Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40].C(=O)([O-])O.[Na+]>C1COCC1>[C:39]([N:23]1[CH2:24][CH2:25][CH:20]([C:18]([N:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:19])[CH2:21][CH2:22]1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccccc2)CC1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
The compound obtained in Example 2 (252 mg, 0.60 mmol), triethylamine (0.201 ml) were dissolved in THF (5 ml), and under ice cooling, to the solution was added acetyl chloride (0.085 ml). The mixture was stirred at the same temperature for 30 minutes. To the mixture was added a saturated aqueous solution of sodium hydrogencarbonate (15 ml) under ice cooling, and the mixture was extracted with ethyl acetate (15 ml×3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1 to 4/1), and the desired fraction was concentrated under reduced pressure. To the concentrate was added ethyl acetate and the insolubles were filtered off. The filtrate was concentrated under reduced pressure to give the titled compound (237 mg, 0.51 mmol, Yield 85%) as colorless oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17]CC=C)=[CH:9][CH:8]=1)[CH3:2].C(O[C:28](=O)[CH:29](OCC)[CH2:30]C1C2C(=CC=CC=2)C(O)=CC=1)C.C(Br)C=C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([CH2:30][CH:29]=[CH2:28])[CH:8]=1)[CH3:2]
Reactant: C=CCOc1ccc(CC(OCC)C(=O)OCC)c2ccccc12
Reactant: CCOC(=O)C(Cc1ccc(O)c2ccccc12)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C=CCBr
Product: C=CCc1cc(CC(OCC)C(=O)OCC)c2ccccc2c1O
Temperature: 160 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
0.87 g (2.65 mmol) [rac]-3-(4-allyloxy-naphthalen-1-yl)-2-ethoxy-propionic acid ethyl ester [prepared from [rac]-2-ethoxy-3-(4-hydroxy-naphthalen-1-yl)-propionic acid ethyl ester (example 150 a] and allylbromide, potassium carbonate in acetone at 60° C.] was stirred for 2 hours at 160° C. without any solvent. The dark residue was purified by flash chromatography (silica gel, hexane/AcOEt=4:1) to yield 0.82 g (94%) of [rac]-3-(3-allyl-4-hydroxy-naphthalen-1-yl)-2-ethoxy-propionic acid ethyl ester as yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:16])C.OO>C([O-])(O)=O.[Na+]>[CH2:1]([C:8]1[CH:13]=[CH:12][N+:11]([O-:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2ccncc2)cc1
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Product: [O-][n+]1ccc(Cc2ccccc2)cc1
Temperature: 85 °C
Yield: 98 %

Procedure:
A mixture of 4-benzylpyridine (5 mL, 30 mmol), acetic acid (30 mL) and 30% hydrogen peroxide (10 mL) was heated at 80-90° C. for 5 h. Concentration under reduced pressure gave an oil that was diluted with NaHCO3 (100 mL) and extracted with CH2Cl2 (2×100 mL). The collected organic phase was washed with brine (100 mL) and evaporated in vacuo to give the title compound as a colorless oil (5.68 g, 98%): 1H NMR (DMSO-d6) δ3.90 (s, 2H), 7.15-7.35 (m, 7H), 8.08 (d, J=6.3 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20](=[O:21])[C:19]3[C:18]([O:22]CC4C=CC=CC=4)=[C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]4=[C:15]([O:34]CC4C=CC=CC=4)[C:14]=3[C:13]2=[O:42])=[C:8]([Cl:43])[CH:7]=1)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:44])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20](=[O:21])[C:19]3[C:18]([OH:22])=[C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]4=[C:15]([OH:34])[C:14]=3[C:13]2=[O:42])=[C:8]([Cl:43])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCc4ccccc4)c4ccccc4c3OCc3ccccc3)C2=O)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(O)c4ccccc4c3O)C2=O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 9.8 %

