Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]([NH2:7])[N:2]=1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:1]1[CH:6]=[CH:5][N:4]=[C:3]([NH:7][C:9]2[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[CH:14]=2)[N:2]=1
Reactant: Nc1nccnn1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2nccnn2)c1=O
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 40 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (100 mL), 1,2,4-triazin-3-amine (1.5 g, 15.6 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (4.2 g, 15.6 mmol), Pd2(dba)3 (458 mg, 1.56 mmol), XantPhos (1.8 g, 3.12 mmol), and cesium carbonate (10 g, 31.2 mmol). After three cycles of vacuum/argon flush, the mixture was stirred at 90° C. for 2.5 h. After this time the reaction was filtered and the filtrate was evaporated in vacuo. The resulting residue was recrystallized from ethyl acetate to afford 172a as a yellow solid (1.76 g, 40%). MS-ESI: [M+H]+ 282.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:34][C:35]=2[CH3:36])=[CH:24][CH:23]=1)(=[O:21])=[O:20])C(OC(C)(C)C)=O.[OH-].[Na+]>O1CCOCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[C:5]([NH:11][S:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][C:31]3[N:32]=[C:33]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[O:34][C:35]=3[CH3:36])=[CH:26][CH:27]=2)(=[O:20])=[O:21])[CH:6]=1
Reactant: COC(=O)c1ccc(Cl)cc1N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(S(=O)(=O)Nc2cc(Cl)ccc2C(=O)O)cc1
Temperature: 90 °C

Procedure:
A solution of the title G compound, 4-chloro-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl-(t-butoxycarbonyl)amino}-benzoic acid methyl ester (300 mg, 0.48 mmol) in dioxane (5 mL) to which 2.4 mL of 1 N aqueous NaOH is added is heated at 90° C. for 3 h. The mixture is concentrated under vacuum, acidified with 1 N aqueous HCl, and extracted twice with EtOAc. The organic solution is dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude product which is triturated with DCM. The solid is collected by filtration to afford 4-chloro-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl-amino}-benzoic acid: m.p. 223-225° C.; ESI-MS 513 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].BrN1C(=O)CCC1=O.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[K]>C(Cl)(Cl)(Cl)Cl.[Cl-].[Na+].O.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:23]1(=[O:33])[N:27]([CH2:1][C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)c1cc(C)ccc1[N+](=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(CN2C(=O)c3ccccc3C2=O)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h
Yield: 130.6 %

