Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[C:7](O)[CH:6]=[CH:5][N:4]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][CH3:27])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>P(Cl)(Cl)(Cl)=O.CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][N:26]([CH3:27])[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:8]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: Oc1ccnc(C(F)(F)F)c1
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ccnc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 28.7 %

Procedure:
A stirred solution of 2-trifluoromethylpyridin-4-ol (12.5 g, 76.6 mmol) and dimethylformamide (3.00 mL) in phosphorus oxychloride (75 mL) is heated under reflux for 2 hours before excess phosphorus oxychloride is removed in vacuo. The residue is poured onto an ice-water mixture and extracted into ethyl acetate (×5). The combined organic extracts dried (sodium sulfate), filtered and concentrated in vacuo. The non-basic components of the mixture are eluted through a SCX column washing with a 1:1 mixture of methanol-dichloromethane. A stirred suspension of the residue, 1-t-butoxycarbonyl-4-[(methylamino)methyl]piperidine (1.11 g, 4.85 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in dimethylformamide (38 mL) is heated at 90° C. for 13 hours. Excess dimethylformamide is removed in vacuo, the residue is taken into chloroform and washed with 2.5% hydrogen chloride solution. The aqueous layer is extracted into chloroform (×3) and the combined organic extracts are dried (sodium sulfate), filtered and concentrated in vacuo. Flash column chromatography eluting with a gradient of 30% ethyl acetate-hexane to 50% ethyl acetate-hexane provides 1-t-butoxycarbonyl-4-{[(methyl)(2-trifluoromethylpyridin-4-yl)amino]methyl}piperidine (520 mg, 2%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[CH2:9])=[CH:6][C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:4][N:3]=1>CO.[Pt]>[Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[CH:4][N:3]=1
Reactant: C=Cc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1Cl
Agent: [Pt]
Solvent: CO
Product: CCc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1Cl
Reaction time: 8 h
Yield: 49.3 %

Procedure:
A suspension of 5% Pt on carbon and 2-chloro-3-vinyl-5-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (Example 26 above, 440 mg, 1.36 mmol) in MeOH (10 mL) were stirred overnight under an atmosphere of hydrogen (balloon). The mixture was filtered and the filtrate was concentrated to afford 2-chloro-3-ethyl-5-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine as a colorless oil (219 mg, 51%): 1H NMR (CDCl3, 300 MHz) δ 1.25 (t, J=7.5 Hz, 3H), 1.42 (s, 9H), 2.32 (m, 2H), 2.71 (q, J=7.5 Hz, 2H), 3.89 (t, J=7.8 Hz, 2H), 4.12 (dd, J=3.0, 9.8 Hz, 1H), 4.30 (m, 1H), 4.50 (m, 1H), 7.16 (d, J=3.1 Hz, 1H), 7.94 (d, J=3.0 Hz, 1H); MS (CI/NH3) m/z 327 (M+H)+. To a solution of the product from above (216 mg, 0.66 mmol) in CH2Cl2 (2 mL) at 0° C. was added trifluoroacetic acid (1.8 miL). The solution was allowed to warm to room temperature, then adjusted to pH 11 with aqueous 10% NaOH, and extracted with CH2Cl2. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed (silica gel; CH2Cl2 /MeOH, 100:3 to 100:15) to afford the free base of the title compound as an oil (60 mg, 40%): 1H NMR (CDCl3, 300 MHz) δ 1.22 (m 3H), 2.38 (m, 2H), 2.71 (q, J=7.5 Hz, 2H), 3.57 (m, 1H), 3.80 (m, 1H), 4.08 (m, 2H), 4.38 (m, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.92 (d, J=3.0 Hz, 1H); MS (CI/NH3) m/z: 227 (M+H)+. The free base was dissolved in THF and treated with 1 M HCl in Et2O to afford the hydrochloride salt, which was triturated with Et2O and dried under vacuum to afford the title compound as a white solid: mp 102-104° C.; [α]D23 -9.68 (c 0.62, MeOH); 1H NMR (D2O) δ 1.24 (t, J=7.5 Hz, 3H), 2.71 (m, 4H), 4.11 (m, 2H), 4.42 (d, J=4 Hz, 2H), 4.95 (m, 1H), 7.51 (d, J=3 Hz, 1H), 8.00 (d, J=3 Hz, 1H). Anal. Calcd. for C11H15N2OCl.1.1 HCl: C, 49.52; H, 6.08; N, 10.50. Found: C, 49.63; H, 5.89; N, 10.20.
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C@@H:21]([C:41]3[O:45][N:44]=[C:43]([C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)[N:42]=3)[CH2:22][C:23]3[CH:31]=[C:30]([CH3:32])[C:29]4[C:25](=[CH:26][N:27](COCC[Si](C)(C)C)[N:28]=4)[CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.FC(F)(F)C(O)=O.C(Cl)Cl>>[O:1]=[C:2]1[C:11]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C@@H:21]([C:41]3[O:45][N:44]=[C:43]([C:46]4[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=4)[N:42]=3)[CH2:22][C:23]3[CH:24]=[C:25]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[NH:28][N:27]=[CH:26]4)=[O:19])[CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)c2nc(-c3ccc(F)cc3)no2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)c2nc(-c3ccc(F)cc3)no2)cc2cn[nH]c12
Yield: 64.8 %

