Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:39]=[C:40]1[NH:45][CH2:44][CH2:43][N:42]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:41]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:49]3[CH2:48][CH2:47][CH:46]([N:42]4[CH2:43][CH2:44][NH:45][C:40](=[O:39])[CH2:41]4)[CH2:51][CH2:50]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CN(C2CCNCC2)CCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCNC(=O)C2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-(3-oxo-piperazin-1-yl)-piperidine hydrochloride to give the title compound. HR-MS (ES, m/z) calculated for C38H47Cl2N6O3 [(M+H)+] 705.3081, observed 705.3081.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][CH:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].CC([O-])(C)C.[K+].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1.CO.C(Cl)Cl>CS(C)=O>[C:2]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:16][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)[CH2:11][CH:12]1[C:13]([OH:15])=[O:14])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: Clc1nccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CC(O)C[C@H]1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2nccc3ccccc23)CC1C(=O)O
Temperature: 25 °C
Yield: 96 %

Procedure:
A suspension of Boc-L-4-hydroxyproline (N-Boc(2S,4R)-hydroxyproline) (3.85 g 16.6 millimole (“mmol”) (CHEM-IMPEX International) in DMSO (60 mL) was cooled in an ice bath for ˜3 minutes, and then t-BuOK (4.66 g, 41.5 mmol) was added. Stirring and cooling in the ice bath was continued for a few minutes until a solid mass formed. At this time the reaction mixture was allowed to warm to rt over 1.5 h to give a clear colorless solution. 1-Chloroisoquinoline (3.0 g, 18.3 mmol) was added in two portions 10 min apart. The reaction was stirred for 24 h at rt. The dark reaction mixture was partitioned between ether (200 mL) and water (600 mL). The aqueous phase was acidified to pH 4 using 4N HCl. The resulting milky yellow solution was extracted with ether (4×200 mL). The combined ether extracts were dried (MgSO4), filtered, and concentrated in vacuo to give a golden oil. Flash chromatography (2–4% MeOH/CH2Cl2) gave 5.69 g (96%) of 4-(isoquinolin-1-yloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester as an off-white solid: LC-MS (Method A, retention time: 3.06 min), MS m/z 359 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:16]([C:31]([NH2:33])=[O:32])=[N:17][CH:18]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[N:20]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH2:34](O)C.N1(CO)C2C=CC=CC=2N=N1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:16]([C:31]([NH2:33])=[O:32])=[N:17][CH:18]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[N:20]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:34])[CH2:10][CH2:9]1
Reactant: NC(=O)c1ncc(Oc2cccc([N+](=O)[O-])c2)nc1Nc1ccc(N2CCNCC2)c(Br)c1
Reactant: CCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: OCn1nnc2ccccc21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2Br)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 3-{[3-bromo-4-(piperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (523 mg) and ethanol (5 mL)-tetrahydrofuran (15 mL) were added 1H-benzotriazole-1-methanol (159 mg) and sodium triacetoxyborohydride (323 mg), followed by stirring at room temperature for 6 hours, then diluting with chloroform, and washing with a saturated aqueous sodium hydrogen carbonate solution. After the organic phase was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-50:1:0.1) to obtain 3-{[3-bromo-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (447 mg) as a pale yellow solid.
