed with saturated NaHCO3, brine, dried over MgSO4, filtered, and concentrated to give the crude product which was directly used in next step without further purification. LCMS: (M+Na)=254.1; (M−100+H)=132.1.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.Br[C:24]1[CH:25]=[CH:26][C:27]([F:34])=[C:28]([CH:33]=1)[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[F:34][C:27]1[CH:26]=[CH:25][C:24]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)c1cc(Br)ccc1F
Solvent: ClCCl
Product: COC(=O)c1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1F

Procedure:
tert-Butyl 4-[4-fluoro-3-(methoxycarbonyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate was synthesized as described for INTERMEDIATE 6 (step A) using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (prepared according to Eastwood, P. R. Tetrahedron Lett., 41, 19, 2000, 3705-3708) and methyl 5-bromo-2-fluorobenzoate as starting material and PdCl2dppf.CH2Cl2 as a catalyst.
Reaction SMILES: N[C:2]1[C:3]([Cl:20])=[CH:4][C:5]([F:19])=[C:6]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])[CH:7]=1.N(OC(C)(C)C)=O.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[CH2:30].[ClH:35]>C(#N)C.[Cu](Cl)Cl>[Cl:20][C:3]1[C:2]([CH2:30][CH:29]([Cl:35])[C:28]([O:32][CH2:33][CH3:34])=[O:31])=[CH:7][C:6]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[C:5]([F:19])[CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)C(Cl)Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3.5 g of N-(5-amino-4-chloro-2-fluorophenyl)-3,4,5,6-tetrahydrophthalimide in 5 ml of absolute acetonitrile were added dropwise to a suspension of 1.9 g of tert-butyl nitrite, 260 g of ethyl acrylate and 1.9 g of anhydrous copper(II) chloride in 200 ml of absolute acetonitrile at 0° C. The mixture was slowly warmed up to room temperature and was stirred at this temperature for 10 hours. 40 ml of dilute hydrochloric acid were then added, and the mixture was extracted three times with methyl tert-butyl ether. The combined organic phases were dried over sodium sulfate and evaporated down. The residue was chromatographed over silica gel (eluent: 2:1 petroleum ether/diethyl ether). Yield: 1.3 g (26%); 1H-NMR (d6-DMSO/TMS): δ=1.18 ppm (t, 3H); 1.74 (bs, 4H); 2.38 (bs, 4H); 3.30 (dd, 1H); 3.47 (dd, 1H); 4.17 (q, 2H); 4.82 (dd, 1H); 7.51 (d, 1H); 7.84 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH2:13][C@H:14]([NH:18][C:19](=[O:30])[CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15](O)=[O:16])=[CH:11][N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]([NH:34][C@@H:35]([CH2:39][SH:40])[C:36]([NH2:38])=[O:37])(=[O:33])[CH3:32].C(N(CC)CC)C.CCCP(=O)=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[C:31]([NH:34][C@H:35]([C:36]([NH2:38])=[O:37])[CH2:39][S:40][C:15](=[O:16])[C@@H:14]([NH:18][C:19](=[O:30])[CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C:12]1[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:9]=[N:10][CH:11]=1)(=[O:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCCC(=O)N[C@@H](Cc1cncn1C(=O)OC(C)(C)C)C(=O)O
Reactant: CC(=O)N[C@@H](CS)C(N)=O
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](CSC(=O)[C@H](Cc1cncn1C(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)C(N)=O
Reaction time: 0.25 h
Yield: 74.3 %

Procedure:
To a stirring suspension at room temperature under N2 of (S)-3-(1-(tert-butoxycarbonyl)-1H-imidazol-5-yl)-2-(3-(tert-butoxycarbonylamino)propanamido)propanoic acid (45c, 35.74 g, 83.80 mmol) and (R)-2-acetamido-3-mercaptopropanamide (45b, 13.59 g, 83.78 mmol) in 500 mL of THF:EtOAc (1:1) was added dropwise triethylamine (26 mL, 186 mmol). After addition, the suspension was stirred for 15 minutes then propylphosphonic anhydride, 50 wt. % solution in EtOAc (55 mL, 92 mmol) was added dropwise. The resultant cloudy solution was stirred at room temperature for 2 h then saturated NaHCO3 solution (˜500 mL) was added. The layers were separated and the organic extract was washed with saturated KH2PO4 and then saturated NaCl solution. The aqueous phases were back extracted (in the same order) with fresh EtOAc (2×500 mL). The combined organic extracts were dried using MgSO4, filtered, concentrated and chromatographed twice (silica gel, 50% THF in EtOAc) to give 35.53 g (74%) of tert-butyl 5-((S)-3-((R)-2-acetamido-3-amino-3-oxopropylthio)-2-(3-(tert-butoxycarbonylamino)propanamido)-3-oxopropyl)-1H-imidazole-1-carboxylate (45d) as white foamy solid. MS (APCI) m/z 571 [M+H]+.
Reaction SMILES: FC(F)(F)C1C=CC(C=C)=CC=1.Br[C:14]1[CH2:18][CH2:17][O:16][N:15]=1.[OH:19][C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1>>[N:22]1[CH:21]=[C:20]([O:19][C:14]2[CH2:18][CH2:17][O:16][N:15]=2)[CH:25]=[N:24][CH:23]=1
Reactant: Oc1cncnc1
Reactant: BrC1=NOCC1
Agent: C=Cc1ccc(C(F)(F)F)cc1
Product: c1ncc(OC2=NOCC2)cn1

