Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH:3]1[CH:12]=[CH:11][C:10]2[CH2:13][CH2:14][N:8]3[C:9]=2[C:4]=1[C@H:5]1[CH2:17][NH:16][CH2:15][C@H:6]1[CH2:7]3.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCCl.CCOCC>[ClH:1].[ClH:1].[CH3:20][N:16]1[CH2:17][C@H:5]2[C@H:6]([CH2:7][N:8]3[CH2:14][CH2:13][C:10]4[CH:11]=[CH:12][CH:3]=[C:4]2[C:9]3=4)[CH2:15]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CC2
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOCC
Product: CN1C[C@H]2CN3CCc4cccc(c43)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of (±)-cis-4,5,7,7a,8,9,10,10a-octahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline free base from EXAMPLE 109 (140 mg, 0.70 mmol) in 10 mL of 1,2-dichloroethane was added 37% aqueous formaldehyde (0.125 mL, 1.4 mmol) and sodium triacetoxyborohydride (0.45 g, 2.1 mmol). The resulting mixture was stirred at ambient temperature for 1 h and then the reaction was quenched with water. The mixture was partitioned between chloroform and saturated aqueous sodium carbonate. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo. The residue was dissolved in 1 mL ethanol and 5 mL of ether and then there was added 2M HCl in ether (1.05 mL, 2.1 mmol). A solid precipitated out of solution. The solvents were decanted and the solid was triturated twice with ether and dried in vacuo to afford 100 mg (50%) of the title compound of EXAMPLE 110 as an off white powder LRMS (ES)+: 214.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[NH:18][C:19]2[C:24]([C:25]=1[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[CH:23][CH:22]=[C:21]([C:32]([O:34][CH3:35])=[O:33])[CH:20]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:37]>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[N:18]([CH3:37])[C:19]2[C:24]([C:25]=1[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[CH:23][CH:22]=[C:21]([C:32]([O:34][CH3:35])=[O:33])[CH:20]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCc3ccccc3)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCc3ccccc3)n(C)c2c1
Reaction time: 12 h
Yield: 80.4 %

Procedure:
NaH (810 mg, 32.1 mmol) was added to a solution of intermediate 2 (9.4 g, 21.4 mmol) in dry DMF. Then, iodomethane (3.64 g, 25.7 mmol) was added at room temperature. After 12 h, the reaction mixture was partitioned between water (pH 6) and AcOEt. Organic layer was dried over anhydrous Na2SO4, filtered and then evaporated. The residue was purified by silica column chromatography (gradient heptane/AcOEt 1:0 to 80:20) to yield 7.8 g (80%) of methyl 2-[2-(benzyloxy)phenyl]-3-cyclohexyl-1-methyl-1H-indole-6-carboxylate 3: m/z=454 (M+H)+.
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[CH2:9][CH2:8]2)[C:2]1=[O:18].[N+:19]([O-])([OH:21])=[O:20]>>[N+:19]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[C:3]1([CH2:4][CH2:5][C:6](=[O:7])[NH:1][C:2]1=[O:18])[CH2:8][CH2:9][C:10]2=[O:17])([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCC2(CCC(=O)c3ccccc32)C(=O)N1
Product: O=C1CCC2(CCC(=O)c3cc([N+](=O)[O-])ccc32)C(=O)N1
Temperature: 0 °C

Procedure:
A total of 14.1 grams (0.06 M) of 2,3-dihydrospiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione was added in small portions to 100 milliliters of nitric acid (d = 1.4) cooled to -5° to -10° C. This temperature was maintained for 15 minutes and then allowed to warm to 0° C. The reaction mixture was poured into an ice-water mixture and filtered. The precipitate was recrystallized from aqueous acetone and then from acetic acid and then from an acetone-isopropyl alcohol-ethyl acetate mixture. Recrystallization from dioxane followed by chromatrographic purification from a silica gel column (eluted by dioxane) gave 2,3-dihydro-6-nitrospiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione, melting point 273°-275° C.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:30])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:31][CH2:32][CH2:33]Br>C(O)C>[CH3:3][O:4][C:5](=[O:30])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:33][CH2:32][Br:31])=[CH:12][CH:13]=1
Reactant: BrCCBr
Reactant: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1ccccc1
Yield: 21.1 %

