Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC(Cl)=O)C1C=CC=CC=1.[CH2:13]([O:20][CH2:21][C:22]([N:24]=[C:25]=[S:26])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[C:44]([F:49])[CH:43]=1.C1(C)C=CC=CC=1>C(O)C>[CH2:13]([O:20][CH2:21][C:22]([N:24]=[C:25]=[S:26])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:13]([O:20][CH2:21][C:22]([NH:24][C:25]([NH:46][C:45]1[CH:47]=[CH:48][C:42]([O:41][C:32]2[C:31]3[C:36](=[CH:37][C:38]([O:39][CH3:40])=[C:29]([O:28][CH3:27])[CH:30]=3)[N:35]=[CH:34][CH:33]=2)=[CH:43][C:44]=1[F:49])=[S:26])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(COCc1ccccc1)N=C=S
Agent: O=C(Cl)COCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)COCc4ccccc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
2-(Benzyloxy)ethanoyl isothiocyanate was prepared using commercially available 2-(benzyloxy)ethanoyl chloride (80 mg) as a starting compound according to the description of the literature. 2-(Benzyloxy)ethanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (38 mg, yield 43%). Mass spectrometry value (ESI-MS, m/z): 522 (M++1)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([CH3:26])([CH3:25])[CH2:21][N:22]([CH3:24])[CH3:23])[CH:15]=2)=[C:11]([CH3:13])[N:12]=1)(C)(C)C>C(Cl)Cl.CO>[CH3:24][N:22]([CH3:23])[CH2:21][C:20]([C:16]1[CH:15]=[C:14]([C:10]2[S:9][C:8]([NH2:7])=[N:12][C:11]=2[CH3:13])[CH:19]=[CH:18][N:17]=1)([CH3:26])[CH3:25]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C(C)(C)CN(C)C)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(N)sc1-c1ccnc(C(C)(C)CN(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound is prepared in analogy to the procedure described in Step 19.1 but using {5-[2-(2-dimethylamino-1,1-dimethyl-ethyl)-pyridin-4-yl]-4-methyl-thiazol-2-yl}-carbamic acid tert-butyl ester (Step 21.2) and stirring the reaction mixture for 2 h at rt. Title compound: ESI-MS: 291.1 [M+H]+; tR=2.48 min (System 1); TLC: Rf=0.11 (DCM/MeOH, 9:1).
Reaction SMILES: C1COCC1.Cl.[C:7]([O:11][C:12](=[O:15])[CH2:13][NH2:14])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.C1C([N:29]=[C:30]=[S:31])=CC2C(OC3(C4C=CC(O)=CC=4OC4C=C(O)C=CC3=4)C=2C=1)=O>C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C.C(Cl)(Cl)Cl>[C:7]([O:11][C:12](=[O:15])[CH2:13][NH:14][C:30]([NH2:29])=[S:31])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(N)=S
Reaction time: 8 h

