Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH:12]=O)[CH2:3][CH2:2]1.Cl.[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[C:16]1[C:24]([NH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:25]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][N:30]2[CH2:29][CH2:28][CH:27]([NH:26][C:24]([C:16]3[O:15][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH:17]=3)=[O:25])[CH2:32][CH2:31]2)[CH2:3][CH2:2]1
Reactant: O=CCC1CCOc2ccccc21
Reactant: O=C(NC1CCNCC1)c1cc2ccccc2o1
Agent: Cl
Product: O=C(NC1CCN(CCC2CCOc3ccccc32)CC1)c1cc2ccccc2o1
Reaction time: 8 h
Yield: 25.7 %

Procedure:
To a stirred solution of 2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethanal (875 mg, 5 mmol) and 4-(2-benzofurancarboxamido) piperidine hydrochloride (1.4 g, 5 mmol) under a nitrogen atmosphere, borane/pyridine complex (0.5 ml, excess) was added. The reaction was stirred overnight (ca 15 h) and evaporated to an oily gum which was neutralized by careful addition of 10% hydrochloric acid. The acidic solution was extracted with diethyl ether. The diethyl ether extracts were discarded. The acidic aqueous layer was basified by dropwise addition of 50% sodium hydroxide. The ethyl acetate layer was washed with distilled water, dried (Na2SO4), filtered and evaporated to afford an oily gum (520 mg). The resulting gum was purified by chromatography on silica (eluant: chloroform/ethanol/ammonium hydroxide; 85/14/1) to afford an oil (260 mg) which was crystallized from diethyl ether to afford the title compound (150 mg, 7%), mp=146-8°. Anal: C25H28N2O3 0.5 H2O, Calc. C, 72.62; H, 7.07; N, 6.77; Found C,72.40; H, 6.94; N, 6.83.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21]Br>CC(O)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18]([Br:21])[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1nc2ccsc2c(=O)n1Cc1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCC(Br)c1nc2ccsc2c(=O)n1Cc1ccccc1
Temperature: 60 °C

Procedure:
3-Benzyl-2-propylthieno[3,2-d]pyrimidin-4(3H)-one (1-5, 0.80 g, 2.81 mmol) was dissolved in AcOH (3.0 mL) and treated with Br2 neat 0.43 mL, 8.44 mmol). The reaction was warmed to 60° C. for 6 h, and then concentrated. The residue was purified by flash column chromatography (SiO2, 0-10% EtOAc/hexanes gradient) to give 3-benzyl-2-(1-bromopropyl)thieno[3,2-d]pyrimidin-4(3H)-one (1-6). 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J=5.2 Hz, 1H), 7.28 (m, 4H), 7.15 (d, J=7.0 Hz, 2H), 6.26 (d, J=16.5 Hz, 1H), 4.93 (d, J=16.5 Hz, 1H), 4.68 (t, J=7.1 H, 1H), 2.43 (m, 1H), 2.25 (m, 1H), 0.73 (t, J=7.0 Hz, 3H); MS 364.8 found 363.2 required.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:21][O:22][C:23]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:23]=4[O:22][CH3:21])[CH2:28]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: COc1ccc2c(c1OC)CCNC2
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccccc3)nc3ccccc13)C2
Yield: 11 %

Procedure:
Reaction of 2-phenylquinazolin-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 19 (11% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.73 and 2.99 (2t, 2H), 3.49 and 4.04 (2t, 2H), 3.69 and 3.75 (2s, 3H), 3.76 and 3.81 (2s, 3H), 4.42 and 4.94 (2s, 2H), 6.63 and 7.01 (2d, 1H), 6.80 and 7.08 (2d, 1H), 7.57-7.60 (m, 3H), 7.77-7.79 (m, 1H), 7.89-8.00 (2d, 1H), 8.07-8.19 (m, 2H), 8.50-8.57 (m, 2H); MS (ESI) m/z 426 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(CC)CC)C>C(O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:7]2[C:2]([NH:32][CH2:31][CH:28]3[CH2:27][CH2:26][N:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)[CH2:30][CH2:29]3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[CH:12][CH:13]=1
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: COc1ccc(NC(=O)c2cccnc2Cl)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2cccnc2NCC2CCN(c3ccncc3)CC2)cc1
Yield: 23.8 %

