Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].Cl.[CH2:33]([NH2:35])[CH3:34].C(N(CC)CC)C.O>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]/[NH:35][CH2:33][CH3:34])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[C@H:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: CCN
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN/C=C1\C(=O)O[C@H](COC)[C@@]2(C)C1=C(O)C(=O)C1=C2[C@H](OC(C)=O)C[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.3 %

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 100 mg of ethylamine hydrochloride and 100 μL triethylamine. The reaction mixture is stirred at room temperature for 24 h. Water is added and the CH2Cl2 is removed, filtered through K2CO3 and concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexanes to give a yellow powder (32 mg, 29%). MS (ESI) m/z 476.22813 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[N:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24](=O)[CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[N:16]=2)[CH2:24][CH3:25])[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CNc2cccc(Cl)n2)COC1(C)C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCN(C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To a stirred solution of (S)-4-[(6-chloro-pyridin-2-ylamino)-methyl]-2,2-dimethyl-oxazo-lidine-3-carboxylic acid tert-butyl ester (528 mg) at r.t. in 1,2-dichloroethane (20 ml) under an argon atmosphere were added molecular sieves 4 A (˜2 g) and acetaldehyde (044 ml). After 30 min stirring at r.t., sodium triacetoxyborohydride (1.02 g) was added, followed by acetic acid (0.13 ml). The mixture was stirred for at r.t. over night, then diluted with CH2Cl2 and washed with sat. aq. Na2CO3. The biphasic mixture was filtered. The aqueous phase of the filtrate was back extracted with CH2Cl2. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2; gradient:cyclohexane->cyclohexane/EtOAc 85:15) to give (S)-4-{[(6-chloro-pyridin-2-yl)-ethyl-amino]-methyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (244 mg, 43%) as viscous yellow oil. MS (ISP): 370.3 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][C:11]2=[O:24])[S:5][C:6]=1[C:7]([OH:9])=O.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl.C(OCC)(=O)C>[CH2:40]([NH:47][C:7]([C:6]1[S:5][C:4]([N:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][C:11]2=[O:24])=[N:3][C:2]=1[CH3:1])=[O:9])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of 4-methyl-2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)thiazole-5-carboxylic acid (0.10 g, 0.29 mmol) and 4-methylmorpholine (0.032 mL, 0.29 mmol) in anhydrous dichloromethane (6 mL) was added isobutylchloroformate (0.044 mL, 0.34 mmol) dropwise at 0° C. After stirring at ambient temperature for 2 hours, the reaction mixture was cooled to 0° C. and benzylamine (0.032 mL, 0.29 mmol) was added dropwise. Stirring at ambient temperature was continued for 18 hours, then the reaction mixture was diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixture of ethyl acetate/dichloromethane 1/1 (10 mL) to afford the title compound as a white solid (0.055 g, 44%): mp 219-220° C. (ethyl acetate/dichloromethane); 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=8.1 Hz, 1H), 7.47-7.15 (m, 10H), 6.22 (dd, J=8.1, 2.6 Hz, 1H), 6.14 (t, J=5.6 Hz, 1H), 6.05 (d, J=2.6 Hz, 1H), 5.03 (s, 2H), 4.58 (d, J=5.6 Hz, 2H), 2.68 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.4, 162.3, 162.0, 153.5, 152.2, 137.8, 134.6, 131.6, 128.9, 128.8, 127.9, 127.8, 127.7, 122.4, 104.1, 97.4, 70.8, 44.1, 17.3; (ES+) m/z 432.2 (M+1).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][N:8]([CH3:41])[C:9]([C:11]1[CH:12]=[C:13]([S:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)=[C:23]([C:28]([NH2:30])=[O:29])[CH:24]=[N:25]3)=[CH:20][C:19]=2[I:40])[CH:14]=[CH:15][CH:16]=1)=[O:10]>CN(C)C=O>[CH3:41][N:8]([CH3:7])[C:9]([C:11]1[CH:12]=[C:13]([S:17]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)=[C:23]([C:28]([NH2:30])=[O:29])[CH:24]=[N:25]3)=[CH:20][C:19]=2[I:40])=[O:1])[CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3cc(Sc4cccc(C(=O)N(C)C)c4)c(I)cc23)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Nc2c(C(N)=O)cnc3cc(S(=O)c4cccc(C(=O)N(C)C)c4)c(I)cc23)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 121.7 %