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([O-:34])=[O:33])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].[CH2:40]([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1>[OH:1][CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([O:34][CH3:40])=[O:33])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)[Si](OCCC1(CCOc2ccccc2C(=O)[O-])CCCCC1)(c1ccccc1)c1ccccc1
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1OCCC1(CCO)CCCCC1
Reaction time: 2 h

Procedure:
To a solution of methyl 2-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethoxy]benzoate (synthesized in Example 35) (547 mg) in tetrahydrofuran (4 mL) was added a 1M tetrabutyl ammonium fluoride/tetrahydrofuran solution (1 mL) at room temperature. The solution was then stirred for 2 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, hexane-ethyl acetate (2:1)] to give the title compound (226 mg).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]1([C:18]2[C:19]3[CH:20]=[CH:21][C:22]([C:38]([O:40][CH3:41])=[O:39])=[CH:23][C:24]=3[N:25]3[CH2:31][C@H:30]([OH:32])[C@H:29](O)[C:28]4[CH:34]=[CH:35][CH:36]=[CH:37][C:27]=4[C:26]=23)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:12]1([C:18]2[C:19]3[CH:20]=[CH:21][C:22]([C:38]([O:40][CH3:41])=[O:39])=[CH:23][C:24]=3[N:25]3[CH2:31][C:30](=[O:32])[CH2:29][C:28]4[CH:34]=[CH:35][CH:36]=[CH:37][C:27]=4[C:26]=23)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)[C@H](O)c1ccccc1-3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Cc1ccccc1-3
Yield: 61.9 %

Procedure:
p-Toluenesulfonic acid (50 mg, 0.29 mmol) was added to methyl 13-cyclohexyl-6,7-dihydro-(5R,6S)-rel-5,6-dihydroxy-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (100 mg, 0.25 mmol) in 50 mL of dry toluene. The solution was heated under reflux for 18 hr with removal of water using a Dean-Stark trap. The solution was diluted with ethyl acetate and washed with brine (3×) and dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified utilizing a Biotage apparatus with a prepacked silica column and using gradients of hexanes:ethyl acetate of from (98:2) to (85:15) to afford the product as a light yellow solid (60 mg, 62%). ESI-MS m/z 388 (MH+); 1H NMR (500 MHz, CHLOROFORM-D) δ 1.22-1.68 (m, 4 H) 1.73-1.83 (m, 2 H) 1.91-1.99 (m, 1 H) 2.02-2.15 (m, 3 H) 2.95 (m, 1 H) 3.57 (d, J=14.04 Hz, 1 H) 3.84 (d, J=14.04 Hz, 1 H) 3.95 (s, 3 H) 4.44 (d, J=18.01 Hz, 1 H) 4.96 (d, J=18.01 Hz, 1 H) 7.35 (d, J=7.63 Hz, 1 H) 7.43 (m, 1 H) 7.48 (t, J=7.32 Hz, 1 H) 7.54 (m, 1 H) 7.81 (d, J=8.55 Hz, 1 H) 7.92 (d, J=8.55 Hz, 1 H) 8.09 (s, 1 H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2/[C:11](=[CH:19]/[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)/[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[N+:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([O-:34])=[O:33]>C(Cl)(Cl)Cl>[O:18]=[C:12]1[NH:13][C:14]2[C:10](/[C:11]/1=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[C:9]([C:5]1[CH:4]=[C:3]([NH:2][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:43][CH:42]=3)[CH:8]=[CH:7][CH:6]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1Nc2cccc(-c3cccc(NC(=O)c4ccc([N+](=O)[O-])cc4)c3)c2/C1=C/c1ccc[nH]1