Procedure:
To a 50 ml round bottom flask equipped with magnetic stirring bar was added a solvent mixture (10 ml THF, 5 ml of CHCl3, and 5 ml of DMF) and 168 mg (1 mmole) of glycine t-butyl ester hydrochloride. The solution was cooled by an ice-water bath and 415 ml (3 mmoles) of triethylamine was added. To the above mixture was added FITC (fluorescein isothiocyanate, 1 mmole, 385 mg) in small portions over 3 hours. The reaction mixture was allowed to stir overnight and then concentrated to a red-brown oil that was dissolved in 100 ml ethyl acetate and washed with 5 ml water followed by 2-10 ml portions of saturated brine. Preparative tlc on silica with 10% methanol in chloroform and a trace of acetic acid gave tlc pure material, 240 mg. Molar extinction coefficient: ε=79,500 M- cm-1 (λmax=494 nm) in 0.5M sodium carbonate, pH 9.53. Anal. calc for C27H24N2O7S·H2O: C, 60.22; H, 4.83; N, 5.20; S, 5.95. Found: C, 60.16; H, 4.85; N, 5.01; S, 6.15.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[CH2:9][C:8]2([CH3:24])[CH3:23])=[O:4].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:17]=1)[CH2:9][C:8]2([CH3:24])[CH3:23])=[O:4]
Reactant: COC(=O)c1cc(C)c2c(c1)C(C)(C)CC(c1cccc(Br)c1)N2
Reactant: C1COCCN1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1cc(C)c2c(c1)C(C)(C)CC(c1cccc(N3CCOCC3)c1)N2
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.4 g, 3.6 mmol), morpholine (4.3 mL, 50 mmol), copper(I) iodide (274 mg, 1.44 mmol), N,N-dimethylglycine hydrochloride (0.3 g, 2.16 mmol), and potassium carbonate (1.49 g, 10.8 mmol) in dimethyl sulfoxide (10 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (150 mL×2), washed with saturated aqueous ammonium chloride solution (50 mL×3) and brine (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30-50% ethyl acetate in petroleum ether) to afford 4,4,8-trimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.4 g, 98%) as a white solid: MS (ESI) M+1=394.2.
Reaction SMILES: C([O:4][C:5]1[C:6](=[O:27])[N:7]([CH2:21][C:22]([O:24]CC)=[O:23])[C:8]([CH3:20])=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([CH3:19])[CH3:18])(=O)C.[OH-].[Na+].Cl>C(O)C>[OH:4][C:5]1[C:6](=[O:27])[N:7]([CH2:21][C:22]([OH:24])=[O:23])[C:8]([CH3:20])=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([CH3:19])[CH3:18]
Reactant: CCOC(=O)Cn1c(C)cc(-c2ccccc2C(C)C)c(OC(C)=O)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-c2ccccc2C(C)C)c(O)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-acetoxy-4-(2-isopropylphenyl)-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 4 above (0.325 g, 0.95 mmol) in ethanol (4 mL) was added aqueous NaOH (2.2 mL of a 1.0 N solution, 2.2 mmol). The resulting solution was stirred at ambient temperature for 18 h. The solution was acidified with aqueous HCl (2.2 mL of a 1.0 N solution, 2.2 mmol) and the solvents were removed in vacuo to give the title compound as an amorphous solid containing NaCl (HPLC RT=18.67 min, method B).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1.P(=O)(O)(O)O>CCO.C1COCC1.O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CNc1ccc(OC)cc1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(NCC(=O)O)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
2M NaOH (aq.) (149 mL, 0.30 mol) was added dropwise to a stirred solution of ethyl 2-((4-methoxyphenyl)amino)acetate (17) (59.2 g, 0.28 mol) in EtOH/THF (300 mL/80 mL). The reaction was stirred at 40° C. for 3 h. The mixture was diluted with water (100 mL) and phosphoric acid (85% wt in water) (35.9 g, 0.31 mol) was added to pH 3. The resulting brown precipitate was collected by filtration and washed with water (100 mL) and dried under vacuum to give 2-((4-methoxyphenyl)amino)acetic acid (18) (45.5 g, 84%) as a brown solid: m/z 182 (M+H)+ (ES+); 180 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 6.78-6.64 (m, 2H), 6.55-6.44 (m, 2H), 3.74 (s, 2H), 3.64 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]2[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)([OH:11])[CH3:10])=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:21][C:18]([CH3:22])([CH2:19][CH3:20])[CH2:17][C:15]1[N:16]=[C:12]([C:9]([OH:11])([CH3:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=3)=[CH:3][CH:4]=2)[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(Br)cc2)n1
Reactant: Fc1ccc(Br)nc1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1

Procedure:
Palladium tetrakis(triphenylphosphine) (221 mg, 0.19 mmol) was added to a degassed, ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxy-1-methylethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Intermediate 11) (900 mg, 1.9 mmol), 2-bromo-5-fluoropyridine (336 mg, 1.9 mmol) and hexamethylditin (626 mg, 1.9 mmol) in 1,4-dioxane (20 mL). After stirring at reflux overnight, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]=[N:42][N:43]([CH3:45])[N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]=[N:42][N:43]([CH3:45])[N:44]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nnn(C)n4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nnn(C)n4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 70.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-methyl-tetrazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.58 g) in methylene chloride (17.4 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.19 g) in methylene chloride (11.6 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-methyl-tetrazol-5-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 234) (420 mg).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:26])[NH:17][C@H:18]([C:23](F)=[O:24])[C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16](=[O:26])[NH:17][C@H:18]([C:23](=[O:24])[NH:7][CH2:8][CH2:9][SH:10])[C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:14])([CH3:12])[CH3:13]
Reactant: NCCS
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)F)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCCS)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 25 mL round-bottom flask charged with a solution of sodium bicarbonate (83.6 mg, 1.0 mmol) in 4.9 mL water was added 2-aminoethanethiol hydrochloride (60.7 mg, 0.53 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25i (113.3 mg, 0.48 mmol) in 4.9 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 26i as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1B(O)O>>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1
Reactant: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(Br)ccc21
Reactant: COc1ccc(B(O)O)c(OC)c1
Agent: OB(O)c1ccccc1
Product: COc1ccc(-c2ccc3c(c2)C(c2cccc(C#N)c2)=NCC(=O)N3C)c(OC)c1
Yield: 49 %