Procedure:
A stirred solution of (R)-1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethyl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (16.2 mg, 0.0224 mmol) in 1:1 trifluoroacetic acid/methylene chloride 91 mL) was stirred at room temperature for 2 h. Removal of the solvents in vacuo followed by purification using preparative HPLC afforded a tan gum (8.6 mg, 65%). 1H-NMR (CDCl3, 400 MHz) δ 8.22 (s, 1H), 8.12-8.01 (m,2H), 7.80 (s, 1H), 7.76-7.45 (m, 5H), 7.35-7.45 (m, 2H), 7.30 (s,1H), 7.20-7.07 (m,2H), 6.28-6.15 (m,1H), 4.42-4.25 (m,2H), 3.57-3.45 (m,2H) 3.31-2.85 (m, 4H), 2.60 (s,3H), 2.09-1.88 (m,2H), 1.70-1.53 (m,2H). Mass spec. 593.28 (MH+).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:15].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.O>[C:1]1([C:7]2[CH:12]=[C:11]([Br:15])[CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccccc1-c1ccccc1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Br)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-phenylanisole (18.27 g, 0.099 mol) in CH2Cl2 (350 mL) was added pyridinium tribromide (34.88 g, 0.109 mol). The resulting mixture was allowed to stir at RT overnight. The mixture was diluted with CH2Cl2 and H2O and the layers were separated, the aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were washed with H2O, brine and dried with MgSO4. The mixture was filtered and the solvents evaporated to give 2-phenyl-4-bromoanisole as a reddish oil (26.05 g, 100%). 1H NMR (300 MHz, CDCl3): δ 3.75 (s, 3H), 6.82 (d, J=8.7 Hz, 1H), 7.28–7.43 (m, 5H), 7.45–7.49 (m, 2H).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:9]([C:10]2[C:19]3[O:18][CH2:17][C@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:15]4[C:26]([N:28]5[CH2:32][CH2:31][C@@H:30]([NH2:33])[CH2:29]5)=[N:27][C:13]([C:14]=34)=[CH:12][CH:11]=2)=[C:8]([CH3:34])[O:7][N:6]=1.C(N(CC)CC)C.Cl[C:43]([O:45][CH3:46])=[O:44]>C(Cl)Cl>[CH3:4][C:5]1[C:9]([C:10]2[C:19]3[O:18][CH2:17][C@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:15]4[C:26]([N:28]5[CH2:32][CH2:31][C@@H:30]([NH:33][C:43](=[O:44])[O:45][CH3:46])[CH2:29]5)=[N:27][C:13]([C:14]=34)=[CH:12][CH:11]=2)=[C:8]([CH3:34])[O:7][N:6]=1
Reactant: COC(=O)Cl
Reactant: Cc1noc(C)c1-c1ccc2nc(N3CC[C@@H](N)C3)n3c2c1OC[C@@H]3c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H]1CCN(c2nc3ccc(-c4c(C)noc4C)c4c3n2[C@@H](c2ccccn2)CO4)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
(3R)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-amine trihydrochloride (35 mg, 0.068 mmol) was stirred in methylene chloride (1.0 mL) with triethylamine (47 μL, 0.34 mmol), followed by addition of methyl chloroformate (10 μL, 0.14 mmol). The mixture was stirred at room temperature for 30 min and concentrated. Purification by preparative LCMS using pH 10 buffer gave the title compound (24 mg, 75%). LCMS calc. for C25H27N6O4 (M+H)+: m/z=475.2. found: 475.3. 1H NMR (300 MHz, CD3OD) δ 8.58 (d, J=4.8 Hz, 1H), 7.69 (td, J=7.8, 1.8 Hz, 1H), 7.32 (dd, J=7.1, 5.3 Hz, 1H), 7.05 (d, J=8.1 Hz, 2H), 6.89 (d, J=8.1 Hz, 2H), 6.59 (d, J=7.9 Hz, 1H), 6.03 (s, 1H), 4.55 (dd, J=11.5, 2.8 Hz, 2H), 4.29-4.09 (m, 1H), 4.00-3.71 (m, 2H), 3.63-3.50 (m, 3H), 3.40 (dd, J=9.8, 4.6 Hz, 1H), 2.23 (s, 3H), 2.23-2.11 (m, 1H), 2.08 (s, 3H), 1.98-1.83 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].[C:16](=[S:18])=[S:17].Cl>CN(C=O)C.O>[CH3:9][C:6]1[CH:7]=[CH:8][C:2]2[S:17][C:16]([SH:18])=[N:4][C:3]=2[CH:5]=1
Reactant: Cc1ccc(Cl)c(N)c1
Reactant: S=C=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2sc(S)nc2c1
Temperature: 150 °C
Yield: 27.3 %

