Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][CH:26]1[CH2:31][O:30][CH2:29][CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>CCO>[F:11][C:10]([F:13])([F:12])[CH2:9][N:8]([CH2:14][C:15]([F:17])([F:18])[F:16])[C:6]([C:5]1[CH:19]=[CH:20][C:2]([NH:24][CH2:25][CH:26]2[CH2:31][O:30][CH2:29][CH2:28][N:27]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=1)=[O:7]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOCC1CN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOCC1CNc1ccc(C(=O)N(CC(F)(F)F)CC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (213 mg, 0.612 mmol) and tert-butyl 3-(aminomethyl)morpholine-4-carboxylate (160 mg, 0.734 mmol) in 10 mL of EtOH containing TEA (0.130 mL, 0.918 mmol). The product was purified by flash chromatography on silica gel using 2:1/hexanes:EtOAc as eluent. Yield: 304 mg (91%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.49 (s, 9H), 3.17 (m, 1H), 3.52 (m, 1H), 3.64 (m, 3H), 3.92 (m, 2H), 4.25 (q, J=8.20 Hz, 6H), 7.57 (d, J=8.59 Hz, 1H), 8.30 (d, J=1.95 Hz, 1H), 8.48 (m, 1H); MS (ESI) 544.75 (MH+).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7](O)=[O:8])[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH2:26]([O:33][C:34](=[O:46])[C@H:35]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:36][C:37](=[O:41])[C@H:38]([CH3:40])[NH2:39])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:26]([O:33][C:34](=[O:46])[C@H:35]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:36][C:37](=[O:41])[C@H:38]([CH3:40])[NH:39][C:7](=[O:8])[C@H:5]([CH3:6])[NH:4][C:1](=[O:3])[CH3:2])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(=O)N[C@@H](C)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)N)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of acetylalanine (0.03 mole) and N-methylmorpholine (0.03 mole) in dry tetrahydrofuran (200 ml) at -20° to -25° is added isobutyl chloroformate (0.03 mole). After 10 minutes, a suspension of the crude alanylleucine benzyl ester hydrochloride (0.03+ mole) and N-methylmorpholine (0.04 mole) in tetrahydrofuran (25 ml) is added in portions over 1/2 hour. The mixture is allowed to warm to room temperature over a period of 2 hours and stirred overnight. The reaction mixture is evaporated to dryness and the residue is purified by chromatography on silica gel (200 gm) and elution with 10% methanol in chloroform to give acetylalanylalanylleucine benzyl ester.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[S:31]1C=[CH:34][CH:33]=[C:32]1CCN>>[S:31]1[CH:32]=[CH:33][CH:34]=[C:12]1[CH2:11][CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCCc1cccs1
Product: O=C(NCCc1cccs1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using thiophene-2-ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 369 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (1H, br. s.) 10.44 (1H, s) 8.30 (1H, t, J=5.56 Hz) 8.06 (1H, d, J=6.25 Hz) 7.85 (1H, d, J=5.47 Hz) 7.37-7.43 (2H, m) 7.29 (1H, dd, J=5.08, 1.17 Hz) 6.89 (1H, dd, J=5.08, 3.32 Hz) 6.86 (1H, dd, J=3.32, 0.98 Hz) 6.78 (1H, d, J=6.44 Hz) 6.59 (1H, d, J=3.51 Hz) 3.42-3.49 (2H, m) 3.00 (2H, t, J=7.13 Hz)
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:31][CH:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH3:33]>>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:37][S:34]([CH:32]([CH3:33])[CH3:31])(=[O:36])=[O:35])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)CO)C1=O
Reactant: CC(C)S(N)(=O)=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C(C)C)C1=O