Procedure:
To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) is added 2-((2-benzoylphenyl)amino)-3-(4-hydroxyphenyl)-propionic acid methyl ester (1.11 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is filtered to remove the solid formed, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (0.30 g, 21%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@:4]([CH2:8][OH:9])([CH3:7])[CH:5]=[CH2:6].[F:11][C:12]([F:20])(S(F)(=O)=O)C(O)=O.O>C(#N)C.[Cu]I>[CH3:1][O:2][C:3](=[O:10])[C@:4]([CH2:8][O:9][CH:12]([F:20])[F:11])([CH3:7])[CH:5]=[CH2:6]
Reactant: C=C[C@](C)(CO)C(=O)OC
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Solvent: CC#N
Solvent: O
Product: C=C[C@](C)(COC(F)F)C(=O)OC
Temperature: 25 °C
Yield: 50.2 %

Procedure:
A solution of (R)-2-hydroxymethyl-2-methyl-but-3-enoic acid methyl ester (288 mg, 2.0 mmol) in acetonitrile (8 mL) was stirred at room temperature under nitrogen. Copper(I) iodide (80 mg, 0.4 mmol) was added followed by difluoro-fluorosulfonyl-acetic acid (356 mg, 0.2 mL, 2.0 mmol) and the reaction mixture was heated at reflux for 30 minutes. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 10:1 to 5:1 to afford the title compound (195 mg, 50%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.40 (s, 3H), 3.75 (s, 3H), 3.86 (d, J=9.4 Hz, 1H), 4.10 (d, J=9.4 Hz, 1H), 5.24 (d, J=17.4 Hz, 1H), 5.24 (dd, J=10.9 Hz, 1H), 5.95 (dd, J=17.4, 10.9 Hz, 1H), 6.22 (t, J=74.3 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:27][C:26]([CH3:29])([CH3:28])[C:25]2[C:20](=[CH:21][C:22]([NH:30][C:31](=[O:39])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[NH2:38])=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1(C)C=CC=CC=1.CC(O)=O>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([NH:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[C:31]([NH:30][C:22]2[CH:21]=[C:20]3[C:25]([C:26]([CH3:28])([CH3:29])[CH2:27][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:17])[CH2:19]3)=[CH:24][CH:23]=2)=[O:39])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3N)ccc2C(C)(C)C1
Reactant: CC(=O)c1ccnc(N)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(Nc1ccccc1C(=O)Nc1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2(C)C)c1ccnc(N)n1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2-amino-pyrimidin-4-yl)-ethanone (Step B, 200 mg, 1.46 mmol) in toluene (15 mL) was added, 7-(2-amino-benzoylamino)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (Example 15, Step A)(288 mg, 0.73 mmol), and HOAc (3 drops). The resulting mixture was heated at 95° C. under N2 for 20 h. The reaction was cooled to RT and NaBH(OAc)3 (620 mg, 2.92 mmol) was added and reheated for 3 h. The reaction was cooled to RT, quenched with Na2CO3 solution (2 M, 5 mL), solvent was evaporated in vacuo. The residue was extracted with CHCl3. The organic layer was washed with saturated NaHCO3, water, brine, dried over MgSO4, and evaporated in vacuo. The crude solid was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH (95:5) gave THE final compound. MS m/z: 517.3 (M+H). Calc'd. for C29H37N6O3-517.63.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](Br)[C:11]([CH3:14])([CH3:13])[CH3:12].[I-].[Na+]>>[CH2:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)CBr
Agent: [I-]
Agent: [Na+]
Product: CC(C)(C)COc1ccc(C=O)cc1
Yield: 99.9 %

