Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24]([OH:26])=O)=[C:20]([O:29][CH3:30])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.CCN=C=NCCCN(C)C.Cl.O.OC1C2N=NNC=2C=CC=1.CN1CCOCC1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24](=[O:26])[N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[C:20]([O:29][CH3:30])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 87 %

Procedure:
A solution of 2-(4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)acetic acid Example 15 (20 mg; 0.045 mmol), piperidine (7 uL; 0.068 mmol), EDC hydrochloride (10 mg; 0.054 mmol) and hydroxybenzotriazole hydrate (8 mg; 0.054 mmol) in 70 uL of DMF and 415 uL of CH2Cl2 was cooled to 0° C. After addition of N-methylmorpholine (6 uL; 0.054 mmol), the solution allowed to warm to rt and stir for 23 h. Following concentration under reduced pressure and dilution with water, the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was triturated in MeOH to afford the title compound (20 mg; 87%) as a white solid. 1H NMR (CDCl3) δ 1.57-1.67 (m, 6H), 3.52-3.59 (m, 4H), 3.90 (s, 3H), 4.81 (s, 2H), 6.91 (dd, J=8.25 Hz, 2.20 Hz, 1H), 6.98 (d, J=2.75 Hz, 1H), 7.09 (d, J=8.25 Hz, 1H), 7.44 (d, J=8.79 Hz, 2H), 7.53 (s, 1H), 7.66 (d, J=8.80 Hz, 2H), 8.13 (s, 1H); 13C NMR (CDCl3) δ 24.42, 25.54, 26.47, 43.27, 46.39, 56.15, 68.65, 111.13, 113.98, 119.14, 120.86, 123.21, 127.65, 129.45, 130.75, 131.54, 135.68, 148.14, 148.28, 149.88, 151.66, 156.75, 157.40, 165.65; HPLC (Method #1): 3.65 min retention time; MS (ES): m/z 510 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH2:9][C:10](O)=[S:11])=[N:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.ClC(OCC(C)C)=O.[CH3:32][N:33]([CH:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)[CH3:34]>O1CCCC1>[CH3:32][N:33]([CH:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:10](=[S:11])[CH2:9][CH2:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)[CH2:37][CH2:36]1)[CH3:34]
Reactant: CN(C)C1CCC(N)CC1
Reactant: Cn1nnnc1CCCC(O)=S
Agent: CC(C)COC(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CN(C)C1CCC(NC(=S)CCCc2nnnn2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
4-(1-Methyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid (45 mmole) is dissolved in tetrahydrofuran (50 ml), and thereto is added DBU (50 mmole). To the mixture is added dropwise with stirring isobutyl chloroformate (50 mmole) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise 4-(N,N-dimethylamino)cyclohexylamine (54 mmole), and the mixture is further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the resulting residue is extracted with chloroform. The chloroform layer is washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and then dried over anhydrous sodium sulfate. Chloroform is distilled off, and the resulting residue is subjected to silica gel column chromatography (Wakogel C-200, eluting solvent, benzene:chloroform=4:1, V/V) to isolate N-[4-(N,N-dimethylamino)-cyclohexyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyramide (yield: 47%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[NH2:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33])=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: NC(CO)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)NC(CO)CO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.2 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (93 mg, 0.221 mmol) obtained in Example 12 in methylene chloride (3 ml), 2-amino-1,3-propanediol (24 mg, 0.265 mmol), 1-hydroxybenzotriazole (30 mg, 0.221 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (51 mg, 0.265 mmol) and 4-methylmorpholine (29 μl, 0.265 mmol) were added, and the resulting mixture was stirred for 17 hours at room temperature. Ethyl acetate was added to the reaction solution, and the mixture was washed sequentially with a saturated solution of sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with methanol:methylene chloride (=1:20) was concentrated under reduced pressure. Ethylacetate-hexane was added to the resulting concentration residue, and the solid thus precipitated was collected by filtration, to obtain the title compound (81 mg, 0.164 mmol, 74%) as a white powder.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])(=O)C.C[CH2:24][N:25](C(C)C)[CH:26](C)C.CS(Cl)(=O)=O.CNC>C(Cl)Cl>[CH3:24][N:25]([CH2:5][C:6]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[CH3:26]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(COC(C)=O)c1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccccc2C)c(CN(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
To a solution of methyl 2-(hydroxymethyl)-2′-methylbiphenyl-4-carboxylate obtained in step 3 (2.12 g; 8.27 mmol) in DCM (63.6 mL) was added at 0° C. DIEA (7.03 mL; 41.36 mmol) and methanesulfonyl chloride (768 μL; 9.93 mmol) at 0° C. and stirred at 25 min. After this time, dimethylamine (12.41 mL; 2 M; 24.81 mmol) was added to the reaction mixture and stirred at RT for 16 hours. Reaction mixture was partitioned between DCM and an aqueous solution of NaOH (5 M). Purification by silica column chromatography (DCM/[DCM/MeOH 2:1] gradient) gave the title compound as a light yellow solid (2.03 g, 86%). 1H NMR (DMSO-d6) δ 8.27 (d, J=1.4 Hz, 1H), 7.95 (dd, J=7.8, 1.9 Hz, 1H), 7.32-7.18 (m, 4H), 7.06 (d, J=7.3 Hz, 1H), 3.94 (s, 3H), 3.24-3.10 (m, 2H), 2.11 (s, 6H), 2.01 (s, 3H). HPLC (Method A) Rt 2.90 min (Purity 100.0%). LC/MS (Method B): 284.1 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][NH:4][C:3]1=[O:10].CN1C(C(OC(C)(C)C)=O)CNC1=O.O=C1N(C(OCC2C=CC=CC=2)=O)[C@H](C(O)=O)CN1.C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:75][C:76]1[CH:81]=[CH:80][C:79]([CH2:82][NH2:83])=[CH:78][C:77]=1[C:84]([F:87])([F:86])[F:85]>ClCCl>[F:75][C:76]1[CH:81]=[CH:80][C:79]([CH2:82][NH:83][C:7]([CH:6]2[CH2:5][NH:4][C:3](=[O:10])[N:2]2[CH3:1])=[O:9])=[CH:78][C:77]=1[C:84]([F:85])([F:86])[F:87]
Reactant: NCc1ccc(F)c(C(F)(F)F)c1
Reactant: CN1C(=O)NCC1C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN1C(=O)NCC1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)NCC1C(=O)NCc1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4.2 %

