Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](=[N:16]\[OH:17])/[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][CH2:35][C:36](O)=[O:37])[CH2:30][CH2:29]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH2:1]/[C:2](=[N:16]\[O:17][C:36](=[O:37])[CH2:35][O:34][CH:31]1[CH2:32][CH2:33][N:28]([C:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])[CH2:29][CH2:30]1)/[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10]
Reactant: O=C(O)COC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1/C(N)=N/O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1/C(N)=N/OC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
The title compound was prepared by a similar method to Preparation 5 from tert-butyl (Z)-(2S)-2-[amino(hydroxyimino)methyl]-1-piperidinecarboxylate [see Preparation 4] and 2-(1-[(benzyloxy)carbonyl]-4-piperidyloxy)acetic acid [see Preparation 92] to afford tert-butyl (Z)(2S)-2-[amino([2-(1-[(benzyloxy)carbonyl]-4 piperidyloxy)acetyl]oxyimino)methyl]-1-piperidinecarboxylate as a brown oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:12])(=O)[CH2:9][CH3:10].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:35][C:36]1[C:44]([O:45][C@@H:46]2[CH2:51][CH2:50][C@H:49]([NH2:52])[CH2:48][CH2:47]2)=[CH:43][C:42]([CH3:53])=[C:41]2[C:37]=1[CH:38]=[N:39][NH:40]2>CN(C)C=O>[CH3:35][C:36]1[C:44]([O:45][C@@H:46]2[CH2:51][CH2:50][C@H:49]([NH:52][C:8](=[O:12])[CH2:9][CH3:10])[CH2:48][CH2:47]2)=[CH:43][C:42]([CH3:53])=[C:41]2[C:37]=1[CH:38]=[N:39][NH:40]2
Reactant: Cc1c(O[C@H]2CC[C@@H](N)CC2)cc(C)c2[nH]ncc12
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)N[C@H]1CC[C@@H](Oc2cc(C)c3[nH]ncc3c2C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 110.1 %

Procedure:
Triethylamine (108 μl, 0.775 mmol), propionic acid (32 μl, 0.429 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (83 mg, 0.433 mmol) and 1-hydroxybenzotriazole (58 mg, 0.429 mmol) were added in that order to a dimethylformamide solution (2 ml) of the cis-4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.386 mmol) obtained in Example 658, and the resulting mixture was stirred at room temperature for 20 hours. The reaction was terminated by the addition of water, followed by extraction with ethyl acetate-toluene (1:1). The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby a crude product was obtained. The crude product was purified by a silica gel chromatography (eluent: chloroform/methanol=100:2) to obtain cis-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide (134 mg, 100%).
Reaction SMILES: Br.[CH3:2][O:3][C:4](=[O:39])[C@H:5]([CH2:20][C:21]1[CH:28]=[C:26]([I:27])[C:25]([O:29][C:30]2[CH:37]=[C:35]([I:36])[C:34]([OH:38])=[C:32]([I:33])[CH:31]=2)=[C:23]([I:24])[CH:22]=1)[NH:6][C:7](=[O:19])[CH2:8][O:9][CH2:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12].[C:40]1(=[O:46])[O:45][C:43](=[O:44])[CH2:42][CH2:41]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:39])[C@H:5]([CH2:20][C:21]1[CH:22]=[C:23]([I:24])[C:25]([O:29][C:30]2[CH:31]=[C:32]([I:33])[C:34]([OH:38])=[C:35]([I:36])[CH:37]=2)=[C:26]([I:27])[CH:28]=1)[NH:6][C:7](=[O:19])[CH2:8][O:9][CH2:10][C:11]([N:13]1[CH2:14][CH2:15][N:16]([C:40](=[O:46])[CH2:41][CH2:42][C:43]([OH:45])=[O:44])[CH2:17][CH2:18]1)=[O:12]
Reactant: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)COCC(=O)N1CCNCC1
Reactant: O=C1CCC(=O)O1
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)COCC(=O)N1CCN(C(=O)CCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-(piperazinocarbonylmethoxyacetyl)thyroxine methyl ester Hydrobromide from step 5 (9.5 g, 0.01 mole) and succinic anhydride (2.0 g, 0.02 mole), in chloroform (400 mL) was added triethylamine (3.3 g, 0.033 mole). The slurry immediately begins to dissolve and the mixture was stirred overnight at room temperature. The next day the solid had all dissolved and the solution was washed with 5% HCl solution (3×100 mL), water (100 mL), saturated NaCl solution (100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed on a rotary evaporator in vacuo. This material was further purified by chromatography using SiO2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:18][N:19]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[CH3:20].CO.N>C(O)CCC>[CH3:20][N:19]([CH2:21][CH:22]([OH:32])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])[CH:5]=[CH:4][N:3]=2)=[CH:30][CH:31]=1)[CH3:18]
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Reactant: Fc1ccc(Nc2ccnc(Cl)n2)c(F)c1
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCCCO
Product: CN(C)CC(O)COc1ccc(Nc2nccc(Nc3ccc(F)cc3F)n2)cc1
Temperature: 100 °C
Yield: 41.5 %