Procedure:
To a suspension of 2-chloro-5-methyl aniline (9, 1.00 g, 7.06 mmol) and K2CO3 (2.80 g, 28.2 mmol) in DMF (20 mL) was added CS2 (0.50 mL, 8.50 mmol) under N2 at room temperature. The reaction mixture was heated at 150° C. for 16 h. After cooling, the reaction mixture was diluted with water (30 mL) and acidified with 1N HCl. The precipitate was collected by filtration, washed with water, and dried over P2O5 under vacuum to yield compound 10 (0.35 g, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[C:15]([O:18][C:19]1[C:24]([CH:25]=O)=[CH:23][C:22]([Cl:27])=[CH:21][N:20]=1)([CH3:17])[CH3:16].N1CCCC1>CO>[CH3:12][O:13][C:14](=[O:28])[C:15]([O:18][C:19]1[C:24](/[CH:25]=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)=[CH:23][C:22]([Cl:27])=[CH:21][N:20]=1)([CH3:17])[CH3:16]
Reactant: COC(=O)C(C)(C)Oc1ncc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)C(C)(C)Oc1ncc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 78.9 %

Procedure:
To the mixture of 6-chlorooxindole (4.9 g, 29.3 mmol) and 2-(5-Chloro-3-formyl-pyridin-2-yloxy)-2-methyl-propionic acid methyl ester (7.2 g, 28 mmol) in methanol (50 mL) was added pyrrolidine (2.3 mL, 28 mmol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give title compound as a yellow solid (9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([C:13](=O)[CH:14]=[C:15](O)[C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:27][NH:28][NH2:29].CN(C=O)C.O>CO>[CH3:27][N:28]1[C:13]([CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:8][CH2:9]2)=[CH:14][C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[N:29]1
Reactant: CNN
Reactant: O=C(C=C(O)c1ccc(Cl)cc1)C1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccc(Cl)cc2)cc1C1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 34.3 %

