Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:17]([O-])([O-])([O:19][CH2:20][CH3:21])[CH3:18].C(O)(=O)C>C1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:2]([N:1]=[C:17]([O:19][CH2:20][CH3:21])[CH3:18])=[C:3]([CH:12]=1)[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCOC(C)([O-])[O-]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(C)=Nc1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
A solution of 11.5 parts of 2-amino-5-chlorobenzophenone, 11.5 parts of ethyl orthoacetate and 6 volume parts of acetic acid in 100 volume parts of benzene is refluxed for 20 minutes, whereby 5-chloro-2-(1-ethoxyethylideneamino)-benzophenone are obtained as crystals. Recrystallization from methanol-water gives colorless needles melting at 62° to 63° C. Yield: 93%.
Reaction SMILES: [CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:20][CH:19]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2].[C:37]([O:43][CH2:44][CH3:45])(=[O:42])[CH2:38][C:39]([O-])=[O:40].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:22][CH:23]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]([C:39](=[O:40])[CH2:38][C:37]([O:43][CH2:44][CH3:45])=[O:42])[CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CCOC(=O)C1NCCc2nc(CC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)N1CCc2nc(CC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2C1C(=O)OCC
Yield: 74 %

Procedure:
A solution of ethyl 2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.72 g), monoethyl malonate (0.94 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.02 g), triethylamine (1.78 g) in dichloromethane (20 ml) is stirred overnight at room temperature. The reaction mixture is washed with water and dried over sodium sulfate and then evaporated. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.57 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([C:21]([O:23]CC)=[O:22])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([C:21]([OH:23])=[O:22])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1CCc2c(cnc3c2cnn3Cc2ccc(OC)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(Cn2ncc3c4c(cnc32)CC(C(=O)O)CC4)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinoline-7-carboxylate (159 mg, 0.44 mmol) in tetrahydrofuran (5 mL), methanol (2 mL) and water (3 mL) was added excess lithium hydroxide (0.5 g). The mixture was stirred at room temperature for 1.5 hours diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried with anhydrous magnesium sulfate and evaporated to dryness to give 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinoline-7-carboxylic acid as an off white solid (157 mg). 1H NMR (DMSO-d6) 400 MHz δ 12.33 (brs, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.16 (d, J=8.0 Hz, 2H), 6.84 (d, J=8.0 Hz, 2H), 5.52 (s, 2H), 3.69 (s, 3H), 3.14-2.97 (m, 4H), 2.82-2.74 (m, 1H), 2.22-2.14 (m, 1H), 1.97-1.87 (m, 1H); LCMS [M+H]: 338.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N([O-])=O.[Na+].[I-:16].[K+].S([O-])([O-])=O.[Na+].[Na+]>Cl.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([I:16])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: [I-]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])[O-]
Solvent: O
Product: O=[N+]([O-])c1cc(I)ccc1F
Temperature: -20 °C

Procedure:
A suspension of 4-fluoro-3-nitroaniline (100 g, 0.64 mol) in conc. hydrochloric acid (500 ml) is cooled to -20° C. A solution of sodium nitrite (48.6 g, 0.7 mol) in 100 ml of water is added with stirring, keeping the temperature below -15° C. Following the addition the mixture is stirred for 45 min. at -20-(-15)° C. To the resulting solution a solution of potassium iodide (132.8 g, 0.8 mol) in 260 ml of water is added at such a rate that the temperature is kept below 0° C. The mixture is stirred until the evolution of nitrogen has ceased. Aqueous sodium sulfite (200 ml, 1 M) is added and the mixture is extracted with diethyl ether. The etheral extract is washed twice with ice-cold 1 M aqueous sodium hydroxide and twice with brine. Finally the extract is dried over magnesium sulfate, concentrated and purified by column-chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1:9) as the eluent. 1cis isolated as an oil, which crystallizes in the refrigerator. Yield: 132.6 g (78%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([NH:11][C@@H:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[N:5]=1)(=[O:3])[NH2:2].[F:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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]>[C:1]([C:4]1[CH:9]=[C:8]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:40][CH:39]=3)=[CH:29][CH:28]=2)[N:7]=[C:6]([NH:11][C@@H:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[N:5]=1)(=[O:3])[NH2:2]
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3)cc2)OC1(C)C
Reactant: COC(=O)[C@H](C)Nc1nc(Cl)cc(C(N)=O)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)[C@H](C)Nc1nc(C(N)=O)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 80 °C
Yield: 89.5 %