Procedure:
2-Chloro-4-(2,4-difluoroanilino)pyrimidine (Reference Example A-2; 174 mg, 0.72 mmol) was dissolved in n-butanol (2 ml) and 4-[3-(N,N-dimethyl)amino-2-hydroxypropoxy]aniline hydrochloride (Reference Example D-1; 198 mg, 0.72 mmol) was added. The resulting suspension was treated with methanol until all the solid dissolved. The reaction mixture was heated at 100° C. for 12 hours and allowed to cool to ambient temperature. The reaction mixture was then basified to pH 9–10 using methanolic ammonia and evaporated onto silica (5 ml). The residue was purified by column chromatography eluting with methanol (15%): DCM:aqueous ammonia(1%). The resulting gum was recrystallized from acetonitrile to give the title product as a solid (124 mg, 41%). NMR (300 MHz): 2.18 (s, 6H), 2.34 (m, 2H), 3.78 (m, 1H), 3.88 (m, 2H), 4.75 (brd, 1H), 6.18 (d, 1H), 6.75 (d, 2H), 7.03 (t, 1H), 7.32 (t, 1H), 7.48 (d, 2H), 7.88 (dd, 1H), 7.95 (d, 1H), 8.88 (s, 1H), 8.95(s, 1H); m/z: (ES+) 416.4 (MH+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:9](=[O:20])[CH2:10][C:11]2[NH:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=2)[CH:6]=[CH:7][CH:8]=1.C[O-].[Na+].[C:24](OC)(=[O:27])[C:25]#[CH:26]>>[F:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([C:10]1[CH:26]=[CH:25][C:24](=[O:27])[N:15]2[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[NH:12][C:11]=12)=[O:20]
Reactant: C#CC(=O)OC
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1cccc(F)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: O=C(c1cccc(F)c1)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 25 with 200 mg (0.51 mmol) of 1-(3-Fluorophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone hydrochloride (example XXXXVI), 55.2 mg (1.02 mmol) of sodium methylate and 42.9 mg (0.51 mmol) methyl propiolate.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]1[O:19][C@@H:18]1[CH2:20]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O>>[O:19]1[CH2:17][C@H:18]1[CH2:20][O:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1cc2c(cc1OC[C@@H]1CO1)OCO2
Yield: 57.4 %

Procedure:
The title compound (2.01 g, 10.35 mmol) was prepared according to Procedure A using the following amounts: sesamol (2.49 g, 18.02 mmol), potassium carbonate (2.74 g, 19.83 mmol) and (2S)-(+)-glycidyl-3-nitrobenzenesulfonate (4.67 g, 18.02 mmol).
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=1[O:13][CH3:14].[F:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:22][O:23][C:19]=2[CH:18]=1>C(O)(C)C>[F:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:15][CH:2]([OH:1])[CH2:3][O:4][C:5]4[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=4[O:13][CH3:14])[CH2:28][CH2:29]3)=[N:22][O:23][C:19]=2[CH:18]=1
Reactant: COc1cc(C=O)ccc1OCC1CO1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC(C)O
Product: COc1cc(C=O)ccc1OCC(O)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 55 °C
Yield: 89.2 %

Procedure:
A stirred mixture of 4-(2,3-epoxypropoxy)-3-methoxyphenyl methanone (4.5 g, 22.5 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5.36 g, 24.3 retool) in isopropyl alcohol (150 ml) was heated at 55° C. for 16 hours. The mixture was cooled and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography over a silica gel column (SiO2, 80 g; eluted with dichloromethane, DCM, and 1% CH3OH in DCM). The oil thus obtained solidified quickly, weight: 9.47 g. Recrystallization from ethanol and isopropyl ether, then toluene provided 8.6 g (86%) of white crystals, m.p.=107°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9](O)=[O:10])=[O:5].[CH3:29][C:30]1[S:31][CH:32]=[C:33]([CH2:35][O:36][NH2:37])[N:34]=1>>[Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([NH:37][O:36][CH2:35][C:33]1[N:34]=[C:30]([CH3:29])[S:31][CH:32]=1)=[O:10])=[O:5]
Reactant: Cc1nc(CON)cs1
Reactant: Cc1ccc(C(=O)O)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Product: Cc1nc(CONC(=O)c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)cs1

