Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]3=[CH:10][N:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.Cl.Cl.[Br:52][C:53]1[CH:58]=[C:57]([CH2:59][NH2:60])[CH:56]=[CH:55][N:54]=1>CN(C=O)C.[Cl-].[NH4+]>[Br:52][C:53]1[CH:58]=[C:57]([CH2:59][NH:60][C:17]([C:16]2[C:11]3[N:12]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][CH:10]=3)[CH:13]=[CH:14][CH:15]=2)=[O:19])[CH:56]=[CH:55][N:54]=1
Reactant: O=C(O)c1cccn2c(-c3ccc(F)cc3)ncc12
Reactant: NCc1ccnc(Br)c1
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccnc(Br)c1)c1cccn2c(-c3ccc(F)cc3)ncc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 3-(4-fluorophenyl)-imidazo[1,5-a]pyridine-8-carboxylic acid (125 mg, 0.488 mmol) and Et3N (0.400 mL, 2.88 mmol) in DMF (3 mL) is added benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyBOP) (0.300 g, 0.577 mmol). After 10 minutes, C-(2-bromopyridin-4-yl)-methylamine di-hydrochloride salt (153 mg, 0.589 mmol) is added and the mixture is stirred at room temperature. After 2 hours, the mixture is diluted with saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (3×7 mL). The combined organic layers are washed with saturated aqueous ammonium chloride (2×10 mL), brine (2×10 mL), dried over magnesium sulfate, filtered and concentrated. The residue is purified by silica gel chromatography eluting with a gradient of 0-2% methanol in dichloromethane. The resulting solid is triturated with ethyl ether to afford the title compound.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:20]2[CH:25]=[CH:24][C:23]([O:26][C@H:27]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+].Cl>C1COCC1.CO>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:20]2[CH:21]=[CH:22][C:23]([O:26][C@H:27]([CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]([OH:30])=[O:29])=[CH:24][CH:25]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(CCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCc1ccc(CCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a mixed solution of ethyl (2R)-2-([4-[1-(4-pentylphenylethyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoate (660 mg, 1.26 mmol) in THF (15 ml) and methanol (7 ml) was added 1N aqueous potassium hydroxide (4.0 ml, 4.0 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give the object compound as an oily substance. 615 mg, (yield 98%)
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=O)[CH:7]([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:40][C@H:41]([OH:51])[C@@H:42]([NH2:50])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:34][CH:33]=1>CN(C=O)C>[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:40][C@H:41]([OH:51])[C@@H:42]([NH:50][C:10](=[O:12])[C@H:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nccs2)cc1)NC(=O)OC(C)(C)C)C(C)C
Reaction time: 0.75 h

Procedure:
Under a nitrogen atmosphere, 1.4 g (8.0 mmol) of N-methoxycarbonyl-(L)-valine, 2.87 g (15 mmol) of EDC and 1.35 g (10 mmol) of HOBT are dissolved in 22 ml of DMF. After 45 min, 4.2 ml (30 mmol) of TEA are added and then a solution of 2.34 g (5.0 mmol) of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane in 45 ml of DMF is added dropwise. After 1.5 hours, the reaction mixture is concentrated by evaporation; the residue is taken up in methylene chloride and washed with water, sat. NaHCO3 solution, water and brine. The aqueous phases are extracted 2× with methylene chloride; the combined organic phases are dried (Na2 SO4) and concentrated by evaporation. Column chromatography (SiO2 ; methylene chloride/ethyl acetate 2:1) and crystallisation from ethyl acetate/ether yield the title compound: m.p: 178°-179° C.; HPLC20-100 : tRet =15.8.
Reaction SMILES: Br[C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:9]1=[O:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P([CH:47]2[CH2:52][CH2:51]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:51]1([C:2]2[C:6](=[O:7])[O:5][CH2:4][C:3]=2[N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:9]2=[O:25])[CH2:52][CH2:47]1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(Br)C(=O)OC1)C2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(C3CC3)C(=O)OC1)C2=O
Temperature: 100 °C