Procedure:
To a mixture of (S)-methyl 2-((4-carbamoyl-6-chloropyrimidin-2-yl)amino)propanoate (0.642 g, 2.48 mmol) in dioxane (12.5 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.861 g, 2.74 mmol), 2M aqueous Na2CO3 (2.50 mL, 5.00 mmol), and PdCl2(dppf) (0.105 g, 0.129 mmol). The reaction vessel was flushed with argon, sealed, and heated at 80° C. for 5 h. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 20-60% acetone in hexanes. The product fractions were evaporated in vacuo to give (S)-methyl 2-((4-carbamoyl-6-(4-(4-fluorophenoxy)phenyl)pyrimidin-2-yl)amino)propanoate as a tan-yellow glass (0.911 g, 2.22 mmol, 89% yield). LC/MS: m/z=411.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]([C:12]1[C:17]([CH:18]=[O:19])=[C:16]([NH:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[N:15]=[C:14]([CH3:26])[N:13]=1)[CH2:6][CH2:5]2.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]([C:12]1[C:17]([CH2:18][OH:19])=[C:16]([NH:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[N:15]=[C:14]([CH3:26])[N:13]=1)[CH2:6][CH2:5]2
Reactant: CCC(CC)Nc1nc(C)nc(N2CCc3cc(Cl)cc(Cl)c32)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC(CC)Nc1nc(C)nc(N2CCc3cc(Cl)cc(Cl)c32)c1CO
Yield: 77.8 %

Procedure:
4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-formyl-2-methylpyrimidine, (50 mg, 0.13 mmol) was stirred with NaBH4 (7 mg, 0.2 mmol) in dry ethanol (2 mL) at 0° C. for 2 h. The reaction was partitioned between EtOAc (100 mL) and water (20 mL) and the EtOAc was washed with brine, dried (MgSO4) and stripped in vacuo. The residue was chromatographed on silica gel using 40% EtOAc/hexanes to give the product, 4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-hydroxymethyl-2-methylpyrimidine (40 mg, 80% yield).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.[O:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C.O1CCCC1>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:42][CH:39]2[CH2:40][CH2:41][O:36][CH2:37][CH2:38]2)[CH2:31][CH2:30]1
Reactant: NC1CCOCC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](NC3CCOCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4′-{[5-Oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.0 g) and tetrahydro-2H-pyran-4-amine (0.43 g) were dissolved in acetic acid (20 mL) and tetrahydrofuran (8 mL), sodium triacetoxyborohydride (1.3 g) was gradually added at room temperature, and the mixture was stirred at room temperature for 24 hr. Water was added, and the solvent was evaporated under reduced pressure. The residue was gradually added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.77 g, 32%).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)=[O:2].CC[N:21]([CH:25]([CH3:27])C)[CH:22]([CH3:24])C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCCC1>CN(C=O)C>[N:21]1([C:11]([C:10]2[CH:9]=[C:8]([CH:16]=[CH:15][CH:14]=2)[O:7][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:18][CH:17]=2)=[O:13])[CH2:22][CH2:24][CH2:27][CH2:25]1
Reactant: O=Cc1ccc(Oc2cccc(C(=O)O)c2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccc(C(=O)N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1 g (4.1 mmol) of 3-(4-formyl-phenoxy)-benzoic acid were dissolved in 25 ml DMF and combined with 0.86 ml (4.95 mmol) of DIPEA and 1.32 g (4.1 mmol) of TBTU, stirred for 5 min at ambient temperature and then 0.29 g (4.1 mmol) of pyrrolidine were added. The mixture was stirred at ambient temperature, filtered through basic Alox, concentrated by rotary evaporation and purified by chromatography (silica gel column, dichloromethane with gradient of 0-10% methanol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11](=[O:35])[NH:12][C@H:13]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:14][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:16])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[CH3:37][O-:38].[Na+].O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11](=[O:35])[NH:12][C@H:13]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:14][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:16])[N:8]=[C:7]([O:38][CH3:37])[N:6]=1)=[O:4]
