Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N+:24]=4[O-:39])=[CH:17][CH:16]=3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccccn2)cc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccc[n+]2[O-])cc1
Yield: 57.5 %

Procedure:
N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino}benzamide (200 mg, 0.5 mmol) was dissolved in dichloromethane (50 mL) and stirred while adding 3-chloroperbenzoic acid (85%, 200 mg). The solution was stirred for one hour at 25° C., then washed twice with sodium bicarbonate solution and dried. The solvent was evaporated to give the title compound as a white solid (120 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.68 (m, 2H), 2.24 (s, 3H), 2.84 (m, 1H), 5.35 (s, 2H), 7.18 (d, 2H), 7.31 (d, 1H), 7.42 (m, 2H), 7.60 (m, 2H), 7.78 (m, 1H), 7.99 (d, 2H), 8.36 (m, 2H), 9.84 (s, 1H); Mass Spectrum: M+H+ 418.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16]O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:6]=2[CH:24]=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16][N:29]4[C:25](=[O:35])[C:26]5=[CH:34][CH:33]=[CH:32][CH:31]=[C:27]5[C:28]4=[O:30])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:6]=2[CH:24]=1
Reactant: OCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccn1)=NC2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 2, 8-chloro-1-(2-hydroxyethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine in dioxane is treated with phthalimide, triphenylphosphine and subsequently with diethyl azodicarboxylate to give 8-chloro-1-(2-phthalimidoethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:52])([F:51])[C:17]1[CH:18]=[C:19]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:20][N:21]([C:38]1[N:39]=[N:40][N:41]([CH3:43])[N:42]=1)[C@H:22]1[CH2:28][CH2:27][CH2:26][NH:25][C:24]2[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:31]([CH3:33])=[CH:32][C:23]1=2.[CH3:53][O:54][C:55](=[O:65])[C:56]1[CH:61]=[C:60]([CH:62]=O)[CH:59]=[CH:58][C:57]=1[OH:64].C(O)(=O)C>C(#N)C.ClCCl>[CH3:53][O:54][C:55](=[O:65])[C:56]1[CH:61]=[C:60]([CH2:62][N:25]2[CH2:26][CH2:27][CH2:28][C@H:22]([N:21]([CH2:20][C:19]3[CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:46]=[C:17]([C:16]([F:51])([F:15])[F:52])[CH:18]=3)[C:38]3[N:39]=[N:40][N:41]([CH3:43])[N:42]=3)[C:23]3[CH:32]=[C:31]([CH3:33])[C:30]([C:34]([F:35])([F:36])[F:37])=[CH:29][C:24]2=3)[CH:59]=[CH:58][C:57]=1[OH:64]
Reactant: COC(=O)c1cc(C=O)ccc1O
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)c1cc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)ccc1O
Reaction time: 24 h
Yield: 59.8 %