Procedure:
The compound was synthesized as in Example 24.1, using 4-hydroxybenzaldehyde (200 mg, 1.64 mmol) and neopentyl bromide (495 mg, 1.97 mmol) in place of 1-chloro-3,3-dimethylbutane (no sodium iodide was used) to give 4-(neopentyloxy)benzaldehyde (315 mg, quant. crude) as a yellow oil that was used without further purification or characterization.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[Cl:39])[C:33](Cl)=[O:34]>C1COCC1>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[Cl:39])[C:33]([NH:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20])=[O:34]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3c(CNC(=O)c4ccc(Cl)c(Cl)c4)cccc3C2=O)C(=O)N1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
Triethylamine (0.5 g, 5.3 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and 3,4-dichlorobenzoyl chloride (0.6 g, 2.9 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL) and concentrated. The residue was stirred with 1N HCl (40 mL) for 1 hour then filtered. The solid was slurried with hot acetone (25 mL) to give 3,4-dichloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide (0.6 g, 62%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.01-2.08 (m, 1H), 2.33-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.40-4.61 (m, 4H, 2CH2), 5.11-5.19 (dd, J=5.0 and 13.2 Hz, 1H, CH), 7.47-7.88 (m, 5H, Ar), 8.12 (d, J=1.9 Hz, 1H, Ar), 9.26 (t, J=5.6 Hz, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.56, 31.16, 39.73, 46.25, 51.58, 121.78, 127.60, 128.34, 129.22, 130.73, 130.81, 131.27, 131.65, 134.16, 134.33, 140.23, 164.09, 168.01, 170.98, 172.81; Anal. calcd. for C21H17N3O4Cl2: C, 56.52; H, 3.84; N, 9.42; Cl, 15.89. Found: C, 56.42; H, 3.79; N, 9.21; Cl, 15.85.
Reaction SMILES: [C:1]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:12]Br.O>C(O)C>[Br:12][CH2:2][C:1]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1)=[O:3]
Reactant: CCOC(=O)C1(C(C)=O)CC1
Reactant: BrBr
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)CBr)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
Ethyl 1-acetylcyclopropanecarboxylate (200 g, 1.28 mol) was dissolved in ethanol (1000 ml), and bromine (72.7 ml, 1.41 mol) was added dropwise while stirring and cooling with ice. After completion of dripping, the temperature of the reaction solution was raised to 30° C. and stirring was performed for 2 hours. After adding water (1000 ml) to the reaction solution while cooling with ice, it was concentrated under a reduced pressure was performed. After extracting the concentrate into ethyl acetate (750 ml×2), it was washed with a 10% aqueous sodium thiosulfate solution (500 ml×2) and saturated sodium bicarbonate water (500 ml×2) in that order and then dried over anhydrous sodium sulfate. After filtering and concentrating the filtrate under a reduced pressure, 291 g (97%) of the title compound was obtained as a yellow, oily substance.
Reaction SMILES: [O:1]=[C:2]([CH:8]=[CH:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]>CO.[OH-].[Pd+2].[OH-]>[O:1]=[C:2]([CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(=O)C=Cc1nccs1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CC(=O)CCc1nccs1
Reaction time: 4 h
Yield: 97.6 %

Procedure:
A mixture of methyl 3-oxo-5-(1,3-thiazole-2-yl)-4-pentenoate (132.0 g) and palladium hydroxide, 20 wt % on carbon (13 g) in MeOH (2600 ml) was stirred under hydrogen atmosphere by balloon for 4 hours. Catalyst was removed by filtration and the filtrate evaporated to give 130.0 g of methyl 3-oxo-5-(1,3-thiazole-2-yl)pentanoate as a brown liquid.
Reaction SMILES: [CH3:1][N:2]([C:8](=[O:31])[CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[NH:26][N:25]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:3][C:4]([O:6]C)=[O:5].O1CCCC1.[OH-].[Li+].Cl>O>[CH3:1][N:2]([C:8](=[O:31])[CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[NH:25][N:26]=3)=[CH:20][CH:21]=2)[CH2:14][CH2:15]1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CN(C)C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(CC(=O)O)C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1