Reactant: C[O-]
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(C(=O)OC)nc(Cl)n1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(C(=O)OC)nc(OC)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butylcarbamoyl)-2-chloro-pyrimidine-4-carboxylic acid methyl ester (74 mg, 0.145 mmol, from Example 42-1) in THF (5 mL) is added sodium methoxide (47 mg, 0.218 mmol) and the mixture is stirred at room temperature for 18 hours. Water is added and the mixture is extracted with EtOAc. The organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure to give 6-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butylcarbamoyl)-2-methoxy-pyrimidine-4-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:18])[C:16]=2[CH3:17])=[CH:13][CH:12]=[CH:11][C:10]=3[C:19](O)=[O:20])=[CH:5][CH:4]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:37]([N:39]([CH2:43][CH3:44])[CH2:40][CH2:41][NH2:42])[CH3:38]>O1CCCC1>[CH2:37]([N:39]([CH2:43][CH3:44])[CH2:40][CH2:41][NH:42][C:19]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[O:8][C:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=1)=[C:16]([CH3:17])[C:15]2=[O:18])=[O:20])[CH3:38]
Reactant: COc1ccc(-c2oc3c(C(=O)O)cccc3c(=O)c2C)cc1
Reactant: CCN(CC)CCN
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1cccc2c(=O)c(C)c(-c3ccc(OC)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of 6.00 g of 4'-methoxy-3-methylflavone-8-carboxylic acid and 2.70 ml of triethylamine in 70 ml of anhydrous tetrahydrofuran was added a solution of 2.03 ml of ethyl chlorocarbonate in 10 ml of anhydrous tetrahydrofuran and the mixture was stirred for 1 hour under ice-cooling. To the reaction mixture was added a solution of 2.25 g of N,N-diethylethylenediamine in 10 ml of anhydrous tetrahydrofuran and the mixture was stirred for 1.5 hours under ice-cooling and further 16 hours at room temperature. The reaction mixture was treated by the same procedure as in Example 3(b), to give 3.55 g of pale yellow crystals, which were recrystallized from ethyl acetate as colorless needles, m.p. 125.5°-127° C. This compound was identical with the product obtained in Example 36(a) in NMR and IR spectra, and mixed m.p.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.CCO.C1COCC1.[ClH:28]>CO.CCOCC>[ClH:28].[NH2:17][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[B:2]([OH:1])[O:3][CH2:4][C:5]=3[CH:10]=2)=[N:13][CH:14]=1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc(Oc2ccc3c(c2)COB3O)nc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 50 mL round-bottom flask fitted with magnetic stirring bar was added 6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile (1.0 g, 4.0 mmol, 1.0 eq.), followed by addition of EtOH (40 mL) and THF (15 mL). The flask was evacuated and recharged with N2 twice. To the stirring solution was added 5% Pd/C (300 mg) and the flask was evacuated and recharged with H2 three times. The resulting suspension was stirred under a H2 balloon at room temperature over 3 days. The mixture was filtered through a short pack of celite and washed with EtOH (3×25 mL). The combined filtrate was concentrated under reduced pressure, the residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give a white solid. The solid was dissolved in minimum amount of MeOH and carefully treated with HCl in Et2O. The precipitate was collected by filtration and washed with Et2O to give 5-(5-aminomethyl-pyridin-2-yloxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride a white solid. 1H NMR (DMSO-d6) δ: 9.95 (br. s., 1H), 8.28 (d, J=2.2 Hz, 1H), 8.11 (dd, J=8.5, 2.4 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.07-7.14 (m, 2H), 7.05 (dd, J=7.9, 2.0 Hz, 1H), 4.94 (s, 2H), 4.14 (t, J=5.6 Hz, 2H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCCCCC>C1COCC1>[F:17][C:14]1[CH:13]=[CH:12][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH:6]([CH2:5][CH2:4][CH2:3][OH:2])[CH2:10][CH2:9]2)=[CH:16][CH:15]=1
Reactant: COC(=O)CCC1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)N2C(CCCO)CCC2c2ccc(F)cc2)cc1

