Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][C:14]=2[CH:22]=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:24][NH:25][S:26]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[CH2:32]2)(=[O:28])=[O:27]>>[CH3:24][NH:25][S:26]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])/[C:32]/2=[CH:22]\[C:14]1[NH:15][C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=2[C:13]=1[CH2:12][CH2:11][CH2:10][N:7]1[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]1)(=[O:28])=[O:27]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)N1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(C(C)=O)CC1)CCCC3)C(=O)N2
Yield: 52.7 %

Procedure:
3-[3-(4-Acetyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (70 mg, 0.22 mmol) was condensed with 5-methylaminosulfonyl-oxindole (50 mg, 1.01eq.) under the same conditions used in Example 1 to give 61 mg of the desired product.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:10])=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].CC(C)([O-])C.[K+].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>O1CCCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[N:3]([C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=2)[C:4]([Br:10])=[C:5]([Br:9])[C:6]=1[C:7]#[N:8]
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1c(Br)c(Br)n(C(=O)c2ccc(Cl)cc2)c1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2,4,5-tribromopyrrole-3-carbonitrile (5.0 g, 0.015 mol) and potassium t-butoxide (2.0 g, 0.018 mol) in dry tetrahydrofuran is stirred for 10 minutes at room temperature, treated dropwise with a solution of p-chlorobenzoyl chloride (3.25 g, 0.018 mol) in tetrahydrofuran, heated at reflux temperature for 3 hours, cooled and diluted with a mixture of water and ethyl acetate. The organic phase is separated, washed with brine, dried over Na and concentrated in vacuo to afford a tan solid residue. Recrystallization from benzene gives the title compound as a cream colored solid, 2.9 g (41.4%), mp 154°-157° C.
Reaction SMILES: [C:1]([C@:9]([C:24]([OH:26])=[O:25])([OH:23])[C@:10]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:14])[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:43]=[CH:42][C:31]2[C@@H:32]3[CH2:40][N:39]([CH3:41])[CH2:38][C@H:33]3[CH2:34][NH:35][C:36](=[O:37])[C:30]=2[CH:29]=1.C([C@](C([O-])=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C([O-])=O)(=O)C1C=CC=CC=1.CO>CO>[Cl:27][C:28]1[CH:43]=[CH:42][C:31]2[C@H:32]3[CH2:40][N:39]([CH3:41])[CH2:38][C@@H:33]3[CH2:34][NH:35][C:36](=[O:37])[C:30]=2[CH:29]=1.[C:15]([C@:10]([C:11]([O-:13])=[O:12])([OH:14])[C@:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:23])[C:24]([O-:26])=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN1C[C@H]2CNC(=O)c3cc(Cl)ccc3[C@@H]2C1
Reactant: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Agent: O=C([O-])[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)[O-])C(=O)c1ccccc1
Solvent: CO
Product: CN1C[C@@H]2CNC(=O)c3cc(Cl)ccc3[C@H]2C1
Reaction time: 1 h

Procedure:
A 12 L, 4-neck, flask was fitted with a mechanical stirrer, temperature probe and then charged with dibenzoyl-D-tartaric acid (189.7 g) and methanol (5.5 kg) under an atmosphere of nitrogen. Example 53 (126.3 g) was dissolved in methanol (1.48 kg) in a separate flask. A portion of the solution (13.5%) of Example 53 in methanol was added over a period of 1 hour to the dibenzoyl-D-tartrate/methanol solution. The solution was then seeded (seed crystals are prepared as described below) with product (250 mg). The remainder of the Example 53 solution was added over 7.5 hours. A rinse of methanol (278 mL) was employed to wash any remaining starting material residue from the 2 L Erlenmeyer flask, and the resultant mixture was pumped into the reaction vessel over 1 hour. The reaction was allowed to proceed for 14 hours. The suspension was filtered, washed with tert-butyl methyl ether (0° C., 2 L) and dried under vacuum to provide the title compound as the dibenzoyl-D-tartrate. The product exhibited an ee of 98.2%, as judged by reverse phase chiral HPLC analysis [Method: Isocratic elution: 70% aqueous (with 5 mM phosphate buffer, pH 6.9): 30% acetonitrile for 15 minutes. Column: Chiralpak® AS-RH (4.6 mm×150 mm) Temperature 35° C. The wavelength that is used for calculations was 210 nm.]. The salt was freebased by the addition of ethyl acetate (1 L) and extraction with 15% aqueous K3PO4 (600 mL) twice. The combined basic aqueous layers were then extracted with ethyl acetate (500 mL). The combined organic layers were then extracted with 20% brine (500 mL) twice. The title compound was obtained by evaporation of the organic layer under vacuum (47.5 g). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.12 (s, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.49 (dd, J=2.5, 8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 3.26 (m, 1H), 3.20 (m, 1H), 3.11 (m, 1H), 3.08 (m, 1H), 2.84 (dd, J=9.0, 10.5 Hz, 1H), 2.62 (m, 2H), and 2.18 (m, 1H); MS (ESI+) m/z 251 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>O1CCCC1>[C:32]([O:22][C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:4]=1)=[O:23])(=[O:34])[CH3:33]
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (1.51 g, 3 mmol) and pyridine (285 mg, 3.6 mmol) were dissolved in tetrahydrofuran (6 mL). Acetyl chloride (234 mg, 3.3 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure. 2 N hydrochloric acid was added to the residue, and it was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated, the residue was recrystallized from n-hexane-ethyl acetate to give the title compound (1.06 g, 83.0%) as a white solid.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[NH:19][CH2:1][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1
Reactant: Nc1nccs1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2nccs2)CC1