Procedure:
A mixture of methyl 5-methyl-2-nitrobenzoate (35.0 g, 179 mmol), N-bromosuccinimide (33.5 g, 188 mmol), and azobisisobutyronitrile (500 mg) in carbon tetrachloride (450 mL) was refluxed for 14 h. The insoluble material formed was removed by filtration and the filtrate was concentrated. The residue was dissolved in DMF (300 mL) and potassium phthalimide (19.41 g, 45 mmol) was added. The mixture was stirred for 2 h at 50° C., poured into brine, and extracted with a 1:1 mixture of toluene and ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 4:1 to 2:1 hexane/ethyl acetate to give 20.0 g of the title compound (33%).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C@@H:20]([OH:33])[CH2:21][C@@H:22]([C:27]([CH2:31][CH3:32])([OH:30])[CH2:28][CH3:29])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[O:41]1[CH2:46][CH2:45][N:44]([CH2:47][C:48]([NH:50][C@H:51](C(O)=O)[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:49])[CH2:43][CH2:42]1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>>[O:41]1[CH2:42][CH2:43][N:44]([CH2:47][C:48]([NH:50][C@H:51]([C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:34][CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)[C@@H:20]([OH:33])[CH2:21][C@@H:22]([C:27]([CH2:28][CH3:29])([OH:30])[CH2:31][CH3:32])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:7])[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:49])[CH2:45][CH2:46]1
Reactant: CCC(O)(CC)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(=O)NC
Reactant: O=C(CN1CCOCC1)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CCC(O)(CC)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CN1CCOCC1)C(=O)NC
Yield: 80 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 100 mg (0.17 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-ethyl-1-hydroxypropyl)-N-methylhexanamide [prepared as described in Example 18(a)], 55 mg (0.19 mmoles) of N-morpholinoacetyl-L-phenylalanine, 0.03 ml (0.20 mmoles) of diethyl cyanophosphate, and 0.08 ml (0.57 mmoles) of triethylamine were used, to obtain 103 mg (yield 79%) of the title compound as a white amorphous substance.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH2:15]([C@H:17]1[CH2:22][O:21][CH2:20][C@H:19]([CH3:23])[NH:18]1)[CH3:16]>C1COCC1>[CH2:15]([C@@H:17]1[N:18]([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=3)[N:6]=2)[C@@H:19]([CH3:23])[CH2:20][O:21][CH2:22]1)[CH3:16]
Reactant: CC[C@H]1COC[C@H](C)N1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Solvent: C1CCOC1
Product: CC[C@H]1COC[C@H](C)N1c1nc2c(C(=O)OC)cccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (750 mg, 3.54 mmol) and (3S,5S)-3-ethyl-5-methylmorpholine (1.00 g, 7.75 mmol) in THF (40 mL) was stirred at ambient temperature overnight. Then the reaction mixture was heated in a 50° C. oil bath for 4.5 h. The reaction mixture was cooled to ambient temperature and most of the THF was removed under reduced pressure. The residue was dissolved in EtOAc (150 mL) and washed with 0.5 N HCl (25 ml), H2O (25 mL), brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, hexanes to 10% EtOAc in hexanes) to give methyl 2-((3S,5S)-3-ethyl-5-methylmorpholino)benzoxazole-4-carboxylate (540 mg, 50%), as a colorless oil. 1H NMR consistent.
Reaction SMILES: [O:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH2:18]Br)[C:12]([NH2:14])=[O:13])[Si](C(C)(C)C)(C)C.[OH2:20]>CC#N.[F-].[K+]>[OH:1][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH2:18][OH:20])[C:12]([NH2:14])=[O:13]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C(N)=O)ccc1CBr
Reactant: O
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1ccc(CO)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of 3-t-butyldimethylsiloxy-4-bromomethylbenzamide (Compound 7.2) (0.101 g, 0.293, mmol) in 8 mL CH3CN, KF.2H2O (0.041 g, 0.44 mmol) in 4 mL H2O was added dropwise. The mixture was then stirred at room temperature for half hour. After the solvent was removed, the residue was absorbed on 500 mg silica gel. The product was obtained by flash chromatography (ethyl acetate:ethyl alcohol=10:1, Rf=0.8) as a white solid (0.0439 g, y==90.7%). 1H NMR (CD3CN) δ4.68(s,2H), 5.95(b,1H), 6.69(b,1H), 7.23-7.26(m,3H), 7.77(b,1H); 13C NMR (CD3Cl) δ60.66, 115.13, 119.44, 128.69, 133.07, 134.94, 156.10, 203.64.
Reaction SMILES: FC1C=C(O)C=CC=1C(OC(CCCCCC)C(F)(F)F)=O.C(OC1C=C[C:35]([C:38]2C=C[C:41]([C:44]([O:46][C:47]3[CH:52]=[CH:51][C:50]([C:53]([O:55]C(CCCCCC)C(F)(F)F)=[O:54])=[C:49](F)[CH:48]=3)=O)=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)CCCCCCC>O1CCCC1>[CH2:44]([O:46][C:47]1[CH:48]=[CH:49][C:50]([C:53]([OH:55])=[O:54])=[CH:51][CH:52]=1)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:35][CH2:34][CH3:33]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)OC(CCCCCC)C(F)(F)F)c(F)c3)cc2)cc1
Agent: CCCCCCC(OC(=O)c1ccc(O)cc1F)C(F)(F)F
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(=O)O)cc1

Procedure:
To a solution of the 1,1,1-trifluoro-2-decyl-6-hydroxynaphthalene-2-carboxylate (0.5 g) obtained in (1) above, the 4-n-octyloxybenzoic acid (0.4 g) obtained in (2) above in tetrahydrofuran (40 ml) were added dicyclohexylcarbodiimide (0.45 g) and dimethylaminopyridine (0.05 g). The solution was stirred at room temperature overnight. The solution was distilled to remove the solvent. The residue was dissolved in dichloromethane (50 ml) and the solution was washed with dilute aqueous hydrochloric acid solution and water in this order. The organic layer collected was dried over anhydrous magnesium sulfate, and distilled to remove the solvent. The residue was purified by silica-gel column chromatography (developer: hexane/ethyl acetate=20/1) to obtain the titled compound (0.39 g) having specific rotation, [α]DD20 =+45.79°.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:8]=[C:9]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=2)[O:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH2:3]1.Cl.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]([NH2:34])[CH3:33])=[CH:28][C:27]=1[O:35][CH3:36]>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]([NH:34][CH:6]2[CH2:2][CH2:3][C@@H:4]([C:7]3[CH:8]=[C:9]([CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=3)[O:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:5]2)[CH3:33])=[CH:28][C:27]=1[O:35][CH3:36]
Reactant: CCOC(=O)COc1cc([C@@H]2CCC(=O)C2)cc(C(F)(F)F)c1
Reactant: COc1cc([C@@H](C)N)ccc1F
Agent: Cl
Product: COc1cc([C@@H](C)NC2CC[C@@H](c3cc(OCC(=O)O)cc(C(F)(F)F)c3)C2)ccc1F