Procedure:
Reduction of (2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid methyl ester with lithium aluminum hydride (1.5 eq.) in THF at RT, aqueous work-up and crystallization from EE/hexane yielded the title compound, white solid, m.p. 93° C. and MS: m/e=378.2 (M+H+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[CH:41]=[C:40]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH:39]=[C:38]([F:48])[CH:37]=1>>[CH3:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH:29][C:34]([NH:35][C:36]4[CH:41]=[C:40]([N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)[CH:39]=[C:38]([F:48])[CH:37]=4)=[O:33])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: O=C(Nc1cc(F)cc(N2CCOCC2)c1)OCC(Cl)(Cl)Cl
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(F)cc(N5CCOCC5)c4)c4ccccc43)cn12

Procedure:
The title compound was prepared starting from Intermediate 96c and intermediate 115a using analogous procedures to those described in Example 99. LCMS (Method 5): Rt 4.70 min, m/z 614 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.55 (3H, d, J=6.3 Hz), 0.59 (3H, d, J=6.3 Hz), 1.35-1.53 (3H, m), 1.63-1.69 (2H, m), 1.72-1.78 (1H, m), 1.82-1.99 (2H, m), 2.00-2.13 (2H, m), 3.03 (4H, t, J=4.8 Hz), 3.08-3.20 (2H, m), 3.65-3.69 (2H, t, J=4.8 Hz), 4.80-4.88 (1H, td, J=8.7, 5.5 Hz), 5.50 (1H, t, J=4.0 Hz), 6.31 (1H, dt, J=12.4, 2.0 Hz), 6.68 (1H, br s), 6.71 (1H, d, J=8.9 Hz), 6.81 (1H, dt, J=11.3, 1.9 Hz), 7.18-7.25 (2H, m), 7.29-7.37 (3H, m), 7.62 (1H, dd, J=9.8, 0.6 Hz), 7.86 (1H, d, J=2.0 Hz), 8.51 (1H, s).
Reaction SMILES: C(OC(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:19])=[O:18])=[CH:9][CH:8]=1)=O)C.N.C(NS(C1C2C(=CC=CC=2)C(O)=CC=1)(=O)=[O:56])CCCCCCCCCCCCCCC>ClCCl>[CH2:21]([NH:20][S:17]([C:10]1([OH:56])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH2:9]1)(=[O:19])=[O:18])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCNS(=O)(=O)c1ccc(O)c2ccccc12
Reactant: CCCCCCCCCCCCCCCCNS(=O)(=O)c1ccc(OC(=O)OCC)c2ccccc12
Agent: N
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNS(=O)(=O)C1(O)CC=Cc2ccccc21
Reaction time: 1 h

Procedure:
4-Ethoxycarbonyloxy-N-hexadecylnaphthalene-1-sulphonamide (21.5 g, 41.4 mmole) was added to liquid ammonia (250 ml), in portions with stirring, at -78° C. (acetone-drycold bath). The mixture was stirred for 1 h, and the excess ammonia allowed to evaporate. The residue was dissolved in ethyl acetate, washed with water and dried (MgSO4). Removal of the solvent gave a pale brown oil which was dissolved in hot dichloromethane (100ml) and then cooled in an ice-bath. The off-white precipitate was collected and dried in air to yield pure N-hexadecyl-4-hydroxynaphthalene-4-sulphonamide, 7.7 g, 42%. TLC analysis (1:3 EtOAc : 40°-60° petrol) showed one spot (Rf =0.4) and spectroscopic data was consistent with the product.
Reaction SMILES: [CH3:1][C:2]1(C)OC(=O)[CH:5]([CH:9]([C:20]2[C:28]3[C:23](=[C:24]([CH2:29][S:30][CH3:31])[CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[C:4](=[O:32])[O:3]1>N1C=CC=CC=1.C(O)C.[Cu]>[CH3:31][S:30][CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[NH:22][CH:21]=[C:20]2[CH:9]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH2:5][C:4]([O:3][CH2:2][CH3:1])=[O:32]
Reactant: CSCc1cccc2c(C(c3ccc4ccccc4c3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1ccc2ccccc2c1)c1c[nH]c2c(CSC)cccc12

Procedure:
1.2 mg (0.02 mmol) of copper powder were added to 882 mg (1.92 mmol) of the compound from Example 20A in 15 ml of pyridine and 5 ml of ethanol. The reaction mixture was heated under reflux for 2 h. It was concentrated, and the crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) and preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 635 mg (82% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:26]([N:33]1[CH2:37][C@H:36]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:35][C@H:34]1[CH:46]=O)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:46][C@@H:34]2[CH2:35][C@@H:36]([O:38][Si:39]([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:41])[CH3:40])[CH2:37][N:33]2[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[CH:9][C:8]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)cc1-c1ccccc1
Reaction time: 8 h
Yield: 18.6 %

Procedure:
To a solution of 0.75 g (2.09 mmol) of [2-phenyl-4-aminobenzoyl]methionine methyl ester (compound 8) and 0.7 g (2.1 mmol) of (2S,4R)-1-Boc-4-[t-butyldimethylsilyloxy]-pyrrolidin-2-aldehyde, prepared as in Example 171B, in 10 ml of methanol were added 1 ml of acetic acid, followed by 0.2 g (3.1 mmol) of sodium cyanoborohydride. The reaction mixture was stirred overnight. After removal of the solvent, the residue was partitioned with ethyl acetate and 5% sodium bicarbonate, and extracted 3 times with ethyl acetate. The combined organic solution was washed with water and brine, dried over magnesium sulfate, and solvent was removed. The residue was flash-chromatographed on silica gel (2:1 hexanes-ethyl acetate) to yield 261 mg (74%) of {4-[(2S,4R)-1-Boc-4-(t-butyldimetylsilyl)oxypyrrolidin-2-ylmethyl]amino-2-phenylbenzoyl}methionine methyl ester as a white solid: mp 48° C.; [α]25D−15.6 (c=1.03, CHCl3);