Procedure:
The title compound was prepared as described in EXAMPLE 25, except using benzyl 4-formyl-1-piperidinecarboxylate (300 mg, 1.21 mmol) and 2-amino-1,3-thiazole (133 mg, 1.33 mmol) as starting materials to give the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[CH:41]([N:44]([CH2:48][C:49]([OH:51])=O)[CH:45]([CH3:47])[CH3:46])([CH3:43])[CH3:42]>>[CH:45]([N:44]([CH:41]([CH3:42])[CH3:43])[CH2:48][C:49]([NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1)=[O:51])([CH3:46])[CH3:47]
Reactant: CC(C)N(CC(=O)O)C(C)C
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN(C(C)C)C(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure described for the parallel synthesis of C-17 amides above, using diisopropylamino-acetic acid as the reacting carboxylic acid. LCMS: m/e 671.7 (M+H)+, 4.99 min (method 3). 1H NMR (599 MHz, <DMSO_CDCl3>) δ=8.45-8.37 (m, 1H), 7.89 (d, J=8.2 Hz, 2H), 7.69-7.65 (m, 1H), 7.24-7.20 (m, 2H), 5.31-5.24 (m, 1H), 4.79-4.73 (m, 1H), 4.67-4.62 (m, 1H), 3.95 (br. s., 2H), 3.66 (d, J=5.9 Hz, 3H), 2.94 (s, 1H), 2.78 (s, 1H), 2.74 (br. s., 1H), 2.63 (d, J=13.5 Hz, 1H), 2.30 (t, J=9.1 Hz, 1H), 2.13 (dd, J=6.2, 16.7 Hz, 1H), 2.07-1.98 (m, 1H), 1.75 (br. s., 1H), 1.72 (s, 4H), 1.69-1.61 (m, 1H), 1.52-1.41 (m, 8H), 1.36-1.33 (m, 3H), 1.33-1.31 (m, 2H), 1.30-1.28 (m, 3H), 1.28-1.25 (m, 3H), 1.09 (s, 6H), 1.01 (s, 6H), 0.93 (br. s., 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])[CH:11]=[C:10]([C:24]([O:26]C(C)(C)C)=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:23])([C:19]([F:20])([F:21])[F:22])[C:15]([F:17])([F:18])[F:16])[CH:11]=[C:10]([C:24]([OH:26])=[O:25])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(O)(C(F)(F)F)C(F)(F)F)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(O)(C(F)(F)F)C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a DCM (7.8 mL) solution of tert-butyl 4′-methyl-5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]biphenyl-3-carboxylate (0.6 g, 1.5 mmol) from step A was added trifluoroacetic acid (7.8 mL). The mixture was stirred at rt for 2 h and concentrated to dryness. The crude title compound was used in step C without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.[H-].[Na+].Br[CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:18][CH:19]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1
Reactant: CCOC(=O)CCCCBr
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Reaction time: 18 h