Procedure:
General procedure A was followed using ethyl 2-[3-[(1R)-3-oxocyclopentyl]-5-(trifluoromethyl)phenoxy]acetate as the ketone and (R)-1-(4-fluoro-3-methoxyphenyl)-ethylamine hydrochloride as the amine. The resulting mixture of isomeric esters was purified and separated by flash chromatography (gradient of 0-80% EtOAc in heptane containing 2.5% NEt3). The faster eluting peak was isolated and subjected to hydrolysis following general procedure B to afford the title compound. 1H NMR (300 MHz, DMSO) δ 7.40 (d, J=8.5 Hz, 1H), 7.17 (dd, J=11.4, 8.3 Hz, 1H), 7.11-6.97 (m, 3H), 6.94 (s, 1H), 4.46 (dd, 2H), 4.10 (q, 1H), 3.84 (s, 3H), 3.16-2.86 (m, 2H), 2.21-2.07 (m, 1H), 1.94-1.58 (m, 5H), 1.45 (d, J=6.6 Hz, 3H).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:31]=[CH:30][C:11]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:20])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.[O:32]1[CH2:34][C@H:33]1[CH2:35][O:36][C:37]1[C:45]2[NH:44][C:43](=[O:46])[NH:42][C:41]=2[CH:40]=[CH:39][CH:38]=1>C(Cl)(Cl)Cl.CO>[CH2:22]([NH:21][C:19]([N:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][NH:4][CH2:34][C@H:33]([OH:32])[CH2:35][O:36][C:37]3[C:45]4[NH:44][C:43](=[O:46])[NH:42][C:41]=4[CH:40]=[CH:39][CH:38]=3)=[CH:31][CH:30]=2)[CH2:18][CH2:17]1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(OCCN)cc2)CC1
Reactant: O=c1[nH]c2cccc(OC[C@@H]3CO3)c2[nH]1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=CO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(OCCNC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)cc2)CC1
Yield: 19.4 %

Procedure:
4-[4-(2-Aminoethoxy)anilino]-N-octyl-1-piperidinecarboxamide formate (0.32 g, 0.733 mmol) was reacted with 4-[(2S)oxiranylmethoxy]-1,3-dihydro-2H-benzimidazol-2-one (0.151 g, 0.732 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.085 g, 0.142 mmol).
Reaction SMILES: [H-].[Na+].[C:3]([N:5]=[C:6]1[NH:10][CH2:9][CH2:8][N:7]1[CH2:11][CH3:12])#[N:4].O1[CH:19]2[CH:14]1[C:15]([CH3:27])([CH3:26])[O:16][C:17]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:18]=12>CS(C)=O>[C:3]([N:5]=[C:6]1[N:7]([CH2:11][CH3:12])[CH2:8][CH2:9][N:10]1[C:19]1[C:18]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:17]=2[O:16][C:15]([CH3:27])([CH3:26])[CH:14]=1)#[N:4]
Reactant: CCN1CCNC1=NC#N
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCN1CCN(C2=CC(C)(C)Oc3ccc(C#N)cc32)C1=NC#N
Temperature: 40 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
60% Dispersion of sodium hydride (0.40 g) in mineral oil was added in small portion at ambient temperature to a solution of 2-cyanoimino-1-ethylimidazolidine (1.38 g) in dimethyl sulfoxide (15 ml). The reaction mixture was stirred for 30 minutes at the same temperature, and 3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1.01 g) was added thereto. The reaction mixture was stirred overnight at the same temperature, heated for 1.5 hours at 40° C., and then poured into ice-water (50 ml). The forming precipitate was collected by filtration, and washed with water. The product was recrystallized from ethanol to give 4-(2-cyanoimino-3-ethylimidazolidin-1-yl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.36 g).
Reaction SMILES: [Br:1][C:2]1[C:13](=[O:14])[N:12]([CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH:23]2[CH2:25][CH2:24]2)[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl>[Br:1][C:2]1[C:13](=[O:14])[N:12]([CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH:23]2[CH2:25][CH2:24]2)[C:5]2[N:6]=[C:7]([S:10]([CH3:11])=[O:34])[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: CSc1ncc2cc(Br)c(=O)n(Cc3c(F)cccc3C3CC3)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ncc2cc(Br)c(=O)n(Cc3c(F)cccc3C3CC3)c2n1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution of 6-bromo-8-(2-cyclopropyl-6-fluorobenzyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (8, 500 mg, 1.2 mmol) in dichloromethane (20 mL) was added 3-chloroperbenzoic acid (77%, 253 mg, 1.1 mmol) in dichloromethane (15 mL) at 0-5° C. and the mixture was stirred at 0-5° C. for 1 h. The reaction mixture was washed with saturated sodium bicarbonate solution (2×30 mL) then with brine (30 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography eluting with chloroform to yield the title compound as a white solid (385 mg, 0.9 mmol, 74%). ESMS m/z 436 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20][CH3:21])[CH:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][C:26](=[O:32])[NH:27]2>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=[N:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:24]=2[CH2:25][C:26](=[O:32])[NH:27]3)=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(Br)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2c1CC(=O)N2
Solvent: CC(=O)O
Product: COc1cc(Br)ccc1C(C)(C)CC(O)(C=Nc1cccc2c1CC(=O)N2)C(F)(F)F
Yield: 58.2 %