Procedure:
Oxone (0.5 g) was added portionwise to a stirred solution of Intermediate 64 (0.12 g) in N,N-dimethylformamide (5 ml). The solution was stirred at room temperature under nitrogen for 21 h. More oxone (0.5 g) was added and the mixture was stirred for a further 3 h, quenched with a solution of sodium sulphite (1.5 g) in water (15 ml), diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried over magnesium sulphate and concentrated in vacuo to give the title compound as a yellow solid (0.15 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[O:9].O[CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15].S(=O)(=O)(O)O>>[CH3:1][C:2]1[C:6]([CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[O:9]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C(NCO)C(F)(F)F
Agent: O=S(=O)(O)O
Product: Cc1[nH]c(C=O)c(C)c1CNC(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 3,5-dimethylpyrrole-2-carboxaldehyde (2.6 g, 0.02 mol) and N-(hydroxymethyl)trifluoroacetamide (3 g, 0.02 mol) was added in portionwise to sulfuric acid (15 ml) keeping the temperature below 10° C. The mixture of reaction was allowed to warm at room temperature for 4 h. The reaction was poured into ice-water (100 ml), the precipitated solid was filtered and washed with water. The white solid (yield, 78%) was used without further purification. M.p. 200° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9](Cl)[C:10]#[CH:11].N1NN=C(COC2C=CC(N3C=NN=N3)=NC=2)C=1>>[CH3:8][C:3]1[C:2]([O:1][CH2:11][C:10]#[CH:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1ncccc1O
Reactant: C#CCCl
Agent: c1cc(-n2cnnn2)ncc1OCc1cn[nH]n1
Product: C#CCOc1cccnc1C

Procedure:
The title compound was synthesized using 3-hydroxy-2-methylpyridine and propargyl chloride in a manner similar to that described in Intermediate 13, Step 2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[C@@H:10]([C:33]([N:35]([CH2:39][C:40]2[CH:41]=[C:42]([CH:51]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:53]=2)[O:43][CH2:44][C@@H:45]2[CH2:47][C@H:46]2[C:48]([OH:50])=[O:49])[CH:36]2[CH2:38][CH2:37]2)=[O:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:74]1[C:82]2[C:77](=[CH:78][C:79](O)=[CH:80][CH:81]=2)[CH2:76][CH2:75]1.[H-].[Na+]>C(Cl)Cl.C1COCC1>[CH:36]1([N:35]([CH2:39][C:40]2[CH:53]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:51]=[C:42]([O:43][CH2:44][C@@H:45]3[CH2:47][C@H:46]3[C:48]([O:50][C:79]3[CH:78]=[C:77]4[C:82](=[CH:81][CH:80]=3)[CH2:74][CH2:75][CH2:76]4)=[O:49])[CH:41]=2)[C:33]([C@@H:10]2[C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]4[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[Cl:32])=[CH:16][CH:15]=3)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]2)=[O:34])[CH2:37][CH2:38]1
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)O)c1
Reactant: Oc1ccc2c(c1)CCC2
Agent: CC(C)COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)Oc2ccc3c(c2)CCC3)c1
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
To a solution of (1R,2R)-2-{[3-{[[((3R,4S)-1-(tert-butoxycarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidin-3-yl)carbonyl](cyclopropyl)-amino]methyl}-5-(3-methoxypropyl)phenoxy]methyl}cyclopropanecarboxylic acid (1 eq.) from Example 4/Step 1 in DCM (0.1 M) at −20° C. was added N-methylmorpholine (1.3 eq.) and isobutylchloroformate (1.3 eq.). The reaction was stirred at −20° C. for 45 min. Meanwhile, a solution of indan-5-ol (2 eq) in THF (0.2) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1 eq.), stirred for 30 min at rt, and added to the reaction at −15° C. The reaction was stirred at rt for 18 h and then quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 35% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[CH3:33][C:34]1[CH:39]=[C:38]([NH:40][CH2:41][CH2:42][CH2:43]N)[CH:37]=[CH:36][N:35]=1.[O-2:45].[Al+3].[O-2].[O-2].[Al+3]>CN(C=O)C.C(#N)C>[CH3:33][C:34]1[CH:39]=[C:38]([NH:40][CH2:41][CH2:42][CH2:43][NH:16][C:11](=[O:45])/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH3:10])[CH:37]=[CH:36][N:35]=1
Reactant: Cc1cc(NCCCN)ccn1
Reactant: [O-2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Al+3]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCC/C=C/C(=O)NCCCNc1ccnc(C)c1
Reaction time: 1 h