Procedure:
Add sodium triacetoxyborohydride (0.115 g, 0.543 mmol) portionwise to a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.200 g, 0.362 mmol), 5-formyl-2-hydroxy-benzoic acid methyl ester (0.195 g, 1.08 mmol) and glacial acetic acid (1 mL) in acetonitrile (10 mL) at room temperature under an atmosphere of nitrogen and stir for 24 h. Quench the reaction with saturated sodium bicarbonate (5 mL) and dilute with dichloromethane (15 mL). Separate the layers and wash the organic layer with saturated sodium bicarbonate and brine (20 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (80:20), to provide the title compound as an off-white foam (0.155 g, 60%). 1H NMR (CDCl3, 300 MHz) δ 10.63 (s, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 7.56 (m, 2H), 7.28 (s, 1H), 6.96 (m, 2H), 5.56 (m, 1H), 4.85-4.98 (m, 2H), 4.14 (s, 3H), 3.89 (s, 3H), 2.95-3.00 (m, 1H), 2.73-2.80 (m, 1H), 2.30 (s, 3H), 2.00-2.13 (m, 2H), 1.43-1.72 (m, 2H), 1.21-1.34 (m, 3H); ESI MS m/z 717 [C32H29F9N6O3+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][N:5]=[C:4]([CH:12]=[O:13])[CH:3]=1.P([O-])(O)(O)=O.[Na+].CC(=CC)C.Cl([O-])=O.[Na+].Cl.[C:30]([OH:34])(C)(C)C>O>[F:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][N:5]=[C:4]([C:12]([O:34][CH3:30])=[O:13])[CH:3]=1
Reactant: COCOc1cnc(C=O)cc1F
Reactant: CC(C)(C)O
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: O
Product: COCOc1cnc(C(=O)OC)cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 4-fluoro-5-(methoxymethoxy)pyridine-2-carbaldehyde (2.43 g), sodium dihydrogen phosphate (4.72 g), 2-methyl-2-butene (7.32 mL), water (4 mL) and tert-butanol (20 mL) was added sodium chlorite (2.23 g), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in DMF (30 mL), potassium carbonate (1.81 g) and methyl iodide (0.820 mL) were added thereto, and the mixture was stirred at 70° C. for 20 min. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.80 g).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)#[N:2].I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=[C:14]([C:6]3[CH:5]=[C:4]([CH2:3][C:1]#[N:2])[CH:9]=[CH:8][CH:7]=3)[C:22]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: N#CCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cccc(CC#N)c2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of (3-Cyanomethylphenyl)boronic acid (18 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA45. ESI-MS (M+H)+ m/z calcd 293.1, found 293.1.
Reaction SMILES: C([N:11]1[CH2:18][C:17]([OH:25])([CH2:19][C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.C(SCCC(N1CC(O)(CC2SC=CC=2)C[C@H]1C(O)=O)=O)(=O)C>>[OH:25][C:17]1([CH2:19][C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: O=C(O)[C@@H]1CC(O)(Cc2cccs2)CN1C(=O)OCc1ccccc1
Agent: CC(=O)SCCC(=O)N1CC(O)(Cc2cccs2)C[C@H]1C(=O)O
Product: O=C(O)[C@@H]1CC(O)(Cc2cccs2)CN1

Procedure:
The N-carbobenzyloxy-4-hydroxy-4-[(2-thienyl)methyl]-L-proline from part (a) is hydrogenated according to the procedure of Example 1 (b) to yield 4-hydroxy-4-[(2-thienyl)methyl]-L-proline. This amino acid is then reacted with 3-acetylthiopropionyl chloride according to the procedure of Example 1 (c) to yield 1-[3-(acetylthio)-1-oxopropyl]-4-hydroxy-4-[(2-thienyl)methyl]-L-proline.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14])=[CH:4][C:3]=1[CH3:15].CCCCCC.C([Li])CCC.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>O1CCCC1.O.C(OCC)(=O)C>[CH2:13]([O:12][CH2:11][CH2:10][O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([B:27]([OH:32])[OH:28])=[C:3]([CH3:15])[CH:4]=1)[CH3:14]
Reactant: CCOCCOc1cc(C)c(Br)c(C)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOCCOc1cc(C)c(B(O)O)c(C)c1
Temperature: -78 °C
Yield: 67.7 %

Procedure:
To a solution of 2-bromo-5-(2-ethoxyethoxy)-1,3-dimethylbenzene (10.0 g, 36.6 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium hexane solution (1.6 M, 25.1 mL, 40.2 mmol) under stirring at −78° C. The reaction mixture was stirred at the same temperature for 30 min and triisopropyl borate (10.5 mL, 45.5 mmol) was added. The mixture was allowed to warm to room temperature, and the mixture was stirred for 3 hr. To the reaction mixture were added 5 M hydrochloric acid (20 mL), ethyl acetate and water to allow partitioning, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane/diethyl ether and dried to give the title compound (5.9 g, yield 68%) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:19])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:24]=[N+:25]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:19])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:24]=[N-:25]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(Cl)cc2)c1N
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Br)nc(-c2ccc(Cl)cc2)c1N=[N+]=[N-]
Yield: 218.7 %

