Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[C:23]([N+:24]([O-])=O)=[CH:22][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[CH3:27].C1COCC1>CCO.[Pd]>[CH3:27][C:7]1[C:8]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:11][CH2:10][C:9]=2[CH:22]=[C:23]2[NH:24][C:3](=[O:2])[CH2:4][O:5][C:6]=12
Reactant: COC(=O)COc1c([N+](=O)[O-])cc2c(c1C)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c2c(cc3c1OCC(=O)N3)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 2 h
Yield: 77.2 %

Procedure:
To a mixture of 967 mg of t-butyl 7-(2-methoxy-2-oxoethoxy)-6-methyl-8-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 25 ml of EtOH was added 97 mg of 10% palladium on carbon under an argon atmosphere, followed by stirring for 2 hours at normal pressure under a hydrogen atmosphere. To the reaction mixture was added 200 ml of THF, then the catalyst was removed using celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 629 mg of t-butyl 11-methyl-3-oxo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a white solid.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:23][C:24](OC)=[O:25]>CCCCCC.C(O)(=O)C.O1CCCC1>[O:25]=[C:24]([CH2:23][CH2:22][C:18]1[O:17][CH:21]=[CH:20][CH:19]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)CCc1ccco1
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)CCc1ccco1)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 32.8 %

Procedure:
A solution of 25 g (0.21 mole) dimethyl methylphosphonate (Aldrich) in 300 ml. dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 80 ml. of 2.67 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 16.0 g (0.104 mole) methyl 3-(2-furyl)propionate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 3.5 hours at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 6 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ml. water, the aqueous phase extracted with 100 ml. portions of chloroform (3x), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator to a crude residue and distilled, b.p. 148°-50° (0.5 mm) to give 8.4 g dimethyl 2-oxo-4-(2-furyl)butylphosphonate (2C).
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[CH2:29][O:28][CH2:27][C@@H:26]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[Cl:18][C:17]1[C:16]([O:19][CH3:20])=[CH:15][C:14]([O:21][CH3:22])=[C:13]([Cl:23])[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[CH2:29][O:28][CH2:27][C@@H:26]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[N:11]=[CH:10]2
Reactant: CC(C)(C)OC(=O)N[C@H]1COC[C@H]1N
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(Cl)ncc3c2)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4COC[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.4 %

Procedure:
A mixture of 2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazoline (1.02 g, 2.76 mmol), tert-butyl ((3R,4S)-4-aminotetrahydrofuran-3-yl)carbamate (0.85 g, 4.20 mmol), and sodium bicarbonate (0.58 g, 6.90 mmol) was stirred in NMP (5.5 mL, 0.5M) at 95° C. for 12 hours. The reaction was removed from the oil bath and while cooling to room temperature was treated with about 90 mL of water and then sonicated and stirred for 20 minutes. A yellow-orange solid was isolated by filtration, rinsed several times with small amounts of water, and dried under vacuum for nearly 1 hour to yield 3.35 g of crude, which was purified by silica gel chromatography to yield 1.10 g (74.5% yield) of tert-butyl ((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)tetrahydrofuran-3-yl)carbamate as a light yellow foam. MS (ES+) C25H28Cl2N4O5 requires: 534, found: 535 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:3]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([O:1][CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][CH2:5][N:4]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH2:3]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CCc3ccccc3C(O)C2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COc1ccc(OC2CN(S(=O)(=O)c3ccc(C)cc3)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
