Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:29][C:28]3[C:23](=[N:24][CH:25]=[CH:26][C:27]=3Cl)[CH:22]=2)=[CH:17][CH:16]=1)[CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:34]=1[OH:42].C(=O)([O-])[O-].[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[F:32][C:33]1[CH:38]=[C:37]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:35][C:34]=1[O:42][C:27]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([CH2:14][N:7]([CH2:8][CH:9]4[CH2:13][CH2:12][CH2:11][O:10]4)[C:6](=[O:31])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:16][CH:17]=3)[S:29][C:28]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(-c2cc3nccc(Cl)c3s2)cc1)CC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1)CC1CCCO1
Temperature: 180 °C
Yield: 19.8 %

Procedure:
To a solution of 77 (1.0 g, 2.18 mmol) in Ph2O (10 ml) was added 2-fluoro-4-nitrophenol (856 mg, 5.45 mmol) and potassium carbonate (904 mg, 6.55 mmol). The reaction mixture was heated at 180° C. for 4 hrs, cooled to room temperature, diluted with DCM, filtered and concentrated. The residue was purified by column chromatography, eluent EtOAc:hexane 8:2, to afford title compound 78 (250 mg, 20% yield). MS (m/z): 580.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]([C:12]([OH:14])=O)[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=O.[NH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:20]1=[O:26]>>[O:26]=[C:20]1[CH:19]([N:18]2[C:12](=[O:14])[C:5]3[C:6](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=3[N+:15]([O-:17])=[O:16])[C:7]2=[O:9])[CH2:24][CH2:23][C:22](=[O:25])[NH:21]1
Reactant: COc1ccc(C(=O)O)c(C(=O)O)c1[N+](=O)[O-]
Reactant: NC1CCC(=O)NC1=O
Product: COc1ccc2c(c1[N+](=O)[O-])C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
reacting 4-methoxy-3-nitro-phthalic acid with 3-aminopiperidine-2,6-dione, in one embodiment, in the presence of a coupling reagent, to form 2-(2,6-dioxopiperidin-3-yl)-5-methoxy-4-nitroisoindoline-1,3-dione;
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:31](=[O:32])[CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Cc1ccccc1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Cc3ccccc3)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and phenylacetyl chloride provided the title compound. ESMS [M+H]+: 422.2
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:18]([F:33])[CH:17]=2)[CH2:11][S:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CO[C:37](OC)([CH3:39])[CH3:38].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:7]1[C@@H:8]2[C@H:13]([C@H:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])=[C:18]([F:33])[CH:17]=3)[CH2:11][S:10][CH2:9]2)[O:14][C:37]1([CH3:39])[CH3:38])=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2ccc(NC(=O)OCc3ccccc3)c(F)c2)[C@@H]1O
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H]2CSC[C@@H](Cc3ccc(NC(=O)OCc4ccccc4)c(F)c3)[C@@H]2OC1(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of [(3R*,4S*,5S*)-5-(4-benzyloxycarbonylamino-3-fluoro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (50.5 g, 102.9 mmol) and acetone dimethylketal (263 mL, 2.06 mol) in CH2Cl2 (500 mL) was added p-TsOH (200 mg, 1 mmol) at 0-5° C. and the reaction mixture was stirred for 4 h at 25° C. The reaction mixture was washed with saturated NaHCO3 solution and water, dried over MgSO4, filtered and evaporated to dryness. The title compound obtained as a yellow oil was used as such in the next step: TLC (toluene-EtOAc 3:1) Rf=0.40; HPLC RtA=2.80 min; ESIMS [M−H]−=529; 1H NMR (400 MHz, CDCl3): δ 7.99 (m, 1H), 7.38 (m, 5H), 6.92 (m, 2H), 6.84 (s, 1H), 5.21 (s, 2H), 3.3-3.6 (m, 2H), 3.03 (m, 2H), 2.52 (m, 2H), 2.38 (dt, 1H), 2.34 (t, 1H), 2.20 (m, 1H), 1.58 (s, 3H), 1.52 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Yield: 36.8 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-[(3,4-dichlorophenyl)sulfonyl]piperidine (200 mg, 0.68 mmol) was reacted with 2-chloro-5-(trifluoromethyl)pyridine (172 mg, 0.96 mmol) to afford the title compound (110 mg), a white solid, in 37% yield.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:19]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[NH:21][C:20]=1[C:29]([O:31]CC)=[O:30])[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[OH-].[K+].Cl>O>[CH2:1]([NH:8][CH:9]([C:19]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[NH:21][C:20]=1[C:29]([OH:31])=[O:30])[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C(NCc1ccccc1)C(=O)NC1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1[nH]c2cc(Cl)ccc2c1C(NCc1ccccc1)C(=O)NC1CCCCC1
Yield: 79.8 %