Temperature: -70 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one hydrochloride (25 mg, 0.074 mmol) (from Example 5 supra) and Et3N (20 μL , 0.150 mmol) in 3 mL of chloroform was cooled to −70° C. and then treated with 4-nitrobenzoyl chloride (16 mg, 0.085 mmol) (Aldrich). The reaction mixture was stirred at −70° C. for 1 hr and then stirred at room temperature for 15 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50% ethyl acetate-hexanes elution) provided pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-4-nitrobenzamide (yield: 24 mg, 72%) as a yellow-brown solid (mp 157-159° C.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1[CH:8]=[C:9]([C:16]([OH:18])=O)[N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12.[NH2:19][C:20]1[CH:21]=[C:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:23]=[CH:24][C:25]=1[CH3:26].[NH4+].[Cl-]>ClCCl.CN(C=O)C.CCN(C(C)C)C(C)C>[N:7]1[CH:8]=[C:9]([C:16]([NH:19][C:20]2[CH:21]=[C:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH:23]=[CH:24][C:25]=2[CH3:26])=[O:18])[N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1N
Reactant: O=C(O)c1cnc2ccccn12
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Oxalyl chloride (10 mL) was added dropwise to a stirred solution of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (3 g, 18.5 mmol) in dry dichloromethane (100 mL) and a few drops of DMF. The resulting solution was stirred at room temperature for 5 hours before it was evaporated to dryness and fresh dichloromethane was added to the resulting acid chloride to make a suspension. In a separate flask, tert-butyl 3-amino-4-methylphenylcarbamate (65) (4.5 g, 20.3 mmol) and DIEA (10 mL) was dissolved in dichloromethane (100 mL) and the above acid chloride solution was added slowly. The resulting solution was stirred overnight at room temperature. Saturated NH4Cl was added to the reaction solution and the phases were separated. The organic layer was dried over Na2SO4 and filtered. After evaporation, the residue was purified over silica gel column using hexane and EtOAc to give tert-butyl 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenylcarbamate (66) as a slightly yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH:20](OCC)=[O:21]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:20]=[O:21])=[CH:6][CH:7]=1
Reactant: CCOC=O
Reactant: O=C(CCc1ccc(Br)cc1)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CC(Cc1ccc(Br)cc1)C(=O)C1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of 2.84 g 3-(4-bromophenyl)-1-cyclohexylpropan-1-one from Step B above in 50 mL anhydrous THF was added 1.15 g 60% sodium hydride followed by one 6.2 mL and five 3.2 mL portions of ethyl formate over one day. The resulting mixture was stirred at room temperature under nitrogen for another day. The solvent was removed under reduced pressure and the residue was partitioned between cold 0.1 N HCl and ether. The combined ether extract was washed with water (2×), 5% NaHCO3 (3×), water, and saturated brine, dried over anhydrous Na2SO4, and evaporated to give crude product as orange solid. It was purified on silica gel using 10˜15% EtOAc in hexanes to give the title compounds as pink oily solid. 1H NMR (CDCl3, 500 MHz) δ 15.43 (d, J=7.1 Hz, 1H), 8.01 (d, J=7.1 Hz, 1H), 7.43˜7.45 (m, 2H), 7.07 (d, J=8.3 Hz, 2H), 3.52 (s, 2H), 2.32 (tt, J=11.5 & Hz, 1H), 1.73˜1.77 (m, 2H), 1.63˜1.68 (m, 1H), 1.49˜1.53 (m, 2H), 1.39˜1.47 (m, 2H), 1.07˜1.25 (m, 