Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:5]([C:8](=O)[CH:9](O)O)=[N:6][CH:7]=1.[F:17][C:18]([F:35])([F:34])[C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[C:27]=2[NH2:33])=[N:23][CH:24]=1.C([O-])(O)=O.[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:5]([C:8]2[N:32]=[C:28]3[N:29]=[CH:30][CH:31]=[C:26]([NH:25][C:22]4[CH:21]=[CH:20][C:19]([C:18]([F:35])([F:34])[F:17])=[CH:24][N:23]=4)[C:27]3=[N:33][CH:9]=2)=[N:6][CH:7]=1
Reactant: O=C(c1ncc(Br)cc1C(F)(F)F)C(O)O
Reactant: Nc1nccc(Nc2ccc(C(F)(F)F)cn2)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1ccc(Nc2ccnc3nc(-c4ncc(Br)cc4C(F)(F)F)cnc23)nc1

Procedure:
Dissolve the crude 1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-2,2-dihydroxyethanone (800 mg, step 3) in 16.0 mL of EtOH, and then add N4-(5-(trifluoromethyl)pyridin-2-yl)pyridine-2,3,4-triamine (162 mg, step 5) followed by NaHCO3 (336 mg). Stir the reaction at room temperature for 18 hours under N2 atmosphere. Concentrate the reaction mixture under vacuum, and purify by column chromatography to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-D6) δ 9.405 (s, 1H), 9.287 (s, 1H), 9.127 (s, 1H), 9.109 (d, 1H, J=1.8 Hz), 8.905 (d, 1H, J=1.8 Hz), 8.728 (s, 1H), 8.380 (s, 1H), 7.883 (dd, 1H, J=0.7 Hz), 7.126(d, 1H, J=2.8 Hz). MS=516.85 (M+H). The IC50 determined as described in Example 6 is less than 1 micromolar.
Reaction SMILES: Cl.[CH2:2]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][NH:5][CH2:4][CH2:3]1.ClCCl.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>O>[CH2:2]1[C:7]2([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[CH2:6][N:5]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:4][CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCCN(C(=O)OCc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a 20 L temperature controlled reactor charge tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (2.06 moles; 600.00 g) followed by dichloromethane (6.00 L), then triethylamine (4.33 moles; 604 mL) is added. Set the jacket of the reactor to 0° C. When the temperature of the reaction mixture reaches 5° C., add benzyl chloroformate (2.10 moles; 311 mL) over about 20 minutes keeping the internal temperature below 20° C. When the addition is complete, warm the jacket to room temperature and stir the mixture overnight. Pour the reaction mixture into water (4 L) and separate the mixture. Concentrate the organics under reduced pressure to give the title compound (838 g; assumed 95.65% purity and 100% yield for the purposes of calculation in the next reaction) mass spectrum (m/z): 411.2 (M+23).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:19]=O)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]1([C:37]([OH:39])=[O:38])[CH2:29][CH2:28][N:27]([C:30](OC(C)(C)C)=O)[CH2:26]1.N[C:41]1(C(O)=O)CCN(C(OC(C)(C)C)=O)CC1.C=O>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19][N:24]([CH3:41])[C:25]4([C:37]([OH:39])=[O:38])[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)O)C1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)O)CC1
Agent: C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CCN(C)C1

Procedure:
4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazoline-6-carbaldehyde was coupled with 3-amino-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (commercially available or may be prepared made using analogous methodology as that described for the preparation of 4-amino-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid in J. Org. Chem. 1996, 61, 7650-7651). The resultant product was deprotected and methylated by reaction with aqueous formaldehyde using analogous methods to those described for the equivalent steps in Example 68 to give 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-1-methylpyrrolidine-3-carboxylic acid as a pale yellow foam; Mass Spectrum: (M+H)+ 474.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=[O:5])C.[OH:13][CH2:14][CH2:15][NH2:16]>C(Cl)Cl.CO>[CH3:12][N:9]1[CH2:8][CH2:7][CH:6]([C:4]([NH:16][CH2:15][CH2:14][OH:13])=[O:5])[CH2:11][CH2:10]1
Reactant: NCCO
Reactant: CCOC(=O)C1CCN(C)CC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(C(=O)NCCO)CC1
Temperature: 60 °C
Yield: 52 %