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) and propane-2-sulfonamide as described in Example 181, Step A. MS (ESI) m/z=551 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Li]CCCC.[CH3:14][C:15]1[C:19]([C:20]2[CH:21]=[C:22]([C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[O:33])[C:23]3[N:27]=[C:26]([O:28][CH2:29][CH3:30])[NH:25][C:24]=3[CH:31]=2)=[C:18]([CH3:40])[O:17][N:16]=1>CC1OCCC1>[Cl:8][C:4]1[N:3]=[C:2]([C:32]([C:22]2[C:23]3[N:27]=[C:26]([O:28][CH2:29][CH3:30])[NH:25][C:24]=3[CH:31]=[C:20]([C:19]3[C:15]([CH3:14])=[N:16][O:17][C:18]=3[CH3:40])[CH:21]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[OH:33])[CH:7]=[CH:6][CH:5]=1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Reactant: Clc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: CC1CCCO1
Product: CCOc1nc2c(C(O)(c3ccccn3)c3cccc(Cl)n3)cc(-c3c(C)noc3C)cc2[nH]1
Reaction time: 0.67 h
Yield: 48.7 %

Procedure:
To a solution of 2-bromo-6-chloropyridine (83 mg, 0.43 mmol) in 2-MeTHF (1.5 mL) cooled to −78° C. was added n-BuLi (1.6 M, 0.27 mL, 0.43 mmol) dropwise and the reaction was allowed to stir for 40 mins. A solution of (6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (100 mg, 0.22 mmol) in 2-MeTHF (0.5 mL) was added to the reaction and the reaction was allowed to stir for an additional 10 mins at −78° C. and then quenched with water. The reaction mixture was extracted three times with EtOAc and combined organic layers were washed once with water, concentrated, and purified by silica gel chromatography to yield (6-chloropyridin-2-yl)(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanol (51 mg, 41%) as a white solid. The solid (26.5 mg, 0.055 mmol) was taken up in EtOH (1 mL) and 4M HCl/dioxane (0.5 mL) and heated for two hours at 65° C. and then concentrated to afford the desired product as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C1COCC1>[CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][N:4]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:3]1=[O:7]
Reactant: CC1(C)CCNC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCN(C(=O)OCc2ccccc2)C1=O
Temperature: -78 °C
Yield: 69.3 %

Procedure:
In an oven-dried 1000 ml flask under argon was dissolved 3,3-dimethyl-2-pyrrolidinone (0.0718 mol, 8.13 g) in 200 ml THF. The resulting solution was cooled to −78° C., and lithium hexamethyldisilazide (0.0790 mol, 79 ml of a 1M solution in THF) was added over 15 min. Stirring was continued for 30 minutes, at which time benzyl chloroformate (0.0790 mol, 13.5 g) was added and the reaction was allowed to warm to room temperature and stir for 16 hr. The mixture was concentrated to ⅓ total volume and diluted with 500 ml ethyl acetate and washed with 1M HCl (2×200 ml), water (1×200 ml), and brine (1×100 ml). The organic phase was dried over MgSO4, filtered and concentrated. Purification of the crude residue on 120 g silica (ethyl acetate/hexanes) yielded 12.3 g (69%) of phenylmethyl 3,3-dimethyl-2-oxo-1-pyrrolidinecarboxylate as a light yellow oil. LCMS (ESI+)=248 m/z (M+), 270 m/z (MNa+). 1H NMR (400 MHz, CDCl3) δ 7.48-7.46 (m, 2H), 7.39-7.36 (m, 3H), 5.31 (s, 2H), 3.77-3.73 (t, 2H, J=6.96 Hz), 1.91-1.88 (t, 2H, J=7.08 Hz), 1.23 (s, 6H). 13C NMR (CDCl3) δ 178.83, 151.86, 135.35, 128.60, 128.34, 128.10, 68.00, 42.79, 42.16, 32.95, 24.28.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[CH:51]=[CH:50][C:24]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([N:34]4[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH:36]([C:47]([O-:49])=[O:48])[CH2:35]4)(=[O:33])=[O:32])=[CH:27][CH:26]=3)=[CH:23][CH:22]=2)=[CH:10][CH:9]=1>ClCCl>[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[CH:22]=[CH:23][C:24]([C:25]3[CH:26]=[CH:27][C:28]([S:31]([N:34]4[CH2:39][CH2:38][NH:37][CH:36]([C:47]([OH:49])=[O:48])[CH2:35]4)(=[O:33])=[O:32])=[CH:29][CH:30]=3)=[CH:50][CH:51]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CC1C(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1CN(S(=O)(=O)c2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 4-(4′-Dibenzofuran-4-ylbiphen-4-yl-sulfonyl)-piperazine-1,2-dicarboxylic acid, 1-tert-butyl ester (120 mg) in anhydrous dichloromethane. The reaction was stirred at room temperature