Procedure:
300 mg (0.812 mmol) of 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is stirred in 1.5 ml of glacial acetic acid with 120.4 mg (0.812 mmol) of 4-amino-1,3-dihydroindol-2-one over a weekend at room temperature. The reaction mixture is evaporated until a dry state is reached, and the residue is put on a Flashmaster column. 235.9 mg (58.1%) of the desired imine is isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH:12]=[CH2:13])[CH:3]=1.Br[CH2:15][C:16]1[C:17](Cl)=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=1.C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[C:9]([N:8]1[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH:12]=[CH:13][C:17]2[N:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=2[CH2:15]1)(=[O:11])[CH3:10]
Reactant: C=Cc1cc(Cl)ccc1NC(C)=O
Reactant: Clc1ccc(CBr)c(Cl)n1
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2ccc(Cl)nc2C=Cc2cc(Cl)ccc21

Procedure:
The title compound was prepared from 9B and 13B by a route analogous to that used for the preparation of 1D. HPLC Rt=2.842 min; LCMS Found: (M+H)+=319.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:24]=[CH:23][C:8]([CH2:9][O:10][C:11](=[O:22])[CH2:12][CH2:13][C:14](=[O:21])[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[CH:7][CH:6]=1.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1.[Cl-].[Zn+2].[Cl-].CCCCCC>[OH:21][CH:14]([CH2:13][CH2:12][C:11]([O:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:24][CH:23]=1)=[O:22])[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16]
Reactant: C=CCOC(=O)C(=O)CCC(=O)OCc1ccc(OC)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C(O)CCC(=O)OCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.1 %

Procedure:
Zinc chloride (1.0 M diethyl ether solution; 8.8 ml, 8.8 mmol) was added to tetrahydrofuran (5 ml), and sodium borohydride (605.3 mg, 16.0 mmol) was added thereto with stirring at 0° C. The mixture was irradiated with ultrasonic waves for 10 minutes using a commercially available ultrasonic cleaner. The mixture was taken out of the ultrasonic cleaner and cooled to −5° C., and a solution of allyl 5-[(4-methoxybenzyl)oxy]-2,5-dioxopentanoate (1.84 g, 6.0 mmol) obtained from Example 2-(1) in tetrahydrofuran (5 ml) was added thereto over a period of 10 minutes. The resulting mixture was stirred for 30 minutes, and then a saturated aqueous solution of ammonium chloride was added thereto to stop the reaction followed by extraction of the product with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure to afford an oily residue. The residue was subjected to chromatography on a silica gel (65 g) column (eluent; ethyl acetate:hexane=3:10˜2:5) to afford the title compound (1.26 g, 68% yield) as a colorless oil.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:27])[NH:6][C:7]1[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][OH:26])[CH:18]=2)[N:9]=[C:10]([C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[CH:11]=1.[CH3:30][C@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:37]1[N:41]2[CH:42]=[C:43]([O:46][C@H:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C@@H:50]([NH2:57])[CH2:49][CH2:48]3)[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1.C[C@H]1CCC[C@@H](C)N1C1N2C=C(O[C@H]3C4C(=CC=CC=4)[C@@H](NC(=O)NC4N(C5C=NN(CCOS(C)(=O)=O)C=5)N=C(C(C)C)C=4)CC3)C=CC2=NN=1>>[C:15]([C:12]([CH3:14])([CH3:13])[C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:57][C@@H:50]2[C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[C@H:47]([O:46][C:43]3[CH:44]=[CH:45][C:40]4[N:41]([C:37]([N:32]5[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]5[CH3:30])=[N:38][N:39]=4)[CH:42]=3)[CH2:48][CH2:49]2)=[O:27])[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][OH:26])[CH:18]=2)[N:9]=1)#[N:16]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C#N)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCO)c2)n1
Agent: CC(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C#N)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12

