Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:6]=1)(=O)=O.[H-].[Na+].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35][OH:36]>>[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:35][O:36][C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:6]=1
Reactant: CCOc1nc(S(C)(=O)=O)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: OCc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: CCOc1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
2-(Methylsulfonyl)-4-ethoxy-5-(4-chlorophenyl)-6-(2,4-dichloro-phenyl)pyrimidine (LRf from Example 123) was reacted with 2 equivalents each of sodium hydride and 3,4-difluorobenzyl alcohol by the procedure described in Example 16 to afford the title compound: HPLC/MS: m/e=521 (M++1); Rt=4.90 min. 1H-NMR 400 MHz (CDCl3): δ 1.35 (t, 3H), 4.45-4.55 (dd, J=9 Hz, J=7 Hz, 2H), 5.20 (s, 2H), 7.02-7.21 (m, 9H), 7.35 (d, J=2 Hz, 1H).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.N1C=CC=CC=1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20]>C(Cl)Cl>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:18])[CH:2]=[O:1]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc(C=O)ccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
A stirred solution and cooled (20° C.) solution of 2 (5.0 g, 32.89 mmol) in CH2Cl2 (30 mL) was treated with pyridine (5.2 g, 65.82 mmol). After 15 min, Tf2O (11.13 g, 39.4 mmol) was added dropwise and stirred at −20° C. for 1 h. Reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with water (50 mL), brine (50 mL) and dried, Solvent was evaporated under reduced pressure and residue purified by column chromatography (Silica gel, 60-120 mesh, hexane:ethyl acetate 93:7) to give 3 (5.7 g, 61%) as a syrup.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[N:17]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].O=C(N1C=CN=C1)[N:29]1C=CN=C1.N>ClCCl.O>[NH2:29][C:22]([C:21]1[CH:20]=[CH:19][C:18]([N:16]2[CH:15]=[C:12]3[C:11]([CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:7])[CH2:14][CH2:13]3)=[N:17]2)=[CH:26][CH:25]=1)=[O:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C(=O)O)cc3)nc2CC1
Agent: N
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C(N)=O)cc3)nc2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[6-{[(1,1-dimethylethyl)oxy]carbonyl}-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzoic acid (may be prepared as described in Description 23) (185 mg, 0.52 mmol) in dichloromethane (10 ml) was added 1,1′-(oxomethanediyl)bis-1H-imidazole (168 mg, 1.04 mmol) and the reaction stirred at room temperature, under argon, overnight. Ammonia (0.88M, 35 mg, 2.07 mmol) was added and stirring continued, under argon, at room temperature for 4 hours. The resulting crude mixture was diluted with water, and extracted with dichloromethane (×2). The combined organic fractions were washed with water (×1), dried over magnesium sulphate and solvent evaporated in vacuo to afford the title compound (D36). MS (ES+) m/e 301 [M-tBu]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:36]=[CH:35][C:28]([O:29][CH2:30][CH:31]2[CH2:34][CH2:33][O:32]2)=[CH:27][C:26]=1[F:37]>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:36]=[CH:35][C:28]([O:29][CH2:30][CH:31]2[CH2:34][CH2:33][O:32]2)=[CH:27][C:26]=1[F:37])=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1cc(OCC2CCO2)ccc1Br