Procedure:
A pressure tube (Aldrich) was charged with 2-chloro-N-(4-methoxyphenyl)pyridine-3-carboxamide (139 mg, 0.524 mmol), 1-(4-pyridyl)piperidine-4-methylamine (100 mg, 0.524 mmol), triethylamine (0.22 mL), and ethanol (3 mL). The mixture was placed in a 110° C. bath for 5 days. The mixture was concentrated and the residue purified by RPHPLC, yielding 52 mg (24%) of the title compound as a hydrochloride salt.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH2:24]([Mg]Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
6-Methoxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (300 mg, 0.974 mmol) obtained in Example 1 was dissolved in THF and 1.2 equivalents of benzylmagnesium chloride were added thereto, followed by stirring for 3 hrs at 0° C. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 50 mg of the titled compound (yield: 13%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:11]=1[CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=NN=N1.[CH2:24]([O:27][P:28]([O:36][CH2:37][CH:38]=[CH2:39])N(C(C)C)C(C)C)[CH:25]=[CH2:26].C([O:44]O)(C)(C)C>>[P:28]([O:13][CH2:12][C:11]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:10]=1[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([O:27][CH2:24][CH:25]=[CH2:26])([O:36][CH2:37][CH:38]=[CH2:39])=[O:44]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Cl)c1CO
Reactant: CC(C)(C)OO
Reactant: C=CCOP(OCC=C)N(C(C)C)C(C)C
Agent: c1nnn[nH]1
Product: C=CCOP(=O)(OCC=C)OCc1c(Cl)cccc1CO[Si](C)(C)C(C)(C)C
Yield: 79 %

Procedure:
According to a similar procedure to that described in Example 1-(10), 2-[(tert-butyldimethylsilyl)oxymethyl]-6-chlorobenzyl alcohol (3.66 g, 12.8 mmol) obtained from Example 27-(1), tetrazole (2.23 g, 31.9 mmol), bis(allyloxy)(diisopropylamino)phosphine (described in Tetrahedron Lett., 30, 4219 (1989); 3.91 g, 16.0 mmol), and tert-butyl hydroperoxide (ca. 80% di-tert-butyl peroxide solution; Merck; 1.8 g, ca. 16 mmol) were reacted, and the reaction mixture was worked up to afford, after extraction, an oily residue. The residue was subjected to chromatography on a silica gel (200 g) column (eluent; ethyl acetate:hexane=1:5˜2:3) to afford the title compound (4.52 g, 79% yield) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.BrN1C(=O)CCC1=O.C1(C(OOC(=O)C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:34][C:35]1[N:40]=[C:39]([SH:41])[N:38]=[C:37]([OH:42])[CH:36]=1>C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>[CH3:34][C:35]1[N:40]=[C:39]([S:41][CH2:1][C:2]2[S:3][C:4]([CH3:7])=[CH:5][N:6]=2)[N:38]=[C:37]([OH:42])[CH:36]=1
Reactant: Cc1cnc(C)s1
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(O)nc(SCc2ncc(C)s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 37.9 %