Procedure:
(E)-4-Hex-2-enoic acid (23 mg, 0.2 mmol) and HBTU (76 mg, 0.2 mmol) were dissolved in a 1:1 mixture of anhydrous DMF and anhydrous acetonitrile (2 ml), after 5 minutes triethylamine (82 μl, 0.6 mmol) and N-(2-Methyl-4-pyridyl)propane-1,3-diamine hydrochloride (40 mg, 0.2 mmol) was added. To the mixture basic aluminium oxide was added, stirring was continued for one hour, the mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 20.2 mg (0.077 mmol, 39%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([Li])CCC.Cl[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>O1CCCC1>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc([N+](=O)[O-])cc21
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
i)—A solution of 6-nitroindole (25 g, 154 mmol) in dry tetrahydrofuran (900 ml) was cooled to −78° C. and treated with n-butyllithium (2.5 M solution in hexanes, 67.0 ml, 169 mmol). After 20 min. stirring, chloro-triisopropyl-silane (33.0 ml, 155 mmol) was added. The cooling bath was removed and the reaction mixture was stirred for 2 h. The mixture was quenched with water and the product was extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (heptane/ethyl acetate 95:5) afforded 6-nitro-1-triisopropylsilanyl-1H-indole (41.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1.[C:12]([O:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21])(=[O:15])[CH2:13][CH3:14]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C(C(C)=O)C>[C:12]([O:16][CH2:17][CH2:18][NH:19][C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1)=[O:21])(=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)OCCN=C=O
Reactant: O=c1oc2ccc(O)cc2s1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCC(C)=O
Product: CCC(=O)OCCNC(=O)Oc1ccc2oc(=O)sc2c1
Reaction time: 12.5 h

Procedure:
5-hydroxy-1,3-benzoxathiol-2-one (16.8 grams) was mixed with 2-(isocyanato)ethyl propionate (15.0 grams) and 10 drops of dibutyltin dilaurate in 200 milliliters of methyl ethyl ketone. The resulting solution was heated at reflux temperature for four hours and fifteen minutes, after which the solvent was removed by evaporation in vacuo, leaving a brown, viscous oil which crystallized upon standing at room temperature for 10 to 15 hours. The crude product was twice recrystallized from toluene. The purified compound, 5-[2-(propionyloxy)ethylcarbamoyloxy]-1,3-benzoxathiol-2-one, was a white, fibrous crystalline substance with a melting point of 78°-79° C. Elemental analysis calculated for C13H13NO6S (percent): carbon--50.15; hydrogen--4.21; nitrogen--4.50. Found: carbon--50.4; hydrogen--4.27; nitrogen--4.45.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:45]([NH:47][C@H:48]([C:53]([OH:55])=[O:54])[CH2:49][C:50](=[O:52])[OH:51])=[O:46])[CH2:40][CH2:41][C:42](=[O:44])[OH:43])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34])=[O:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.N1CCCCC1.C(O)(=O)C>CS(C)=O>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:45]([NH:47][C@H:48]([C:53]([OH:55])=[O:54])[CH2:49][C:50](=[O:51])[OH:52])=[O:46])[CH2:40][CH2:41][C:42](=[O:43])[OH:44])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])=[O:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(C)C[C@H](NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O

Procedure:
Fmoc-D-Trp-L-Leu-Gly-L-Arg-L-Glu-L-Asp-OH (50 mg), was dissolved in 0.5 ml of dimethylsulfoxide and 0.5 ml of piperidine was added to the solution. After reacting for an hour, the reaction mixture was neutralized with acetic acid under cooling.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C1C(=O)N([Br:18])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2ccccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1csc2ccccc12
Yield: 42.2 %

Procedure:
3-Methylbenzo[b]thiophene (9.9 g, 67 mmol) is heated in carbon tetrachloride (133 ml) to near reflux in the presence of n-bromosuccinimide (11.9 g, 67 mmol, 1.0 eq.). 2,2′Azobisisobutyronitrile (2.2 g, 13.3 mmol, 0.2 eq.) is added and the resulting mixture is refluxed for two hours. After cooling, the reaction mixture is filtered through a glass-fritted funnel, and the filtrate is concentrated. The residue is triturated with petroleum ether and toluene to afford 6.42 g of 3-Bromomethylbenzo[b]thiophene (42%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Yield: 105.5 %

Procedure:
A solution of 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.35 g, 1.2 mmol) (as prepared in the previous step) in methanol was hydrogenated over 10% Pd/C at 20 psi for 1 h. The solution was filtered and concentrated to give 0.35 g (100%) of the title compound as a yellow solid: Mass spectrum (ESI, m/z): Calcd. for C16H24N2O2, 277.2 (M+H). found 277.1.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH2:10]([K])[CH3:11].C(Cl)(=O)C(Cl)=O.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:19]([NH:27][C:3](=[O:5])[CH:2]1[O:1][CH:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C1OC1C(=O)O
Reactant: CC[K]
Reactant: NCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: CCOC(=O)C1OC1C(=O)NCCc1ccccc1
Yield: 54.8 %