Procedure:
1-(4-Chlorobenzyl)-4-(3-hydroxy-1-oxo-3-(4-chlorophenyl)-prop-2-en-1-yl)piperidine obtained from Example 1 (264 mg) and methyl hydrazine (62 mg) were stirred in methanol (5 ml) and DMF (2 ml) for 16 h. Water was added, the mixture extracted with ethyl acetate (3×20 ml), the combined organic layers washed with water and brine, dried (MgSO4), evaporated in vacuo, and purified by preparative thin layer chromatography, eluding with dichloromethane:methanol: triethylamine (98:2:1 v/v) to give 1-methyl-5-(1-(4-chlorobenzyl)-4-piperidinyl)-3-(4-chlorophenyl)pyrazole (93 mg): oxalate salt.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[N:23]([CH3:24])[C@H:12]1[CH2:11]3.C([O-])(=O)C.[Na+].Cl.[OH:33][CH2:34][CH2:35][CH2:36][NH2:37]>CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:37][CH2:36][CH2:35][CH2:34][OH:33])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[N:23]([CH3:24])[CH:13]3[C:14]12[O:21][CH3:22]
Reactant: NCCCO
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@@H]3[C@H](CN21)N3C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC12C(CO)C3=C(C(=O)C(C)=C(NCCCO)C3=O)N1CC1C2N1C
Product: NC(=O)O
Reaction time: 24 h
Yield: 61 %

Procedure:
To a solution of 50 mg(0.13 mmol) of N-methylmitomycin A in 10 ml of anhydrus methanol, a solution of 82 mg (1 mmol) sodium acetate in 2.5 ml of methanol and a solution of 130 mg (1 mmol) of 3-hydroxypropylamine hydrochloride in 2.5 ml of methanol were added alternatively with vigorous stirring, over a period of 10 minutes. The progress of the stirred reaction was checked frequently by TLC and appeared to be complete in 24 hours. The solvent was evaporated under reduced pressure and the residue was chromatographed using silica-gel as adsorbent. The fraction obtained by eluting the column with ethyl acetate was evaporated. Recrystallization from a mixture of methylene chloride and hexane gave 31 mg. (61% yield) of the desired product as purple-colored crystals having a melting point of 139°-140° (decomposing) and providing the following analysis:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:17][CH3:18])=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=2)[CH:12]=O)=[C:5]([CH3:19])[O:4][N:3]=1.[C:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:17][CH3:18])=[CH:9][C:10]([O:15][CH3:16])=[C:11](/[CH:12]=[CH:21]/[C:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[O:22])[CH:14]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2c(C)noc2C)cc1C=O
Product: COc1cc(OC)c(-c2c(C)noc2C)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 7 %

Procedure:
The title compound was prepared by condensing 5-(3,5-dimethyl-isoxazol-4-yl)-2,4-dimethoxy-benzaldehyde (Ex-33A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp>260° C., 7% yield. 1H-NMR (DMSO-d6) δ 8.15 (d, J=8 Hz, 2H), 8.04 (d, J=16 Hz, 1H), 8.02 (d, J=8 Hz, 2H), 7.89 (s, 1H), 7.81 (d, J=16 Hz, 1H), 6.79 (s, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 2.23 (s, 3H) 2.05 (s, 3H) MS m/z=407 ([M]+, 60%), 376 (100%). HMRS (EI) calcd. for C23H21NO6: 407.1369; found: 407.1375.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][C:14]([CH3:17])([CH3:16])[CH2:15][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN([CH:26]=[O:27])C>C1COCC1>[C:1]([NH:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][C:14]([CH3:17])([CH3:16])[CH2:15][C:10]=2[C:9]=1[CH:26]=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)Cc2cc(C(=O)NC(C)(C)C)sc2C1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Cc2sc(C(=O)NC(C)(C)C)c(C=O)c2C1
Temperature: -70 °C
Reaction time: 6 h
Yield: 79.9 %

