Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH:21](O)[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:21]([C:14]2[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[CH:18][C:13]=2[F:12])[CH3:22])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cccc(F)c1C(C)O
Reactant: O=[N+]([O-])c1cc(O)ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(F)c1C(C)Oc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-fluoro-3-nitrophenol (this compound was synthesized according to the procedure described in the International publication WO97/39064) (0.2 g), 1-(2-fluoro-6-methoxyphenyl)ethanol (0.22 g) and triphenylphosphine (0.4 g) in tetrahydrofuran (1.5 mL) was added diisopropyl azodicarboxylate (40% toluene solution, 0.84 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=8/1) to give 2-fluoro-5-[1-(2-fluoro-6-methoxy -phenyl)ethoxy]-1-nitrobenzene (0.15 g). This material was dissolved in tetrahydrofuran (3 mL). To the solution were added methanol (3 mL), nickel (II) bromide (5 mg) and sodium borohydride (55 mg) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give the title compound (0.11 g).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:19])[CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:11][C:4]=2[CH:3]=1.C(O)(=O)/C=C\C(O)=O.ClC1[N:34]=[N:33]C2CCNCC=2C=1.C1(C(Cl)=O)CCCCC1>C(O)C>[NH:33]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:19])[CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:11][C:4]=2[CH:3]=1)[NH2:34]
Reactant: Clc1cc2c(nn1)CCNC2
Reactant: O=C(C1CCCCC1)N1CCc2nnc(Cl)cc2C1
Agent: O=C(Cl)C1CCCCC1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: NNc1cc2c(nn1)CCN(C(=O)C1CCCCC1)C2

Procedure:
The 3-chloro-6-hexahydrobenzoyl-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be produced in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and cyclohexanecarboxylic acid chloride. M.P. 144°-146° (decomp., from absolute ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18]3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18]3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNc2ccnc(Nc3cccc(Cl)c3)n2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CC[C@@H](CNc2ccnc(Nc3cccc(Cl)c3)n2)C1
Temperature: 50 °C
Yield: 68 %

Procedure:
To a solution of tert-butyl (3S)-3-[({2-[(3-chlorophenyl)-amino]pyrimidin-4-yl}amino)methyl]pyrrolidine-1-carboxylate, 19, (356 mg, 0.88 mmol) in THF (2 mL) is added lithium aluminum hydride (2 M in THF, 1.32 mL, 2.64 mmol). The reaction is heated to 50° C. for 3 days, cooled to room temperature, quenched with NaOH (1 N, 2 mL) and stirred for an additional hour. The reaction mixture is extracted with EtOAc (2×25 mL) and the combined organic layers are dried (MgSO4), concentrated in vacuo, and purified over silica (MeOH/CH2Cl2) to afford 190 mg (68% yield) of the desired product: 1H NMR (DMSO, 300 MHz) δ 1.40-1.50 (m, 1H), 1.86-1.96 (m, 1H), 2.23 (s, 3H), 2.25-2.33 (m, 1H), 2.34-2.41 (m, 1H), 2.42-2.54 (m, 5H), 5.96 (d, J=5.7 Hz, 1H), 6.89 (dt, J=7.5, 0.9 Hz, 1H), 7.22 (t, J=8.4 Hz, 1H), 7.39 (bs, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.74-7.85 (m, 2H), 8.15 (bs, 1H), 9.21 (s, 1H); HRMS calcd for C16H20ClN5, 318.1485 m/z (M+H)+; observed 318.1485 m/z.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl.Cl[CH2:14][C:15]1[C:16]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:10][C:5]1[CH:6]=[C:7]([C:2]([O:1][CH2:14][C:15]2[C:16]([C:21]3[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=3)=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:3][N:4]=1)[CH:8]=[O:9]
Reactant: Cn1nccc1-c1ncccc1CCl
Reactant: COc1cc(C=O)c(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OCc2cccnc2-c2ccnn2C)cn1
Temperature: 70 °C