for 2 hours (TLC control). The resultant brown oil was reconstituted and concentrated from methanol (3×10 mL) and then from dichloromethane (2×10 mL) to give the title compound as a white solid (101 mg, 100%): Rf 0.10 (20% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz): δ 8.19 (2H, t, J=9 Hz, Ar—H), 8.08 (4H, m Ar—H), 7.94 (4H, m, Ar—H), 7.74 (2H, t, J=9, 4 Hz, Ar—H), 7.54 (2H, m, Ar—H), 7.44 (1H, t, J=8 Hz, Ar—H), 4.38 (1H, m, CHN), 3.71 (1H, m), 3.46 (2H, m), 3.19 (1H, m), 2.98 (1H, m), 2.83 (1H, m), 1.41 (9H, s, CMe3); ESI-LCMS e/z calcd for C29H24N2O5S 612.700, found 635 (M+Na)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:44][C:45](=[O:54])[C@H:46]([CH2:48][CH2:49][C:50]([O:52]C)=[O:51])[NH2:47]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:47][C@H:46]([C:45]([OH:44])=[O:54])[CH2:48][CH2:49][C:50]([OH:52])=[O:51])=[O:36])=[CH:38][CH:39]=2)=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)N[C@@H](CCC(=O)O)C(=O)O)cc2)cc1

Procedure:
The product from Example 233 and L-glutamic acid dimethyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.33-12.71 (br.s, 1 H), 11.89-12.26 (br.s, 1 H), 8.94 (s, 1 H), 8.12 (d, 1 H), 7.23 (m, 7 H), 6.99 (m, 7 H), 6.82 (d, 2 H), 4.22 (m, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.94 (t, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.28 (m, 4 H), 1.95 (m, 3 H), 1.77 (m, 1 H); MS (ESI+) m/z 704 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][C:10](=[O:27])[C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1)[NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH3:8].[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1B(O)O>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:7]([O:9][C:10](=[O:27])[C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:30]2[CH:29]=[CH:28][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH:21]=1)[NH:12][C:13](=[O:18])[C:14]([F:15])([F:16])[F:17])[CH3:8]
Reactant: CCOC(=O)[C@H](Cc1cccc(O)c1)NC(=O)C(F)(F)F
Reactant: OB(O)c1ccc2ccccc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1cccc(Oc2ccc3ccccc3c2)c1)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
Pyridine (0.22 ml, 2.72 mmol) was added to a suspension of N-trifluoroacetyl-3-hydroxy-L-phenylalanine ethyl ester (159 mg, 0.521 mmol), 2-naphthaleneboronic acid (186 mg, 1.08 mmol), molecular sieves 4A powder (204 mg) and copper (II) acetate (153 mg, 0.842 mmol) in methylene chloride (7 ml) and the mixture was stirred under air atmosphere (without argon) at room temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate (30 ml) and the insoluble materials were filtered off (celite (Trade mark)) and washed with ethyl acetate. The filtrate and washings were combined and washed with 10% hydrochloric acid and brine in turn and then dried. The solvent was distilled off under reduced pressure. The resultant residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=10) to give N-trifluoroacetyl-3-(2-naphthyloxy)-L-phenylalanine ethyl ester (200 mg, 89%) as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:12]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.O>CN1CCCC1=O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[C:11]1[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:22]=[CH:23][N:24]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:3]=2)[S:9][CH:10]=1
Reactant: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(Cl)c3)n2)c(C)c1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(N4CCOCC4)c3)n2)c(C)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