Procedure:
To a solution of ethyl(3-chloro-4-{1,3-dioxo-4,9-bis[(phenylmethyl)oxy]-1,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetate (0.505 g, 0.84 mmol) in DCM (30 ml), cooled to −78° C. under an atmosphere of argon, was added boron tribromide (0.24 ml, 2.50 mmol) drop wise. Stirred at −78° C. for 25 minutes. The reaction mixture was quenched with water and warmed to room temperature. This was extracted twice with DCM using a hydrophobic frit. The organic phase was evaporated to an orange solid. Hot trituration in DCM resulted in a yellow solid which was collected by filtration (0.189 g, 0.44 mmol). The filtrate was purified by chromatography on silica gel, eluting with ethyl acetate (0-70%) in hexane to give the title compound as a yellow solid (0.035 g, 0.082 mmol). LC/MS: Rt=3.22, [MH]+ 426.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:18][CH2:17][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.[CH3:20][NH2:21]>>[CH3:20][NH:21][C:14]([C:11]1[CH:12]=[CH:13][C:8]2[O:7][C:6]3[CH2:17][CH2:18][CH:3]([N:2]([CH3:19])[CH3:1])[CH2:4][C:5]=3[C:9]=2[CH:10]=1)=[O:15]
Reactant: CN(C)C1CCc2oc3ccc(C(=O)Cl)cc3c2C1
Reactant: CN
Product: CNC(=O)c1ccc2oc3c(c2c1)CC(N(C)C)CC3
Yield: 21.1 %

Procedure:
Beginning with 0.011 gm (0.04 mMol) 2-dimethylamino-1,2,3,4-tetrahydrodibenzofuran-8-carbonyl chloride and 0.08 mMol methylamine, 0.0023 gm (20%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([C:15](OC)=[O:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(OC(C1C=CC(C(O)=O)=CC=1Cl)=O)(C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)OC(C)(C)C)c(Cl)c1
Agent: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(CO)cc1Cl
Temperature: 25 °C