Procedure:
Compound 424 (50 mg, 0.12 mmol) and O-(2-Methyl-thiazol-4-ylmethyl)-hydroxylamine (36 mg, 0.25 mmol) were treated as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: graduated from 67/33 to 100/0) provided the title compound. 1H NMR (CDCl3) δ 10.0-9.0 (bs, 1H), 7.76 (dd, 1H), 7.67 (d, 1H), 7.42-7.30 (m, 3H), 7.15 (s, 1H), 7.00-6.84 (m, 3H), 6.75 (dd, 1H), 5.98 (bs, 1H), 5.04 (s, 2H), 2.64 (s, 3H), 2.45 (s, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].C(N1C=CN=C1)(N1C=CN=C1)=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:14]([O:15][CH3:16])[CH3:13])=[O:9])=[CH:5][N:4]=1
Reactant: COc1ccc(C(=O)O)cn1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1ccc(C(=O)N(C)OC)cn1

Procedure:
In analogy to example 158, step 3, 6-methoxynicotinic acid was reacted with N,O-dimethylhydroxylamine hydrochloride and 1,1′-carbonyldiimidazole to give the title compound as a colorless oil, MS (ESI+): m/z=197.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:18]3[N:17]=[C:16]([C:19]4[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][C:20]=4[Br:26])[NH:15][C:14]=3[C:13]3[C:8](=[CH:9][C:10]([Br:27])=[CH:11][CH:12]=3)[C:6]=2[CH:7]=1.[H-].[Na+].[CH3:30][Si:31]([CH2:34][CH2:35][O:36][CH2:37]Cl)([CH3:33])[CH3:32].O>C1COCC1>[Br:27][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[N:15]=[C:16]([C:19]4[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][C:20]=4[Br:26])[N:17]([CH2:37][O:36][CH2:35][CH2:34][Si:31]([CH3:33])([CH3:32])[CH3:30])[C:18]=3[C:5]3[C:6](=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[C:8]=2[CH:9]=1
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1c1[nH]c(-c3c(Br)cccc3Br)nc21
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(-c2c(Br)cccc2Br)nc2c3ccc(Br)cc3c3cc(Br)ccc3c21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
To a suspension of 6,9-dibromo-2-(2,6-dibromophenyl)-1H-phenanthro[9,10-d]imidazole from Step 1 (61.8 g, 0.1 mol) in THF (980 mL) at 0° C., was added sodium hydride (60% dispersion in mineral oil, 10 g, 0.25 mol). The suspension was stirred at 0° C. for 15 minutes, followed by addition of SEMCl (45 mL, 0.25 mol). The mixture was warmed to room temperature and stirred for 3 h, after which it was poured into water. The aqueous phase was extracted with ethyl acetate, the organic layer washed once with brine, dried over Na2SO4, filtered and concentrated. The crude material was swished in hexanes/diethyl ether for 4 h, then filtered to obtain 6,9-dibromo-2-(2,6-dibromophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-phenanthro[9,10-d]imidazole as a beige powder (71.5 g, 95%).
Reaction SMILES: C([O:8][N:9]([C:16](=[O:48])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([O:40]CC1C=CC=CC=1)[C:22](=[O:39])[CH2:23][CH2:24][CH2:25][CH2:26][N:27]([O:31]CC1C=CC=CC=1)[C:28](=[O:30])[CH3:29])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])C1C=CC=CC=1.[ClH:49]>CO.[Pd]>[ClH:49].[OH:8][N:9]([C:16](=[O:48])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([OH:40])[C:22](=[O:39])[CH2:23][CH2:24][CH2:25][CH2:26][N:27]([OH:31])[C:28](=[O:30])[CH3:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: CC(=O)N(CCCCC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)N(O)CCCCC(=O)N(O)CCCCC(=O)N(O)CCCCCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound (9) (1.000 g, 1,522 mmol) was dissolved in CH3OH (210 mL), followed by addition of 0.1N HCl (from concentrated HCl and methanol, 16.75 mL, 1.675 mmol) and 10% Pd-C. (0.6 g). The mixture was stirred under H2 (1 atm) at room temperature overnight. The catalyst was filtered and the solvent was removed. The residue was purified by Sephadex LH-20 column chromatography, eluting with 15% MeOH/toluene, to generate 560 mg (86%) of [A] as a colorless solid: NMR (CD3OD) δ 1.30-1.97 (m, 14 H) , 2.17 (s, 3 H), 2.60 (t, 4 H, J=6), 3.00 (t, 2 H, J=6), 3.70 (t, 6 H, J=6). Anal. (C17H35ClN4O6) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1
Yield: 94.4 %

