Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[C:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH:9][C:10]=1[CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[O:5])[CH3:2].CO.[OH-].[Li+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[C:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH:9][C:10]=1[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCc1[nH]c(C(=O)OC(C)(C)C)c(C)c1C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CCC(=O)O)[nH]c(C(=O)OC(C)(C)C)c1C
Reaction time: 1 h
Yield: 110.4 %

Procedure:
5-(2-Ethoxycarbonyl-ethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1d (23.6 g, 66.8 mmol) was dissolved in 190 ml of tetrahydrofuran and 90 ml of methanol under stirring, and added with aqueous lithium hydroxide solution (80 ml, 10 mol/L, 0.8 mol) at room temperature. The color of the reaction solution gradually turned from light yellow to cyan, and stirred for another 1 hour. After thin lay chromatography showed the disappearance of starting materials, the resulting mixture was concentrated under reduced pressure to evaporate organic solvent. The residue was adjusted pH to 2 with hydrochloric acid solution (2 mol/L) in an ice-water bath under stirring. White precipitates were formed. The mixture was filtered, and the filter cake was dried to obtain the title compound 5-(2-carboxy-ethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1e (24 g, yield 98%) as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:31]=3[O:30][CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C=O)c1OC
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1OC

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,3-dimethoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 529;
Reaction SMILES: [BH4-].[Na+].COCCOCCOC.Br[CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][O:16][C:15]2[CH:24]=[CH:25][C:26]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:14]1=2>O>[CH:27]1[C:14]2[CH2:13][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]=2[CH:24]=[CH:25][C:26]=1[CH2:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)Cc1ccc2c(c1)C(Br)c1ccccc1CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: COC(=O)Cc1ccc2c(c1)Cc1ccccc1CO2

Procedure:
A mixture of 6.0 g. of sodium borohydride, 26 ml. of diglyme, 14 ml. of water, and 4.8 g. of methyl 6,11-dihydro-11-bromodibenz[b,e]oxepin-2-acetate is heated at 50° for one hour. Water is added and the mixture is extracted with ether. The ether extracts are dried with sodium sulfate, filtered, and concentrated in vacuo to provide methyl 6,11-dihydrodibenz[b,e]oxepin-2-acetate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[F:13][C:14]1[CH:15]=[C:16]([N:31]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[C:32]([C:34]2([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]2)=[O:33])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[CH:27]=[C:28](I)[S:29][C:22]=12.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1>O.CCO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:28]2[S:29][C:22]3[C:23](=[N:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]3[CH:18]=[CH:17][C:16]([N:31]([C:40]4[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=4)[C:32]([C:34]4([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]4)=[O:33])=[CH:15][C:14]=3[F:13])[CH:27]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c3s2)cc1
Temperature: 80 °C
Yield: 12.5 %

Procedure:
A sealable vial, was charged with 4-carbamoylphenylboronic acid (0.0312 g, 0.189 mmol), N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 0.100 g, 0.0947 mmol), Cs2CO3 (0.0309 g, 0.0947 mmol), toluene (2 mL) and EtOH (1 mL). Under nitrogen Pd(PPh3)4 (0.00547 g, 0.00473 mmol) was added and the reaction heated to 80° C. for 18 hours. The mixture was then cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL) and MeOH (2 mL). The organics were dried over sodium sulfate, filtered and concentrated to get crude product. The crude product was purified by reverse phase C-18 column chromatography to get product (6.9 mg, 13%) as a white solid. LRMS (esi+) 585 m/z (M+1) detected. 1H NMR (d6-DMSO, 400 MHz) δ 8.48 (d, J=6 Hz, 1H), 7.96 (m, 5H), 7.87 (m, 1H), 7.57 (m, 2H), 7.37 (m, 2H), 7.07 (t, J=9.0 Hz, 2H), 6.65 (d, J=6 Hz, 1H), 1.64 (s, 4H).
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([OH:5])=O.[C:22]([NH:26][CH2:27][CH3:28])([CH3:25])([CH3:24])[CH3:23]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([N:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:27][CH3:28])=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CCNC(C)(C)C
Product: CCN(C(=O)C(C)=CCCC(C)=CCCC(C)=CCCC(C)=O)C(C)(C)C

Procedure:
Starting material: 2,6,10-trimethyl-14-oxo-2,6,10-pentadecatrienoic acid and tert-butylethylamine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1[C:19]2[CH:18]([CH2:20][O:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([OH:31])=[O:30])=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)C(C)C)C.[C:41]([OH:46])(=[O:45])[C@H:42]([CH3:44])O>C(Cl)Cl.CN(C)C=O>[CH:16]1[C:17]2[CH:18]([CH2:20][O:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([O:31][C@@H:42]([CH3:44])[C:41]([OH:46])=[O:45])=[O:30])=[O:23])[C:19]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@H](O)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](OC(=O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 0 °C
Yield: 71.3 %