Procedure:
To CCl4 (100 mL) in a 250 mL round bottom flask were added 2,5-dimethyl-1,3-thiazole (1.7 g, 15 mmol), 1-bromopyrrolidine-2,5-dione (2.94 g, 16.5 mmol), and benzoyl benzenecarboperoxoate (180 mg, 0.75 mmol). The reaction mixture was heated at 80° C. for 4 hours. The solvent was then removed under vacuum. The crude product was dissolved in ethanol (30 mL). 6-methyl-2-sulfanylpyrimidin-4-ol (700 mg, 5 mmol) and triethylamine (1.4 mL) were added, and the mixture was stirred at room temperature for 2 hours. After removal of the solvent, the crude product was purified by column chromatography (0-8% methanol in DCM) to provide the title compound as a white solid (480 mg, 40% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.25 (s, 3H), 2.50 (s, 3H), 4.56 (s, 2H), 6.03 (br, 1H), 7.55 (s, 1H); M+254.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7]Br.BrCCC=CCC.[C:16]([O:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:18])[CH3:17].[CH:26]([OH:32])=[CH:27][CH2:28][CH2:29]CC.[CH2:33]([OH:39])[CH2:34]CCC=C>>[Br:1][CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH3:7].[C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH2:29][CH2:28][CH2:27][CH2:26][O:32][C:33](=[O:39])[CH3:34])(=[O:18])[CH3:17].[C:16]([O:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:18])[CH3:17]
Reactant: BrCCC=CCCBr
Reactant: C=CCCCCO
Reactant: CCCCC=CO
Agent: CCC=CCCBr
Agent: CCCCC=COC(C)=O
Product: CC(=O)OCCCCC=CCCCCOC(C)=O

Procedure:
With reference to FIG. 25, olefin metathesis provides, however, an affordable method to produce 8-bromooctan-1-ol. The symmetrical 1,6 dibromo-3-hexene is made by the cross-metathesis of 1-bromo-3-hexene (removing the volatile 3-hexene under vacuum). 1-Bromo-3-hexene is prepared from commercially available leaf alcohol (Bedoukian, Danbury Conn.) that sells for approximately $50 U.S./Kg, and 1,10-diacetoxy-5-decene is prepared by the cross-metathesis of hexenyl acetate. Hexenyl acetate is prepared from hexenol by conventional methods. 5-Hexenol sells for approximately $50 U.S./Kg and is available from Degussa-Huls, Somerset, N.J.
Reaction SMILES: C1(=O)[O:6][C:4](=[O:5])[C:3]2=CC=CC=[C:2]12.[C:12]1(=[O:22])[O:17][C:15](=O)[CH:14]2[CH2:18][CH2:19][CH2:20]CC12>>[C:4]([OH:6])(=[O:5])[CH:3]=[CH2:2].[C:12]1(=[O:22])[O:17][CH2:15][CH2:14][CH2:18][CH2:19][CH2:20]1
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: O=C1OC(=O)c2ccccc21
Product: C=CC(=O)O
Product: O=C1CCCCCO1
Temperature: 125 °C