4H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[NH:16][C:15]([C:17]([C:54]4[C:59]([CH3:60])=[CH:58][C:57]([CH3:61])=[CH:56][C:55]=4[CH3:62])=[C:18]4[N:53]=[C:21]([C:22]([C:43]5[CH:48]=[CH:47][C:46]([C:49](OC)=[O:50])=[CH:45][CH:44]=5)=[C:23]5[NH:42][C:26](=[C:27]([C:33]6[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[CH:35][C:34]=6[CH3:41])[C:28]6[CH:29]=[CH:30][C:31]=2[N:32]=6)[CH:25]=[CH:24]5)[CH:20]=[CH:19]4)=[CH:14][CH:13]=3)=[CH:7][CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:2][CH2:3][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[NH:16][C:15]([C:17]([C:54]4[C:59]([CH3:60])=[CH:58][C:57]([CH3:61])=[CH:56][C:55]=4[CH3:62])=[C:18]4[N:53]=[C:21]([C:22]([C:43]5[CH:48]=[CH:47][C:46]([CH2:49][OH:50])=[CH:45][CH:44]=5)=[C:23]5[NH:42][C:26](=[C:27]([C:33]6[C:34]([CH3:41])=[CH:35][C:36]([CH3:40])=[CH:37][C:38]=6[CH3:39])[C:28]6[CH:29]=[CH:30][C:31]=2[N:32]=6)[CH:25]=[CH:24]5)[CH:20]=[CH:19]4)=[CH:14][CH:13]=3)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(-c2c3nc(c(-c4c(C)cc(C)cc4C)c4ccc([nH]4)c(-c4ccc(C(=O)OC)cc4)c4nc(c(-c5c(C)cc(C)cc5C)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2c3nc(c(-c4ccc(CO)cc4)c4ccc([nH]4)c(-c4c(C)cc(C)cc4C)c4nc(c(-c5ccc(CO)cc5)c5ccc2[nH]5)C=C4)C=C3)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
A solution of 14 (407 mg, 0.500 mmol) in anhydrous THF (50 mL) was treated with LiAlH4 (76 mg, 2.0 mmol). The reaction mixture was stirred at room temperature. After 15 min, the reaction was quenched with methanol and concentrated. The dark residue was suspended in CHCl3 and poured on to a pad of alumina. The alumina pad was eluted with CHCl3/methanol (4:1) until the eluant was colorless. The solvent was evaporated under vacuum. Chromatography [silica, CHCl3/methanol (4:1)] afforded a purple solid (340 mg, 89%): 1H NMR δ −2.63 (s, 2H), 1.84 (s, 12H), 2.63 (s, 6H), 5.07 (s, 4H), 7.28 (s, 4H), 7.75 (d, J=8.0 Hz, 4H), 8.22 (d, J=8.0 Hz, 4H), 8.69 (d, J=4.8 Hz, 4H), 8.80 (d, J=4.4 Hz, 4H); LD-MS obsd 758.54, calcd 758.3621 (C52H46N4O2); λabs 419, 515, 549, 593, 647 nm.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:14]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:14]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2cccnc2N)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncccc1C(=O)NCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (9 ml) was added to a solution of 2-amino-N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (2.2 g; prepared in a similar manner to that described above) in dichloromethane (50 ml) and the mixture stirred at ambient temperature for 1 hour. The solvent was removed in vacuo to give crude 2-amino-N-(4-piperidylmethyl)pyridine-3-carboxamide trifluoroacetate.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:59])[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([NH:33][C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[C:40]([N:44]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[N:39][CH:38]=[CH:37]4)[C:30]([OH:32])=[O:31])=[CH:25][CH:24]=2)[CH:16]=[CH:17][CH:18]=1)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][CH2:12][C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:59])[CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([CH:29]([NH:33][C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[C:40]([N:44]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])=[N:39][CH:38]=[CH:37]4)[C:30]([OH:32])=[O:31])=[CH:27][CH:28]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(NC(C(=O)O)c3ccc(OCC(=O)Nc4cccc(CNC(=O)OCc5ccccc5)c4)cc3)ccc12
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(NC(C(=O)O)c3ccc(OCC(=O)Nc4cccc(CN)c4)cc3)ccc12
Reaction time: 0.33 h
Yield: 67.1 %

Procedure:
To a solution of 66D (152 mg) in 10 mL MeOH, was added 10% Pd/C (ca. 20 mg). The mixture was hydrogenated at 5 psi for 20 min. The reaction mixture was filtered, concentrated and purified by flash chromatography (0 to 25% MeOH in DCM) to give 66E (85 mg, 68%). MS (ESI) m/z 672.4(M+H)+.