Procedure:
To a suspension of 2-methyl-4-nitroaniline (0.76 g, 5 mmol) in toluene (25 mL) was added neat benzoyl chloride (0.59 mL, 5.08 mmol). The reaction mixture was refluxed for 16 hr, cooled and filtered to give N-(2-methyl-4-nitrophenyl)benzamide (1.21 g, 95%) as a beige solid. ES-MS (M+H)+=257.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][N:8]=[C:7]1SC)=[O:5].[NH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>COCCOCCOC.O>[N:18]1([N:17]2[C:2]3[C:3](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:4](=[O:5])[N:6]3[CH2:10][CH2:9][N:8]=[C:7]23)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NN1CCCCC1
Reactant: CSC1=NCCN1C(=O)c1ccccc1F
Solvent: COCCOCCOC
Solvent: O
Product: O=C1c2ccccc2N(N2CCCCC2)C2=NCCN12
Yield: 71 %

Procedure:
A solution of 10.0 g (42.0 mmoles) of the product of Example 1 and 25 ml of 1-aminopiperidine in 50 ml of 2-methoxyethyl ether (diglyme) was heated at reflux for 15 hours. The solution as diluted while hot with about 5 ml of water and allowed to cool. The resulting white needles were collected, washed with ethanol, and air-dried to give 8.10 g of 2,10-dihydro-10-(1-piperidinyl)imidazo[2,1-b]quinazolin-5(3H)-one. Melting point 229°-231° C. Total yield 71%.
Reaction SMILES: [H-].[Na+].C(O[C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[CH:11]=2)=[O:7])C.Br[CH2:23][CH2:24][CH2:25]C(OCC)=O>CN(C=O)C>[O:7]=[C:6]1[C:8]2=[CH:16][C:15]3[C:10]([N:9]2[CH2:25][CH2:24][CH2:23]1)=[CH:11][C:12]([C:17]([OH:19])=[O:18])=[CH:13][CH:14]=3
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2cc3n(c2c1)CCCC3=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
To a stirred suspension of NaH (260 mg of 60 wt % in mineral oil, 6.50 mmol) in DMF (5 mL) under an atmosphere of dry nitrogen was added 1H-indole-2,6-dicarboxylic acid diethyl ester (see Example 1) (1.50 g, 5.74 mmol) in DMF (40 mL) over 5 min. Ethyl 4-bromobutyrate (1.40 g, 7.2 mmol) was added dropwise, and the reaction was stirred at room temperature for 20 h. The reaction was quenched with water and extracted into methylene chloride (3×50 mL). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. The crude tri-ester intermediate was taken up in dry THF (30 mL) and to this solution was added potassium tert-butoxide (20 mL of a 1.0 M solution in THF, 20 mmol). After stirring at room temperature for 16 h, the reaction was quenched with water (60 mL) and concentrated HCl (75 mL) and refluxed for 5 h. The resulting suspension was cooled, filtered, then washed with water followed by hexanes. The resulting solid was dried in a vacuum oven to give 9-oxo-6,7,8,9-tetrahydro-pyrido[1,2-a]indole-3-carboxylic acid (1.25 g, 95%) as an analytically pure purple powder.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][N:4]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:3]1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26].C([O-])(O)=O.[Na+]>C(#N)C>[CH:8]1([C@@H:7]2[CH2:6][CH2:5][N:4]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:3][C@H:2]2[NH:1][C:25]([O:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:26])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C1CCCCC1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3S,4S)-benzyl 3-amino-4-cyclohexylpiperidine-1-carboxylate (23 mg, 0.073 mmol), 4-nitrophenyl chloroformate (16 mg, 1.1 equiv) and powdered NaHCO3 (13 mg, 2 equiv) were mixed with acetonitrile (3 mL). The mixture was stirred 1 h at rt. LC-MS showed the reaction was complete. The reaction mixture was concentrated to afford (3S,4S)-benzyl 4-cyclohexyl-3-((4-nitrophenoxy)carbonylamino)piperidine-1-carboxylate which was used directly in the next step. LC-MS (3 min) tR=2.24 min., m/z 482 (M+1).
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[S:10]([CH3:13])(=[O:12])=[O:11].C(O)(=O)C>CCOCC>[OH:4][CH:5]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:3])=[O:21])[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: C=[N+]=[N-]
