Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([OH:8])[C:3]#[C:4][CH:5]([OH:7])[CH3:6].[OH:9][CH:10]([CH3:16])[C:11]#[C:12][C:13](=[O:15])[CH3:14]>S(=O)(=O)(O)O.O.CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][C:2](=[O:8])[C:3]#[C:4][C:5](=[O:7])[CH3:6].[OH:15][CH:13]([CH3:14])[C:12]#[C:11][C:10](=[O:9])[CH3:16]
Reactant: CC(O)C#CC(C)O
Agent: [Cr+6]
Agent: CC(=O)C#CC(C)O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)C#CC(C)=O
Reaction time: 1 h

Procedure:
To prepare Hex-3-yne-2,5-dioxe: Chromium trioxide (100 g) in concentrated sulphuric acid (90 ml) and water (550 ml) was added with vigorous stirring over 2 hours to hex-3-yne-2,5-diol (28 g) and 5-hydroxyhex-3-yn-2-one (28 g) in acetone (400 ml) at -5° to 0° C. After 1 hour, water (150 ml) was added and the solution extracted with ether. The extract was washed (aqueous NaHCO3), dried (MgSO4) and distilled to give crude hex-3-yne-2,5-dione (3-6 g), B.P. 50° (bath) at 0.15 m Hg ad 5-hydroxy-hex-3-yne-2-one (B.P. 50°-75° at 0.2 mm Hg) 23 g.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:15]2[CH:28]=[C:11]([CH:12]=[CH:13][N:14]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][C:3]1=[O:29].C1C(=O)N([Br:37])C(=O)C1>C(#N)C>[Br:37][C:8]1[CH:7]=[CH:6][C:5]2[NH:4][C:3](=[O:29])[C@H:2]([CH3:1])[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:15]3[CH:28]=[C:11]([CH:12]=[CH:13][N:14]=3)[C:10]=2[CH:9]=1
Reactant: C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2ccccc2NC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2cc(Br)ccc2NC1=O
Temperature: 75 °C
Yield: 89.8 %

Procedure:
To a suspension of 45G (616 mg, 1.558 mmol) in acetonitrile (15.200 ml) in a sealed vial was added NBS (277 mg, 1.558 mmol). The reaction was sealed and heated at 75° C. overnight. Additional NBS (300 mg, 1.686 mmol) was added and heat at 75° C. overnight. The mixture was concentrated and purified by silica gel chromatography to afford 137A as a white solid (664 mg, 90%). MS (ESI) m/z: 476.0 (M+H)+.
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Br:14]Br.[OH-].[Na+]>CCOCC>[Br:14][C:3]1[CH:2]=[N:1][C:9]2[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: BrBr
Reactant: c1cnc2c(c1)CCC2
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: Brc1cnc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6,7-dihydro-5H-[1]pyrindine (20 gm) and AlCl3 (56 gm) at 100° C. was added 10 mL of bromine over 2 hours, stirred an additional 15 minutes, cooled to room temperature, and poured over ice. The pH of the reaction was adjusted until it was basic with NaOH and then celite and ether were added and the mixture filtered. The filter cake was washed well with additional ether and the filtrate was extracted from the aqueous layer. The ether layer was washed with saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated to dryness. The residue was chromatographed on silica gel using 10:1 hexane/ethyl acetate as the eluant to yield 4 gm of compound. 1H NMR (CDCl3): d 8.35 (s, 1 H), 7.60 (s, 1 H), 2.90 (m, 4 H), 2.10 (m, 2 H).
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2([CH2:27][NH:28][C:9](=[O:11])[CH2:8][S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Reactant: O=C(O)CSc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C2(CNC(=O)CSc3ccccc3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 14.6 %