Yield: 74.7 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (147 mg, 0.96 mmol, 1 eq.), 3-(chloromethyl)-2-(1-methyl-1H-pyrazol-5-yl)pyridine hydrochloride (236 mg, 0.96 mmol, 1 eq.), and K2CO3 (532 mg, 3.85 mmol, 3 eq.) in DMF (3.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-methoxy-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (232.5 mg, 75%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.77 (dd, J=4.7, 1.7 Hz, 1H), 8.03 (dd, J=7.9, 1.7 Hz, 1H), 7.93 (s, 1H), 7.55 (d, J=1.9 Hz, 1H), 7.44 (dd, J=7.9, 4.8 Hz, 1H), 7.11 (d, J=0.4 Hz, 1H), 6.43 (d, J=1.9 Hz, 1H), 5.20 (s, 2H), 3.97 (s, 3H), 3.92 (s, 3H). LRMS (M+H+) m/z 325.1.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[Br:7][C:8]1[S:9][C:10]2[CH2:11][CH2:12][C:13]3[CH:28]=[CH:27][CH:26]=[CH:25][C:14]=3[C:15](=[C:18]3[CH2:23][CH2:22][N:21](C)[CH2:20][CH2:19]3)[C:16]=2[CH:17]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Br:7][C:8]1[S:9][C:10]2[CH2:11][CH2:12][C:13]3[CH:28]=[CH:27][CH:26]=[CH:25][C:14]=3[C:15](=[C:18]3[CH2:23][CH2:22][N:21]([C:1]([O:2][CH2:3][CH3:4])=[O:5])[CH2:20][CH2:19]3)[C:16]=2[CH:17]=1
Reactant: CN1CCC(=C2c3ccccc3CCc3sc(Br)cc32)CC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(=C2c3ccccc3CCc3sc(Br)cc32)CC1
Yield: 62 %

Procedure:
Ethyl chlorocarbonate (32 mL, 336 mmol) was added to a toluene (200 mL) solution of the compound obtained in Example 1 (21.0 g, 56 mmol), and the mixture was refluxed while heating for 6 hours. The mixture was allowed to cool in the air, and the reaction mixture was added to a saturated aqueous sodium hydrogencarbonate solution to allow the separation of an organic layer. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate, the solvents were then distilled off under a reduced pressure, and the residue was purified by column chromatography (hexane:ethyl acetate=19:1), to give 15.0 g (62%) of the captioned compound in the form of an oily product.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][N:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:38][CH3:39])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:40][N:41]([CH3:46])[CH2:42][C:43](O)=[O:44]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][N:30]5[CH2:35][CH2:34][N:33]([C:43](=[O:44])[CH2:42][N:41]([CH3:46])[CH3:40])[CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:38][CH3:39])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)NN2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CC(=O)O
Product: COc1cc(C(=O)NN2CCN(C(=O)CN(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperazin-1-yl)benzamide using a procedure that is analogous to that described in connection with amide formation except that N,N-dimethylglycine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.89 (m, 10H) 2.19 (s, 6H) 2.89 (br. s., 2H) 2.94 (br. s., 2H) 3.31 (s, 3H) 3.54 (br. s., 2H) 3.63 (br. s., 2H) 3.93 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 4.46 (m, 1H) 7.42 (d, J=8.0 Hz, 1H) 7.44 (s, 1H) 7.91 (s, 1H) 8.21 (s, 1H) 8.28 (d, J=8.33 Hz, 1H) 9.52 (s, 1H). [M+H] calculated for C30H41F2N9O4, 630. found 630.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22]CC)=[O:21])[CH:15]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].Cl>CCO>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:20]([OH:22])=[O:21])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:5])[CH3:6]
Reactant: CCOC(=O)c1cccc(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)O)c2)CC1
Temperature: 40 °C
Yield: 43.5 %

Procedure:
To a solution of 1-Boc-4-[3-(ethoxycarbonyl)phenyl]piperazine (200 mg, 0.6 mmol) in EtOH (1 ml), 2M NaOH (1 ml, 2 mmol) was added. The reaction was heated for 2 hours at 40° C. until HPLC revealed the disappearance of the starting material. The solution was neutralized to pH 7 with aqueous 25% HCl. The precipitate was filtrated and washed with Et2O to afford the desired final compound as beige solid (80 mg, 40%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH:18]3[CH2:23][CH2:22][CH:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19]3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C1COCC1>[C:24]([C@H:21]1[CH2:22][CH2:23][C@H:18]([O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][CH2:9][CH2:10]3)[CH2:19][CH2:20]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OC3CCC(C(C)(C)C)CC3)ccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CCN3)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-(4-tert-butyl-cyclohexyloxy)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.92 g, 2.5 mmol) in THF (10 mL) was added 4 M HCl in dioxane (6 mL, 25 mmol). The mixture was stirred at room temperature for 48 hrs to form white precipitate. This mixture was partitioned between dichloromethane and aqueous sodium bicarbonate, and the organic phase was dried over MgSO4, filtered and concentrated. The crude was purified with a silica gel column eluted with methanol in dichloromethane from 0 to 8% to give precipitate (0.67 g, yield: 99%). ESI-MS: 274.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[O:3][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH:15]=[C:7]1[C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3][C:2]1=[O:1])[CH3:14]
Reactant: Cc1cc(=O)cc(O)o1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC1=CC(=O)C(=CN(C)C)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75340.3 %

Procedure:
A suspension of 2-hydroxy-6-methyl-4H-pyran-4-one (23.92 g, 0.189 mmol) and dimethylformamide dimethyl acetal (45.2 mL, 0.34 mmol) in toluene (100 mL) was stirred at room temperature for 4 hours and concentrated to provide 25.8 g (75%) of the desired product of sufficient purity for subsequent use. MS (DCI/NH3) m/z 182 (M+H)+; 1H NMR (CDCl3) δ 8.22 (s, 1H), 5.67 (s, 1H), 3.47 (s, 3H), 3.39 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(O[C:13]([N:15](C)[C@@H:16]([CH3:53])[C:17]([NH:19][C@H:20]1[C:26]2([CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[O:25][C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[N:22]([CH2:36][C:37]2[C:46]([O:47][CH3:48])=[CH:45][CH:44]=[C:43]3[C:38]=2[CH:39]=[CH:40][C:41]([C:49]([OH:51])=[O:50])=[CH:42]3)[C:21]1=[O:52])=[O:18])=O)(C)(C)C>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH3:48][O:47][C:46]1[C:37]([CH2:36][N:22]2[C:21](=[O:52])[C@@H:20]([NH:19][C:17](=[O:18])[C@@H:16]([NH:15][CH3:13])[CH3:53])[C:26]3([CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[O:25][C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]2=3)=[C:38]2[C:43](=[CH:44][CH:45]=1)[CH:42]=[C:41]([C:49]([OH:51])=[O:50])[CH:40]=[CH:39]2
Reactant: COc1ccc2cc(C(=O)O)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C2(CCOCC2)Oc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3cc(C(=O)O)ccc23)c2ccccc2OC12CCOCC2
Reaction time: 1 h
Yield: 83.1 %

Procedure:
TFA (0.2 mL, 56.4 μmol, Eq: 1.00) was added to a solution of 5-(((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-5 (4H)-yl)methyl)-6-methoxy-2-nap hthoic acid (36.5 mg, 56.4 μmol, Eq: 1.00) in DCM (1 mL). After 1 h, the mixture was concentrated, the residue dissolved in MeCN/H2O, and lyophilized to afford the title compound (31.0 mg, 83%) as an off-white solid. MS m/z 548.4 (MH+)
Reaction SMILES: Br[C:2]1[C:3]([F:25])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[NH:22][N:21]=[C:20]([CH3:23])[CH:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:24]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C@:32]([OH:36])([C:34]#[CH:35])[CH3:33])[N:28]=1>>[F:25][C:3]1[C:2]([C:35]#[C:34][C@@:32]([OH:36])([C:29]2[N:28]=[C:27]([CH3:26])[O:31][N:30]=2)[CH3:33])=[CH:24][C:6]2[C:7]3[N:8]([C:12]([C:18]4[NH:22][N:21]=[C:20]([CH3:23])[CH:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: Cc1cc(-c2c(C(N)=O)nc3n2CCOc2cc(F)c(Br)cc2-3)[nH]n1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Product: Cc1cc(-c2c(C(N)=O)nc3n2CCOc2cc(F)c(C#C[C@@](C)(O)c4noc(C)n4)cc2-3)[nH]n1