Procedure:
A mixture of 3-methyl-2-oxo-4-imidazolidinecarboxylic acid (86 mg, 0.6 mmol) (prepared as described in Example 28 from 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate, itself prepared as described in step (iii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid), N-ethyl morpholine (0.380 ml, 3.00 mmol), 1-hydroxybenzotriazole hydrate (110 mg, 0.720 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138 mg, 0.720 mmol) in dichloromethane (9 ml) was stirred at room temperature for 10 minutes, under an argon atmosphere. {[4-Fluoro-3-(trifluoromethyl)phenyl]methyl}amine (127 mg, 0.660 mmol) was added and the reaction was stirred overnight under an argon atmosphere. The reaction mixture was diluted with dichloromethane (10 ml) and the solution was washed with saturated sodium hydrogen carbonate solution (10 ml), water (10 ml) and brine (10 ml). The organic solution was dried and the solvent was evaporated in vacuo. The residue was purified by mass-directed automated HPLC. Fractions containing product were collected and the solvent was evaporated in vacuo to give N-{[4-fluoro-3-(trifluoromethyl)phenyl]methyl}-3-methyl-2-oxo-4-imidazolidinecarboxamide (8 mg, 4% yield) as a white solid. LC/MS [M+H]+=320, retention time=1.87 minutes.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:49])(=O)=O.[CH:52]1(B(O)O)[CH2:54][CH2:53]1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[CH:52]1([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:40])([CH3:39])[CH3:41])([CH3:36])[CH3:37])[CH2:30][CH2:31]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:49])[CH2:54][CH2:53]1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(C3CC3)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Yield: 67.9 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-{1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (81.7 mg, 0.109 mmol) was dissolved in dimethoxyethane (4.1 mL), and the solution was treated with cyclopropylboronic acid (28.0 mg, 0.327 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (7.1 mg, 0.0087 mmol), potassium carbonate (75.0 mg, 0.545 mmol) and water (0.058 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=12/1) to obtain 4-cyclopropyl-7-{1-(tert-butoxycarbonyl)-5-[4-(2-tert-butyldimethylsilyloxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (47.7 mg, yield 68%).
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C=O)C.C(Cl)(=O)C([Cl:25])=O>C1(C)C=CC=CC=1>[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([Cl:25])=[O:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ncoc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of commercially available 5-phenyl-oxazole-4-carboxylic acid (67 mg, 0.35 mmol) in toluene (1.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.08 mL, 0.91 mmol) and the resulting yellow solution was stirred at rt for 1 h. The solvent was then removed under reduced pressure (co-evaporation with toluene) to give 5-phenyl-oxazole-4-carbonyl chloride as a brown oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[C:16]2[C:11](=[N:12][C:13]([CH3:20])=[CH:14][C:15]=2[CH:17]([OH:19])C)[S:10][C:9]=1[C:21]([NH2:23])=[O:22].[NH4+].[Cl-]>C1COCC1>[NH2:7][C:8]1[C:16]2[C:11](=[N:12][C:13]([CH3:20])=[CH:14][C:15]=2[CH:17]=[O:19])[S:10][C:9]=1[C:21]([NH2:23])=[O:22]
Reactant: Cc1cc(C(C)O)c2c(N)c(C(N)=O)sc2n1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(C=O)c2c(N)c(C(N)=O)sc2n1
Reaction time: 1 h
Yield: 29 %