Procedure:
Oxalyl chloride (2.34 mL, 26.7 mmol) was added dropwise to a solution of (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid (Fmoc-Pro-OH) (6.00 g, 17.8 mmol) and N,N-dimethylformamide (69 μL, 0.889 mmol) in methylene chloride (71 mL) with stirring at 0° C. under a nitrogen atmosphere, and the reaction mixture was then stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the resulting residue was mixed with methylene chloride (71 mL), N-ethyldiisopropylamine (DIPEA) (46.6 mL, 267 mmol) and L-(+)-lactic acid (24.0 g, 267 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was washed with 1 N hydrochloric acid twice and a saturated aqueous sodium chloride solution twice, dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-(((S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carbonyl)oxy)propanoic acid (Fmoc-Pro-Lac-OH) (Compound SP633) (5.2 g, 12.7 mmol, 71%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:11])[CH2:7][C:8](=O)[CH3:9].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(O)(=O)C>C1C=CC=CC=1>[F:12][C:13]([F:21])([F:22])[C:14]1[CH:15]=[C:16]([NH:17][C:8]([CH3:9])=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:11])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COCCOC(=O)CC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COCCOC(=O)C=C(C)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 4.81 g (30 mmol) 2-methoxyethyl-3-oxobutanoate in 90 ml benzene are added 4.83 g (30 mmol) 3-(trifluoromethyl)aniline and 1.80 g (30 mmol) acetic acid. The mixture is stirred under reflux for four hours using a Dean-Stark trap to remove water. After removal of the solvent in vacuo, the residue is purified by preparative HPLC (column: YMC C18 ODS-AQ 250 mm×30 mm, 11 μm; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: ca. 900 μl ethanol solution; number of injections: 9). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:22]([C@@H:24]1[CH2:26][C@H:25]1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=1)=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH:41]1([CH2:45]Br)[CH2:44][CH2:43][CH2:42]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:45][CH:41]2[CH2:44][CH2:43][CH2:42]2)=[CH:19][CH:20]=1)[C:22]([C@@H:24]1[CH2:26][C@H:25]1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=1)=[O:23])[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccc(F)cn1)c1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccc(F)cn1)c1ccc(OCC2CCC2)cc1)NC(=O)OC(C)(C)C
Temperature: 55 °C
Yield: 89.3 %

Procedure:
A mixture of ((1S,2S)-1-{[[(1R,2R)-2-(5-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-(4-hydroxy-phenyl)-amino]-methyl}-2-methyl-butyl)-carbamic acid tert-butyl ester (51 mg, 0.11 mmol), K2CO3 (69 mg, 0.5 mmol) and cyclobutylmethyl bromide (22 mg, 0.15 mmol) in DMF was stirred at 55° C. for over night. After cool to rt, the mixture was filtered through a silica pad (EtOAc). The filtrate was concentrated and the residue was subjected to ISCO (12 g column, 0-40% EtOAc in hexane over 25 min) to give the titled compound (53 mg). MS (MH+ 540).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[N:8]1[C@H:11]([C@@H:12]([CH3:31])[C:13]([C:15]2[S:19][C:18]3=[C:20]([C:23]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[O:24])[N:21]=[CH:22][N:17]3[CH:16]=2)=O)[C@@H:10]([C@H:32]([OH:34])[CH3:33])[C:9]1=[O:35])=[O:6])[CH:2]=[CH2:3]>C1(C)C=CC=CC=1>[OH:34][C@@H:32]([C@H:10]1[C:9](=[O:35])[N:8]2[C:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[C:13]([C:15]3[S:19][C:18]4=[C:20]([C:23]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)=[O:24])[N:21]=[CH:22][N:17]4[CH:16]=3)[C@H:12]([CH3:31])[C@H:11]12)[CH3:33]
Reactant: C=CCOC(=O)C(N1C(=O)[C@H]([C@@H](C)O)[C@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1=C(c2cn3cnc(C(=O)c4cccnc4)c3s2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 79.1 %

Procedure:
Toluene (20 ml) was added to 0.76 g of (3S,4R)-1-[allyloxycarbonyl(triphenylphosphoranylidene)methyl]-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one, and the mixture was heated under reflux for 2 hr. The reaction solution was concentrated by removing the solvent, and the concentrate was purified by column chromatography on silica gel (eluted with 5 to 10% methanol/ethyl acetate). The eluate containing the contemplated product was concentrated, and the resultant solid was washed with a hexane:ethyl acetate=1:1 solution to give 0.38 g of allyl (1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate. This product was analyzed by NMR. The results were in agreement with the results of analysis in Example 26.
Reaction SMILES: [O:1]=O.[B:3]1([O-:6])[O:5][O:4]1.O.O.O.O.[Na+:11]>>[B:3]1([O-:6])[O:5][O:4]1.[OH2:1].[OH2:4].[OH2:4].[OH2:4].[Na+:11].[B:3]([O:4][O-:5])=[O:6].[OH2:4].[Na+:11]
Reactant: O=O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: O
Product: O=BO[O-]