Procedure:
To a solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) (1.0 equiv.) in dimethylformamide (0.10 M) 22° C. was added 60% dispersion of sodium hydride in mineral oil (1.5 equiv.) and the resulting mixture was allowed to stir for 30 min At this point, ethyl 5-bromopentanoate (1.2 equiv.) was added to this mixture. The reaction mixture was then allowed to stir for 18 hours, after which it was diluted with ethyl acetate and water. The biphasic layers were separated and the organic layer was washed twice with water. The organic layer was dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by RP-HPLC using a 10-50% MeCN in water gradient. The resulting trifluoroacetate salt was then converted to the free base form by utilizing a StratoSpheres™ PL-SO3H SPE ion exchange resin, delivering ethyl 5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenoxy)pentanoate as a solid. 1H NMR (Acetone-d6): δ 8.80 (s, 1H), 8.74 (s, 1H), 8.33 (d, 1H), 7.47 (s, 1H), 7.24 (d, 1H), 7.17 (d, 2H), 6.85 (d, 2H), 4.10 (q, 2H), 3.97 (t, 2H), 3.25 (t, 2H), 3.07 (t, 2), 2.50 (s, 3H), 2.37 (t, 3H), 1.74-1.84 (m, 4H), 1.21 (t, 3H). LRMS [M+H]=458.2
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].C(N[C@H](C(O)=O)COCC1C=CC=CC=1)(OC(C)(C)C)=O.NC1C=CC=CC=1.ON1C2C=CC=CC=2N=N1.C(O)(C(F)(F)F)=O>CS(C)=O.C(Cl)CCl>[CH2:29]([O:28][CH2:27][CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[C:18](=[O:19])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(COCc1ccccc1)C(=O)Nc1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: Nc1ccccc1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(COCc1ccccc1)C(=O)Nc1ccccc1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-benzyloxy-N-phenyl-propionamide (prepared by reaction of N-Boc-O-benzyl-L-serine with aniline in the presence of N-hydroxy-benzotriazole and EDC, followed by deprotection with TFA) in DMSO to provide the title compound in good yield.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=[O:40]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: O=C(Cl)OC1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC3CCCCC3)cc1)n2C)c1ccccc1
Yield: 25 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and cyclohexyl chloroformate. Yield: 25% of theory, C34H38N6O5 (610.7) Rf value: 0.44 (silica gel; dichloromethane/ethanol=19:1) ##EQU64##
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C@H:17]([CH3:32])[C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]1)=[O:19])[CH2:12][CH2:11][CH2:10]2>>[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C@H:17]([CH3:32])[C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26]3[CH:27]=[CH:28][C:29]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:30][CH:31]=3)[CH2:24][CH2:25]1)=[O:19])[CH2:12][CH2:11][CH2:10]2
Reactant: C[C@H](C(=O)N1CCN(c2ccccc2)CC1)N1CCCc2cc(Cl)ccc21
Reactant: O=S(=O)(O)Cl
Product: C[C@H](C(=O)N1CCN(c2ccc(S(=O)(=O)Cl)cc2)CC1)N1CCCc2cc(Cl)ccc21
Temperature: 0 °C
Yield: 10 %

Procedure:
To a 0° C. solution of chlorosulfonic acid, was added (R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-1-(4-phenylpiperazin-1-yl)propan-1-one over 5 minutes. The resultant solution was heated to 120° C. for 2 hrs. The reaction mixture was cooled and carefully poured into ice-water (750 mL). The solution was extracted with methylene chloride (4×250 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification via silica gel chromatography using 40-70% ethyl acetate in hexane gave 4-(4-((R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)benzene-1-sulfonyl chloride as a yellow oil (760 mg, 10%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=482.3; tR=3.65 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[C:4]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:3]=1.[H-].[Na+].[CH2:21](I)[CH3:22]>CN1CCCC1=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:21][CH3:22])[N:9]=[CH:10][C:5]2=[C:4]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:3]=1
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cn[nH]c2n1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21

Procedure:
To 6-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (0.418 mmol), NaH (60% in oil, 2.1 mmol) and ethyl iodide (2.1 mmol) is added N-methylpyrrolidinone (1 mL). After 5 min the reaction mixture is heated in the microwave at 175 C for 10 min. Reverse phase HPLC gave the product.
Reaction SMILES: I[CH2:2][CH3:3].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][C:26]([CH3:27])=[C:21]3[NH:20][C:19]2=[O:28])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][C:26]([CH3:27])=[C:21]3[N:20]([CH2:2][CH3:3])[C:19]2=[O:28])=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCI
Reactant: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2nccc(C)c21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Iodoethane (0.289 mL) was added to a mixture of 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (998 mg) and cesium carbonate (1.96 g) in DMF (10 mL) at room temperature. The mixture was stirred at 50° C. for 4 h. The mixture was diluted with water at room temperature and extracted with AcOEt. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 15%-30% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (801 mg) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15]>O1CCOCC1>[Br:1][C:2]1[S:6][C:5]([S:7]([NH:15][CH2:14][CH2:13][O:12][CH3:11])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: C1COCCO1
Product: COCCNS(=O)(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.2 %