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@H:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[CH2:23](I)[CH2:24][CH2:25][CH3:26]>>[CH2:23]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C@@H:13]4[CH2:14][NH:15][CH2:16][CH2:17][C@@H:12]4[N:10]([C:9]=23)[CH2:11][CH2:2]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCI
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Product: CCCCN1CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12

Procedure:
Utilizing the material from Example 255 Step A, the title compound was prepared in analogous fashion using n-butyl iodide as the alkyl halide and following the procedure of Step B-D of Example 255, as a viscous brown liquid. 1H NMR (CDCl3, 300 MHz) δ 0.95 (t, 3H), 1.30-1.45 (m, 2H), 1.50-1.65 (m, 2H), 1.95-2.15 (m, 2H), 2.65-2.80 (m, 2H), 2.65-2.80 (m, 2H), 2.85-3.08 (m, 1H), 3.08-3.22 (m, 3H), 3.22-3.40 (m, 6H), 3.68-3.78 (m, 1H), 6.38 (d, J=7.1 Hz), 6.46 (d, J=7.1 Hz, 1H), 6.66 (t, J=7.7 Hz, 1H) ppm. MS (CI): 436 (M+H+).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)=[O:5])#[N:2].CO/[CH:17]=[CH:18]/[C:19](=O)[CH3:20].N12CCN(CC1)CC2.Cl>COCCOCCO>[F:14][C:9]1[CH:8]=[C:7]([N:6]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:3]([C:1]#[N:2])[C:4]2=[O:5])[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: N#CCC(=O)Nc1ccc(F)c(F)c1
Reactant: CO/C=C/C(C)=O
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: COCCOCCO
Product: Cc1ccc(C#N)c(=O)n1-c1ccc(F)c(F)c1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 49 %

Procedure:
A mixture of 2-cyano-N-(3,4-difluorophenyl)acetamide (6.0 g, 30.6 mmol), (3E)-4-methoxybut-3-en-2-one (4.29 g, 42.8 mmol) and 2-(2-methoxyethoxy)ethanol (60 mL) was stirred at 90° C. for 20 min. 1,4-Diazabicyclo[2.2.2]octane (3.77 g, 33.6 mmol) was added, and the mixture was stirred at 125° C. for 5 hr. After cooling to room temperature, the mixture was adjusted to pH 5 with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate/hexane (=1/1) and collected by filtration to give the title compound (3.69 g, 49%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.C([N:22]=[C:23]=[S:24])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:23]([NH2:22])=[S:24])=[CH:9][CH:8]=2)=[CH:5][N:6]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1ncc(-c2ccc(N)cc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(-c2ccc(NC(N)=S)cc2)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.7 %

Procedure:
To a solution of 4-(2-methyl-oxazol-5-yl)phenylamine (470 mg, 2.7 mmol, CAS 89260-50-4) in tetrahydrofurane (6 mL) was added drop wise under benzoyl isothiocyanate (402 uL, 2.8 mmol). The reaction was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in methanol (7 mL) and a solution of potassium carbonate (1119 mg, 8.1 mmol) in water (3.6 mL) was added. A solid precipitated and the reaction was stirred over night at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in methanol (20 mL), tetrahydrofurane (10 mL) and 1M aqueous sodium hydroxide solution (8.1 mL). The reaction was stirred over night at room temperature, diluted with water and extracted three times with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was suspended in water and extracted three times with methylene chloride. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified on silica gel using methylene chloride and methylene chloride/methanol (19:1 v/v) as eluent to yield the title compound (105 mg, 17%) as a light brown solid. MS ISP (m/e): 234.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.79 (s, 1H), 7.59 (d, 1H), 7.52 (d, 2H), 7.45 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[F:22]>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[CH:17][C:16]=1[F:22]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Br)c(F)c1
Product: O=C(Nc1ccc(Br)c(F)c1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 4-Bromo-3-fluoro-phenylamine to produce N-(4-Bromo-3-fluoro-phenyl)-4-chloro-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 13A, 13B and 13C to provide the title product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](I)=[N:11][C:12]([CH2:15][OH:16])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[C:10]([C:24](=[CH2:25])[C:23]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][C:12]([CH2:15][OH:16])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(OCc2ccccc2)c(I)n1
Reactant: C=CC(=O)OCC
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C(=O)OCC)c1nc(CO)ccc1OCc1ccccc1
Temperature: 120 °C
Yield: 62 %

Procedure:
To a solution of 3-benzyloxy-6-hydroxymethyl-2-iodopyridine (1.20 g, 3.50 mmol) in DMF (6.4 ml) and water (0.32 ml) were added potassium acetate (0.83 g, 8.5 mmol) palladium acetate (32 mg, 0.14 mmol) and ethyl acrylate (1.1 ml, 1.01 g, 10 mmol). The mixture was placed under nitrogen and stirred and heated at 120° C. for 1.25 h. By hplc the solution yield was 62%.