Procedure:
To 24.9 g of 2-chloro-4-(methoxycarbonyl)benzoic acid and 2 mL of Sulfuric Acid in 350 mL of DCM was added isobutylene gas at −78° C. until the solvent was saturated and capped off securely. Let go several days at room temperature and re-cool to −78° C. before removing cap. Concentrate solvent, extract with Ethyl Acetate and bicarbonate, dry with Magnesium Sulfate, filter and concentrate to give 31.4 g of 1-tert-butyl 4-methyl 2-chloroterephthalate. 3.35 g of 1-tert-butyl 4-methyl 2-chloroterephthalate was hydrolyzed via Procedure M. 2.5 g of 4-(tert-butoxycarbonyl)-3-chlorobenzoic acid was was cooled to 0° C. in 25 mL of THF before a solution of 19.5 mL of 1M BH3-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at ˜50% complete by TLC. The reaction is re-cooled to 0° C. and another 19.5 mL of BH3-THF is added dropwise before the ice bath is removed. Upon completion, the reaction is re-cooled to 0° C. and quenched with 3N HCl dropwise. The aqueous layer was extracted two times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 564 mg of tert-butyl 2-chloro-4-(hydroxymethyl)benzoate was cooled to 0° C. in 5 mL of DCM before adding 665 mg of Triphenylphosphine and 417 mg of NBS. Reaction was concentrated and directly purified via ISCO Combi-Flash to give pure tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 147 mg of tert-butyl 4-(bromomethyl)-2-chlorobenzoate was reacted with 2,2,2-trifluoroethanamine in DMSO via Procedure P. 141 mg of tert-butyl 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoate was treated with 4N HCl in Dioxane at 45° C. and concentrated to give 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 75 mg of 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to give pure 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2,2,2-trifluoroethylamino)methyl)benzamide. MS (Q1) 454.6 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH:18]=[C:19]([CH3:21])[O:20][C:16]=3[C:15]([C:22](O)=[O:23])=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2N=N1.CN(C=O)C.C1(N)CCCCC1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH:18]=[C:19]([CH3:21])[O:20][C:16]=3[C:15]([C:22]([NH:30][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:33]3)=[O:23])=[CH:14][C:12]=2[N:13]=1
Reactant: Cc1cc2c(o1)c(C(=O)O)cc1nc(Nc3ccccc3Cl)[nH]c12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: NC1CCCCC1
Product: Cc1cc2c(o1)c(C(=O)NC1CCCCC1)cc1nc(Nc3ccccc3Cl)[nH]c12
Yield: 25.9 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(2-chlorophenyl)amino]-7-methyl-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-11, 0.050 g, 0.146 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.094 g, 0.293 mmol), TEA (1.0 mL), DMF (1.0 mL), THF (5.0 mL) and cyclohexyl amine (0.029 g, 0293 mmol) to afford 0.016 g of the desired product. 1HNMR (DMSO-d6): δ 1.23-1.39 (m, 4H), 1.39-1.52 (m, 1H), 1.58 (m, 1H), 1.74 (m, 2H), 1.90 (m, 2H), 3.33 (m, 3H), 3.88 (m, 1H), 6.85 (s, 1H), 7.05 (m, 1H), 7.40 (t, J=7.2 Hz, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.61-7.70 (m, 2H), 8.62 (s, 1H), 10.20 (s, 1H), 11.25 (s, 1H); MS [M+H]+: 423.41.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH:29]1[O:33][CH2:32][CH2:31][O:30]1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][CH:29]2[O:33][CH2:32][CH2:31][O:30]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCC1OCCO1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCC2OCCO2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (200 mg, 0.73 mmol) was suspended in dimethylformamide (80 ml). To the suspension were added potassium carbonate (150 mg, 1.1 mmol) and 2-(2-bromoethyl)-1,3-dioxolane (0.14 ml, 1.1 mmol) in order. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (163 mg, yield 60%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=O)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[C:33]([C:34]#[N:35])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c(N)c2)c1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: COc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c3cccc(C#N)c3)c2)c1

Procedure:
Prepared from (3-amino-3′-methoxy-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G25) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a beige solid (238 mg).
Reaction SMILES: Cl.[S:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][N:5]1[CH2:4][CH2:3][S:2][CH2:7][CH2:6]1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCSCC1
Agent: Cl
Product: O=C(CN1CCSCC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 33.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-thiomorpholinoacetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 266, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-thiomorpholinoacetamido)propanamide (14.2 g, 33.9%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.96 (d, 1H), 7.60 (d, 2H), 7.28-7.34 (m, 5H), 7.19-7.23 (m, 2H), 6.98-7.04 (m, 4H), 4.68-4.69 (m, 1H), 4.52 (s, 2H), 3.70-3.77 (m, 2H), 3.01 (s, 2H), 2.67-2.73 (m, 4H), 2.60-2.63 (m, 4H). MS (EI) for C28H30FN3O4S. found 524.6 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[CH:6]=[C:5]2[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25].[CH:26]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:26]1([CH2:31][C:32]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][CH3:12])[CH:6]=[C:5]3[CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(N)ccc21
Reactant: O=C(O)CC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
A mixture of the ester (H) described above (used without further characterization) (4.43 g), cyclopentylacetic acid (1.85 g), 4-(dimethylamino)pyridine (1.76 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.26 g), was dissolved in methylene chloride (100 ml), under an atmosphere of nitrogen, and stirred at room temperature for 18 hours. The mixture was poured into 1M hydrochloric acid (25 ml), the separated aqueous layer extracted with dichloromethane (2×100 ml), the combined organic extracts washed with water, brine, dried (MgSO4) and evaporated. The residual oil was crystallized from ethanol to give off-white needles which were recrystallized from methylene chloride/hexane to give methyl 4-[5-(2-cyclopentylacetamido)-1-ethylindol-3-ylmethyl]-3-methoxybenzoate (I) as a white powder (5.12 g, 87%); mp 144°-146° C.; partial NMR (250 MHz, DMSO-d6): 1.17(m, 2H), 1.32(t, 3H), 1.4-1.8(m, 6H), 2.25(m, 3H), 3.82(s, 3H, OCH3), 3.92(s, 3H, OCH3), 3.97 (s, 2H, ArCH2), 4.09(q, 2H, CH2CH3), 9.61(s, 1H, NH).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[CH2:7][O:8]C(=O)C)(=[O:3])[NH2:2].C(OC[C@@H](C1C=CC=CC=1)COC(=O)C)(=O)N>>[C:1]([O:4][CH2:5][C@@H:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:19])([F:21])[F:20])[CH2:7][OH:8])(=[O:3])[NH2:2]
Reactant: CC(=O)OC[C@@H](COC(N)=O)c1ccccc1C(F)(F)F
Agent: CC(=O)OC[C@@H](COC(N)=O)c1ccccc1
Product: NC(=O)OC[C@H](CO)c1ccccc1C(F)(F)F
Yield: 63.5 %