Procedure:
To a solution of 282e (1.5 g, 6.0 mmol) in anhydrous THF (60 mL) cooled at −70° C. was added the solution of n-butyl lithium (10.0 mL, 25 mmol, 2.5 Min hexane) over a period of 5 minutes. It was stirred at −70° C. for 6 h. DMF (1.3 g, 18.0 mmol) was added over a period of 5 minutes and the result mixture was stirred at room temperature for overnight. It was then quenched with saturated NH4Cl (40 mL) and concentrated under reduced pressure. The residue was extracted with ethyl acetate (2×30 mL). The combined organic layer was dried over anhydrous Mg2SO4 and filtered. The filtrate was evaporated under reduced pressure to afford 282f as yellow solid (1.34 g, 80%). MS-ESI: [M+H]+ 280.3
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1.[CH3:25][C:26]1([CH3:40])[C:30]([CH3:32])([CH3:31])[O:29][B:28]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[O:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[CH3:16][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:37][C:36]2[CH:38]=[CH:39][C:33]([B:28]3[O:27][C:26]([CH3:40])([CH3:25])[C:30]([CH3:31])([CH3:32])[O:29]3)=[CH:34][CH:35]=2)[CH:18]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CNc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Yield: 88.6 %

Procedure:
2′,6′-dimethyl-4′-(3-(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-carbaldehyde (1.0 g) synthesized according to a method described in [WO 2008/001931 pamphlet, (Reference Example 18)] and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.63 g) were dissolved in methylene chloride (10 mL), and to the resultant solution, sodium triacetoxyborohydride (1.84 g) was added, followed by stirring the resultant reaction mixture at room temperature for 14 hours. To the reaction mixture, water (20 mL) was added, followed by extracting the reaction mixture with methylene chloride (20 mL) twice, and the resultant organic phase was washed sequentially with water (50 mL) and a saturated saline (50 mL) and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure to obtain the subject compound (1.4 g) as a colorless amorphous solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]([N:10]1[CH2:14][CH2:13][C:12](=O)[CH2:11]1)=[O:9].C(=O)([O-])[O-].[K+].[K+]>CCOCC.C1(C)C=CC=CC=1>[N:1]1([C:12]2[CH2:11][N:10]([C:8]([O:7][CH3:6])=[O:9])[CH2:14][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)N1CCC(=O)C1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)N1CC=C(N2CCCC2)C1

Procedure:
Pyrrolidine (25 ml) is slowly added dropwise to a stirred suspension of 28.63 g of N-methoxycarbonyl-3-oxo-tetrahydropyrrole [prepared according to J Med Chem 5, 752 (1962)] and 29.5 g of anhydrous potassium carbonate in 200 ml ether and 100 ml toluene at 0°-5° under a nitrogen atmosphere. After 3 hours the suspension is filtered and the filtrate evaporated under reduced pressure to yield 3-pyrrolidino-N-methoxycarbonyl-2,5-dihydropyrrole as an oil. NMR (CDCl3): 4.12 (s), 4.01 (m), 3.63 (s), 3.00 (m), and 1.85 (m).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([NH:8][C:9](=[O:15])[C:10]([O:12]CC)=O)[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.[CH3:19][NH:20][NH2:21]>CO>[CH3:18][C:2]1([CH3:1])[CH2:7][CH:6]([NH:8][C:9]([C:10]([NH:21][NH:20][CH3:19])=[O:12])=[O:15])[CH2:5][C:4]([CH3:16])([CH3:17])[NH:3]1
Reactant: CCOC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Reactant: CNN
Solvent: CO
Product: CNNC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1