Procedure:
17.1 g. (0.1 mole) 1-Methylpiperidine-4-carboxylic acid ethyl ester (literature: J.A.C.S., 74, 3831/1952). are heated to 60° C. for 48 hours with 9 ml. (0.15 mole) 2-hydroxyethylamine and purified over a silica gel column with methylene chloride/methanol (9:1 v/v). There are obtained 9.5 g. of base in the form of a viscous oil. Yield 52% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=5)[C:33](O)=[O:34])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCN(C5C=CC(C(O)=O)=CC=5)C=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.[CH3:99][N:100]([CH3:104])[CH2:101][CH2:102][NH2:103]>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=5)[C:33]([NH:103][CH2:102][CH2:101][N:100]([CH3:104])[CH3:99])=[O:34])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:41][CH:42]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)O)c3)cn2)cc1
Reactant: CN(C)CCN
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)NCCN(C)C)c3)cn2)cc1
Yield: 68.6 %

Procedure:
Using 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (38.2 mg, 0.0579 mmol) obtained in Step A in Example 1-D-53 instead of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid, and N,N-dimethyl ethylenediamine (15.1 μl, 0.116 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of 3-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-dimethylamino-ethyl)-benzamide as a yellow liquid (29 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-55) as a yellow powder (17.2 mg, 61%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:34])[C:20]([OH:33])([C:25]3[CH:26]=[N:27][C:28]([O:31]C)=[CH:29][CH:30]=3)[C:21]([F:24])([F:23])[F:22])=[C:15]([Cl:35])[CH:14]=2)[CH:9]=[CH:10][C:11]=1[Cl:12])=[O:5])C.Cl.[OH-].[Na+]>O1CCOCC1.O1CCCC1.CO>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:34])[C:20]([OH:33])([C:25]3[CH:30]=[CH:29][C:28](=[O:31])[NH:27][CH:26]=3)[C:21]([F:24])([F:23])[F:22])=[C:15]([Cl:35])[CH:14]=2)=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc(OC)nc3)C(F)(F)F)c(Cl)c2)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: C1CCOC1
Product: CC(c1ccc(-c2ccc(Cl)c(C(=O)O)c2)cc1Cl)C(O)(c1ccc(=O)[nH]c1)C(F)(F)F

Procedure:
In analogy to Example 175, step 6, 4,3′-dichloro-4′-[3,3,3-trifluoro-2-hydroxy-2-(6-methoxy-pyridin-3-yl)-1-methyl-propyl]-biphenyl-3-carboxylic acid ethyl ester (Example 180) was treated first with aqueous HCl in dioxane, followed by aqueous NaOH in tetrahydrofuran/methanol to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=484.1 [M−H+].
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][C:73]([C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)/[C:27]([NH:29][C@@H:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=4)=[O:58])=[C:34]([CH:37]=P(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:92]1[CH:97]=[C:96]([CH:98]=O)[CH:95]=[N:94][CH:93]=1.C(OC(C)C)(C)C.CCCCCC>ClCCl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][C:73]([C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)[C:86]2[CH:87]=[CH:88][CH:89]=[CH:90][CH:91]=2)/[C:27]([NH:29][C@@H:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:62]=[CH:63][C:64]([O:67][CH3:68])=[CH:65][CH:66]=4)=[O:58])=[C:34](/[CH:37]=[CH:98]\[C:96]4[CH:95]=[N:94][CH:93]=[N:92][CH:97]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cncnc1
Reactant: COc1ccc(COC(=O)C2=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Solvent: CC(C)OC(C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(/C=C\c3cncnc3)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1

Procedure:
p-Methoxybenzyl 7β-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(triphenylphosphoranylidene)methyl]-3-cephem-4-carboxylate (4 g) and 5-pyrimidinaldehyde (0.8 g) were stirred for 12 hours in dichloromethane (40 ml). The reaction mixture was concentrated to about 15 ml and then subjected to chromatography on a silica gel column. Relevant fractions were combined and concentrated, whereby an oily matter was obtained. It was added dropwise to a mixed solvent of isopropyl ether (20 ml) and n-hexane (80 ml). The resulting precipitate was collected by filtration, whereby the title compound (1.5 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[N:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:21])=[N:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c[nH]c2ccc(OC)nc2c1=O
Product: CCOC(=O)c1cnc2ccc(OC)nc2c1Cl
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (110.0 g, 407.67 mmol, 1.0 eq) in phosphorus oxychloride (650 mL) is refluxed for 4 hours. Then the reaction mixture is cooled to room temperature and the solvent is evaporated. The residue is poured into ice water and the resulting mixture is basified with 25% ammonium hydroxide to pH=8˜9 and extracted with ethyl acetate (3×500 mL). The combined organic layers are dried over sodium sulfate, filtered and evaporated to give a brown solid as crude product, which is then purified by column chromatography (silica gel, eluent: ethyl acetate:petroleum ether, 1:4, v/v) to afford 4-chloro-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester as a light yellow solid (78 g, 62% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[CH:12]=[C:13]([CH3:15])[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Cl:16][C:17]([Cl:22])([Cl:21])[C:18](Cl)=[O:19]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:11]2[C:12]([C:18](=[O:19])[C:17]([Cl:22])([Cl:21])[Cl:16])=[C:13]([CH3:15])[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc2nc(C)cn12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cccc2nc(C)c(C(=O)C(Cl)(Cl)Cl)n12
Yield: 60.3 %