Procedure:
A 20 mL scintillation vial was charged with the product from Example 26D (12 mg, 0.027 mmol). 80% tetrahydrofuran in water, and lithium hydroxide (2.00 mg, 0.048 mmol) and shaken for 6 hours. After this time the reaction mixture was acidified with 1N HCl, filtered, and evaporated to dryness to afford the title product. The NMR spectrum includes a mixture of rotamers, with the major rotamer being reported. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.02-1.20 (m, 2H), 1.41-1.55 (m, 2 H), 1.74-1.91 (m, 5 H), 2.22-2.31 (m, 2 H), 2.78-2.80 (m, 1 H), 2.96-3.10 (m, 3 H), 3.98 (s, 2 H), 7.05-7.19 (m, 1 H), 7.27-7.45 (m, 2 H), 7.60-7.85 (m, 2 H), 13.98 (s, 1 H); MS (ESI) m/z 424[M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:25]([O:24][C:16]([CH:17]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:23])[CH3:26]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCCCCCCOCc1ccccc1
Product: CCOC(=O)C(CCCCCCOCc1ccccc1)C(=O)OCC
Yield: 60 %

Procedure:
Ethyl 2-ethoxycarbonyl-8-benzyloxyoctanoate was prepared from 6-benzyloxyhexyl bromide (3.52 g, 13 mmol) and diethyl malonate (2.29 g, 14 mmol) according to the general procedure given above. Yield 60%, bp 152°-158° C./0.15 torr. 1H-NMR: 1.24 (t, 6H), 1.2-1.9 (m, 1OH), 3.43 (t, 2H), 4.18 (q, 4H), 4.45 (s, 2H), 7.27 (m, 5H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[N:24]=[N+]=[N-])(=[O:3])[CH3:2].CO>[Pd].C1COCC1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH2:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](N=[N+]=[N-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](N)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 12 h
Yield: 85.9 %

Procedure:
Palladium catalyst (10% on carbon, 20.0 mg) was added in one portion to a solution of 2,3,4,6-tetra-O-acetyl-β-D-galacto-pyranosyl azide (6)(500 mg, 1.34 mmol) in abs. methanol (5 ml) under a hydrogen atmosphere. A small amount of abs. THF was added to dissolve the sugar. The solution was allowed to stir for 12 hours. The catalyst was subsequently filtered off, and the solvent evaporated. Purification by column chromatography gave (11) (400 mg, 86%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[N:26][N:27]([CH:29]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]2)[CH:28]=1>CO.O>[C:19]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:6]2[C:5]([Cl:22])=[CH:4][N:3]=[C:2]([NH:23][C:24]3[CH:25]=[N:26][N:27]([CH:29]4[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]4)[CH:28]=3)[N:7]=2)[CH2:18][CH2:17]1)(=[O:20])[NH2:21]
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)C1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)C1

Procedure:
A stirred solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.150 g, 0.446 mmol), 4-amino-1-(1-Boc-pyrrolidin-3-yl)-1H-pyrazole (0.225 g, 0.892 mmol) in MeOH (10 mL) and water (1.0 mL) was heated at 70° C. for 2 days. Additional 4-amino-1-(1-boc-pyrrolidin-3-yl)-1H-pyrazole (0.125 g, 0.446 mmol) was added and the mixture was heated for a further 16 hours at reflux. After cooling the solvent was removed to afford a crude red oil which was purified by silica gel column chromatography (0-100% EtOAc in cyclohexane) to give the title compound A21 as a red oil (0.164 g, 67% yield). LCMS-C: rt 5.51 min; m/z 551.9 [M+H]+.
Reaction SMILES: Cl.[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH3:22])=[O:19])[NH2:17])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:30]1([CH:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37](O)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C>[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@@H:21]([C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)[CH3:22])=[O:19])[NH:17][C:37](=[O:38])[CH:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: C[C@@H](NC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1)c1ccc(O)cc1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(O)cc1
Yield: 19.8 %