Procedure:
Prepared from 3-(7-bromo-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 14 using the same method described for Example 1 and instead of using benzene boronic acid, we used 2,4-dimethoxyphenyl boronic acid. The title compound (135 mg) was obtained as a yellow solid, (yield=49%).
Reaction SMILES: O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:13]([O:15][C:16]([CH:18]1[NH:23][C:22](=[O:24])[CH:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[N:20]([OH:29])[C:19]1=[O:30])=[O:17])[CH3:14].[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1>ClCCl>[CH2:13]([O:15][C:16]([CH:18]1[NH:23][C:22](=[O:24])[CH:21]([CH2:25][CH:26]([CH3:27])[CH3:28])[N:20]([O:29][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][O:31]2)[C:19]1=[O:30])=[O:17])[CH3:14]
Reactant: C1=COCCC1
Reactant: CCOC(=O)C1NC(=O)C(CC(C)C)N(O)C1=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1NC(=O)C(CC(C)C)N(OC2CCCCO2)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.45 g of p, toluenesulfonic acid hydrate was added to 60 ml of a solution of 6.15 g of 3-ethoxycarbonyl-1-hydroxy-6-isobutylpiperazine-2,5-dione and 4 ml of 3,4-dihydro-2H-pyran in anhydrous dichloromethane. The mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with an aqueous solution saturated with sodium hydrogen carbonate and then dried with anhydrous magnesium sulfate. The resulting mixture was subjected to distillation to remove the solvent to obtain 9.67 g of 3-ethoxycarbonyl-6-isobutyl-1-(2-tetrahydropyranyloxy)piperazine-2,5-dione as an orange oily substance.
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:34])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:15]=[N:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:33][C@@H:30]1[O:29][C:28]([C:25]2[NH:24][C:23]([C:21]3[CH:22]=[C:6]([CH:7]=[C:8]([O:9][C:10]4[CH:15]=[N:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=4)[CH:20]=3)[O:5][C@@H:4]([CH3:34])[CH2:3][OH:2])=[CH:27][CH:26]=2)=[N:32][CH2:31]1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CN=C(c2ccc(-c3cc(Oc4cnc(S(C)(=O)=O)cn4)cc(O[C@@H](C)CO)c3)[nH]2)O1
Reaction time: 1.5 h
Yield: 58.4 %

Procedure:
2-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-5-(methylsulfonyl)pyrazine (426 mg, 0.88 mmol) synthesized in Example 99 was dissolved in methylene chloride (10 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 1.76 mL, 1.76 mmol) was added at −78° C. under nitrogen atmosphere. Subsequently, the temperature was brought back to room temperature, followed by stirring for 1.5 hours. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with methylene chloride. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (243 mg, yield 59%) as a white solid.
Reaction SMILES: C1C2C(COC(=O)[N:17]([CH2:24][CH2:25][CH2:26][CH2:27][C:28](=[O:59])[NH:29][C:30]3[CH:35]=[CH:34][C:33]([N:36]4[C:39](=[O:40])[CH:38]([CH2:41][CH2:42][CH:43]([OH:50])[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[CH:37]4[C:51]4[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=4)=[CH:32][CH:31]=3)C3C=CC=CC=3)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>CN(C)C=O>[OH:50][CH:43]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:42][CH2:41][CH:38]1[C:39](=[O:40])[N:36]([C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:28](=[O:59])[CH2:27][CH2:26][CH2:25][CH2:24][NH2:17])=[CH:35][CH:34]=2)[CH:37]1[C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCN(C(=O)OCC3c4ccccc4-c4ccccc43)c3ccccc3)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCN)cc2)cc1

Procedure:
570 mg (0.78 mmol) of product 8 and 0.8 ml of diethylamine are solved in 5 ml of DMF (dimethylformamide). It is evaporated after 1 h at room temperature. The residue is purified by flash chromatography (methylenechloride/methanol/conc. ammoniac 30:10:3) 220 mg (56%) of product 9 is obtained in form of an amorphic solid compound: C30H35N3O4 (501.63) MS (ESI+) 502.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[CH:32]=[CH:31][O:30][CH:29]=1)(=[O:27])=[O:26].[CH3:33][Zn]C.C1(C)C=CC=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:33])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[CH:32]=[CH:31][O:30][CH:29]=1)(=[O:26])=[O:27]
Reactant: C[Zn]C
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2Cl)c(-c2ccnc(Cl)n2)s1
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide (130 mg, 0.255 mmol) and dimethyl zinc in toluene (0.255 mL, 0.510 mmol), the title compound was obtained as a solid (35 mg, 26% yield). MS (ESI): 489 [M+H]+.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2].Cl.[NH2:17][OH:18].C(N(CC)CC)C>CCO>[NH2:2]/[C:1](=[N:17]\[OH:18])/[CH:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCOCC1C#N
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOCC1/C(N)=N/O