Procedure:
Phenylsulfanyl-acetic acid (33.6 mg, 0.200 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (47.1 g, 0.200 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (83.6 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (76.0 mg, 0.200 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (11.3 mg, 0.0293 mmol, 14.6%) ESI-MS m/z calc. 385.2, found 386.0 (M+1)+. Retention time of 3.12 minutes.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]4[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=4)=[N:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH:4]=[N:3]1.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33].N1CCOCC1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:20]([C:21]4[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:32](=[O:33])[CH2:31][O:30][CH3:29])=[CH:27][CH:28]=4)=[N:19][CH:18]=[CH:17][N:16]=3)[CH2:13][CH2:14]2)[CH:4]=[N:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1c(CN2CCN(c3nccnc3-c3ccc(CN)cc3)CC2)cnn1C
Solvent: ClCCl
Solvent: C1COCCN1
Product: COCC(=O)NCc1ccc(-c2nccnc2N2CCN(Cc3cnn(C)c3C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
Dissolve 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzylamine (0.2 g, 0.53 mmol) in methylene chloride (5 mL). Add methoxy-acetyl chloride (1 eq., 0.058 g, 0.53 mmol). Add polymer bounded morpholine (1.1 eq., 0.234 g, 0.58 mmol). Stir at room temperature for 3 hr. Purify by SCX followed by reverse phase chromatography to give free base N-{4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzyl}-2-methoxy-acetamide, (0.051 g, 21%). MS (ES): m/z=450.3 [M+H].
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][C:6]=1[S:17]([NH:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]([NH2:30])=O)[CH2:24][CH2:23]1)(=[O:19])=[O:18]>C1COCC1>[NH2:30][CH2:28][C@H:25]1[CH2:24][CH2:23][C@H:22]([CH2:21][NH:20][S:17]([C:6]2[CH:7]=[C:8]([O:11][CH2:12][C:13]([F:14])([F:15])[F:16])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C:2]([F:32])([F:1])[F:31])(=[O:18])=[O:19])[CH2:27][CH2:26]1
Reactant: NC(=O)[C@H]1CC[C@H](CNS(=O)(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)CC1
Solvent: C1CCOC1
Product: NC[C@H]1CC[C@H](CNS(=O)(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)CC1
Temperature: 0 °C

Procedure:
To a solution of trans-4-{[2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonylamino]-methyl}-cyclohexanecarboxylic acid amide (2.7 g, 5.5 mmol) in THF (20 mL) was added a solution of 1 M BH3 in THF (20 mL, 20 mmol) over 40 min. The mixture was stirred at reflux for 2 hr. After cooling to 0° C., the mixture was quenched with water (7 mL). To the mixture were added 4 M HCl in EtOAc (28 mL) and MeOH (50 mL) and the mixture was concentrated. To the residue was added MeOH (50 mL) and the mixture was once again concentrated. The resulting HCl-salt was recrystallized from Et2O and subsequently neutralized with 1 M aqueous sodium hydroxide. The aqueous layer was extracted with CH2Cl2 (twice), the combined organic layers were dried over sodium sulfate, and concentrated under reduced pressure to give trans-N-(4-aminomethyl-cyclohexylmethyl)-2,5-bis-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide as a white solid (1.5 g, 57%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[C:17]([Cl:18])=[C:16]([O:19][CH3:20])[CH:15]=[C:14]([O:21][CH3:22])[C:13]=3[Cl:23])[CH:8]=2)[N:3]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CC(N(C)C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:23][C:13]1[C:14]([O:21][CH3:22])=[CH:15][C:16]([O:19][CH3:20])=[C:17]([Cl:18])[C:12]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[N:11]=[CH:10]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(Cl)ncc3c2)c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1Cl
Temperature: 125 °C
Yield: 45.3 %

Procedure:
A mixture of 2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazoline (0.1 g, 0.27 mmol), tert-butyl ((1S,2S)-2-aminocyclohexyl)carbamate (75 mg, 0.35 mmol), Cs2CO3 (176 mg, 0.54 mmol), X-Phos (13 mg, 0.027 mmol) and Pd2dba3 (12.5 mg, 0.013 mmol) in DMA (1.8 mL) was degassed with N2 for 5 mins and heated in a microwave reactor at 125° C. for 30 mins. The mixture was cooled to room temperature, filtered through celite and washed with water followed by saturated brine solution. The residue was purified by silica gel column chromatography to afford tert-butyl ((1S,2R)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)cyclohexyl)carbamate (67 mg, 45%). MS (ES+) C27H32Cl2N4O4 requires: 546, found: 547 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[CH:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([CH3:13])[CH:7]=1>>[CH3:1][Si:2]([CH3:5])([CH3:4])[O:12][C:11]1[CH:6]=[CH:7][C:8]([CH3:13])=[CH:9][CH:10]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1ccc(O)cc1
Product: Cc1ccc(O[Si](C)(C)C)cc1