Procedure:
The title compound was synthesized in a similar manner to that of Example XXII, except that (S)-3-acetoxy-2-(o-trifluoromethylphenyl)propanol carbamate, instead of (S)-3-acetoxy-2-phenylpropanol carbamate, was used as a starting material. Yield 63.5%. Purity 99.4%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[C@@H:5]([O:43][CH2:44][CH3:45])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[C:16](/[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:42])=[CH:31][CH2:32][O:33]C[Si](C(C)(C)C)(C)C)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)\[CH3:17])=[CH:9][CH:8]=1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:46])[C@@H:5]([O:43][CH2:44][CH3:45])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14]/[CH:15]=[C:16](/[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27](/[C:30](/[CH3:42])=[CH:31]/[CH2:32][OH:33])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)\[CH3:17])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(C(C)=CCOC[Si](C)(C)C(C)(C)C)cc3)cc2)cc1)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(/C(C)=C/CO)cc3)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A solution of E)(E)(S) 3-{4-[3-(4′-{3-[(tert-butyidimethylsilanyl)-methoxy]-1-methylpropenyl}-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid ethyl ester (1.18 g, 1.84 mmol) in dry THF was cooled on ice and slowly added a 1.1M solution of tetrabutylammonium fluoride in THF (1.93 mL, 1.93 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with water and ethyl acetate, the aqueous layer collected and further extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (MgSO4) and evaporated to give 0.94 g of (E)(E)(S) 2-ethoxy-3-(4-{3-[4′-{3-hydroxy-1-methyl-propenyl)-biphenyl-4-yl]-but-2-enyloxy}-phenyl)-propionic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]12[CH2:14][CH2:13][CH:12]1[CH2:11][N:10](C(OCC1C=CC=CC=1)=O)[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[Pd+2].[OH-].[C]>[C:1]([O:5][C:6]([C:8]12[CH2:14][CH2:13][CH:12]1[CH2:11][NH:10][CH2:9]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C12CCC1CN(C(=O)OCc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C12CCC1CNC2
Yield: 136.5 %

Procedure:
To a solution of 368 mg (1.02 mmol) of 1-tert-butoxycarbonyl-3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane in methanol (20 ml) was added 400 mg of 20% palladium hydroxide-carbon, followed by vigorous stirring in an atmosphere of hydrogen gas. After removing insoluble material by filtration through celite, the resulting filtrate was concentrated to give 274.6 mg of the title compound as a crude product.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:10]([C:13]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=1[NH2:20])([O-:12])=[O:11].C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.C(N(CC)CC)C>C(#N)C>[NH2:20][C:14]1[CH:15]=[CH:16][C:17]([NH:19][C:7](=[O:9])[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:18][C:13]=1[N+:10]([O-:12])=[O:11]
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)Cn1ccnc1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1ccc(NC(=O)Cn2ccnc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 77.6 %