Procedure:
LiAlH4 (0.31 g) was added to a suspension of 0.60 g of 3-amino-6-methyl-thieno[2,3-b]pyridine-2,4-dicarboxylic acid 2-amide 4-(methoxy-methyl-amide) (see Example 15) in 15 mL dry THF at −10° C. and stirred 1 h under Ar. Aqueous NH4Cl was added slowly and the mixture was filtered through diatomaceous earth, washing with H2O and EtOAc. The aqueous phase was separated and extracted 3 times with more with EtOAc and the combined organics were and concentrated in vacuo to a resin that was flashed chromatographed eluting with 30% acetone-petroleum ether to afford 163 mg 3-amino-4-formyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amide as a dark resin.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[F:17][C:18]([F:29])([F:28])[O:19][C:20]1[CH:27]=[CH:26][C:23](CBr)=[CH:22][CH:21]=1>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 802.5 %

Procedure:
N-Boc-4-hydroxy piperidine (2.01 g, 1.0 mmol) was dissolved in DMF (30 mL), added sodium hydride (60%, 0.6 g, 15 mmol) in ice-bath, stirred for 30 min, added p-trifluoromethoxy benzyl bromide (3.06 g, 12 mmol), after which resumed to stir for 15 h at room temperature, added ice water (30 mL) in ice-bath to quench reaction. Extracted by dichloromethane (30 mL*2), combined organic phases, the organic phases were washed by water and saturated saline respectively, dried by anhydrous sodium sulfate, concentrated column chromatography (petroleum ether: ethyl acetate=10:1) to give 2.9 g light yellow liquid, yield was 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:24])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=[C:12]([C:14](OC)=[O:15])[CH:13]=1.BrC1C(=O)N(C2C=CC=CC=2)C=C(C(OC)=O)C=1.Cl.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:24])[N:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=[C:12]([CH2:14][OH:15])[CH:13]=1
Reactant: COC(=O)c1cc(-c2ccccc2Cl)c(=O)n(-c2ccccc2)c1
Agent: COC(=O)c1cc(Br)c(=O)n(-c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=c1c(-c2ccccc2Cl)cc(CO)cn1-c1ccccc1
Temperature: -78 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
36 mg of 3-(2-chlorophenyl)-5-methoxycarbonyl-1-phenyl-1,2-dihydropyridin-2-one synthesized by the method of Referential Example 3 from 3-bromo-5-methoxycarbonyl-1-phenyl-1,2-dihydropyridin-2-one and 2-chloroboronic acid, was dissolved in 20 ml of toluene. After cooling to −78° C., 0.1 ml diisopropyl aluminumhydride (1.5M tetrahydrofuran solution) was added dropwise thereinto. While heating from −78° C. to room temperature, the mixture was stirred overnight. Then, 1N hydrochloric acid was added thereto, followed by stirring. The mixture was neutralized with an aqueous solution of sodium hydrogen carbonate, and then extracted with ethyl acetate. Then, the extract was successively washed with water and brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 12 mg of the title compound.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Mg]Br)C.[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1.[Cu]Br>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:25][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]Br
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCc1ccc(OCc2ccccc2)cc1
Temperature: 65 °C
Reaction time: 0.67 h
Yield: 71.9 %