A mixture of 2-chloro-N-(4-mesitylthiazol-2-yl)isonicotinamide (500.0 mg, 1.4 mmol, 1.0 equiv) and morpholine (1.5 mL, 16.8 mmol, 12 equiv) in methylpyrrolidone (15.0 mL) was stirred at 150° C. for 16 h. The mixture was poured into icy H2O (20.0 mL), and the resultant solids were filtered to provide N-(4-mesitylthiazol-2-yl)-2-morpholinoisonicotinamide (358.6 mg, 0.90 mmol) as yellow solids in 63% yield: 1H NMR (DMSO-d6, 500 MHz) δ 8.30 (d, J=5.1 Hz, 2H), 7.50 (s, 1H), 7.22 (d, J=5.1 Hz, 2H), 7.10 (s, 1H), 6.92 (s, 2H), 3.70-3.73 (m, 4H), 3.53-3.55 (m, 4H), 2.26 (s, 3H), 2.05 (s, 6H); ESI-MS: m/z 409.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([Cl:8])=[N:6][CH:7]=1.ClCCCl.C(N(CC)CC)C.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: COCCOCCl
Reactant: Oc1cc(Br)cnc1Cl
Solvent: CO
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COCCOCOc1cc(Br)cnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
A dry 100 mL one neck round bottom flask was charged with 5-bromo-2-chloropyridin-3-ol (2.1454 g, 10.3 mmol), 40 mL dry DCE, and a stirbar. The slurry was fitted with an inert atmosphere inlet and cooled with an ice-water bath. To the stirring solution was added triethylamine (4.29 ml, 30.9 mmol) followed by 2-methoxyethoxymethyl chloride (1.17 ml, 10.3 mmol). The reaction was stirred at ice bath temperature for 1 h, and then at room temperature for 2 h. The reaction was cooled to 0° C. and treated with 2 mL MeOH. The slurry was filtered cold, and the solids were washed with DCE (2×50 mL). The filtrate was concentrated in vacuo and purified using 200 g SiO2 wet packed with DCE. A fraction that eluted from 500- to 1500 mL was isolated. The solvent was removed in vacuo to afford 5-bromo-2-chloro-3-((2-methoxyethoxy)methoxy)pyridine (1.28 g, 41.9% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.38 (s, 3H) 3.55-3.59 (m, 2H) 3.86-3.89 (m, 2H) 5.36 (s, 2H) 7.71 (d, J=2.05 Hz, 1H) 8.12 (d, J=2.05 Hz, 1H). HPLC-MS: 2.04 min (>99%@215 nm; >99% @254 nm; m/z=295.9, calculated for C9H1179BrClNO3+H+=296.0; m/z=297.9, calculated for C9H1179BrClNO3+H+=298.0).
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])[CH3:8])[CH:4]([CH3:6])C.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:26]=[C:25]([C:27]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH3:35])[N:31]=2)=[O:28])[CH:24]=[C:23]([O:36][C@@H:37]([CH3:40])[CH2:38][OH:39])[CH:22]=1)[C:14](O)=[O:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.C12CC(C1)CN2>CN(C=O)C.C(OCC)(=O)C>[CH:7]12[CH2:8][CH:6]([CH2:9]1)[CH2:4][N:3]2[C:14]([C:13]1[CH:17]=[CH:18][C:19]([O:20][C:21]2[CH:26]=[C:25]([CH:24]=[C:23]([O:36][C@@H:37]([CH3:40])[CH2:38][OH:39])[CH:22]=2)[C:27]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH3:35])[N:31]=2)=[O:28])=[C:11]([F:10])[CH:12]=1)=[O:15]
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)O)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: C1NC2CC1C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CC4CC3C4)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.1 %

Procedure:
DIPEA (0.80 mL, 4.32 mmol) was added to a suspension of 3-fluoro-4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)benzoic acid (230 mg, 0.54 mmol), HATU (430 mg, 1.29 mmol) and 2-azabicyclo[2.1.1]hexane hydrochloride salt (96 mg, 0.81 mmol) in DMF (4 mL) and the mixture stirred at RT for 24 hours. Ethyl acetate was added and washed with water (3×30 mL), brine (30 mL), dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-10% methanol in DCM, to give the desired compound (51 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:34])=[C:4]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C:5]([I:28])=[C:6]([C:26]=1[I:27])[C:7]([NH:9][CH:10]([CH:16]([O:22][C:23](=[O:25])[CH3:24])[CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:11][O:12][C:13](=[O:15])[CH3:14])=[O:8].[C:35]([O:38][CH:39]([CH:43]([O:49][C:50](=[O:52])[CH3:51])[CH2:44][O:45][C:46](=[O:48])[CH3:47])[C:40](Br)=[O:41])(=[O:37])[CH3:36]>>[C:35]([O:38][CH:39]([CH:43]([O:49][C:50](=[O:52])[CH3:51])[CH2:44][O:45][C:46](=[O:48])[CH3:47])[C:40]([NH:1][C:2]1[C:3]([I:34])=[C:4]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C:5]([I:28])=[C:6]([C:26]=1[I:27])[C:7]([NH:9][CH:10]([CH:16]([O:22][C:23](=[O:25])[CH3:24])[CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:11][O:12][C:13](=[O:15])[CH3:14])=[O:8])=[O:41])(=[O:37])[CH3:36]