Procedure:
An acid-terminated caprolactone acrylate was prepared by combining 37.0 g of phthalic anhydride, 19.25 g of hexahydrophthalic anhydride, and 129.0 g of TONE Monomer M-100 in a glass, four-neck reaction flask equipped with a stirrer, a thermometer, an air inlet and an air outlet, and heating them at 125° C. for 3.5 hours. The product was recovered and found to have an Acid Number of 114 and a viscosity of 1690 cp when measured at 25° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][C:25]([O:29][CH3:30])([CH3:28])[CH2:24][CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:31][C:32]1[CH:57]=[CH:56][C:35]([CH2:36][CH2:37][O:38][C:39]2[CH:44]=[CH:43][C:42](B3OC(=O)CN(C)CC(=O)O3)=[CH:41][CH:40]=2)=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:42]2[CH:41]=[CH:40][C:39]([O:38][CH2:37][CH2:36][C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:57][CH:56]=3)=[CH:44][CH:43]=2)[C:3]=1[N:22]1[CH2:27][CH2:26][C:25]([O:29][CH3:30])([CH3:28])[CH2:24][CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC1(C)CCN(c2c(Br)c(C)nc(C)c2[C@H](OC(C)(C)C)C(=O)OC(C)C)CC1
Reactant: CN1CC(=O)OB(c2ccc(OCCc3ccc(F)cc3)cc2)OC(=O)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC1(C)CCN(c2c(-c3ccc(OCCc4ccc(F)cc4)cc3)c(C)nc(C)c2[C@H](OC(C)(C)C)C(=O)OC(C)C)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
PD(Ph3P)4 (143 mg, 0.124 mmol) was added to an argon-degassed solution of (S)-isopropyl 2-(5-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (300 mg, 0.618 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (177 mg, 0.68 mmol), potassium phosphate tribasic (984 mg, 4.63 mmol) in dioxane (5 ml) and water (1 ml) stirred in a screw-capped pressure vessel for 16 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (0-50% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate 300 mg (78%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.39-7.37 (m, 2H), 7.21-7.12 (m, 3H), 7.04-7.00 (m, 3H), 5.98 (br. s, 1H), 4.96-4.93 (m, 1H), 4.24-4.21 (m, 2H), 3.42-3.40 (m, 2H), 3.26-3.21 (m, 1H), 3.07-3.05 (m, 2H), 2.90-2.86 (m, 1H), 2.81 (s, 3H), 2.44 (s, 3H), 2.05 (s, 3H), 1.53-1.42 (m, 2H), 1.33-1.25 (m, 2H), 1.18 (d, J=6.2 Hz, 3H), 1.14-1.12 (m, 12H), 1.00/0.81 (s, 3H). UPLC (M+H)=621.6.
Reaction SMILES: [C:1](Cl)(=[O:8])[O:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.Cl.Cl.[F:13][C:14]1[CH:38]=[CH:37][CH:36]=[CH:35][C:15]=1[CH2:16][C:17]1[N:21]2[N:22]=[CH:23][CH:24]=[CH:25][C:20]2=[C:19]([C:26]2[N:31]=[C:30]([NH2:32])[C:29]([NH2:33])=[C:28]([NH2:34])[N:27]=2)[N:18]=1>N1C=CC=CC=1>[CH:1]([OH:8])=[O:2].[NH2:34][C:28]1[C:29]([NH:33][C:1](=[O:8])[O:2][CH:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)=[C:30]([NH2:32])[N:31]=[C:26]([C:19]2[N:18]=[C:17]([CH2:16][C:15]3[CH:35]=[CH:36][CH:37]=[CH:38][C:14]=3[F:13])[N:21]3[C:20]=2[CH:25]=[CH:24][CH:23]=[N:22]3)[N:27]=1
Reactant: O=C(Cl)OC1CCCC1
Reactant: Nc1nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc(N)c1N
Agent: Cl
Solvent: c1ccncc1
Product: Nc1nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc(N)c1NC(=O)OC1CCCC1
Product: O=CO

Procedure:
At 0° C., 37.5 mg (0.25 mmol) of cyclopentyl chlorocarbonate were added to 100 mg (0.25 mmol) of 2-[7-(2-fluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidine-4,5,6-triamine (Example 9A) in 2 ml of pyridine. The reaction mixture was concentrated and the residue was purified by preparative HPLC (acetonitrile:water (+0.1% formic acid) gradient). This gave 41 mg (32% of theory) of the target compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:8][NH:9]C(=O)C1C=CC(OCCCCCl)=CC=1)([CH3:4])([CH3:3])[CH3:2].N1CCOCC1.CN(C=O)C>CCOC(C)=O>[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:8][NH2:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(OCCCCCl)cc1)NS(=O)(=O)c1ccccc1
Solvent: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1