Procedure:
To a solution of 8.03 g (39.3 mmol) of 5-ethoxycarbonyl-2-methylimidazo[1,2-a]pyridine and 14.41 g (118 mmol) of 4-dimethylaminopyridine in 80 ml of chloroform was added dropwise 21.45 g (118 mmol) of trichloroacetyl chloride. The mixture was heated for 15 hours under reflux. After cooling, the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, drid over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent:ethyl acetate/n-hexane=2:1) to give 8.29 g of the desired compound (60.3%, pale yellow solid).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][CH:39]=[CH:38]5)[CH:35]=[CH:34][CH:33]=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:43])[NH:19][C@:18]2([C:45]([O:47]CC)=[O:46])[CH2:44][C@H:17]2[CH2:16][C:15]([F:51])([F:50])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][CH:39]=[CH:38]5)[CH:35]=[CH:34][CH:33]=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:43])[NH:19][C@:18]2([C:45]([OH:47])=[O:46])[CH2:44][C@H:17]2[CH2:16][C:15]([F:50])([F:51])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4c4ccccc34)CN2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of (2R,6S,13aS,14aR,16aS)-ethyl 6-(tert-butoxycarbonylamino)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclo pentadecine-14a-carboxylate (Example 19c, 320 mg, 0.451 mmol) in tetrahydrofuran (1505 μl), water (752 μl), and ethanol (752 μl) was added lithium hydroxide monohydrate (123 mg, 2.93 mmol) at room temperature The mixture was stirred at room temperature for 16 h and then heated at 37° C. for 6h. The mixture was cooled to room temperature and then eluted through a pad of silica gel with 10% methanol/dichloromethane,and evaporated under reduced pressure. The crude materal was purified by flash chromatography on silica gel (10% methanol/dichloromethane) to provide the title compound (2R,6S,13aS,14aR,16aS)-6-(tert-butoxycarbonylamino)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadeca hydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (215 mg, 70.0% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[F:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]5[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]5)=[O:29])=[CH:26][C:25]=4[F:40])=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1CCC(NC(=O)c2ccc(N)c(F)c2)CC1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)CC(C)O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCCC3)CC3(CC3)C(=O)N4C)c(F)c2)CC1
Temperature: 160 °C

Procedure:
2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 200 mg, 0.62 mmol), 4-amino-3-fluoro-N-(1-methylpiperidin-4-yl)benzamide (Intermediate 65; 157 mg, 0.62 mmol) and p-toluenesulfonic acid monohydrate (296 mg, 1.56 mmol) were suspended in 4-Methyl-2-pentanol (5 mL) and sealed into a microwave tube. The reaction was heated at 160° C. for 30 minutes in the microwave reactor and then allowed to cool to room temperature.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16](O)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[C:8]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.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.[NH2:66][C:67]1([C:72]([NH:74][C:75]2[CH:80]=[CH:79][C:78](/[CH:81]=[CH:82]/[C:83]([O:85]CC)=[O:84])=[CH:77][CH:76]=2)=[O:73])[CH2:71][CH2:70][CH2:69][CH2:68]1>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:66][C:67]4([C:72]([NH:74][C:75]5[CH:76]=[CH:77][C:78](/[CH:81]=[CH:82]/[C:83]([OH:85])=[O:84])=[CH:79][CH:80]=5)=[O:73])[CH2:68][CH2:69][CH2:70][CH2:71]4)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([N:22]([CH3:23])[CH3:24])=[O:21])[C:8]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C/c1ccc(NC(=O)C2(N)CCCC2)cc1
Reactant: COc1ccc(-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2CC(=O)N(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2c(C3CCCCC3)c3ccc(C(=O)NC4(C(=O)Nc5ccc(/C=C/C(=O)O)cc5)CCCC4)cc3n2CC(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 11 %