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OCC2CCO2)cc1F)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and rac-2-(4-bromo-3-fluoro-phenoxymethyl)-oxetane (Intermediate 27) in analogy to Example 1a): colorless gum.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:16]2[CH2:28][CH2:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([Cl:29])[CH:24]=4)[NH:19][C:18]=3[CH2:17]2)([F:15])[C:11]([NH:13][CH3:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:37](C(OC(C)(C)C)=O)[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:41]([O:40][C:38]([N:19]1[C:18]2[CH2:17][CH:16]([C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])([F:15])[C:11](=[O:12])[NH:13][CH3:14])[CH2:28][CH2:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[C:23]([Cl:29])[CH:24]=2)=[O:37])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CNC(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)C(F)(C1CCc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Yield: 78.5 %

Procedure:
0.924 g (0.002 mol) of (RS, SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-N-methyl-acetamide were dissolved in 20 mL CH2Cl2 at RT. Then, 0.59 mL triethylamine (0.004 mol, 2 eq), 26 mg DMAP (0.2 mmol, 0.1 eq) and 0.556 g BOC2O (0.003 mol, 1.2 eq) were added. The reaction mixture was stirred for 2H30. The reaction was quenched with a saturated NH4Cl aqueous solution, and the product extracted with CH2Cl2. The combined organic phases were dried on Na2SO4, filtered and evaporated. The crude material was precipitated in diethyl ether. The solvent was removed and the remaining solid was dried under vaccum to yield to 0.840 g (74%) of (RS, SR)-2-(benzenesulfonyl-fluoro-methylcarbamoyl-methyl)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester as a white solid, MS: 552 (MNH4+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCOc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(OCCCC(=O)O)cc2)CC(C)(C)C1
Yield: 84.1 %

Procedure:
The hydrolysis procedure described for 11 (example 5, step 3) was used. A solution of ethyl 4-({4-[(4-fluorophenyl) (3,3,5,5-tetramethylcyclohexylidene) methyl]phenyl}oxy) butanoate) (12) (0.665 g, 1.47 mmol) in THF/EtOH (1:1, 10 mL) was treated with 1 N NaOH (5 mL, excess) at 70° C. for 1 h. The reaction mixture was cooled and poured into 20% aqueous HCl (40 mL). Standard work-up followed by purification afforded 0.525 g (84%) of the title compound 13 as a white foam. 1H NMR (300 MHz, DMSO-d6): δ12.13 (br s, 1H), 7.15 (d, J=6.6 Hz, 2H), 7.12 (d, J=9.6 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 3.94 (t, J=6.3 Hz, 2H), 2.37 (t, J=7.2 Hz, 2H), 1.93 (s, J=2H), 1.89 (s, 2H), 1.76 (quintet, J=6.3 Hz, 2H), 1.27 (s, 2H), 0.89 (s, 12H). LCMS (ESI): m/z 423 (M−H)−. Anal. Calcd for C27H33FO3, C, 76.39, H, 7.83, F, 4.47. Found: C, 76.30, H, 7.90, F, 4.52.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][CH2:24][CH2:25][NH2:26].CN(C=O)C>O>[O:10]1[C:9]2[CH:14]=[CH:15][C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:26][CH2:25][CH2:24][O:23][CH3:22])=[CH:7][C:8]=2[O:13][CH2:12][CH2:11]1
Reactant: COCCN
Reactant: O=C(CCl)Nc1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCNCC(=O)Nc1ccc2c(c1)OCCO2
Temperature: 100 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A mixture of 2-chloro-N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide (2 mmol), potassium carbonate (10 mmol), 2-methoxyethylamine (2 mmol) and anhydrous DMF (4 mL) was stirred for 2 hours at 100° C. (monitored by TLC). The mixture was cooled to room temperature, treated with cold water (30 mL). The precipitate was collected by filtration, washed with diethyl ether and dried to afford N-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-(2-methoxy-ethylamino)-acetamide (Compound XIa, 96 mg, 36%). 1H NMR (300 MHz, CDCl3/TMS): δ=9.29 (s, 1H), 7.24 (d, 1H, J=2.4 Hz), 6.97 (dd, 1H, J=8.7, 2.4 Hz), 6.78 (d, 1H, J=8.7 Hz), 4.32-4.15 (m, 4H), 3.46 (t, 2H, 4.8 Hz), 3.36 (s, 3H), 3.34 (s, 2H), 2.82 (t, 2H, J=4.8 Hz), 2.17 (s, 1H). 13C NMR (75 MHz, CDCl3/CD3OD/TMS): δ=169.48, 143.16, 139.87, 131.43, 116.84, 112.74, 108.89, 71.41, 64.28, 64.12, 58.68, 52.57, 49.35.