Procedure:
N-(2,2,6,6-tetramethyl-4-piperidinyl)-N'-methylaminooxamide was prepared by reacting ethyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate with 97% methyl hydrazine in methanol.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:35]=[CH:34][C:16]2[NH:17][C:18]([CH2:20][C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][C:29]([C:31]([OH:33])=O)=[CH:30][C:23]=4[N:22]=3)=[N:19][C:15]=2[CH:14]=1.ON1C2C=CC=CC=2N=N1.Cl.C[N:48](C)[CH2:49][CH2:50][CH2:51][N:52]=C=NCC.NCCCN.CN1CCOCC1>C(Cl)Cl.CN(C=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:35]=[CH:34][C:16]2[N:17]=[C:18]([CH2:20][C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][C:29]([C:31]([NH:48][CH2:49][CH2:50][CH2:51][NH2:52])=[O:33])=[CH:30][C:23]=4[N:22]=3)[NH:19][C:15]=2[CH:14]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cn1c(Cc2nc3cc(CN4C(=O)c5ccccc5C4=O)ccc3[nH]2)nc2cc(C(=O)O)ccc21
Agent: Cl
Agent: NCCCN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cn1c(Cc2nc3ccc(CN4C(=O)c5ccccc5C4=O)cc3[nH]2)nc2cc(C(=O)NCCCN)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.5 %

Procedure:
2-[5-(1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylmethyl]-1-methyl-1H-benzoimidazole-5-carboxylic acid (0.05 g, 0.108 mmol), 1-hydroxybenzotriazole (0.016 g, 0.118 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.023 g, 0.12 mmol) and the mono-BOC protected derivative of 1,3-diaminopropane were dissolved at 0° C. in methylene chloride (1 mL) and DMF (minimal amount sufficient to effect a solution). The solution was adjusted to pH-8 with N-methylmorpholine and the mixture was allowed to slowly warm to room temperature and then stirred for 20 hours. The mixture was transferred to a separatory finnel, diluted with methylene chloride, washed with 0.1N HCl solution and then saturated NaHCO3 solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparatory TLC (10% methanol/ethyl acetate) to provide 2-[6-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylmethyl]-1-methyl-N-(3-aminopropyl)-1H-benzoimidazole-5-carboxamide (0.02 g, 28% yield); 1H-NMR (300 Mhz, CDCL3): 7.75-7.81 (m, 4H), 7.61-7.68 (m, 3H), 7.33 (br s, 1H), 7.27 (d, 1H, J=8.6 Hz), 7.15 (d, 1H, J=9.3 Hz), 5.10 (br t, 1H), 4.90 (br s, 2H), 4.57 (s, 2H), 3.71 (s, 3H), 3.49 (q, 2H, J=7.2 Hz), 3.24 (q, 2H, J=7.2 Hz), 1.72 (m, 2H), 1.41 (s, 9H);
Reaction SMILES: O1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][C:14]([NH:16][NH:17][C@@:18]([CH3:31])([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([OH:30])[CH:24]=1)[C:19]([OH:21])=[O:20])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P([O-])([O-])([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[CH2:2]([N:17]([C@@:18]([CH3:31])([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([O:30][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:24]=1)[C:19]([O:21][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:20])[NH:16][C:14]([O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15])[C:3]1[CH:4]=[CH:3][CH:2]=[CH:5][CH:4]=1
Reactant: C[C@@](Cc1ccc(O)c(O)c1)(NNC(=O)OCc1ccccc1)C(=O)O
Reactant: BrCc1ccccc1
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@](Cc1ccc(O)c(OCc2ccccc2)c1)(C(=O)OCc1ccccc1)N(Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.8 %

Procedure:
To a 500 mL round bottom flask were added (S)-2-(2-((benzyloxy)carbonyl)hydrazinyl)-3-(3,4-di hydroxyphenyl)-2-methylpropanoic acid compound with tetrahydrofuran (1:1), Compound 1, (10 g, 84 wt %, 19.42 mmol) and 100 mL DMF. Cesium carbonate (11.39 g, 35 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The mixture was cooled in an ice bath. Benzyl bromide (7.38 mL, 62.2 mmol) was added portionwise. The mixture was stirred in the ice bath overnight. The slurry was filtered, and the cake was washed with methyl t-butyl ether. The filtrate was mixed with water, and the layers were separated. The aqueous layer was extracted with methyl t-butyl ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude was purified by flash chromatography using a 220 g silica column (0-30% ethyl acetate in heptanes) to afford Compound 2 as a colorless thick oil (1.20 g, 9.8%).