To a solution of 1-hydroxy-2,3,4,5-tetrahydro-3-(p-toluenesulfonyl)-3-benzazepine (15 g, 47 mmole), p-methoxyphenol (7 g, 57 mmole) and triphenylphosphine (15 g, 57 mmole) in 300 ml benzene, cooled with an ice bath, was slowly dropped a solution of diethyl azodicarboxylate (10 g, 57 mmole) in 100 ml benzene. After stirring two hours at ambient temperature, the reaction mixture was filtered to remove sym-dicarbethoxyhydrazine (8 g, 96%, m.p. 130°-132° C.), then evaporated to an oil which was purified by column chromatography (silica gel, dichloromethane) to give an oil. This oil was crystallized from hexane-ether to give 6 g (30%) of 1-(p-methoxyphenoxy)-2,3,4,5-tetrahydro-3-(p-toluenesulfonyl)-3-benzazepine, m.p. 84°-85° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][CH2:23][NH:22][C:21]2=[O:25])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].[N:32]#[C:33]Br>C(Cl)Cl>[CH3:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:33]#[N:32])[CH2:16][CH2:15]2)=[N:6][CH:5]=[C:4]([N:20]2[CH2:24][CH2:23][NH:22][C:21]2=[O:25])[CH:3]=1
Reactant: N#CBr
Reactant: Cc1cc(N2CCNC2=O)cnc1OCC[C@@H]1C[C@@H]1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(N2CCNC2=O)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(5-methyl-6-{2-[(1S,2R)-2-piperidine-4-ylcyclopropyl]ethoxy}pyridine-3-yl)imidazolidin-2-one (12 mg, 0.035 mmol) in 1.5 mL of DCM was added K2CO3 (14.5 mg, 0.105 mmol, in 0.5 mL of water) at room temperature followed by addition of cyanogen bromide (0.014 mL of 3M soln in DCM, 0.042 mmol) via syringe at room temperature. The mixture was then stirred for 30 min at room temperature and then diluted with 2 mL DCM. The solution was washed with sat'd NaHCO3 aq. soln, separated, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. The crude product was used without further purification. LCMS (ESI) m/z 370 [M+H]+.
Reaction SMILES: C(O[C:5](=[O:22])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C=C.CC1C2C(=CC=CC=2)C(C)=C2C=1C=CC1C2=CC=CC=1.[NH2:43][C:44]1[CH:64]=[CH:63][C:47]([C:48]([NH:50][CH:51]([CH3:62])[C:52]([N:54]2[CH2:58][CH2:57][CH2:56][CH:55]2C(O)=O)=[O:53])=[O:49])=[CH:46][C:45]=1[Cl:65].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.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>[O:12]=[C:10]1[O:9][CH:8]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:7]([NH:6][C:5]([CH:55]2[CH2:56][CH2:57][CH2:58][N:54]2[C:52](=[O:53])[CH:51]([NH:50][C:48](=[O:49])[C:47]2[CH:63]=[CH:64][C:44]([NH2:43])=[C:45]([Cl:65])[CH:46]=2)[CH3:62])=[O:22])[CH2:11]1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1c2ccccc2c(C)c2c1ccc1ccccc12
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a solution of (5-oxo-2-phenethyloxy-tetrahydro-furan-3-yl)-carbamic acid allyl ester (194 mg, 0.54 mmol) (prepared as described for (40) using phenethyl alcohol) in anhydrous CH2Cl2 (5 mL) at 0° C. was added DMBA (196 mg, 1.26 mmol) and Pd(PPh3)4 (32 mg, 0.03 mmol). The solution was stirred for 15 min and a solution of 97a (prepared from 96a by treatment with TFA in CH2Cl2) (166 mg, 0.49 mmol) and DIEA (68011, 3.90 mmol) in CH2Cl2 (2 mL) was added followed by HOBT (98 mg, 0.73 mmol) and EDC (122 mg, 0.63 mmol). The solution was stirred at 0° C. for 15 min then at room temperature for 18 hours. The solvent was removed in vacuo and the residue dissolved in EtOAc then washed with 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine. Dried over anhydrous Na2SO4 and evaporated to give an orange solid which was purified by flash column chromatography, using CH2Cl2/MeOH (99/1 to 97/3%) to yield the title compound as a white solid (190 mg, 73% yield). 