Procedure:
The title compound was prepared using Intermediate 20e and Intermediate 2 in an analogous fashion to the procedure described for Intermediate A step d. LCMS (Method 3): Rt 3.39 min, m/z 690.4 [MH+].
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[C:11]([OH:13])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:40][CH2:41][C:42]([NH:44][CH2:45][CH:46]1[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]1)=[O:43].[OH-].[Na+]>C(Cl)(Cl)Cl>[NH2:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[C:11]([NH:40][CH2:41][C:42]([NH:44][CH2:45][CH:46]1[CH2:47][CH2:48][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:50][CH2:51]1)=[O:43])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)CN)CC1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)c2cc(Cl)ccc2N)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.75 mL, 5.4 mmol), 2-amino-5-chlorobenzoic acid (840 mg, 4.9 mmol), EDCI (940 mg, 4.9 mmol) and HOBt (660 mg, 4.9 mmol) were added to a chloroform (25 mL) solution of 4-[(glycylamino)methyl]-1-(tert-butoxycarbonyl)piperidine (1.33 g, 4.90 mmol). The resulting mixture was stirred at room temperature for 3 hours, and a 2 M aqueous solution of NaOH (20 mL) was then added to the mixture. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by column chromatography (SiO2, ethyl acetate) to thereby provide 4-[[(N-(2-amino-5-chlorobenzoyl) glycyl)amino]methyl]-1-(tert-butoxycarbonyl)piperidine as a solid (1.63 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.CCO>[Pd].CCOC(C)=O>[NH2:12][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([Cl:1])[CH:3]=1)[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: O=C1Cc2cc([N+](=O)[O-])cc(Cl)c2N1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(Cl)c2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-chloro-5-nitro-1,3-dihydro-2H-indol-2-one (6.1 g, 28.7 mmol) from Step 1 of this example was dissolved with stirring in 1:1 EtOH and EtOAc (287 ml). Palladium on carbon (10%, 1.8 g) was added and the slurry degassed, placed under an atmosphere of hydrogen (3×) and stirred at RT for 3 hours. The mixture was filtered through CELITE, the filter cake washed with EtOAc (3×100 ml), the filtrates combined and the volatiles removed in vacuum to give the titled compound.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[CH3:7][C:8]1([CH3:22])[CH2:13][CH2:12][C:11](=O)[CH:10]2[C:15]([CH3:21])([CH3:20])[CH:16]3[CH2:19][C:9]12[CH2:18][CH2:17]3>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1CCCCC1>[CH:1](=[C:11]1[CH:10]2[C:15]([CH3:20])([CH3:21])[CH:16]3[CH2:19][C:9]2([CH2:18][CH2:17]3)[C:8]([CH3:22])([CH3:7])[CH2:13][CH2:12]1)[CH3:2]
Reactant: CC1(C)C2CCC3(C2)C1C(=O)CCC3(C)C
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCCCC1
Product: CC=C1CCC(C)(C)C23CCC(C2)C(C)(C)C13
Temperature: 25 °C
Reaction time: 78 h
Yield: 61.9 %

Procedure:
Potassium tert-butoxide (13.0 g, 0.116 mol) and ethyltriphenylphosphonium bromide (41.6 g, 0.112 mol) were added to a solution of 2,2,7,7-tetramethyltricyclo[6.2.1.01,6]undecan-5-one (1, 20.0 g, 0.091 mol) in cyclohexane (200 ml), the reaction mixture was stirred at room temperature for 78 h and filtered through Celite®. The filtrate was concentrated and distilled under reduced pressure to give (at 95° C./0.1 mbar) 5-ethylidene-2,2,7,7-tetramethyltricyclo[6.2.1.01,6]undecane (2b, 13.1 g, 62% yield, colourless liquid).