Procedure:
The procedure of Example 2 was perfomred with 40 moles each of trimethylchlorosilane and p-cresol. The reactor temperature went to about 122° C. About 7.2 kg/h of trimethyl-p-cresyloxysilane was produced. B.p. 198° C., D.4/20 0.9183.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:24][CH2:25][CH:26]([OH:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[CH3:23])=[CH:17][CH:16]=1)(OC)=[O:8].O.[OH-].[Na+]>O1CCCC1>[OH:8][CH2:7][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:24][CH2:25][CH:26]([OH:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=2)[CH3:23])=[CH:17][CH:16]=1
Reactant: COC(=O)CCCOc1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(Cc1ccc(OCCCCO)cc1)NCC(O)c1cccc(C(F)(F)F)c1
Yield: 60.1 %

Procedure:
To a slurry of lithium aluminium hydride (200 mg) in dry tetrahydrofuran (20 ml) was added dropwise, with stirring, a solution of N-[2-(4-(3-carbomethoxypropoxy)phenyl)-1-methylethyl)-2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (800 mg) in dry tetrahydrofuran (30 ml). The mixture was stirred and heated under reflux for 2 hours after which time it was cooled in ice. Water (0.2 ml), 2 M sodium hydroxide (0.2 ml) and water (1 ml) were successively added, the resulting mixture filtered, the tetrahydrofuran dried (magnesium sulphate) and evaporated to leave an oil. Crystallisation from hexane gave N-[2-(4-(4-hydroxybutoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (450 mg) m.p. 69°-76° as a 45:55 mixture of diastereoisomers.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:15]([O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:21][CH:22]=1)[CH3:14]
Reactant: CCOc1ccc(N)cc1
Reactant: CC(=O)CCC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOc1ccc(-n2c(C)ccc2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-phenyl-1,4-pentanedione (1.06g, 6.0 mmol) and toluene (50 mL) was added p-phenetidine (0.78 mL, 6.0 mmol) and 5 drops of glacial acetic acid. The mixture was heated at reflux overnight. After cooling to rt, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (15-25% EtOAc/hexanes) to give 1-(p-ethoxyphenyl)-5-methyl-2-phenyl-pyrrole as a yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.17-7.13 (m, 2H), 7.10-7.05 (m, 5H), 6.89-6.84 (m, 2H), 6.35 (d, 1H), 6.08 (d, 1H), 4.04 (q, 2H), 2.13 (s, 3H), 1.44 (t, 3H); MS (ESI) 278 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.[N+]([O-])([O-])=O.[Ce].[NH4+]>C(#N)C.O>[CH3:1][C:2]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:4][C:5](=[O:6])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(C)CCC(=O)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
Ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (Int-18b, 2.09 g, 9.17 mmol) was dissolved in acetonitrile (100 mL) and water (50 mL). Ammonium cerium nitrate (503 mg, 0.92 mmol) in water (50 mL) was added and the resulting mixture was heated up to 70° C. and stirred for 1 h. After being cooled down to room temperature, water (100 mL) was added and the mixture was extracted with ether (100 mL×3). The combined organics were washed with water, brine and dried. After concentration, the residue was purified on a column (silica gel, 0-30% ethyl acetate in hexane) which gave ethyl 1-methyl-4-oxocyclohexanecarboxylate (Int-18c) (1.72 g) as an oil.
Reaction SMILES: C(N)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[CH3:18][O:19][C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl-].[NH4+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:18][O:19][C:20]([C:22]1([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]1)=[O:21]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)N
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of isopropylamine (1.34 ml, 9.559 mmol) in THF (40 ml) at 0° C. was added n-butyllithium (3.65 ml of a 2.5M sol. In hexanes, 9.125 mmol). The resulting LDA solution was added via cannula to a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4 methyl ester (2.11 g, 8.690 mmol) in THF (40 ml) and HMPA (8 ml) at −78° C. and stirring continued for 1 hour. Benzyl bromide (1.19 ml, 9.994 mmol) in THF (5 ml) was then added and the solution warmed to room temperature over 2 hours. After stirring for 18 h, saturated aqueous ammonium chloride (200 ml) was added and the aqueous phase extracted with diethyl ether (2×100 ml). Organic phases were combined, dried over magnesium sulphate and concentrated to dryness. Purification by silica column chromatography (0.5% methanol in DCM) gave the ester as an oil (1.816 g, 63%). LC/MS: (LCT) Rt 7.67 [M+H]+333.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[C:5]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH:4]=1)#[N:2].[OH-].[Na+].Cl>CO>[C:22]([CH2:21][O:20][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:19]=[CH:18][C:6]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]2[B:15]([OH:16])[O:14][CH2:13][C:12]=2[CH:17]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)COc1cc(C#N)ccc1Oc1ccc2c(c1)COB2O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