Procedure:
The mixture of 10 (28 mg), EtOH (0.5 mL), water (0.5 mL), KOH (10 mg) was reflux for 5 h. After cooling, the reaction mixture was acidified with 1M HCl (pH˜6). Then the mixture was extracted with DCM (10 mL×3). The combined organic layer was dried over sodium sulfate. After evaporation of the solvent, 21 mg of yellow solids (74%) was obtained. HPLC/MS: tR=12.10 min; m/z=440.4 [M+H]+ HRMS: C24H27N3O3Cl, 440.1741 (calcd.), 440.1721 (found). 1H NMR (600 MHz, DMSO, a mixture of rotamers): 0.85-1.63 (m, 16H), 3.57 (m, 2H), 4.17 (ABd, 1H, J=16.2 Hz), 4.22 (ABd, 1H, J=15.6 Hz), 4.67 (ABd, 1H, J=16.8 Hz), 4.88 (ABd, 1H, J=15.6 Hz), 6.10 (s, 1H), 6.51 (m, 1H), 6.60 (s, 1H), 6.78 (m, 2H), 6.91-7.28 (m, 7H), 7.66-7.91 (m, 4H), 8.27 (s, 1H), 8.34 (s, 1H), 11.56 (s, 1H), 11.88 (s, 1H), 13.15 (br.s, 1H), 13.53 (br.s, 1H). 13C NMR (150 MHz, DMSO, a mixture of rotamers): 25.0, 25.1, 25.5, 32.5, 32.6, 47.0, 48.5, 56.2, 112.4, 121.3, 122.4, 125.2, 125.8, 126.7, 126.8, 127.1, 127.7, 127.9, 129.0, 129.3, 136.4, 138.0, 164.2, 168.8.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:23])C(=O)C1>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[Cl:23]
Reactant: Brc1cccc(NCC2CCOCC2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Clc1ccc(NCC2CCOCC2)nc1Br
Temperature: 80 °C
Yield: 53.1 %

Procedure:
To a solution of 6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (20 g, 74 mmol) in acetonitrile (240 mL) was added NCS (9.85 g, 74 mmol). The mixture was heated to 80° C. for 3 hr. The reaction mixture was allowed to cool to ambient temperature and concentrated in vacuo. The resulting residue was diluted with brine (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, EtOAc/heptane=0/100 to 50/50] providing 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (12 g) and a mixture of 6-bromo-3,5-dichloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine/6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (5 g, ratio ˜2:3).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36][O:37]S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36][O:37][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH2:6][CH3:7])[C:4]([OH:23])=[O:3])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(CC)(Cc1ccc(O)cc1)Oc1ccccc1
Product: CCC(Cc1ccc(OCCc2nc(-c3cccs3)oc2C)cc1)(Oc1ccccc1)C(=O)O