Procedure:
Methyl 3-amino-6-bromo-2-(4-chlorophenyl)isonicotinate (3.86g, 11 3 mmol) was dissolved in TFA (57 mL) and the solution was cooled in an ice bath. Solid sodium nitrite (1.72 g, 24 9 mmol) was added slowly with stirring to give a brown solution with gas evolution. After 30 min solid sodium azide (7.35 g, 113 mmol) was added in portions over 5 min with gas evolution. Et2O (57 mL) was slowly added and a precipitate formed. After stirring for 0.5 h, water was added and the mixture was extracted with EtOAc. The combined organic phases were washed with water (3×) and brine (1×) and then saturated aqueous Na2CO3 solution (so that the aqueous phase was basic) and brine (1×). After drying with sodium sulfate, the solvent was removed to leave methyl 3-azido-6-bromo-2-(4-chlorophenyl)isonicotinate (2.41 g, 6.56 mmol, 58.0% yield) as a fluffy yellow solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.79 (1H, s), 7.68-7.73 (2H, m), 7.42-7.47 (2H, m), 4.00 (3H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:3]=1.[NH2:23][C:24]1[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[Se:26][C:25]=1[C:33]([NH2:35])=[O:34].CN(C=O)C.[OH-].[Na+]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2[N:3]=[C:2]([NH:23][C:24]3[CH:28]=[C:27]([C:29]([CH3:32])([CH3:30])[CH3:31])[Se:26][C:25]=3[C:33]([NH2:35])=[O:34])[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: COc1cc2nc(-c3ccc(Cl)cc3)nc(Cl)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3ccc(Cl)cc3)nc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c2cc1OC

Procedure:
The reaction of 4-chloro-2-(4-chlorophenyl)-6,7-dimethoxyquinazoline with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a white color solid, mp 268-270° C. 1H NMR (400 MHz, CDCl3): δ 12.03 (1H, s, exchangeable with D2O), 9.05 (1H, s), 8.49 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz), 7.37 (1H, s), 7.32 (1H, s), 5.37 (2H, s, exchangeable with D2O), 4.11 (3H, s), 4.06 (3H, s), 1.52 (9H, s); 13C NMR (100 MHz, CDCl3): δ 168.6, 168.5, 158.1, 155.0, 154.8, 149.9, 148.5, 148.1, 137.7, 136.0, 129.4, 128.5, 122.0, 109.3, 108.4, 108.0, 100.3, 56.3, 56.2, 37.3, 32.7; LC-MS (negative ion mode): m/z 541, 543, 545 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2.FC1C=CC(N)=C2C=1C=CC=N2.[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH3:37])[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:25]([O:29][C:30](=[O:31])[NH:32][C@H:33]([C:34](=[O:35])[NH:12][C:9]1[CH:10]=[CH:11][C:2]([F:1])=[C:3]2[C:8]=1[NH:7][CH2:6][CH2:5][CH2:4]2)[CH3:37])([CH3:26])([CH3:27])[CH3:28]
Reactant: Nc1ccc(F)c2c1NCCC2
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccc(F)c2cccnc12
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)c2c1NCCC2
Temperature: 0 °C
Yield: 73 %