Procedure:
To a solution of 1H-imidazole-1-ylacetic acid (284 mg, 2.25 mmol) and 2-nitrobenzene-1,4-diamine (324 mg, 2.12 mmol) in acetonitrile (20 mL) was added 3-diethoxyphosphoryloxy-1,2,3-benzotriazin-4(3H)-one (DEPBT, 632 mg, 2.11 mmol) and triethylamine (600 μL, 4.4 mmol). The mixture was stirred for 4 d at room temperature. The red precipitate was collected by filtration and washed with acetonitrile to give N-(4-amino-3-nitrophenyl)-2-(1H-imidazol-1-yl)acetamide (430 mg, 88% yield), 98% pure. A solution of N-(4-amino-3-nitrophenyl)-2-(1H-imidazol-1-yl)acetamide (430 mg, 1.65 mmol) in ethanol (20 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (100 mg, 0.09 mmol) at room temperature overnight. The mixture was filtered, giving a blue solution. Removal of the solvent under reduced pressure gave N-(3,4-diaminophenyl)-2-(1H-imidazol-1-yl)acetamide (413 mg) as a blue semi-solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(CC)CC)C.[C:64]([O:68][C:69]([N:71]1[CH2:76][CH2:75][C@H:74]([NH2:77])[C@H:73]([O:78][CH3:79])[CH2:72]1)=[O:70])([CH3:67])([CH3:66])[CH3:65]>ClCCl.O.[OH-].[Na+]>[C:64]([O:68][C:69]([N:71]1[CH2:76][CH2:75][CH:74]([NH:77][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH:73]([O:78][CH3:79])[CH2:72]1)=[O:70])([CH3:67])([CH3:66])[CH3:65]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2OC)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a mixture of 0.100 g (0.156 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.0654 g (0.17 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.13 mL of triethylamine, and 3 mL of dichloromethane was added followed by 0.0395 g (0.17 mmole) of (rac)-cis-4-amino-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester. The mixture was stirred for 1 hour, then diluted with 4 mL of dichloromethane, 4 mL of water and 0.2 mL of 1M sodium hydroxide. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (gradient, 100:0-0:100) to give 0.0643 g of rac-(3S,4R)-4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester (I-56).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:10][C:5]2=[CH:4][CH:3]=1.[C:16]1([C:22](B(O)O)=[CH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.CC(O)=O.CC(O)=O.[Pd]>[C:16]1([C:22]([C:2]2[N:7]=[C:6]3[S:8][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:10][C:5]3=[CH:4][CH:3]=2)=[CH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1nc2ccc(Cl)nc2s1
Reactant: C=C(B(O)O)c1ccccc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=C(c1ccccc1)c1ccc2nc(C(=O)OCC)sc2n1
Temperature: 90 °C

Procedure:
A mixture of ethyl 5-chlorothiazolo[5,4-b]pyridine-2-carboxylate (500 mg, 2.06 mmol), 1-phenylvinylboronic acid (366 mg, 2.47 mmol), Pd(Oac)2 (18.5 mg, 82.4 μmol), cesium carbonate (1.343 g, 4.12 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos; 33.8 mg, 82.4 μmol) in toluene (10.0 mL) was sparged with argon, then heated at 90° C. for 21.5 h. The resulting brown solution was diluted with dichloromethane (30 mL) and filtered through a pad of silica gel (washing pad with ethyl acetate (3×30 mL)). The filtrate was concentrated in vacuo, and the residue was purified via column chromatography (silica gel, 0-70% EtOAc/hexanes) to afford ethyl 5-(1-phenylvinyl)thiazolo[5,4-b]pyridine-2-carboxylate as a light yellow solid. MS (ESI) m/z: Calculated: 310.1; Observed: 311.1 (M++1).