Reactant: CS(=O)(=O)N(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)CCCCCCN(CCCC(O)COc1ccc(F)cc1)S(C)(=O)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approximately 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 7-{N-[4-hydroxy-5-(4-fluorophenoxy)pentyl]methanesulfonamido }heptanoic acid (12.3 g., 0.03 mole) (Example 1, Step E) in ether (50 ml.). The resulting solution is allowed to stand at room temperature for 4 hours. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 7-{N-[4-hydroxy-5(4-fluorophenoxy)pentyl]methanesulfonamido }heptanoate as a viscous oil.
Reaction SMILES: Br[CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN(C)C=O.C(OCC)(=O)C>[N:10]1([CH2:9][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CC(C)Br
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
To a solution of ethyl 3-bromobutanoate (6.0 mL, 42 mmol) in N,N-dimethylformamide (20 mL) at 0° C. was added piperidine (8.0 mL, 80 mmol) and the mixture was warmed to room temperature then stirred 16 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with a solution of brine and 2.0M aqueous sodium hydroxide (4:1 v/v). The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated to give ethyl 4-piperidin-1-ylbutanoate (6.8 g, 81% yield) as brown oil. MS (EI) for C11H21NO2: 200 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Br[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH3:20]>CN(C=O)C.O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:19]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:2]2[CH3:1])[CH3:20])=[CH:22][CH:23]=1
Reactant: CC(Br)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1c(C)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)n(C(C)c2ccc(Cl)cc2)c2ccccc12
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a solution of ethyl 2-methyl-1H-indole-3-carboxylate (250 mg, 1.23 mmol) in anhydrous DMF (2 mL) was added NaH (60% in mineral oil, 74 mg, 1.85 mmol) at room temperature under N2. The reaction was stirred at 50-60° C. for 30 min. Then the reaction was cooled to 0° C. and a solution of 1-(1-bromoethyl)-4-chlorobenzene (from Example 35; 400 mg, 1.85 mmol) in DMF (1 mL) was added drop-wise. The reaction was stirred at room temperature overnight. Then the mixture was diluted with water and extracted with EtOAc. The organic extract was combined, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography using an eluent of petroleum ether/EtOAc (60:1) to afford the title compound as a yellow oil. (210 mg, yield 50.1%) 1H NMR (Methanol-d4, 400 MHz) δ 8.07-8.04 (m, 1H), 7.33-7.29 (m, 2H), 7.16-7.15 (m, 2H), 7.14-7.08 (m, 1H), 7.07-6.96 (m, 2H), 5.97 (q, J=7.2 Hz, J2=14.4 Hz, 1H), 4.37 (d, J=7.2 Hz, 2H), 2.76 (m, 3H), 1.95 (d, J=6.8 Hz, 3H), 1.43 (d, J=14.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[N:9][CH:10]=[C:4]2[CH:3]=1.[NH2:11][C:12]1[C:21]2[C:16](=[C:17](Br)[C:18]([CH3:22])=[CH:19][CH:20]=2)[N:15]=[N:14][C:13]=1[C:24]([NH2:26])=[O:25]>>[NH2:11][C:12]1[C:21]2[C:16](=[C:17]([C:2]3[CH:7]=[CH:6][N:5]4[CH:8]=[N:9][CH:10]=[C:4]4[CH:3]=3)[C:18]([CH3:22])=[CH:19][CH:20]=2)[N:15]=[N:14][C:13]=1[C:24]([NH2:26])=[O:25]
Reactant: Brc1ccn2cncc2c1
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccn2cncc2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 96 using 7-bromoimidazo[1,5-a]pyridine and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 2.44 (s, 3 H), 6.64 (dd, J=7.07, 1.52 Hz, 1 H), 7.44 (s, 1 H), 7.50 (s, 1 H), 7.71 (d, J=8.59 Hz, 1 H), 8.23 (d, J=8.84 Hz, 1 H), 8.35 (d, J=7.07 Hz, 1 H), 8.42 (s, 1 H); ESI-MS m/z [M+H]+ 319.1.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[Br:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[F:41])[C:35](Cl)=[O:36]>CN(C=O)C>[Br:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[F:41])[C:35]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]1[CH3:27])=[O:36]
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccc(F)c(Br)c1

Procedure:
1-(3-Bromo-4-fluorobenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)-ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 3-bromo-4-fluorobenzoyl chloride following the procedure described above in Example 1.