Procedure:
Mixtures are used which contain 1.05 g active oxygen and either 10.5 g sodium perborate tetrahydrate (product 4R), or 6.6 g sodium perborate monohydrate obtained according to test 3R (product 3R) or 4.4 g super-oxidized sodium perborate obtained in test 1 (product 1) and 42 g of a commercial powder without enzymes, the composition of which is given in Table III.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[C:30]1([S:36]C2C=CC=CC=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Na]>CN(C)C=O>[CH3:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH2:14][CH2:13][C:12]([C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([CH2:2][S:36][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:4][CH:5]=4)=[O:11])=[CH:18][C:17]=3[CH:19]=2)=[CH:28][CH:27]=1
Reactant: c1ccc(Sc2ccccc2)cc1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ccccc4)cc2)CCO3)cc1
Yield: 113.9 %

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methyl-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15g) and sodium phenyl sulfide (0.05g) in dimethylformamide (10ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-(4-methylphenyl)-N-(4-(phenyl-thiomethyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 82) (0.13g) as colorless crystals.
Reaction SMILES: [Cl:1]CCCC(C1C=CC(F)=CC=1)=O.[CH3:14][C:15]1([O:21][CH3:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[I-].[K+]>C1(C)C=CC=CC=1>[ClH:1].[CH3:14][C:15]1([O:21][CH3:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: COC1(C)CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cl