Procedure:
To a solution of trimethylsilyl acetylene (851 μL, 6.02 mmol) in tetrahydrofuran (20 mL) was added ethyl magnesium bromide (3 M diethyl ether solution, 1.86 mL, 5.59 mmol) under nitrogen atmosphere at room temperature, which was stirred for 40 minutes at 65° C. The reaction solution was cooled to room temperature, and copper (I) bromide (308 mg, 2.16 mmol) and 4-benzyloxybenzyl chloride (1.00 g, 4.30 mmol) were added to the reaction solution and stirred for 8 hours and 45 minutes at 65° C. Saturated ammonium chloride solution was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=30:1) to obtain the title compound (911 mg, 72%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH:11]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]=1[S:23](Cl)(=[O:25])=[O:24])([CH3:13])[CH3:12]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:23]([C:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[S:18][C:14]=1[CH:11]([CH3:13])[CH3:12])(=[O:24])=[O:25]
Reactant: Cc1noc(N)c1Br
Reactant: CC(C)c1sc2ccccc2c1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(C(C)C)sc3ccccc23)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-i-propylbenzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 using 4-bromo-3-methyl-5-aminoisoxazole (0.55 mmoles, 9.7 mg), NaH (1.4 mmoles, 5.5 mg), 2-i-propylbenzo[b]thiophene-3-sulfonyl chloride (0.60 mmoles, 0.17 g) and THF (2 ml). Recrystallization from chloroform and hexanes provided 89 mg (39%) of a tan crystalline solid, m.p. 157.5-159° C.
Reaction SMILES: C(Cl)CCl.[CH3:5][C@H:6]([NH:14]CCCCN)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C>O.O1CCOCC1>[NH2:14][CH:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:5]
Reactant: C[C@@H](Cc1ccccc1)NCCCCN
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(N)Cc1ccccc1
Temperature: 22.5 °C
Reaction time: 0.25 h

Procedure:
To BSA (24.8 mg) in water (4 ml) was added NHS (22.2 mg, 0.193 mmol) in water (0.5 ml) followed by EDC (41 mg, 0.199 mmol) in water (0.5 ml). The mixture was shaken for 15 minutes at 20-25° C. N-[(1S)-1-methyl-2-phenylethyl]butane-1,4-diamine (2.7 mg, 0.013 mmol) in dioxan (0.2 ml) followed by di-isopropylethylamine (0.02 ml). The mixture was shaken for 18 hours at 20-25° C. The above material was dialysed against 50 mM Tris buffer at pH 7.4 containing sodium azide using a 10,000 molecular weight cut off membrane. BCA protein assay after dialysis gave a concentration of 1.6 mg/ml.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[CH:40]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[CH:40]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: Cc1cccc(COC(=O)Cl)c1
Product: Cc1cccc(COC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c1

Procedure:
3-Methylbenzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (60 mg, 0.20 mmol) and 3-methylbenzyl carbonochloridate (63.5 mg, 0.22 mmol) according to General Procedure H to give 30 mg (33.4%) of white solid. Anal. Calcd. for C27H34N4O2 m/z 446.3, found: 447.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.45 (d, J=8.8 Hz, 2H), 7.19 (m, 1H), 7.12 (m, 2H), 6.97 (dd, J=8.8 Hz, J=2.8 Hz, 2H), 4.98 (m, 2H), 3.71 (m, 1H), 3.59 (m, 1H), 3.28 (m, 1H), 2.97 (m, 1H), 2.74 (m, 1H), 2.66 (m, 1H), 2.50 (m, 1H), 2.31 (s, 3H), 2.04 (m, 1H), 1.92 (m, 2H), 1.78 (m, 3H), 1.62 (m, 1H), 1.28 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:12][C:13]([OH:15])=[O:14])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)c(Br)c1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(F)c(Br)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
3-Bromo-4-fluoro-benzaldehyde (5.0 g, 24.6 mmol), malonic acid (5.6 g, 53.7 mmol), and piperidine (0.5 mL, 4.9 mmol) were added to pyridine (11.4 mL). The reaction mixture was stirred at 100° C. for 3 hours and then concentrated under reduced pressure. Distilled water was added to the reaction mixture, which was then filtered. The resulting solid was recrystallized from ethanol to give 3.3 g of the titled compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl.C(OCC)(=O)C>[CH3:16][S:17]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1ccccc1O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccccc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of 2-hydroxybenzaldehyde (0.30 mL, 2.8 mmol) and pyridine (0.91 mL, 11.2 mmol) in 5.6 mL of dichloromethane was added methanesulfonyl chloride (0.65 mL, 8.4 mmol) at 0° C. After being stirred at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=75/25 to 50/50) to obtain the title compound as a white solid (553 mg, 98%).