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Br
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NC(COC(C)=O)C(COC(C)=O)OC(C)=O)c1I
Product: CC(=O)OCc1c(I)c(NC(=O)C(OC(C)=O)C(COC(C)=O)OC(C)=O)c(I)c(C(=O)NC(COC(C)=O)C(COC(C)=O)OC(C)=O)c1I
Yield: 45 %

Procedure:
5-Amino-3-acetoxymethyl-N-(1,3,4-triacetoxybut-2-yl)-2,4,6-triiodobenzamide (20 g, 24.5 mmol) was acylated with 2,3,4-triacetoxybutanoyl bromide (15.9 g, 49.0 mmol) according to the procedure given in example 80a. The yield was 45%.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[CH2:14]([O:21][C:22]([NH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](O)=[O:28])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]([NH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([NH:1][C@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:28])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Reactant: N[C@H]1CCc2ccccc2NC1=O
Product: CC(C)(CC(=O)N[C@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1

Procedure:
Prepared from 3(S)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step B) and 3-benzyloxycarbonylamino-3-methylbutanoic acid (Example 1, Step E) by the procedure described in Example 1, Step F. FAB-MS: calculated for C23H27N3O4 409; found 410 (M+H,100%). [a]D =- 160° (c=1,CHCl3).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].C1C=C(Cl)C=C(C(OO)=[O:32])C=1>>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:32])=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCC(C)=O

Procedure:
The general method described in Parts I and J of Example 28 was used to aminate 5-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one (2.15 g, 6.95 mmol) by reaction with m-CPBA (1.71 g, 7.64 mmol) to provide 5-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one followed by reaction with p-toluenesulfonyl chloride (1.46 g, 7.64 mmol) and ammonium hydroxide solution (10 mL) to provide 5-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one as an off-white solid, mp 173-176° C.
Reaction SMILES: [OH-].[NH4+:2].[C:3]([N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[N:18][C:19]([NH2:22])=[N:20][CH:21]=3)=[CH:15][C:10]=2[N:9]=[C:8]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:33]=[C:32](C(Cl)(Cl)Cl)[O:31][N:30]=1)([CH3:6])([CH3:5])[CH3:4].O>CN(C=O)C>[NH2:2][C:32]1[O:31][N:30]=[C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:8]2[N:7]([C:3]([CH3:5])([CH3:6])[CH3:4])[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:17]=[N:18][C:19]([NH2:22])=[N:20][CH:21]=4)=[CH:15][C:10]=3[N:9]=2)[N:33]=1
Reactant: CC(C)(C)n1c(-c2ccccc2-c2noc(C(Cl)(Cl)Cl)n2)nc2cc(-c3cnc(N)nc3)ccc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1c(-c2ccccc2-c2noc(N)n2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
To a stirred solution of ammonium hydroxide (0.02 mL, 0.39 mmol) in DMF (2 mL) at room temperature is added 5-{1-tert-butyl-2-[2-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-phenyl]-1H-benzimidazol-5-yl}-pyrimidin-2-ylamine (395 mg, 0.26 mmol). The reaction mixture is stirred at room temperature for 0.5 hours. Water is added to the reaction mixture and the product is extracted into EtOAc (3×) and the combined organics are then dried (Na2SO4), filtered, and concentrated. Purification via flash chromatography (10 g silica gel, 3-6% MeOH/CH2Cl2) affords the title compound (20.6 mg, 17%). LCMS (ESMS): m/z 427.29 (M++1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1c(F)cccc1F
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1c(F)cccc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 2,6-difluoroaniline to yield 2-[(2,6-difluorophenyl)amino]phenylacetic acid.