Reaction SMILES: C(P(C(C)(C)C)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C)(C)C.[OH-].[OH-].[C:24]1([B+2])C=CC=CC=1.ClC1C=CC(C)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:24][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[CH:6]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:17][CH:16]=1
Reactant: [B+2]c1ccccc1
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: Cc1ccc(Cl)cc1
Product: Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (4.5 mg, 0.015 mmol, 1.5 mol %), phenylboron dihydroxide (183 mg, 1.5 mmol), additive (3.0 mmol), and 4-chlorotoluene (0.12 mL, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (2 mL) was added through a rubber septum. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was then diluted with ethyl acetate (30 mL) and poured into a separatory funnel. The mixture was washed with 2.0M NaOH (20 mL), followed by brine (20 mL). The organic layer was submitted for GC analysis giving the results tabulated below.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]=O)[C:4]=2[O:3][CH2:2]1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][N:22]3[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]3)[C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cccc2c1OCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCO3)CC1
Reaction time: 0.08 h
Yield: 63.9 %

Procedure:
A solution of 1,3-benzodioxole-4-carbaldehyde (96 mg, 0.64 mmol) in ethanol (2 mL) and acetic acid (0.2 mL) at room temperature was treated with tert-butyl-1-piperazine carboxylate (2.5 eq, 1.60 mmol, 297 mg) and stirred for 5 minutes. Sodium cyanoborohydride (0.95 eq, 0.60 mmol, 38 mg) was added portionwise and the reaction then stirred for 16 h. Concentration in vacuo and preparative tlc purification (CH2Cl2-MeOH, 95:5) gave the product (131 mg, 62%) as a colourless oil; δH (500 MHz, CDCl3) 1.47 and 1.48 (2 s, 9H, C(CH3)3), 1.99 (s, br, 1H, piperazine NCHAHA), 2.44 (t, J=4.7 Hz, 2H, piperazine NCH2), 2.54-2.63 (m, 1H, piperazine NCHAHA), 3.45 (t, J=4.9 Hz, 4H, piperazine N(CH2)2), 3.55 (s, 1H, NCHAHA), 4.70 (s, 1H, NCHAHA), 5.97 (s, 1H, OCHAHB), 5.99 (s, 1H, OCHAHB), 6.75-6.96 (m, 3H, phenyl H-4, H-5, H-6);
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]([N:18]4[CH2:22][CH2:21][C@@:20]5([C:30]6[CH:29]=[CH:28][N:27]=[CH:26][C:25]=6[C:24](=[O:31])[O:23]5)[CH2:19]4)=[O:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.[CH3:36]S(C)=O.C(=O)([O-])[O-].[K+].[K+].CI>>[CH3:36][N:3]1[C:4]2[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=2[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]([N:18]4[CH2:22][CH2:21][C@@:20]5([C:30]6[CH:29]=[CH:28][N:27]=[CH:26][C:25]=6[C:24](=[O:31])[O:23]5)[CH2:19]4)=[O:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[C:2]1=[O:1]
Reactant: CS(C)=O
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-n5c(=O)[nH]c6ccccc65)cc4)CC3)C2)c2ccncc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1c(=O)n(-c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4cnccc45)CC3)cc2)c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of (1R)-1′-({1-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (50 mg, 0.0001 mol) in dimethyl sulfoxide (1 mL, 0.01 mol) were added potassium carbonate (16.3 mg, 0.000118 mol) and methyl iodide (6.67 μL, 0.000107 mol), and the mixture was stirred at room temperature for. 2 hours. The crude product was purified by prep-HPLC. LC/MS: 480.2 (M+H+).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([O:41][CH3:42])=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([NH:23][CH2:24][C:25](=[O:32])[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=O)=[CH:18][C:17]4[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([O:41][CH3:42])=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:32][C:25]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:24][N:23]=4)=[CH:18][C:17]4[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCC(=O)CNC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)CCc1cnc(C2=Cc3cc(OC)ccc3-c3c(C4CCCCC4)c4ccc(C(=O)OC)cc4n3C2)o1