Procedure:
10-bromo-9-fluoro-3-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2-tert-butoxycarbonyl-5-methyl-pyrazol-3-yl)boronic acid similarly to as described in Example 4 to produce crude 10-bromo-9-fluoro-3-(3-methyl-1H-pyrazol-5-yl)-5,6dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide. 10-bromo-9-fluoro-3-(3-methyl-1H-pyrazol-5-yl)-5,6dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 5.8 mg (6.6%) 9-fluoro-10-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]-3-(3-methyl-1H-pyrazol-5-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase purification. M+1=478.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1>>[CH:32]1([NH:36][C:24]([C:7]2[C:6](=[O:29])[N:5]([CH2:4][C:3]([N:2]([CH3:31])[CH3:1])=[O:30])[C:14]3[C:9]([C:8]=2[OH:23])=[N:10][CH:11]=[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:13]=3)=[O:25])[CH2:35][CH2:34][CH2:33]1
Reactant: NC1CCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NC2CCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclobutylamine employing methods similar to those described in Example 245. The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.34 (1H, br), 8.49 (1H, br), 7.77 (1H, br), 7.30 (2H, m), 7.12 (2H, t, J=8.8 Hz), 5.10 (2H, br s), 4.39 (1H, m), 4.09 (2H, br s), 3.11 (3H, s), 2.81 (3H, s), 2.27 (2H, m), 1.99 (2H, m), 1.70 (2H, m); HRMS calcd for C24H25FN4O4+H+: 453.1938. Found: 453.1937.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[CH2:22](O)[CH3:23]>>[CH2:22]([O:19][C:18](=[O:20])[C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[NH2:17])[CH3:23]
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To Nε-carbobenzoxy-L-lysine (69.7 g) was added ethanol (1000 ml) which had been saturated with anhydrous hydrogen chloride. The resulting solution was stirred at room temperature for three days. Ethanol was evaporated in vacuo and the residue was taken up in chloroform (500-600 ml). The chloroform was washed twice with saturated aqueous sodium bicarbonate, filtered and evaporated to afford the desired product as a colorless oil (69.9 g).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:19]([C:22]1[C:34]([NH2:35])=[C:33]([CH:36]([CH3:38])[CH3:37])[C:25]2[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:24]=2[CH:23]=1)([CH3:21])[CH3:20]>C1(C)C=CC=C(C)C=1>[CH:19]([C:22]1[C:34]([N:35]2[CH2:2][CH2:3][N:4]=[C:5]2[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:33]([CH:36]([CH3:38])[CH3:37])[C:25]2[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:24]=2[CH:23]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1cc2c(oc3ccccc32)c(C(C)C)c1N
Reactant: O=C(NCCCl)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1cccc(C)c1
Product: CC(C)c1cc2c(oc3ccccc32)c(C(C)C)c1N1CCN=C1c1ccccc1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
N-(2-chloroethyl)benzamide (4.12 g, 22.44 mmol) and phosphorous pentachloride (7.01 g, 33.7 mmol) were refluxed in m-xylene under nitrogen for 2 h. The reaction mixture was cooled to room temperature. To the reaction was then added 2,4-diisopropyldibenzo[b,d]furan-3-amine (6 g, 22.44 mmol). The reaction was refluxed for 16 h. After cooled to room temperature, the precipitate was collected by filtration, and washed thoroughly with toluene and hexanes. Sodium hydroxide solution was added to the solid and then ethyl acetate. The organic layer was separated and dried over MgSO4. The solvent was evaporated. 7.4 g (83% yield) of product was obtained.