1H-NMR (500 MHz, CD3OD) δ 1.29 (d, 0.6H), 1.41 (d, 2.4H), 1.78 (m, 1H), 2.08 (m, 3H), 2.56 (m, 1H), 2.77 (dd, 1H), 2.94 (t, 2H), 3.53 (m, 0.3H), 3.67 (m, 0.8H), 3.85 (m, 2H), 3.96-4.08 (m, 1H), 4.40 (m, 2H), 4.62 (m, 1H), 4.67-4.79 (m, 1H), 5.57 (d, 0.7H), 5.60 (d, 0.3H), 6.78 (dd, 1H), 7.21 (m, 5H), 7.58 (m, 1H), 7.79 (m, 1H), 8.26 (d, 1H). Analytical HPLC 14.52 min. LC-MS (ES+) m/e=543.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2.[CH:16]1(O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:16]1([O:1][C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OC1CCCCC1
Reactant: COc1cc2cc(O)cnc2cc1OC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2cc(OC3CCCCC3)cnc2cc1OC

Procedure:
To a THF solution (30 mL) at 0° C. is added 3-hydroxy-6,7-dimethoxyquinoline (0.237 g, 1.15 mmol), cyclohexanol (0.347 g, 3.46 mmol), Ph3P (0.908 g, 3.46 mmol). Diethylazodicarboxylate is added portionwise until the solution retained a deep red color (0.663 g, 3.81 mmol). After 4 hours the solution is concentrated and the residue chromatographed (50% EtOAc in hexanes). The product is recrystallized from isopropanol/hexanes as the HCl salt as a white solid (m.p. 229-232° C., dec.).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14](O)=[O:15])[N:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:9]=[CH:8]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:49][C@@H:50]([CH2:55][CH2:56][N:57]([CH3:59])[CH3:58])[C:51]([O:53][CH3:54])=[O:52].C(N(CC)CC)C>ClC(Cl)C.ClCCl>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:49][C@@H:50]([CH2:55][CH2:56][N:57]([CH3:59])[CH3:58])[C:51]([O:53][CH3:54])=[O:52])=[O:15])[N:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:9]=[CH:8]2
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)O)cc21
Reactant: COC(=O)[C@@H](N)CCN(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COC(=O)[C@H](CCN(C)C)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Reaction time: 3 h
Yield: 71 %

Procedure:
5-(2,4-Difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (17d; prepared according to Example 110) (0.396 g, 1.14 mmol) was stirred with HOBt (0.192 g, 1.26 mmol) and EDCI (0.241 g, 1.26 mmol) in dichloroethane (2 mL) for 10 minutes at room temperature. This mixture was then added to a suspension of (S)-methyl 2-amino-4-(dimethylamino)butanoate dihydrochloride (0.280 g, 1.20 mmol) and triethylamine (1 mL, 6.9 mmol) in dichloromethane (6 mL). The reaction mixture was stirred for 3 hours and then was concentrated under reduced pressure. The residue was diluted with chloroform (50 mL) and washed with 1N HCl (2×25 mL), saturated K2CO3 (2×50 mL), water (25 mL), brine (25 mL), and dried over MgSO4. The filtered solution was concentrated under reduced pressure to provide yellow oil. The oil was chromatographed eluting with 5% MeOH in dichloromethane to afford a viscous colorless oil that solidified upon drying under high vacuum (0.393 g, 71% yield). MS (ESI+) m/z 489 (M+1) detected; 1H NMR (400 mHz, CDCl3) δ 8.91 (d, 1H), 8.36 (s, 1H), 7.86 (s, 1H), 7.16 (m, 1H), 7.03 (m, 1H), 7.00 (s, 1H), 6.93 (m, 1H), 4.88 (m, 1H), 4.21 (d, 2H), 3.74 (s, 3H), 2.34 (m, 3H), 2.06 (s, 6H), 2.01 (m, 2H), 0.92 (d, 6H).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:23]([O:27][C:28]([N:30]1[CH2:37][C@H:36]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH2:35][C@H:31]1[C:32]([OH:34])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].[N:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[C:47]([NH:55][C:56](=[O:75])[C@@H:57]2[CH2:61][C@@H:60]([NH:62][C:63](=[O:74])[C@H:64]([OH:73])[CH2:65][CH2:66][C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[CH2:59][NH:58]2)[CH:46]=1>ClCCl.C(N(CC)CC)C>[N:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[C:47]([NH:55][C:56](=[O:75])[C@@H:57]2[CH2:61][C@@H:60]([NH:62][C:63](=[O:74])[C@H:64]([OH:73])[CH2:65][CH2:66][C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[CH2:59][N:58]2[C:32](=[O:34])[C@@H:31]2[CH2:35][C@@H:36]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH2:37][N:30]2[C:28]([O:27][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:29])[CH:46]=1