Procedure:
A stirring solution of 24-4 (500 mg, 1.0 mmol), morpholine (437 gL, 5.0 mmol), and DMF (5 mL) was heated at 80° C. for 20 hours. The cooled reaction mixture was diluted with EtOAc and then washed with H2O and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAc) gave 24-5 as a yellow solid. TLC Rf 0.14 (silica, EtOAc);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([N:11]([CH2:33][CH3:34])[CH:12]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[C:23]([CH3:24])=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[CH:26]=3)[NH:21][N:20]=2)=[O:18])[CH2:13]1)[CH3:10]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:32]#[C:31][C:27]2[CH:26]=[C:25]([C:22]3[NH:21][N:20]=[C:19]([C:17]([N:14]4[CH2:15][CH2:16][CH:12]([N:11]([CH2:33][CH3:34])[CH2:9][CH3:10])[CH2:13]4)=[O:18])[C:23]=3[CH3:24])[CH:30]=[CH:29][CH:28]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: C#Cc1cccc(-c2[nH]nc(C(=O)N3CCC(N(CC)CC)C3)c2C)c1
Product: CCN(CC)C1CCN(C(=O)c2n[nH]c(-c3cccc(C#Cc4ccc(Cl)cc4)c3)c2C)C1
Yield: 74 %

Procedure:
In analogy to the procedure described in Example 31F], 1-chloro-4-iodobenzene and (3-diethylamino-pyrrolidin-1-yl)-[5-(3-ethynyl-phenyl)-4-methyl-1H-pyrazol-3-yl]-methanone (Example 31E]) gave the title compound in 74% yield light yellow powder. MS: 461.1 (MH+, 1 Cl).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[CH2:14]([O:21][C:22]([NH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](O)=[O:28])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]([NH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([NH:1][C@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:28])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@H]1CCc2ccccc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Product: CC(C)(CC(=O)N[C@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1

Procedure:
Prepared from 3(S)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-on (Example 1, Step B) and 3-benzyloxycarbonylamino-3-methylbutanoic acid (Example 1, Step E) by the procedure described in Example 1, Step F. FAB-MS: calculated for C23H27N3O4 409; found 410 (M+H,100%). [a]D =-160° (C=1,CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][CH:6]=[C:5]([O:13][CH3:14])[C:4]=1B(O)O.[CH3:18][O:19][C:20](=[O:48])[C@H:21]([CH2:33][C:34]1[CH:39]=[CH:38][C:37](OS(C(F)(F)F)(=O)=O)=[CH:36][CH:35]=1)[NH:22][C:23](=[O:32])[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31]>>[CH3:18][O:19][C:20](=[O:48])[C@H:21]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:4]2[C:5]([O:13][CH3:14])=[CH:6][CH:7]=[C:8]([O:9][CH2:10][O:11][CH3:12])[C:3]=2[O:2][CH3:1])=[CH:38][CH:39]=1)[NH:22][C:23](=[O:32])[C:24]1[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COCOc1ccc(OC)c(B(O)O)c1OC
Product: COCOc1ccc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)c1OC

Procedure:
2,6-Dimethoxy-3-methoxymethoxybenzeneboronic acid and N-(2,6-dichlorobenzoyl)-O-(trifluoromethanesulfonyl)-L-tyrosine methyl ester were coupled by a similar method as described in Example 7-2) to give N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxy-3-methoxymethoxyphenyl)-L-phenylalanine methyl ester.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:23]=1)[C@@H:9]([OH:20])[CH2:10][C@H:11]([C:13](=[O:19])[NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:12])(C)(C)C.[ClH:37]>O1CCOCC1>[Cl-:37].[CH2:29]([O:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][C@H:8]([NH3+:7])[C@@H:9]([OH:20])[CH2:10][C@H:11]([C:13](=[O:19])[NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:12])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](Cc1cccc(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reactant: Cl
Solvent: C1COCCO1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H]([NH3+])Cc1cccc(OCc2ccccc2)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
[(1S*,2S*,4R*)-1-(3-Benzyloxy-benzyl)-4-butylcarbamoyl-2-hydroxy-pentyl]-carbamic acid tert-butyl ester (660 mg, 1.3 mmol) is dissolved in 4M HCl in dioxane (14 ml) and stirred at rt for 75 min. Evaporation of the solvent and washing the residue with diethyl ether gives a white foam (535 mg).
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([Br:9])[S:4][C:3]=1[C:10]([OH:12])=O.S(Cl)(Cl)=O.C(#[N:19])C.C(Cl)Cl.N.O1CCOCC1>Cl>[Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([Br:9])[S:4][C:3]=1[C:10]([NH2:19])=[O:12]
Reactant: CC#N
Reactant: N#Cc1c(Br)sc(C(=O)O)c1Br
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N#Cc1c(Br)sc(C(N)=O)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
3,5-Dibromo-4-cyanothiophene-2-carboxylic acid (5.90 g, 18.6 mmol) was added to a solution of thionyl chloride (27.1 mL, 371 mmol) in acetonitrile (40.0 mL, 766 mmol). The mixture was refluxed for 30 min then cooled to rt. The solvent was evaporated in vacuo to dryness to yield a lightly yellow solid. Methylene chloride (100 mL, 2000 mmol) was added to dissolve the solid, then the solution was cooled to 0° C. Under a nitrogen atmosphere, a solution of 0.500 M ammonia in 1,4-dioxane (111.5 mL, 55.7 mmol) was slowly added, and the mixture was brought to room temperature for 1 h. The mixture was evaporated in vacuo to give a solid residue. 100 mL of 1N HCl was added and the suspension was stirred for 1 h at room temperature. The solid product was collected by filtration and dried under high vacuum to give product (5.64 g, yield 98%). LCMS: (FA) ES−, 308, 310, 312.
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)C1C=CC=CC=1.C(O)(=O)CC(O)=O.S(Cl)([Cl:29])=O>N1C=CC=CC=1.N1CCCCC1>[C:1]([Cl:29])(=[O:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1ccccc1
Agent: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: O=Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)C=Cc1ccccc1