Reaction SMILES: [C:1]1(=[O:16])[N:5]([CH2:6][CH2:7][CH2:8][CH:9]=O)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[CH3:17][O:18][C:19](=[O:40])[CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:40])[CH:20]=[CH:9][CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]2[C:1]1=[O:16]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Product: COC(=O)C=CCCCN1C(=O)c2ccccc2C1=O
Yield: 95.8 %

Procedure:
4-Phthalimidobutanal (120.9 g, 556 mmol) was then dissolved in 600 ml of CH2Cl2 and treated with methyl(triphenylphosphoranylidene)acetate (186 g, 556 mmol) in 600 ml of CH2Cl2. After 1 h the mixture was concentrated in vacuo and chromatographed in seven equal portions (Merck Kieselgel 60; 7×14 cm column; eluent 30% ethyl acetate in hexane) to give 145.6 g (96%) of methyl-6-phtalimidohex-2-enoate as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20]([OH:22])=O)=[CH:11][C:12]3[N:16](C)[CH:15]=[N:14][C:13]=3[C:18]=2[F:19])=[C:4]([Cl:23])[CH:3]=1.C1C=CC2N(O)N=[N:30][C:28]=2C=1.C(N(CC)CC)C.CN.CCN=C=NCCCN(C)C>CN(C)C=O.C(OCC)(=O)C.O>[CH3:28][NH:30][C:20]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[Cl:23])=[C:18]([F:19])[C:13]2[N:14]=[CH:15][NH:16][C:12]=2[CH:11]=1)=[O:22]
Reactant: On1nnc2ccccc21
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid 10c (0.029 g, 0.076 mmol) is dissolved in N,N-dimethylformamide (1.1 mL). HOBT (0.016 g, 0.10 mmol), triethylamine (0.028 mL, 0.20 mmol), methylamine (0.059 mL, 0.12 mmol, 2 M solution in tetrahydrofuran), and EDCI (0.019 g, 0.10 mmol) are added consecutively to the reaction mixture at room temperature. The solution is stirred at room temperature for 16 hours under N2. The reaction mixture is poured into a separatory funnel and diluted with ethyl acetate and water and the layers separated. The ethyl acetate layer is washed successively with aqueous saturated NH4Cl (2×), brine (1×), aqueous saturated sodium bicarbonate (2×), water (1×), and brine (1×), dried (MgSO4) and concentrated under reduced pressure. The resulting solid is purified by FCC (eluting with 19:1 methylene chloride:methanol) to yield 0.013 g (42%) of the pure desired product. MS APCI (+) m/z 397, 399 (M+, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (broad s, 1H), 8.69 (m, 1H), 8.41 (s, 1H), 7.76 (s, 1H), 7.63 (d, 1H), 7.30 (dd, 1H), 6.50 (dd, 1H), 2.76 and 2.75 (s and s, 3H total, amide rotamers). 19F NMR (376 MHz, DMSO-d6) −132.69 (s).
Reaction SMILES: CN1CCOCC1.[Cl-].[C:9]([C:12]1([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][NH+:26]=3)=[CH:21][CH:20]=2)[CH2:16][CH2:15][C:14](=[O:17])[NH:13]1)([OH:11])=O.[Cl-].[Na+].[NH2:34][CH2:35][CH:36]([OH:43])[CH2:37][C:38]([CH3:42])([CH3:41])[CH2:39][CH3:40].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][C:12]3([C:9]([NH:34][CH2:35][CH:36]([OH:43])[CH2:37][C:38]([CH3:42])([CH3:41])[CH2:39][CH3:40])=[O:11])[CH2:16][CH2:15][C:14](=[O:17])[NH:13]3)=[CH:24][CH:23]=2)=[N:26][CH:27]=1
Reactant: CCC(C)(C)CC(O)CN
Reactant: O=C1CCC(Cc2ccc(-c3ccc(F)c[nH+]3)cc2)(C(=O)O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(C)(C)CC(O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CCC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-methylmorpholine (0.37 mL, 3.32 mmol) was added to an ambient temperature solution of 2-{4-[(2-carboxy-5-oxopyrrolidin-2-yl)methyl]phenyl}-5-fluoropyridinium chloride/sodium chloride (1:3) (388 mg, 0.74 mmol), 1-amino-4,4-dimethylhexan-2-ol (214 mg, 1.48 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (170 mg, 0.89 mmol) and 1-hydroxybenzotriazole (136 mg, 0.89 mmol) in methylene chloride (5 mL). After stirring at ambient temperature overnight, the reaction mixture was poured into ethyl acetate and washed successively with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated in vacuo to afford 2-[4-(5-fluoropyridin-2-yl)benzyl]-N-(2-hydroxy-4,4-dimethylhexyl)-5-oxopyrrolidine-2-carboxamide which was used in the subsequent step without further purification.