Procedure:
Prepared according to the method described in Example 3(c) above from (R)-N5 -(Cbz)-(S)-N-[1-(4-hydroxyphenyl)ethyl]ornithine amide hydrochloride (3.3 g; 7.8 mmol; from step (b) above), diphenylacetic acid (1.82 g, 8.6 mmol), BOP (3.79 g; 8.58 mmol) and triethylamine (4.0 mL; 1.1 eq.) in 300 mL acetonitrile, yielding 895 mg of the sub-title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)#[N:13].CC(C)([O-])C.[K+].Cl>CN(C)C=O>[Cl:11][C:4]1[N:3]=[C:2]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: N#Cc1ccc(N)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Nc2nc(Cl)ccc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,6-Dichloro-3-nitropyridine (II-1, 193 mg, 1 mmol) and p-cyanophenylamine (III-1, 236 mg, 2 mmol) were dissolved in N,N-dimethylformamide (DMF, 3 mL). While cooling in ice bath, potassium t-butoxide (224 mg, 2 mmol) was added in batch, followed by reacting at room temperature for 2 h. The reaction solution was poured into ice water, and adjusted with diluted HCl to a pH of 5-6, followed by stirring for 30 min, to precipitate a solid. The solid was filtered out, washed with water until neutral, dried, and separated via a silica gel column (dichloromethane as eluant), to obtain compound IV-1 (186 mg, 68%), a pale yellow solid, mp 175-178° C. 1H NMR (CDCl3) δ 10.47 (1H, br s, NH), 8.53 (1H, d, J=8.4 Hz, ArH-4), 7.86 (2H, d, J=8.8 Hz, ArH-2′, 6′), 7.70 (2H, d, J=8.8 Hz, ArH-3′, 5′), 6.96 (1H, d, J=8.4 Hz, ArH-5); MS (m/z): 275 (M+).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[CH:10]=[CH:11][C:12](O)=[O:13]>C1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[CH:10]=[CH:11][C:12]([Cl:3])=[O:13]
Reactant: COc1cccc(C=CC(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1cccc(C=CC(=O)Cl)c1

Procedure:
Thionyl chloride (38 g.) was added dropwise to a mixture of 3-methoxycinnamic acid (50 g.) and benzene (500 ml.), and the resulting mixture was heated under reflux for 1.5 hours, then evaporated under reduced pressure on a rotary evaporator to give an oil. The oil solidified on standing at room temperature, giving 59 g. of the product. Analytical sample (m.p. 43°-45° ) was obtained by recrystallization from petroleum ether.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[O:4].Cl.CN(C)CCCN=C=NCC.Cl.[CH2:27]([O:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][O:35][CH2:36][CH3:37])[CH3:28].C(N(C(C)C)CC)(C)C>ClCCl>[C:7]([O:9][CH2:10][C:11](=[O:13])[N:32]([CH2:33][CH2:34][O:35][CH2:36][CH3:37])[CH2:31][CH2:30][O:29][CH2:27][CH3:28])(=[O:8])/[CH:6]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)/C=C/C(=O)OCC(=O)O
Reactant: CCOCCNCCOCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCCN(CCOCC)C(=O)COC(=O)/C=C/C(=O)OC
Yield: 14.7 %

Procedure:
Following general procedure B2,2-[(2E)-3-(methoxycarbonyl) prop-2-enoyloxy]acetic acid (23) (0.80 g, 6.14 mmol) was activated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) (1.40 g, 7.37 mmol) in 20 mL of dichloromethane (DCM) at ca. 0° C. bis(2-Ethoxyethyl)amine hydrochloride (1.18 g, 7.37 mmol) (1.18 g, 7.37 mmol) and diisopropylethylamine (DIEA) (1.34 mL, 0.99 g, 7.67 mmol) were added to the activated carboxylic acid. After work-up and isolation, and purification by silica gel flash column chromatography (Biotage) using ethyl acetate (EtOAc) and hexanes (1:1) afforded 0.30 g (15% yield) of the title compound (27) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 6.97 (d, J=15.6 Hz, 1H), 6.94 (d, J=1.6 Hz, 1H), 5.01 (s, 2H), 3.80 (s, 3H), 3.56-3.43 (m, 12H), 1.19 (q, J=7.6 Hz, 6H). MS (ESI): m/z 332.20 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[C:17]([CH2:20][CH2:21][C:22](=[O:38])[C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10].[OH-].[Na+]>>[Cl:1][C:2]1[C:18]([Cl:19])=[C:17]([CH2:20][CH2:21][C:22](=[O:38])[C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)C(C)(C)CCCOc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(CCCOc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O

Procedure:
5-(2,3-Dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2,2-dimethylpentanoic acid is prepared from methyl 5-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2,2-dimethylpentanoate according to general procedure F using 10 equivalents of 2N sodium hydroxide solution.