A mixture of 5-[4-Cyano-2-(ethoxycarbonylmethoxy)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (D16) (216 mg, 0.612 mmol) and 1 M NaOH (2 mL in methanol (8 mL) was stirred at room temperature for 1 h. The mixture was acidified with 1 M HCl and extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with hexane to give 5-[2-(Carboxymethoxy)-4-cyanophenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (82 mg, 41%)
Reaction SMILES: [C:1]([NH:4][C@:5]1([C@@H:58]([CH2:60][CH3:61])[CH3:59])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:11]([NH:13][C@@H:14]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:15]([C@H:24]2[CH2:28][C@@H:27]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[CH2:26][N:25]2C(OC(C)(C)C)=O)[O:16][Si](C(C)(C)C)(C)C)=[O:12])[C:6]1=[O:57])(=[O:3])[CH3:2].CCN(CCO)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[C:1]([NH:4][C@:5]1([C@@H:58]([CH2:60][CH3:61])[CH3:59])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:11]([NH:13][C@@H:14]([CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C@H:15]([OH:16])[C@H:24]2[CH2:28][C@@H:27]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:30])=[O:31])[CH2:26][NH:25]2)=[O:12])[C:6]1=[O:57])(=[O:3])[CH3:2]
Reactant: CCCS(=O)(=O)[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)[C@H](CCc2ccccc2)N2CC[C@](NC(C)=O)([C@H](C)CC)C2=O)N(C(=O)OC(C)(C)C)C1
Agent: CCN(CC)CCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCS(=O)(=O)[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CCc2ccccc2)N2CC[C@](NC(C)=O)([C@H](C)CC)C2=O)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
Step 22 (F): (2R,4R)-tert-butyl 2-((1S,2S)-2-((S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-4-phenylbutanamido)-1-(tert-butyldimethylsilyloxy)-3-phenylpropyl)-4-(propylsulfonyl)pyrrolidine-1-carboxylate. A solution of the compound of Preparation A (22 mg, 0.06 mmol) dissolved in 2 mL of dichloromethane was treated with DEEA (40 mg, 0.3 mmol) and HATU (30 mg, 0.078 mmol). After stirring at rt for 5 min, the amine from step 22 (E) (32 mg, 0.06 mmol) was added and the reaction solution was allowed to stir for 16 h at rt. The reaction solution was then partitioned between ethyl acetate and water, the organic layer was concentrated, and the crude product was purified by chromatography eluting with a gradient of 40% to 80% ethyl acetate in hexanes to provide 45 mg (85%) of the desired amide. 1H NMR (500 MHz, Solvent) δ ppm 0.08 (s, 6 H) 0.18 (s, 2 H) 0.73 (d, J=6.71 Hz, 3 H) 0.99 (s, 9 H) 1.10 (m, 6 H) 1.37 (t, J=6.41 Hz, 6 H) 1.49 (s, 9 H) 1.52 (d, J=3.97 Hz, 4 H) 1.68 (m, 1 H) 1.86 (m, 2 H) 2.09 (m, 1 H) 2.58 (m, 1 H) 2.73 (m, 1 H) 3.05 (dd, J=9.16, 6.41 Hz, 2 H) 3.23 (m, 2 H) 3.54 (s, 1 H) 3.76 (m, 2 H) 4.02 (m, 2 H) 4.09 (m, 1 H) 4.26 (s, 1 H) 4.41 (d, J=8.55 Hz, 1 H) 7.22 (m, 10 H) 8.18 (s, 1 H). MS (ESI) (M+H)+=883.41
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:16]([CH3:33])[C:17](=[O:32])[CH2:18][N:19]2[C:24]3[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:23]=3[O:22][CH2:21][C:20]2=[O:31])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[F:34].[CH3:35][S:36]([NH:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)(=[O:38])=[O:37].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:30][C:26]1[C:27]([Cl:29])=[CH:28][C:23]2[O:22][CH2:21][C:20](=[O:31])[N:19]([CH2:18][C:17]([N:16]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:43]4[CH:42]=[CH:41][C:40]([NH:39][S:36]([CH3:35])(=[O:37])=[O:38])=[CH:45][CH:44]=4)=[C:3]([F:34])[CH:4]=3)[CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH3:33])=[O:32])[C:24]=2[CH:25]=1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(Br)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2ccc(NS(C)(=O)=O)cc2)c(F)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 9.5 %