Procedure:
Methyl 13-cyclohexyl-3-(methyloxy)-6-(((5-(methyloxy)-2,5-dioxopentyl)amino)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (1.60 g, 2.79 mMol) was suspended in 38 ml of toluene along with phosphorus oxychloride (0.58 mL, 6.34 mMol). The mixture was heated to reflux under nitrogen for 3 hrs, cooled and poured into a sepratory funnel containing ice and saturated aqueous sodium bicarbonate solution. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed sequentially with aqueous saturated bicarbonate, brine and dried over magnesium sulfate. Removal of volatiles and drying in vacuuo produced the title product in quantitative yield (1.55 g). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.27 (1 H, br. s.), 1.36-1.45 (2 H, m), 1.59 (2 H, br. s.), 1.78 (2 H, d, J=9.77 Hz), 1.96 (1 H, br. s.), 2.06 (2 H, br. s.), 2.71 (2 H, t, J=7.48 Hz), 2.81-2.90 (1 H, m), 3.04 (2 H, t, J=7.32 Hz), 3.70 (3 H, s), 3.95 (3 H, s), 3.98 (3 H, s), 4.37 (1 H, d, J=11.60 Hz), 5.93 (1 H, d, J=12.51 Hz), 6.91 (1 H, s), 7.02 (1 H, d, J=2.75 Hz), 7.07 (1 H, dd, J=8.70, 2.59 Hz), 7.53 (2 H, s), 7.74 (1 H, d, J=8.55 Hz), 7.85 (1 H, d, J=8.55 Hz), 8.38 (1 H, s). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% trifluoroacetic acid; % B=90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial % B=50; Final % B=100; Gradient=5 min; Runtime=6 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Phenomenex Luna 3.0 mm×50 mm S10; Retention Time=4.48 min, purity 96%. Flow injection Mass Spectrometry: MS m/z 555(MH+).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH3:16])[C:8]([CH3:15])=[C:9]([CH2:11][C:12]([OH:14])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:19]O>>[C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH3:16])[C:8]([CH3:15])=[C:9]([CH2:11][C:12]([O:14][CH3:19])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(CC(=O)O)cc(C(C)(C)C)c(O)c1C
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1cc(C(C)(C)C)c(O)c(C)c1C
Temperature: 68 °C

Procedure:
11.8 grams of 5-tert.-butyl-2,3-dimethyl-4-hydroxyphenylacetic acid was added at 20°C to 200 ml of methanol previously saturated with hydrogen chloride gas. The slightly pinkish solution was heatd at reflux (68°C) for 3 hours after which about one-half of the solvent was removed at reduced pressures and the reaction mixture then poured into about 500 ml of an ice-water mixture with stirring until all the ice had melted. The precipitated crystals were filtered, washed with water and dissolved in benzene. The benzene solution was successively washed with water, saturated sodium bicarbonate solution and finally with water to pH 7, the benzene solution being dried over anhydrous sodium sulfate. The clear benzene solution, freed of drying agent by filtration, was concentrated at reduced pressure. The resulting solid residue was triturated with hexane to remove color bodies. After recrystallization from methanol, the desired product was obtained as white crystals melting at 117° to 119°C (Compound 14).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11])[NH2:5].[CH:14]([C:16]1[CH:27]=[CH:26][C:19]2[C:20]([CH3:25])=[C:21]([C:23]#[N:24])[O:22][C:18]=2[CH:17]=1)=O>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:14][C:16]2[CH:27]=[CH:26][C:19]3[C:20]([CH3:25])=[C:21]([C:23]#[N:24])[O:22][C:18]=3[CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:11])([F:12])[F:13]
Reactant: Cc1c(C#N)oc2cc(C=O)ccc12
Reactant: Nc1ccc(OC(F)(F)F)c(Br)c1
Product: Cc1c(C#N)oc2cc(CNc3ccc(OC(F)(F)F)c(Br)c3)ccc12

Procedure:
The title compound was prepared as described in general reductive amination procedure, starting from 3-bromo-4-(trifluoromethoxy)aniline and 6-formyl-3-methylbenzofuran-2-carbonitrile, Intermediate 4. LCMS retention time=1.64 minutes (LC method 3); MS (m+1)=426.0.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C1N=CN([C:15](N2C=NC=C2)=[O:16])C=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:16]=[C:15]1[O:1][N:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[NH:9]1