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2cnc3ccccc3c2)C1)[C@H](O)CCc1ccccc1
Reactant: CN(C)CC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CC(=O)N[C@@H]1C[C@@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Triethylamine (33 μL), 1-hydroxybenzotriazole (30 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (46 mg) were added to a suspension of the crude N-tert-butoxycarbonyl-trans-4-(N,N-dimethylglycylamino)-L-proline (B) and trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide (Compound D101 (H), 84 mg) in dichloromethane (5 mL) at 0° C. After stirring at 0° C. for 30 min and at room temperature for 14 hr, the solvent was removed in vacuo. The residue was diluted with saturated sodium hydrogen carbonate and extracted with chloroform-methanol (10:1,v/v). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (Whatman, PLK5F Silica Gel 150, chloroform:methanol=10:1, v/v) to afford the title compound (76 mg) as a colorless glassy solid: mass spectrum (EI+) m/e 715 (M+); (FAB+) m/e 716 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:19][CH2:18][CH2:17][N:8]3[C:9]4[CH:10]=[CH:11][C:12]([OH:16])=[CH:13][C:14]=4[CH:15]=[C:7]3[C:6]2=[O:20])[CH2:3][CH2:2]1.[CH:21]([N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>>[CH:1]1([CH2:4][N:5]2[CH2:19][CH2:18][CH2:17][N:8]3[C:9]4[CH:10]=[CH:11][C:12]([O:16][CH:27]5[CH2:28][CH2:29][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:25][CH2:26]5)=[CH:13][C:14]=4[CH:15]=[C:7]3[C:6]2=[O:20])[CH2:2][CH2:3]1
Reactant: O=C1c2cc3cc(O)ccc3n2CCCN1CC1CC1
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCCN(CC3CC3)C2=O)CC1
Yield: 45 %

Procedure:
The title compound was synthesized in analogy to example 1, from 2-cyclopropylmethyl-9-hydroxy-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one, 1-isopropyl-piperidin-4-ol (commercially available), triphenylphosphine and di-tert-butylazodicarboxylate, to give the desired product as a light yellow solid (45%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C@H:7]1[C@H:11]([N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)[CH2:10][N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][C@H:7]1[C@H:11]([N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)[CH2:10][N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](n2ccnn2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](n2ccnn2)[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Methyl sulfonyl chloride (2.84 g, 24.8 mmole) was added slowly to an ice cooled solution of trans 3-hydroxy-4-(1,2,3-triazol-1-yl)-1-N-(tert.-butoxy carbonyl) pyrrolidine (3.16 g, 12.4 mmol) and triethylamine (4.36 ml, 31.3 mmol) in dry CH2Cl2 (10 ml). The reaction mixture was stirred under N2 at room temperature for 22 hrs and washed with saturated NaHCO3 and brine solution. The dichloromethane layer was dried over Na2SO4 and concentrated to give the title product. Yield 4.0 g (97%). 1H NMR (CDCl3) δ: 1.5 (S, 9H), 3.07 (s, 3H), 4.07 (m, 4H), 5.43 (m, 2H), 7.70 (S, 1H), 7.90 (S, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][CH2:12]O>S(=O)(=O)(O)O>[CH2:11]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[N:3][CH:4]=1)[CH3:12]
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(N)nc1
Yield: 92 %

Procedure:
A solution of 6-aminonicotinic acid (2.0 g, 14.4 mmol) in anhydrous EtOH (70 mL) and concentrated sulfuric acid (14 mL) was heated to reflux for 16 h. The solution was concentrated under reduced pressure, neutralized with saturated aqueous Na2CO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to give 6-aminonicotinic acid ethyl ester (2.18 g, 92%) as a white powder. 1H NMR (CDCl3) δ 1.37 (t, 3H, J=6.0 Hz), 4.34 (q, 2H, J=7.0 Hz), 4.89 (br s, 2H (NH2)), 6.46 (d, 1H, J=7.5 Hz), 8.02 (d, 1H, J=7.5 Hz), 8.73 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([OH:18])=O)[CH3:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([NH:34][CH:31]3[CH2:33][CH2:32]3)=[O:18])[CH3:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: CC(Oc1ncn(-c2cccc(Br)c2)n1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(Oc1ncn(-c2cccc(Br)c2)n1)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Three g of the compound of Example 38 was dissolved in 20 ml of dimethylformamide, 2.4 g of carbonyldiimidazole was added, and the solution was stirred at room temperature for 20 minutes. To it was added 1.1 g of cyclopropylamine, and the mixture was stirred for 16 hours more. It was then poured over ice-water, and the product was collected, dried and recrystallized from ethanol to obtain 2.1 g of the desired product, m.p. 134°-135°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>ClCCl>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)=[O:6]
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(F)c(F)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cc(F)c(F)cc1Br)N1CCOCC1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
2-Bromo-4,5-difluorobenzoic acid (2.00 g, 8.44 mmol), DIPEA (2.18 g, 16.88 mmol) and HATU (3.85 g, 10.13 mmol) were stirred at room temperature for 20 min in dichloromethane (120 mL). Morpholine (0.88 g, 10.13 mmol) was added then the reaction was stirred for 2 hours. The dichloromethane was removed and the resulting residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were passed through a phase separation cartridge and concentrated. The resulting residue was purified via silica gel column chromatography (0-100% ethyl acetate/isohexane) to afford (2-Bromo-4,5-difluorophenyl)(morpholino)methanone (2.5 g, 97%). 1H NMR (400 MHz, CDCl3): δ 7.44 (dd, J=9.42, 6.99 Hz, 1H), 7.14 (dd, J=9.57, 7.88 Hz, 1H), 3.88-3.69 (m, 5H), 3.64-3.57 (m, 1H), 3.33-3.17 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21](O)=[O:22])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.ON1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2N=N1.C(CN)C1C=CC=CC=1.[CH:43]1([N:49]=[C:50]=NC2CCCCC2)CCCCC1>O.CN(C)C=O>[CH2:43]([N:49]([CH3:50])[C:21]([C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH:8]=[C:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])=[CH:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=1)=[O:22])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: On1nnc2ccccc21
Reactant: O=C1NC(=O)C(=Cc2ccc(-c3cccc(C(=O)O)c3)cc2)S1
Agent: NCCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)c1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Reaction time: 18 h
Yield: 60.6 %

Procedure:
500 mg (1.54 mmol) of 4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-carboxylic acid (prepared in Example 23(c)), 5 ml of dimethylformamide, 230 mg (1.7 mmol) of 1-hydroxybenzotriazole and 200 μl (1.5 mmol) of benzylmethylamine are introduced into at three-necked flask under a stream of nitrogen. At 0° C., 350 mg (1.7 mmol) of dicyclohexylcarbodiimide are added portionwise. The mixture is stirred for 18 hours while allowing the temperature to rise. The reaction medium is immersed in water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated. The residue obtained is washed with dichloromethane and filtered. 400 mg (61%) of the desired product are obtained.