Procedure:
A mixture of 5-bromothiophene-2-sulfonyl chloride (1 g, 3.82 mmol) and 2-methoxyethanamine (0.43 g, 5.73 mmol, 1.5 eq) in 1,4-dioxane (20 mL) was stirred at r.t. for 2.5 h. The mixture was evaporated under reduced pressure. The residue was purified by column chromatography (PE100%-EtOAc100%) to afford 5-bromo-N-(2-methoxyethyl)thiophene-2-sulfonamide (1 g, 87%). LC-MS (m/z)=301 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][C:13]=2[F:27])[CH2:11][CH2:10]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[C:35](=[CH2:46])[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Si:5]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:35](=[CH2:46])[C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])=[CH:14][C:13]=2[F:27])[CH2:11][CH2:10]1)([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:7])[CH3:6]
Reactant: CC1(C)OB(c2ccc(C3(O[Si](C)(C)C(C)(C)C)CC3)c(F)c2)OC1(C)C
Reactant: C=C(Br)C(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C=C(C(=O)OCc1ccccc1)c1ccc(C2(O[Si](C)(C)C(C)(C)C)CC2)c(F)c1
Temperature: 95 °C
Yield: 37.2 %

Procedure:
To a stirred and degassed (degassed with Argon) suspension of tert-butyl(1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropoxy)-dimethylsilane (10.23 g, 26.09 mmol, leg), Cs2CO3 (30.69 g, 78.27 mmol, 3 eq), and benzyl 2-bromoacrylate (9.59 g, 39.14 mmol, 1.5 eq) in DMF (100 mL) was added Pd(dppf)Cl2 (1.06 g, 1.305 mmol, 0.05 eq) and the mixture heated to 90-100° C. for 1 h. The reaction mixture was filtered through celite pad, diluted with water (100 mL) and extracted with ethyl acetate (250 mL). The ethyl acetate layer was washed with water (150 mL), brine (200 mL), dried (Na2SO4) and the solvent evaporated to get crude benzyl 2-(4-(1-(tert-butyldimethylsilyloxy)-cyclopropyl)-3-fluorophenyl)acrylate (4.14 g) as a yellow oil which was used for the next stage without purification (TLC system: EtOAc/PE (1:49), Rf: 0.5).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([CH3:13])=[CH:5][C:4]=1[OH:14].O[CH2:16][CH:17]=[C:18]([CH3:42])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:41])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:40])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:39])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:38])[C:35]([OH:37])=[O:36]>>[C:35]([C:34]([CH3:38])=[CH:33][CH2:32][CH2:31][C:30]([CH3:39])=[CH:29][CH2:28][CH2:27][C:26]([CH3:40])=[CH:25][CH2:24][CH2:23][C:22]([CH3:41])=[CH:21][CH2:20][CH2:19][C:18]([CH3:42])=[CH:17][CH2:16][C:5]1[C:4]([OH:14])=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]=1[CH3:13])([OH:37])=[O:36]
Reactant: CC(=CCO)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: COc1c(C)cc(O)c(OC)c1OC
Product: COc1c(C)c(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O)c(O)c(OC)c1OC
Yield: 59.8 %

Procedure:
The procedures of Example 1 were repeated except that 5 g of 2,3,4-trimethoxy-5-methylphenol and 3.2 g of 20-hydroxy-2,6,10,14,18-pentamethyl-2,6,10,14,18-eicosapentaenoic acid were employed as the starting materials to give 2.8 g of the title compound as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:29])[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[O:16]2)=[C:11]([O:30]C)[CH:10]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.C([O-])(=O)C.[Na+]>C(Cl)Cl>[OH:30][C:11]1[CH:10]=[C:9]([OH:8])[CH:18]=[C:17]2[C:12]=1[C:13](=[O:29])[CH:14]=[C:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[O:16]2
Reactant: COc1ccc(-c2cc(=O)c3c(OC)cc(OCc4ccccc4)cc3o2)cc1OC
Agent: CC(=O)[O-]
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(=O)c3c(O)cc(O)cc3o2)cc1OC
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
7-benzyloxy-3',4',5-trimethoxy flavone (565 mg, 1.35 mmol) was dissolved in 17 mL of methylenechloride, and then 1M of boron trichloride (3.79 mL, 3 equivalents) was added at temperature of 0° C. Then the reaction mixture was stirred for 30 minutes. When aqueous sodium acetate solution (5 mL) was added to the resultant reaction mixture, the product was obtained as a yellow crystal. The product was triturated with hexane and filtered to give the titled product (271 mg, 64%).