Procedure:
Following the procedure of Example 1, monoethyl potassium epoxysuccinate (1.0 g) was successively treated with oxalyl chloride (0.75 g) and phenethylamine (1.3 g) to give 0.72 g of ethyl N-phenethyl-2,3-epoxysuccinamate (Compound No. 15) as colorless needles melting at 80°-82° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[OH:24])=[CH:15][N:16]=1>O.CO>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([OH:24])=[C:17]([C:14]2[S:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:25])=[O:4])=[N:16][CH:15]=2)[CH:22]=1
Reactant: COC(=O)CCCCCCc1ncc(-c2cc(Cl)ccc2O)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCc1ncc(-c2cc(Cl)ccc2O)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
Add a solution of sodium hydroxide (2.60 g, 65 mmol) in water (50 mL) to a solution of 7-[5-(5-chloro-2-hydroxyphenyl)thiazol-2-yl]heptanoic acid methyl ester (5.76 g, 16 mmol) in methanol (100 mL) at 0° C. under nitrogen, warm the mixture to room temperature, and stir for a total of 1.5 hours. Remove the solvent under reduced pressure, dilute the residue with water (200 mL), cool to 0° C., and acidify to pH 1 with 1 N HCl. Collect the precipitate by filtration to afford 7-[5-(5-chloro-2-hydroxyphenyl)thiazol-2-yl]heptanoic acid (5.21 g, 95%): APCI mass spectrum m/z 338 [C16H18ClNO3S−H]−.
Reaction SMILES: Br[C:2]1[C:3](=[O:22])[N:4]([C:9]2[CH:10]=[C:11]([CH:17]=[C:18]([F:21])[C:19]=2[CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:23][C:24]([CH3:40])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:25].C(N(C(C)C)C(C)C)C>O1CCOCC1.O>[Br:8][C:6]1[N:7]=[C:2]([NH:25][C:24]([CH3:40])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:23])[C:3](=[O:22])[N:4]([C:9]2[CH:10]=[C:11]([CH:17]=[C:18]([F:21])[C:19]=2[CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=1
Reactant: CC(C)(N)c1ccccc1OCc1ccccc1
Reactant: CCOC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(Br)c2=O)c1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC(C)(C)c3ccccc3OCc3ccccc3)c2=O)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 99.9 %

Procedure:
3-(3,5-Dibromo-2-oxo-1(2H)-pyrazinyl)-5-fluoro-4-methyl-benzoic acid, ethyl ester (Example 169d, 1.137 g, 2.62 mmol) was dissolved in dioxane (10 mL). α,α-Dimethyl-2-(phenylmethoxy)-benzenemethanamine (Example 134a, 0.63 g) and N-ethyldiisopropylamine (0.67 mL, 3.93 mmol) were added under nitrogen and the resulting solution was stirred at 100° C. for 10 h. The reaction mixture was diluted with water (50 mL), and extracted with ethyl acetate (100 mL×2). The combined organics were dried (MgSO4), filtered and evaporated to afford the crude product. This was purified by (SiO2 chromatography eluting with dichloromethane) to afford the subtitle product (1.55 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([S:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[Cl:21])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH3:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCOC(C)=O.O>C(Cl)Cl>[Cl:21][C:15]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=1[S:13][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=1[S:9]([N:27]1[CH2:28][CH2:29][CH:24]([N:23]([CH3:30])[CH3:22])[CH2:25][CH2:26]1)(=[O:11])=[O:10]
Reactant: CN(C)C1CCNCC1
Reactant: N#Cc1ccc(Sc2cc(Cl)ccc2Cl)c(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)C1CCN(S(=O)(=O)c2cc(C#N)ccc2Sc2cc(Cl)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of compound 29 (0.100 g, 0.26 mmol) in DCM (8.00 mL) was added 4-dimethylaminopiperidine (0.044 g, 0.34 mmol) and TEA (0.034 g, 0.34 mmol). The reaction was monitored with TLC (25% EtOAc in hexanes, Rf=0.0). After stirring at room temperature for 2 hrs, the reaction was complete as indicated by the absence of the starting material (TLC). Water was added and aqueous layer was extracted twice with DCM. Combined extracts were washed sequentially with water and brine, dried over MgSO4, filtered, and evaporated in vacuo to form a clear oil. The oil was dissolved in DCM and purified with chromatography with a gradient from 0 to 30% MeOH in DCM. Pure fractions were combined, evaporated in vacuo, triturated with DCM and hexanes, and then filtered to yield compound 83 as a white powder (0.068 g, 100% HPLC purity, 56% yield). 1H NMR (500 MHz, DMSO-d6): δ 8.26 (d, J=2 Hz, 1H), 7.89 (m, 2H), 7.78 (d, J=9 Hz, 1H), 7.71 (dd, J1=3 Hz, J2=9 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 3.79 (d, J=12 Hz, 2H), 2.85 (t, J=13 Hz, 2H), 2.22 (m, 1H), 2.12 (s, 6H), 1.79 (m, 2H), 1.40 (m, 2H); MS (ESI, EI+): m/z=470 (MH+); melting point: 140-143° C.