Procedure:
A solution of the product of Step 3 (1 eq.), hydroxylamine hydrochloride (1.4 eq.) and triethylamine (1.7 eq.) in EtOH (0.5 M) was refluxed under nitrogen for 5 hours. Mixture was concentrated and residues taken up in EtOAc and washed with water and brine. Combined organics were dried over Na2SO4 and evaporated giving the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[C:11]([NH2:13])[N:10]([CH3:14])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:15][C:16]1NN=C(C2C=CN=C(NC)C=2)C=1>>[NH2:13][C:11]1[N:10]([CH3:14])[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:15][CH3:16])[CH:7]=2)[CH:12]=1
Reactant: CNc1cc(-c2cc(N)[nH]n2)ccn1
Reactant: Cn1nc(-c2ccnc(Cl)c2)cc1N
Product: CNc1cc(-c2cc(N)n(C)n2)ccn1
Yield: 79 %

Procedure:
This title intermediate was prepared starting from 23.A (2.10 g, 10.0 mmol) according the procedure described above for conversion of 18.0 to 18.D. The crude product was purified by flash chromatography using 0-10% MeOH/CH2Cl2 for elution to provide 23.B as white solid (1.61 g, 79%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][O:14][C:15]1[C:16]2[C:21]([C:22]([O:33][CH3:34])=[C:23]3[C:28]=1[CH:27]=[C:26]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[CH:24]3)=[CH:20][CH:19]=[CH:18][CH:17]=2.O1CCCC1>C(N(CC)CC)C>[CH3:13][O:14][C:15]1[C:16]2[C:21]([C:22]([O:33][CH3:34])=[C:23]3[C:28]=1[CH:27]=[C:26]([S:29]([O:1][N:2]1[C:3](=[O:12])[C:4]4=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]4[C:6]1=[O:7])(=[O:31])=[O:30])[CH:25]=[CH:24]3)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COc1c2ccccc2c(OC)c2cc(S(=O)(=O)Cl)ccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c2ccccc2c(OC)c2cc(S(=O)(=O)ON3C(=O)c4ccccc4C3=O)ccc12

Procedure:
A mixture of 0.98 g of N-hydroxyphthalimide, 2.02 g of 9,10-dimethoxyanthracene-2-sulfonyl chloride and 40 ml of tetrahydrofuran was stirred on an ice bath, and 0.34 g of triethylamine was added.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:18])[C@@H:6]([CH2:16][OH:17])[NH:7][C:8](=[O:15])[C@H:9]([CH2:11][C:12](=[O:14])[OH:13])[NH2:10])([CH3:3])[CH3:2].C([O:22][C:23](=O)[C@@H:24]([CH3:39])[NH:25]C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)N)(C)C>>[CH:1]([O:4][C:5](=[O:18])[C@@H:6]([CH2:16][OH:17])[NH:7][C:8](=[O:15])[C@H:9]([CH2:11][C:12](=[O:13])[OH:14])[NH:10][C:23](=[O:22])[C@@H:24]([CH3:39])[NH2:25])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)[C@@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)N
Reactant: CC(C)OC(=O)[C@@H](CO)NC(=O)[C@@H](N)CC(=O)O
Product: CC(C)OC(=O)[C@@H](CO)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)N

Procedure:
This compound was prepared from 1.9 g α-L-aspartyl-D-serine isopropyl ester and 2.2 g N-benzyloxycarbonyl-D-alanine N-hydroxysuccinimide ester in a manner similar to Example 16 (C) and (D). Yield: 1.8 g, m.p.: 222.5°-234° C.
Reaction SMILES: [CH3:1][N:2]1CCCC1=O.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:17][N:16]=2)=[CH:11][CH:10]=1.[Cu]C#N.Cl>[Fe](Cl)Cl.O>[C:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:17][N:16]=2)=[CH:11][CH:10]=1)#[N:2]
Reactant: CN1CCCC1=O
Reactant: CCCCCCCCc1ccc(-c2ccc(Br)cc2)nc1
Agent: Cl[Fe]Cl
Agent: N#C[Cu]
Agent: Cl
Solvent: O
Product: CCCCCCCCc1ccc(-c2ccc(C#N)cc2)nc1

Procedure:
94 ml of N-methylpyrrolidone was added to the 47.6 g (0.138 mol) of the 2-(p-bromophenyl)-5-octylpyridine. Then 19.3 g (0.216 mol) of copper (I) cyanide was added and the solution was refluxed for 2 hours. A mixture of 69 g of iron (II) chloride, 13.8 ml of concentrated hydrochloric acid and 69 ml of water was added to the mixture solution and the organic layer was extracted with chloroform. The extract was washed with a 10% aqueous solution of potassium hydroxide and then three times with water. Chloroform was removed by distillation. The residue was distilled under reduced pressure (210° to 220° C./2 mmHg) and recrystallized from methanol to obtain 33 g (0.1113 mol) of 2-(p-cyanophenyl)-5-octylpyridine.