Procedure:
The title compound was prepared from 2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the method of Example 46. 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, 1H, J=3.6, 0.8 Hz), 7.37 (dd, 1H, J=5.2, 1.2 Hz), 7.33-7.27 (m, 2H), 7.09-7.05 (m, 2H), 7.02-6.96 (m, 4H), 6.78-6.73 (m, 2H), 4.16 (t, 2H, J=6.6 Hz), 3.29 (s, 2H), 2.94 (t, 2H, J=6.6 Hz), 2.34 (s, 3H), 2.14 (qd, 1H, J=14.8, 7.6 Hz), 2.07 (qd, 1H, J=14.8, 7.6 Hz), 0.91 (t, 3H, J=7.6 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:19])[NH:15][CH2:16][CH2:17][CH3:18])(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([NH:15][CH2:16][CH2:17][CH3:18])=[O:19]
Reactant: CCCNC(=O)c1ccccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCNC(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Propylcarbamoyl-phenyl)-carbamic acid tert-butyl ester (0.570 g, 0.00205 mol) was dissolved in Methylene chloride (5.0 mL, 0.078 mol) and Trifluoroacetic Acid (3.0 mL, 0.039 mol) was added to the mixture. The reaction was allowed to stir overnight at room temperature. The reaction mixture was reduced under nitrogen and the crude product (360 mg, 99%) was used in subsequent chemistry without further purification. The excess TFA will be neutralized in the next synthetic step. LC/MS (ESI): 179.24.
Reaction SMILES: [N+]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][C:8]=2[C:18]=1[CH2:19][C:20]#[N:21])([O-])=O.[OH:22]S(O)(=O)=O.O>O.C(O)(=O)C.[Zn]>[C:12]1([C:10]2[O:11][C:7]3[C:8]([N:9]=2)=[C:18]2[C:4](=[CH:5][CH:6]=3)[NH:21][C:20](=[O:22])[CH2:19]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CCc1c([N+](=O)[O-])ccc2oc(-c3ccccc3)nc12
Reactant: O=S(=O)(O)O
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2c(ccc3oc(-c4ccccc4)nc23)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of (5-nitro-2-phenyl-benzoxazole4-yl)-acetonitrile (1.10 g, 3.98 mmol) (Starting Material 5) was suspended in concentrated H2SO4 /H2O (1/1, 25 mL) and stirred at 100° C. for 30 min. The resulting solution was diluted with water and extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude acid. To a solution of the crude acid in acetic acid (10 mL) heated at reflux was added excess zinc dust (1.57 g, 24.2 mmol) portionwise during thirty minutes or until the reaction solution clarified. The mixture was filtered through a Celite® (Fisher Scientific) pad and washed with hot DMF. The solvent was removed in vacuo and residue was suspended and stirred for 30 minutes in 3M hydrochloric acid. The insoluble solid material was collected, washed with water, and air dried to give 2-phenyl-6,8-dihydro-oxazolo[4,5-e]indol-7-one. (Yield 180 mg, 18%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH3:20])=[CH:6]2.[H-].[Na+].F[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>CN(C=O)C>[CH3:20][C:7]1[C:8]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:9]([O:13][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=2)[C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(C)cc2c1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 70 °C
Yield: 40.8 %

Procedure:
A solution of crude 3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenol (7) (1.83 g) in DMF (8 mL) was slowly added dropwise to an ice-water cooled suspension of NaH (60% dispersion in oil) (0.179 g, 4.48 mmol) in DMF (8 mL) with stirring under N2. The ice-water bath was removed and the reaction mixture was allowed to stir at RT for 10 min. To the reaction mixture was added a solution of 4-fluorobenzaldehyde (0.9 mL, 1.04 g, 8.39 mmol) in DMF (3 mL). The reaction mixture was heated at 70° C. for 18 h. The reaction mixture was partially concentrated and the crude product was partitioned between CH2Cl2 and H2O. The organic phase was separated, dried over MgSO4, filtered, and the filtrate was concentrated to give the crude title compound. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (9:1) to give 1.04 g (66%) of compound (8) as a yellow amorphous solid. 1H NMR (400 MHz; DMSO-d6): δ 2.19 (s, 3H), 3.88 (s, 3H), 6.78 (d, J=8.6 Hz, 2H), 7.09 (dd, J=2.6 Hz, 9.1 Hz, 1H), 7.19 (m, 2H), 7.24 (m, 1H), 7.30 (m, 2H), 7.38 (d, J=2.4 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.70 (d, J=8.7 Hz, 2H), 7.75 (s, 1H), 9.78 (s, 1H). AP LRMS m/z 369 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[C:32]1([S:42]([NH2:45])(=[O:44])=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:45][S:42]([C:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=[CH:34][CH:33]=3)(=[O:43])=[O:44])=[O:31])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: NS(=O)(=O)c1cccc2ccccc12
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2cccc3ccccc23)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 1-naphtylsulfonamide (Arnswald, M.; Neumann, W. P. Chem. Ber., 1991, 124, 1997; Khorgami, M. H. Synthesis, 1972, 574).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27](O)=[O:28])=[CH:20][C:19]=3[CH:30]=2)=[CH:11][CH:10]=1)[CH2:7][CH3:8])[CH3:2].S(Cl)(Cl)=O.[CH3:35][N:36]([CH:38]=O)[CH3:37]>>[CH2:1]([O:3][CH2:4][CH2:5][N:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:30]=[CH:19][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([NH:6][C:9]4[CH:14]=[CH:13][C:12]([CH2:38][N:36]([CH3:35])[CH:37]5[CH2:5][CH2:4][O:3][CH2:1][CH2:2]5)=[CH:11][CH:10]=4)=[O:28])=[CH:20][C:17]=3[CH:16]=2)=[CH:13][CH:14]=1)[CH2:7][CH3:8])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Solvent: O=S(Cl)Cl
Product: CCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1

Procedure:
In DMF (5 ml) was dissolved 7-[4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.2 g). To the solution was added, under ice-cooling, thionyl chloride (0.09 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (25 ml). The solution was added dropwise a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.20 g) and triethylamine (0.35 ml) in THF (5 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere stirred at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-[4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 5) (0.23 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Oc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2Cl)CC1
Temperature: 65 °C
Yield: 50.2 %