Procedure:
To a room temperature solution under nitrogen containing 0.20 g of N-[1-(4-bromo-3-fluorophenyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (0.348 mmols) in 3.5 mL of dry DMF was added 0.09 g of {4-[(methylsulfonyl)amino]phenyl}boronic acid (0.418 mmols), 0.014 g of (dppf)PdCl2 (0.017 mmols), and 0.70 mL of Na2CO3 solution (2M in water). The reaction mixture was heated to 80° C. After 18 h the reaction was cooled to ambient temperature and filtered through a 0.2 □m syringe filter. The resulting DMF solution was purified by preparative HPLC (Phenomenex 50×100 mm column, 90 mL/min flow rate, A: 0.1% TFA in acetonitrile B: 0.1% TFA in water, A: 10 to 100% over 15 min, UV detection at 215 nm) to give 0.022 g (9%) of the title compound as a light brown solid. MS (ES) m/e 666, 667 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:48])[C@@H:7]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](=[O:47])[NH:40][C:41]1[NH:42][CH2:43][CH2:44][CH2:45][N:46]=1)(=[O:32])=[O:31])[CH2:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:13][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:42]1[CH2:43][CH2:44][CH2:45][N:46]=[C:41]1[NH:40][C:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[S:30]([NH:29][C@@H:7]([CH2:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:26][CH2:25][CH2:24][CH2:23][N:22]=2)=[CH:13][CH:12]=1)[C:6]([OH:48])=[O:5])(=[O:32])=[O:31])=[O:47]
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccccc1C(=O)NC1=NCCCN1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2C(=O)NC2=NCCCN2)C(=O)O)cc1)NC1=NCCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
54 mg (0.08 mmol) of (2S)-2-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid was added. The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile/water (1/1) and lyophilized. Yield 34 mg. MS (ES+): m/e=627 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7](=[NH:11])OCC.[NH3:17]>C(O)C>[ClH:2].[Cl:2][C:3]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([NH2:11])=[NH:17]
Reactant: N
Reactant: CCOC(=N)COc1cccc(Cl)c1Cl
Agent: Cl
Solvent: CCO
Product: N=C(N)COc1cccc(Cl)c1Cl
Reaction time: 72 h

Procedure:
11.8 g (0.041 mole) of ethyl 2-(2,3-dichlorophenoxy)acetimidate hydrochloride are added rapidly to a solution, cooled to 10° C., of 3.5 g (0.21 mole) of ammonia in 100 ml of absolute ethanol. The reaction mixture is left for 3 days at room temperature. After removal of a few suspended particles by filtration, the reaction mixture is concentrated to dryness under reduced pressure. The solid residue obtained is purified by washing with ether and recrystallization from isopropanol. Yld: 8.0 g (75%), m.p. 204.5°-206.5° C.