Procedure:
A solution (0.04 M) of 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-(4 methoxyphenyl)-1H-indole-6-carboxylic acid (from Step 4) in DMF was treated with DIPEA (3 eq.), HATU (2 eq.) and ethyl (2E)-3-(4-{[(1-aminocyclopentyl)carbonyl]amino}phenyl)acrylate (1.1 eq.). The solution was stirred at 25° C. for 12 h. The mixture was diluted with EtOAc then washed sequentially with aqueous HCl (1N), NaOH (2 N) and brine. The dried organic layer was concentrated and the residue dissolved in a solution 1:1 of THF/H2O. The resulting solution was treated with LiOH monohydrate (3 eq.) and stirred at 50° C. for 5 h. The mixture was concentrated under reduced pressure and the residue was treated with aqueous HCl (1 N). Purification by HPLC (stationary phase: Water Symmetry C18 19×300 mm) gave the title compound (11%) as a solid. 1H NMR (400 MHz, DMSO-d6, 300K) δ 1.11-1.40 (m, 3H), 1.62-1.91 (m, 11H), 2.05-2.16 (m, 2H), 2.28-2.44 (m, 2H), 2.50-2.62 (m, 1H), 2.80 (s, 3H), 2.92 (s, 3H), 3.85 (s, 3H), 4.83 (s, 2H), 6.40 (d, J 16.0, 1H), 7.08 (d, J 8.6, 2H), 7.24 (d, J 8.6, 2H), 7.52 (d, J 16.0, 1H), 7.60 (d, J 8.3, 2H), 7.66 (d, J 8.3, 2H), 7.71 (d, J 8.3, 1H), 7.78 (d, J 8.3, 1H), 7.83 (s, 1H), 8.26 (s, 1H), 9.67 (s, 1H), 12.40 (br s, 1H); MS (ES+) m/z 691 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]3[CH2:37][C:36]([CH3:39])([CH3:38])[C:35]3=[O:40])[CH2:24][CH:23]2[OH:41])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]3[CH2:37][C:36]([CH3:38])([CH3:39])[C:35]3=[O:40])[CH2:24][C:23]2=[O:41])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: CC1(C)CN(c2ccccc2N2CCC(NC(=O)C3(NC(=O)c4cc5ccccc5o4)CCCCC3)C(O)C2)C1=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)CN(c2ccccc2N2CCC(NC(=O)C3(NC(=O)c4cc5ccccc5o4)CCCCC3)C(=O)C2)C1=O
Temperature: 0 °C
Reaction time: 10 h
Yield: 86 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-(3,3-dimethylazetidin-2-one-1-yl)phenyl]piperidin-3-ol (0.14 g) obtained in Step 4 in 3 ml of dimethylsulfoxide (DMSO), was added 0.16 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.15 g) was added slowly to the reaction mixture, which was stirred for about 10 hours at room temperature. The reaction mixture was diluted with 20 ml of ethyl acetate, washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was filtered and dried to give 120 mg of the titled compound as white color.
Reaction SMILES: [NH2:1][C:2]1([CH3:17])[C:7](=[O:8])[N:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5](=[O:15])[NH:4][C:3]1=[O:16].C(N1C(=O)C(C)(N2[C:35](=[O:36])[C:34]3[C:29](=[C:30]([F:40])[C:31]([F:39])=[C:32]([F:38])[C:33]=3[F:37])[C:28]2=[O:41])C(=O)NC1=O)C>>[CH:9]1([N:6]2[C:7](=[O:8])[C:2]([CH3:17])([N:1]3[C:28](=[O:41])[C:29]4[C:34](=[C:33]([F:37])[C:32]([F:38])=[C:31]([F:39])[C:30]=4[F:40])[C:35]3=[O:36])[C:3](=[O:16])[NH:4][C:5]2=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Reactant: CC1(N)C(=O)NC(=O)N(C2CCCCC2)C1=O
Product: CC1(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C(=O)NC(=O)N(C2CCCCC2)C1=O

Procedure:
Compound 19h was prepared from 5-amino-1-cyclohexyl-5-methylbarbituric acid (0.36 g, 1.50 mmol) using the same procedure described for 19f. The crude product was recrystallized from EtOH to give 1-cyclohexyl-5-methyl-5-(tetrafluorophthalimido)barbituric acid (19h) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C1C[O:38][CH2:37][CH2:36]1.[CH3:40][CH2:41][O:42][C:43]([CH3:45])=[O:44]>>[CH2:41]([O:42][C:43](=[O:44])[CH2:45][CH2:36][C:37]([NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])=[NH:9])[S:11][C:12]=2[S:32][CH3:33])(=[O:17])=[O:16])[CH:19]=1)=[O:38])[CH3:40]
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Product: CCOC(=O)CCC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Temperature: 50 °C

Procedure:
{[4-(2′-Amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (38.5 mg, 0.07 mmol, Example 25: step c) and 3-chlorocaxbonyl-propionic acid ethyl ester (13 μL, 0.09 mmol) were dissolved into THF (1 mL) and heated to 50° C. for one hour. The reaction was dissolved into EtOAc and washed with brine. The combined organic layers were dried, (MgSO4) and the solvents were removed in vacuo. Purification by preparative TLC (30% EtOAc/hexanes) yielded the title compound. ESI-MS (m/z): Calcd. for C30H35N3O7S3: 646.2 (M+1); found: 645.8.