Procedure:
To a stirred solution of 2-chlorophenol (20 g, 0.155 mole) in DMF (200 mL), was added cesium carbonate (101 g, 0.311 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (43.45 g, 0.155 mole). The reaction mixture was heated at 65° C. for 7 hours. The mixture was then filtered and concentrated under reduced. The resulting residue was diluted with ice cold water and the solid obtained was filtered and washed with water. The solid was dissolved in ether, washed with 2.5N aqueous NaOH solution, dried over sodium sulfate and concentrated under reduced pressure to afford 24.24 g (50%) of 4-(2-chloro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 312.13 (M+1)+, 98.35%. A solution of 4-(2-chloro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (24.2 g, 0.0776 mole) in dioxane.HCl (30 mL), was stirred at ambient temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 19.13 g (99.6%) of 4-(2-chloro-phenoxy)-piperidine hydrochloride. LCMS: 248.05 (M+1)+, 92.79%. 1H NMR (DMSO-d6): δ 9.3-8.9 (bs, 2H), 7.5-7.42 (d, 1H), 7.38-7.24 (m, 2H), 7.04-6.94 (t, 2H), 4.8-4.7 (m, 1H), 3.3-3.0 (bd, 4H), 2.2-2.05 (bs, 2H), 2.0-1.8 (bs, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17](O)[CH2:18][N:19]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[S:20]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.C(N(S(F)(F)[F:47])CC)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([F:47])[CH2:18][N:19]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[S:20]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1cccc(N(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Product: COc1cccc(N(CC(F)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
An oven dried 20 ml scintillation vial containing N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)-4-nitrobenzenesulfonamide (18.3 mg, 0.027 mmol; see representative procedure 3 above) was purged with N2 and charged with anhydrous dichloromethane (1.5 ml, 0.018 M). The sealed vial was cooled in a dry ice acetone bath before the dropwise addition of diethylaminosulfur trifluoride (DAST, 7 ul, 0.053 mmol). The reaction temperature was maintained at −78° C. for an hour and then slowly warmed to room temperature and stirred overnight. The reaction was quenched with 2.0 ml of saturated NaHCO3 solution and diluted with 6 ml CH2Cl2 and extracted three times. The combined organics were dried over Na2SO4, filtered and condensed. Crude product carried forward. Quantitative yield.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]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:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:49]=1[CH2:50][NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][CH2:50][C:49]4[CH:52]=[CH:53][C:54]([F:56])=[CH:55][C:48]=4[F:47])=[O:42])[CH2:36][CH2:35]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:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccc(F)cc1F
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2ccc(F)cc2F)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(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]-piperidin-4-yl}-acetic acid was reacted with 2,4-difluorobenzylamine (Aldrich) to give the title product. LC-MS (ES+) 790 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([O:12]C)=[O:11])=[CH:4][C:3]=1[I:14].[OH-].[Li+].Cl>CO.O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[I:14]
Reactant: COC(=O)c1cc(I)c(N)nc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1nc(N)c(I)cc1C(=O)O
Temperature: 70 °C
Yield: 97.4 %

Procedure:
To a solution of methyl 6-amino-5-iodo-2-(methyloxy)-3-pyridinecarboxylate (1.4 g, 4.54 mmol) in methanol (30 ml), 1M aqueous lithium hydroxide (9 ml, 9 mmol) was added and the mixture was heated at 70° C. for 2 h. After cooling to room temperature, the mixture was concentrated in vacuo to give a solid. The residual solid was dissolved in water (50 ml) and acidified (pH=5) by addition of 2N aqueous hydrochloric acid. The resultant solid was collected by filtration, washed with water and dried in vacuo under 60° C. to give 1.3 g (92%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O.C(=O)([O-])O.[Na+]>C(O)C>[Br:8][C:7]1[C:2]2[N:3]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:1]=2)[CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: Nc1ncc(Cl)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(-c2cn3cc(Cl)cc(Br)c3n2)cc1
Reaction time: 6 h

Procedure:
17 g (82 mmol) of 2-amino-3-bromo-5-chloropyridine dissolved in 150 ml of ethanol are reacted with 29 g of 2-bromo-1-(4-chlorophenyl)-1-ethanone and 14 g of sodium hydrogen carbonate. The mixture is brought to the refluxing temperature for 6 h and cooled. The precipitate is filtered off and rinsed with CH2Cl2, and the filtrate is concentrated under reduced pressure. After recrystallization of the evaporation residue in ethyl acetate, the compound melts at 178° C.