Reactant: CCOC(=O)C(=N)NO
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1noc(=O)[nH]1
Temperature: 80 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of ethyl 2-(hydroxyamino)-2-iminoacetate (2 g, 15.14 mmol) in dioxane (15.00 mL) is added CDI (2.7 g, 16.65 mmol) and DBU (2.5 ml, 16.65 mmol) at room temperature. After stirring for 1 hour at 80° C., the reaction is quenched with 1N HCl, and the crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give ethyl 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylate (2.4 g). HPLC retention time=0.72 minutes (condition D); MS 159.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:23]([Si:27](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH2:10][O:11][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 17 h
Yield: 93.8 %

Procedure:
A solution of N2-(tert-butoxycarbonyl)-N-methoxy-N-methyl-D-serinamide (1, 1.93 g, 7.78 mmol) and imidazole (1.21 g, 17.81 mmol) in DMF (9 ml) stirred under N2 at room temperature, was treated with neat tert-butyl(chloro)diphenylsilane (2.2 ml, 8.56 mmol) and further stirred for 17 h. Diluted with EtOAc, washed with 5% KHSO4 in water, then sat NaHCO3, dried over Na2SO4, filtered and concentrated. Purified through a chromatographic cartridge of silicagel (50 g) eluted with 10% to 60% EtOAc in hexane to give 3.55 g (94% yield) of title compound as colorless oil. MS: m/z=509.2 (MNa+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CO>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([N:34]1[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CN1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(C(=O)C(C)(C)NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-benzyloxycarbonylamino-2-methyl-propionic acid (2.37 g) in tetrahydrofuran (20 mL) was added 1,1′-carbonylbis-1H-imidazole (1.78 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1-methylpiperazine (2.0 mL), and the mixture was stirred at 40° C. for 3.5 days. To the reaction mixture was added methanol, and the resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give 1-(2-benzyloxycarbonylamino-2-methyl-propionyl)-4-methylpiperazine (1.99 g). This material was dissolved in methanol (10 mL). To the solution was added 10% palladium-carbon powder (0.4 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (1.14 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][CH:10]=[N:9][CH:8]=1.[O:12]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28](O)=[O:29])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:12]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([C:10]2[O:11][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][N:9]=2)=[O:29])=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(-c2cnco2)nc1
Reactant: O=C(O)CCc1ccc(COc2ccccc2)cc1
Product: O=C(CCc1ccc(COc2ccccc2)cc1)c1ncc(-c2ccccn2)o1
Yield: 32 %

Procedure:
The title compound (11e) was prepared from 5-(2-pyridyl)oxazole and 3-(4-(phenoxymethyl)phenyl)propanoic acid (S27) using General Procedure B. PTLC (SiO2, 50% EtOAc-hexanes) afforded 11e (40 mg, 0.10 mmol, 32%) as a pale yellow solid: 1H NMR (CDCl3, 400 MHz) 8.68-8.66 (m, 1H), 7.89 (s, 1H), 7.88-7.85 (m, 1H), 7.81 (td, 1H, J=7.9, 1.5 Hz), 7.38 (d, 2H, J=8.2 Hz), 7.34-7.27 (m, 5H), 6.99-6.94 (m, 3H), 5.03 (s, 2H), 3.48 (t, 2H, J=7.4 Hz), 3.13 (t, 2H, J=7.5 Hz); 13C NMR (CDCl3, 100 MHz) 187.2, 158.7, 157.1, 153.3, 150.1, 146.2, 140.1, 137.1, 137.0, 129.4, 128.6, 127.8, 126.9, 124.1, 120.8, 120.3, 114.7, 69.6, 40.5, 29.3; IR (film) νmax 2923, 1694, 1601, 1504, 1470, 1428, 1380, 1241, 1171, 1125, 1080, 1032, 1017, 989, 962, 911, 869, 815, 788, 760, 693 cm−1; ESI-TOF m/z 385.1550 (C24H20N2O3+H+ requires 385.1547).