Procedure:
A solution of 20.1 g (0.1 m) of gamma-chloro-p-fluorobutyrophenone, 30 g (0.2 m) of 4-methyl-4-methoxy-piperidine and 0.1 g. of potassium iodide in 150 ml of toluene is heated in a glass autoclave for 15 hours at 100°-110° C. The KI and the 4-methyl-4-methoxy-piperidine hydrochloride formed in the reaction are separated by filtration and the solvent removed from the filtrate by evaporation under a vacuum on a steam bath. The obtained base is dissolved in ether and the hydrochloride is precipitated with alcoholic HCl. The reaction product is purified by recrystallization from ethanol-ether. Yield 22 g. Melting point 182° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])=[O:13].[C:21](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.C(OCC)C.O>CC(=O)CC>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH3:21])[CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(O)ccc(C(=O)c2ccccc2O)c1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCC(C)=O
Solvent: CCOCC
Product: CCCc1c(OC)ccc(C(=O)c2ccccc2O)c1O
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a stirred solution of three grams of (2,4-dihydroxy-3-propylphenyl)(2-hydroxyphenyl)methanone in 50 ml of 2-butanone were added 3.04 g of potassium carbonate and 0.52 ml of dimethyl sulfate. The mixture was stirred at reflux temperature overnight, cooled to 25° C., and poured into diethyl ether/water. The layers were separated. The organic layer was washed twice with water, once with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated providing 2.94 g of the desired title product as an oil.
Reaction SMILES: [F:1][C:2]([F:24])([C:20]([F:23])([F:22])[F:21])[C:3]([F:19])([F:18])[C:4]([F:17])([F:16])[C:5]([F:15])([F:14])[C:6]([F:13])([F:12])[C:7]([CH2:10][OH:11])([F:9])[F:8].C(N(CC)CC)C.[F:32][C:33]([F:39])([F:38])[S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[F:1][C:2]([F:24])([C:20]([F:21])([F:22])[F:23])[C:3]([F:18])([F:19])[C:4]([F:16])([F:17])[C:5]([F:15])([F:14])[C:6]([F:13])([F:12])[C:7]([CH2:10][O:11][S:34]([C:33]([F:39])([F:38])[F:32])(=[O:36])=[O:35])([F:9])[F:8]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 40 g of (pentadecafluoroheptyl)methanol, 11 g. of triethylamine, and 200 ml. of methylene chloride is stirred at -20° C. while a solution of 18 g. of trifluoromethanesulfonyl chloride in 50 ml. of methylene chloride is added. The solution is stirred for one hour at room temperature and then washed with ice-cold 10% hydrochloric acid, saturated aqueous sodium bicarbonate solution, and water; dried over anhydrous magnesium sulfate; and evaporated. The residual brown liquid is distilled to yield the product as a colorless liquid.
Reaction SMILES: Br[C:2]([CH3:31])([CH3:30])[C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:7]=1)=[O:4].C(N)C.[CH3:35][OH:36]>>[O:28]=[S:20]1(=[O:29])[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH2:23][N:17]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([O:36][CH3:35])([CH3:31])[CH3:30])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[N:9]=2)[CH2:18][CH2:19]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C(C)(C)Br)c2c1
Reactant: CO
Agent: CCN
Product: COC(C)(C)C(=O)Nc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropanamide (80 mg, 0.159 mmol, prepared in Example 40-2) in methanol (5 mL) was added ethylamine (1 mL), the resulting mixture was heated under reflux overnight. After being cooled to room temperature, the resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (eluting with 33% ethyl acetate in hexanes) to afford 15 mg of the title compound as a light powder (yield was 21%). MS obsd. (ESI+) [(M+H)+] 454, 1H NMR (400 MHz, CD3OD) δ ppm 7.94-7.89 (m, 3 H), 7.58 (m, 2 H), 7.43-7.39 (m, 3 H), 5.17 (s, 2 H), 4.50 (brs, 2 H), 3.59 (m, 2 H), 3.50 (s, 3 H), 2.46 (s, 3 H), 1.56 (s, 6 H).
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]([NH2:43])=[N:27][CH2:28][CH2:29][CH2:30][C@H:31]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:32]([OH:34])=[O:33])(=[O:24])=[O:23])=[CH:18][CH:17]=1.C1CCC(N=C=NC2CCCCC2)CC1.C(N(C(C)C)CC)(C)C.N[C@H](C(O)=O)CCCNC(=N)N.C1C=NC(C2C=C(Br)C=CC=2F)=C(F)C=1>CN(C=O)C.C(Cl)Cl>[NH:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:31]([C:32]([OH:34])=[O:33])[CH2:30][CH2:29][CH2:28][NH:27][C:26](=[NH:43])[NH:25][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1)(=[O:24])=[O:23].[CH:1]([NH2:14])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC(N)=NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Fc1ccc(Br)cc1-c1ncccc1F
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
Benzhydrylamine-resin (40.44g 0.5 mmol/g, 20.22 mmol) was coupled with Boc Arg (Tos)-OH(34.6g, 80.7 mmol) in 25% DMF-CH2Cl2 with DCC (16.78g, 81.4 mmol) for 2h followed by the addition of 1% diisopropylethylamine and reacted for 0.5 h longer. The resultant Boc-Arg (Tos)-BHA-resin was washed with CH2Cl2 (3×250 mL), MeOH(3×250 mL), CH2Cl2 (3×250 mL) and dried. The couplings and washing procedures were repeated and an aliquot was hydrolyzed (1 mL of 6M propionic acid/HCl at 130° for 2 h). Amino acid analysis showed a substitution of 0.35 mmol of Arg per gram of resin. The remaining amino groups were acetylated with AC2 0-Pyridine. Yield 48.88g (Boc-Arg(Tos)-BHA-resin, 4).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)=[O:2].[I:9]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[I:9][C:5]1[S:6][CH:7]=[CH:8][C:4]=1[NH:3][CH:1]=[O:2]
Reactant: O=C1CCC(=O)N1I
Reactant: O=CNc1ccsc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=CNc1ccsc1I
Temperature: 2.5 °C
Yield: 90.5 %

Procedure:
3-Formylamino-thiophene (21 g), N-iodosuccinimide (37.2 g) and tetrachlormethane (200 ml) were refluxed together for 3 hours. The reaction mixture was cooled to 0-5° C. and filtered. The solids were dissolved in ethyl acetate, washed three times with sodium hydroxide (10% solution), washed with brine and dried over sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel (hexane:ethyl acetate 2:1) yielded 37.8 g of product (m.p. 100-107° C.) which was directly used in Step B.
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1)(C)(=O)=O.[CH2:16]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:5][CH2:6][C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(C#CCCS(C)(=O)=O)c1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(C#CCCN2CCC(Cc3ccccc3)CC2)c1
Yield: 31.5 %

Procedure:
A mixture of 1-mesyl-4-(3-methylphenyl)but-3-yne (214 mg, 0.900 mmol), 4-benzylpiperidine (189 mg, 1.08 mmol) and K2CO3 (370 mg, 2.67 mmol) in 10 mL of CH3CN is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×15 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as an oil (90 mg, 31%): 1H NMR (CDCl3) 1.40 (m, 2 H), 1.51 (m, 1 H), 1.65 (m, 2 H), 2.05 (t, J=6.6 Hz, 2 H), 2.31 (s, 3 H), 2.54 (m, 2 H), 2.68 (m, 4 H), 2.97 (d, J=11.4 Hz, 2 H), 7.13-7.28 (m, 9 H).