Procedure:
A cinnamic acid is first prepared by reacting a benzaldehyde with malonic acid in pyridine and piperidine. The cinnamic acid is then reacted with thionyl chloride to produce a cinnamoyl chloride derivative. The PECN is finally synthesized by reacting PECN with the cinnamoyl chloride derivative in an inert solvent (such as chloroform, nitrobenzene, chlorobenzene, or the like). The reaction mixture is diluted with methanol, filtered, dried in a vacuum, and milled by a vibrating mill, whereupon the PECN is obtained.
Reaction SMILES: C([O:14][C:15]1[C:26]2[C:25](=[O:27])[N:24]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH:23](O)[C:22]=2[C:21]([O:37][CH3:38])=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:39]C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:24]2[C:25](=[O:27])[C:26]3[C:22](=[C:21]([O:37][CH3:38])[C:20]4[N:19]=[CH:39][CH:18]=[N:17][C:16]=4[C:15]=3[OH:14])[CH2:23]2)=[CH:30][CH:31]=1
Reactant: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncn(Cc4ccccc4)c13)C(=O)N(Cc1ccc(F)cc1)C2O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c2c(c(O)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2
Reaction time: 1 h
Yield: 100 %

Procedure:
4-Benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-7-hydroxy-8-methoxy-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one 260 (28 mg, 0.047 mmol, 1 equiv.) was added to CH2Cl2 (1 mL) under a nitrogen atmosphere. Triethylsilane (200 μL) was added, followed by trifluoroacetic acid (200 μL). The reaction was allowed 1 hour and concentrated in vacuo until thoroughly dried. Hexanes/Ethyl ether (15 mL, 1/1 ratio) was added to the oil and sonicated. The resulting solid was then filtered and washed in Hexanes and air dried to give 7-(4-fluoro-benzyl)-5-hydroxy-9-methoxy-7,8-dihydro-pyrrolo[3,4-g]quinoxalin-6-one 261 (100%, 20 mg, 0.047 mmol) as a light gray powder. 1H NMR (300 MHz) CDCl3 δ 9.11 (bs 1 H), 7.86 (s, 1 H), 7.33-7.23 (m, 5 H), 7.01 7.07 (s, 4 H), 5.57 (s, 2 H), 4.71 (s, 2 H), 4.37 (s, 2 H), 3.57 (s, 3 H). 19F NMR (300 MHz) CDCl3 δ 62.25. MS: 418.2 (M+1)