Procedure:
3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-168a and I-168b were prepared in 2 steps from 1-(trifluoromethyl)-4-vinylbenzene using the cycloaddition conditions from Method 1. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypyrimidine to provide racemic compound I-168 using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=309.8 m/z. Activity: B
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([C:14]2[CH:67]=[CH:66][C:17](OCC3C=CC(C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)COCC[Si](C)(C)C)C=CC=6)C5)=NC=4C(OCC)=O)=CC=3)=[CH:16][CH:15]=2)[C:3]=1[C:68]#[N:69].NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[S:92]1[C:96]2[CH:97]=[CH:98][CH:99]=[CH:100][C:95]=2[N:94]=[C:93]1[N:101]([CH2:128][O:129][CH2:130][CH2:131][Si:132]([CH3:135])([CH3:134])[CH3:133])[C:102]([C:104]1[CH:105]=[CH:106][CH:107]=[C:108]2[C:113]=1[CH2:112][N:111]([C:114]1[S:115][C:116]([C:124]#[C:125][CH2:126][OH:127])=[C:117]([C:119]([O:121][CH2:122][CH3:123])=[O:120])[N:118]=1)[CH2:110][CH2:109]2)=[O:103].NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC=C(O)C=2)C=1C#N>>[NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([C:14]2[CH:15]=[C:16]([CH:17]=[CH:66][CH:67]=2)[O:127][CH2:126][C:125]#[C:124][C:116]2[S:115][C:114]([N:111]3[CH2:110][CH2:109][C:108]4[C:113](=[C:104]([C:102](=[O:103])[N:101]([C:93]5[S:92][C:96]6[CH:97]=[CH:98][CH:99]=[CH:100][C:95]=6[N:94]=5)[CH2:128][O:129][CH2:130][CH2:131][Si:132]([CH3:135])([CH3:133])[CH3:134])[CH:105]=[CH:106][CH:107]=4)[CH2:112]3)=[N:118][C:117]=2[C:119]([O:121][CH2:122][CH3:123])=[O:120])[C:3]=1[C:68]#[N:69]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1C#CCO
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: CC(C)(C)OC(=O)n1nc(-c2cccc(O)c2)c(C#N)c1N
Product: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1C#CCOc1cccc(-c2nn(C(=O)OC(C)(C)C)c(N)c2C#N)c1

Procedure:
Compound 36C was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34D and compound 31F with compound 36B and compound 36A, respectively as a mixture of two inseparable isomers: MS (ESI(+)): m/z 932 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9].[Cl:29][C:30]1[C:37]([CH2:38][CH2:39][OH:40])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[Cl:29][C:30]1[C:37]([CH2:38][CH2:39][OH:40])=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][N:26]1[CH2:25][CH2:24][C:22]2([O:21][CH2:20][CH2:19][N:18]([C:16]([C:14]3[N:15]=[C:11]([CH:8]([CH3:10])[CH3:9])[S:12][CH:13]=3)=[O:17])[CH2:23]2)[CH2:28][CH2:27]1
Reactant: O=Cc1cccc(CCO)c1Cl
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4Cl)CC3)C2)cs1
Reaction time: 0.08 h

Procedure:
A solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.325 g) in NMP (3 mL) was treated with acetic acid (0.067 mL) and stirred for 5 minutes. A solution of 2-chloro-3-(2-hydroxyethyl)benzaldehyde (example 80, step d) (0.217 g) in NMP (4 mL) was then added, the resulting solution was stirred for 1 hour and then treated with sodium triacetoxyborohydride (1.025 g). The mixture was stirred overnight at room temperature, then poured into saturated sodium bicarbonate and extracted twice with ethyl acetate. The combined extracts were washed three times with water, once with brine, then dried over anhydrous magnesium sulphate and purified by flash chromatography on silica eluted with 1:2:97 triethylamine:methanol:dichloromethane to afford the subtitled compound as a colourless gum. Yield 0.411 g.
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:9])[CH2:7][OH:8].Br[CH2:11][CH:12]=[C:13]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[CH:12][CH2:11][O:8][CH2:7][CH2:6][OH:9])=[CH:19][CH:18]=1
Reactant: Clc1ccc(C(=CCBr)c2ccc(Cl)cc2)cc1
Reactant: OCCO
Agent: [Li]CCCC
Solvent: O
Product: OCCOCC=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of n-butyllithium in hexanes (15.0 ml, 2.5 M) was added dropwise under a nitrogen atmosphere to ethylene glycol (30 ml) at 10° C. When addition was complete the mixture was stirred for 0.5 h at room temperature. 3-Bromo- 1,1-bis(4-chlorophenyl)-1-propene (13.0 g, 38 mmol, prepared similarly to the method described in Example 23) was added and the reaction mixture was stirred at room temperature for 72 h. The mixture was poured into water (100 ml) and extracted with ethyl acetate (2×75 ml). The combined organic extracts was dried over sodium sulphate and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (200 g) using a mixture of n-heptane and ethyl acetate (3:2) as eluent provided 8.1 g (66%) of 2-(3,3-bis(4-chlorophenyl)-2-propen-1-yloxy)ethanol, M.P. 93°-95° C.