Procedure:
To an ice-cooled mixture of the 5-fluoro-1,2,3,4-tetrahydroquinolin-8-ylamine and 5-fluoroquinolin-8-ylamine from the previous step (70.4 mg, 0.424 mmol), (S)-2-tert-butoxycarbonylaminopropionic acid (88.3 mg, 0.466 mmol) and HOAt (57.7 mg, 0.424 mmol) in DCM (6 mL) was added EDCI HCl (97.7 mg, 0.51 mmol). The reaction mixture was stirred in the ice bath for 2 h, then diluted with DCM, washed with aqueous Na2CO3 and then water. The organic layer was dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 20-50% EtOAc in cyclohexane) affording the title compound as a purple gum (105 mg, 73%). LCMS (Method B): RT 3.35 min [M+H]+ 338.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].[N:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([N:46]4[CH2:47][CH2:48][N:43]([C:40]5[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=5)[CH2:44][CH2:45]4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCN(c5ccncc5)CC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of 10-(2-methyl-2′-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step F (0.50 g, 1.02 mmol), 1-(4-pyridinyl)-piperazine (0.20 g, 1.23 mmol) and 1-hydroxybenzotriazole monohydrate (0.15 g, 1.11 mmol) in N,N-dimethylformamide (4 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.22 g, 1.15 mmol) followed by N,N-diisopropylethyl amine (0.27 mL, 1.55 mmol). The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification by flash chromatography using a solvent system of 10% methanol in chloroform provided 0.39 g of the title product which was dissolved in dichloromethane and concentrated in vacuo to a white foam.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]1[C:16]2[N:17]([C:21]([CH3:28])=[C:22]([C:24](OC)=[O:25])[N:23]=2)[CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>O1CCCC1>[CH2:7]([O:14][C:15]1[C:16]2[N:17]([C:21]([CH3:28])=[C:22]([CH2:24][OH:25])[N:23]=2)[CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1nc2c(OCc3ccccc3)cccn2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CO)nc2c(OCc3ccccc3)cccn12
Temperature: 3 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled suspension of LiAlH4 (1.03 g) in tetrahydrofuran (THF) (200 ml) there was added 8-benzyloxy-2-methoxycarbonyl-3-methyl-imidazo[1,2-a]pyridine (13.3 g) obtained according to Example VI in several portions over 20 minutes. The temperature was maintained below +8° C. After all the substance hadbeen added, stirring with cooling was continued for 30 min. and thereafter the mixture was stirred at room temperature for another hour. The reactionmixture was cooled to 3° C. and to the stirred mixture there was first added 1.09 ml of water, then 1.63 ml of 10% aqueous NaOH and finally3.27 ml water. The resulting mixture was stirred for 5 min. on the ice bathand 5 min. at room temperature and then filtered. The solid was washed with2×100 ml of hot THF and the wash fluid was added to the original filtrate. The solution was stripped to yield a brown powder which was triturated for 1 hr. in 150 ml CHCl3. After filtration and washing a slightly impure product was obtained (m.p. 172°- 175° C.).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])[CH:8]=[C:7]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=2)=[O:22])[CH:6]=1)(=O)C.C[O-].[Na+].Cl>C1COCC1.CO>[N+:30]([C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:21](=[O:22])[C:7]2[CH:6]=[C:5]([OH:4])[CH:10]=[C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]#[N:20])[CH:8]=2)=[N:25][CH:26]=1)([O-:32])=[O:31]
Reactant: CC(=O)Oc1cc(OCc2ccccc2C#N)cc(C(=O)Nc2ccc([N+](=O)[O-])cn2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccccc1COc1cc(O)cc(C(=O)Nc2ccc([N+](=O)[O-])cn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
A suspension of 3-{[(5-nitropyridin-2-yl)amino]carbonyl}-5-[(2-cyanobenzyl)oxy]phenyl acetate (5710 mg) in THF (35 ml) was treated with 25% NaOMe in methanol (6 ml). Stirred at ambient temperature for 30 minutes. Acidified with 2m hydrochloric acid (25 ml), then extracted with ethyl acetate (100 ml). The extract was washed with water (50 ml), brine (50 ml), dried over MgSO4. Volatile material was removed by evaporation to give a solid. This was washed with hot methanol to give the title compound (4358 mg) as a solid, LCMS rt=2.38 min (90.5%). ES+ 391.45 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33]C(C1N(C)C(C(S(C2C=CC=CC=2)(=O)=O)N)=CC(=O)C=1OCC1C=CC=CC=1)=O>>[CH3:32][NH:33][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])(=[O:19])=[O:20])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:31]
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Reactant: Cn1c(CNS(=O)(=O)c2ccccc2Cl)cc(=O)c(OCc2ccccc2)c1C(=O)O
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2Cl)n1C
Yield: 58.24 %

Procedure:
3-Benzyloxy-6-[(2-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-03) (210.0 mg, 58.24%) was synthesized as a brown solid from 3-benzyloxy-6-[(2-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-03) (350.0 mg, 0.758 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyoxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-01).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[F:14][C:11]1([F:15])[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCC(F)(F)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(F)(F)CC1
Reaction time: 8 h

Procedure:
Allow the solution of (4,4-difluoro-cyclohexyl)-carbamic acid tert-butyl ester in 20 mL of TFA to stand at room temp for overnight. Concentrate the mixture under vacuum. Pass the residue through a SCX column to yield 251 mg of the title product: mass spectrum (m/z): 136 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:41])[C@@H:14]([NH:22][C:23](=[O:40])[C@H:24]([CH2:36][C:37](=[O:39])[NH2:38])[NH:25]C(OCC1C=CC=CC=1)=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:42])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:41])[C@@H:14]([NH:22][C:23](=[O:40])[C@H:24]([CH2:36][C:37](=[O:39])[NH2:38])[NH2:25])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Yield: 84.6 %

Procedure:
A solution of 1.75 g of N-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl] amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester in 100 ml ofethanol was hydrogenated over 10% palladium-on-carbon for 64 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residual gum was partitioned between ethyl acetate and 2M hydrochloric acid. The aqueous phase was made basic with dilute sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate extract was evaporated to give 1.14 g of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester as a white, solid foam; MS: m/e 449 [M+H]+.