Procedure:
In a microwave vial, tert-butyl 2-(4-bromo-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (90 mg, 0.22 mmol) was dissolved in toluene (2 mL) and water (0.2 mL). Potassium phosphate (138 mg, 0.650 mmol), tricyclohexylphosphine (18 mg, 0.065 mmol), cyclopropylboronic acid (74.5 mg, 0.867 mmol) and palladium acetate (4.87 mg, 0.022 mmol) were added. The reaction mixture was de-gassed and heated at 100° C. for 12 hours. After cooling to room temperature, the reaction mixture was concentrated and the resulting residue was dissolved in EtOAc (50 mL), washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, and filtered. Removing the solvent gave crude product that was purified by column chromatography eluting with 0-100% EtOAc/hexane gradient to yield the title compound. 1H NMR (500 MHz, CDCl3) δ 5.20 (s, 2H), 4.22 (m, 2H), 3.99 (m, 2H), 3.05 (m, 2H), 2.09 (m, 2H), 1.92 (m, 2H), 1.60 (m, 2H), 1.56 (m, 10H), 1.02 (m, 2H), 0.82 (m, 2H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3[C:20]([CH3:30])=[CH:21][C:22]([CH3:29])=[C:23]([S:25](O)(=[O:27])=[O:26])[CH:24]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:33])=O>CN(C=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C:19]3[CH:24]=[C:23]([S:25]([Cl:33])(=[O:27])=[O:26])[C:22]([CH3:29])=[CH:21][C:20]=3[CH3:30])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(C)c(S(=O)(=O)O)cc1NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)Cl)cc1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2,4-dimethylbenzenesulfonic acid (5 g, 11.8 mmol) in DMF (5.9 mL) was added thionyl chloride (4.3 mL, 59.0 mmol). The reaction was stirred at room temperature for three hours and then quenched by the addition of water. The colorless precipitate was then collected by filtration and dried in vacuo to afford 9H-fluoren-9-ylmethyl[5-(chlorosulfonyl)-2,4-dimethylphenyl]carbamate as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[NH:10]2)[CH:6]=[CH:7][CH:8]=1.[F:16][C:17]([F:25])([F:24])[C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[C:18]([OH:23])([C:17]([F:25])([F:24])[F:16])[C:12]1[C:13](=[O:14])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:10][C:11]=1[CH3:15]
Reactant: COC(=O)C(=O)C(F)(F)F
Reactant: COc1cccc(-n2[nH]c(C)cc2=O)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C)[nH]n(-c2cccc(OC)c2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 1-(3-methoxyphenyl)-3-methyl-5-pyrazolone (102 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a pale yellow solid (180 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:42][CH2:43][C:44]([O:46]C)=[O:45])[C:8]([C:10]1[CH:41]=[CH:40][C:13]2[N:14]([CH3:39])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:38])[NH:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:28])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[OH-].[Na+].CO.C(O)(=O)C>O.C(OCC)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])[C:8]([C:10]1[CH:41]=[CH:40][C:13]2[N:14]([CH3:39])[C:15]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25](=[NH:38])[NH:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:28])=[CH:23][CH:24]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)O)c4ccccn4)ccc3n2C)cc1
Reaction time: 1 h
Yield: 80 %

Procedure:
0.7 g (1.1 mmol) of 1-methyl-2-[N-[4-(N-n-octyloxycarbonylamidino)phenyl]aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)amide was stirred in a mixture of 0.12 g (3.0 mmol) of sodium hydroxide, 5 mL of water, and 10 mL of methanol for one hour at room temperature. Then the mixture was diluted with 20 mL of water and adjusted to pH 6 with glacial acetic acid. Then about 5 mL of diethylether were added and the mixture was vigorously stirred for one hour. The product thus precipitated was suction filtered, washed with a little water, then with diethylether and dried. Yield: 80% of theory, C34H41N7O5 (627.8); EKA mass spectrum: (M+H)+=628; (M+H+Na)++=325.7; (M+Na)+=650; (M+2Na)++=337.7.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH2:19][CH:20]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:21]([OH:38])[CH:22]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[C:34]([O:33][C:31]([NH:30][CH:22]([CH:21]([OH:38])[CH:20]([NH:19][C:6](=[O:8])[C@H:2]([CH:3]([CH3:4])[CH3:5])[NH:1][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A solution of 39 mg (0.16 mmol) of Cbz-Val-OH, 52 mg (0.14 mmol) of the resultant compound of Example 11, and 23 mg (0.17 mmol) of 1-hydroxybenzotriazole in 2 ml of dimethylformamide was treated with 0.019 ml (0.17 mmol) of 4-methylmorpholine, cooled to 0° C., and treated with 33 mg (0.17 mmol) of N-ethyl-N'-(dimethylaminopropyl)-carbodiimide hydrochloride. After being stirred at ambient temperature overnight, the solution was diluted with ethyl acetate, washed sequentially with 10% citric acid, water, and aqueous NaHCO3, dried over Na2SO4, and concentrated in vacuo. Separation of the desired compounds by flash chromatography using methanol in chloroform gave 80 mg (95%) of the desired compound (Rf 0.40, 10% methanol in chloroform) as a white solid, m.p. 187°-187.5° C. Mass spectrum (M+H)+ =604.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[O:20][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:18][C:17]=1[C:27](Cl)=[O:28].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27]([C:17]1[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:20][C:16]=1[CH3:15])=[O:28]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 75.7 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0454 g, 0.193 mmol), 5-methyl-2-phenyl-1,3-oxazole-4-carbonyl chloride (0.044 g; 0.193 mmol), and triethylamine (0.0676 mL; 0.481 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 20% of ethyl acetate in dichloromethane gave 0.0555 g (76%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-methyl-2-phenyloxazole-4-carboxamide as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:19]3[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([CH2:15][CH2:16][CH2:17][CH2:18]3)[N:13](O)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:27]>[Zn].CO>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:19]3[C:14]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)([CH2:15][CH2:16][CH2:17][CH2:18]3)[NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CN(O)C3(c4ccccc4)CCCCC23)cc1OC
Agent: Cl
Agent: [Zn]
Solvent: CO
Product: COc1ccc(C2CNC3(c4ccccc4)CCCCC23)cc1OC

Procedure:
Zinc powder (20 g) was added to a stirred solution of 6.5 g (0.018 mole) of 3-(3,4-dimethoxyphenyl)-hexahydro-1-hydroxy-7a-phenylindoline, 150 ml of methanol and 150 ml of 1N hydrochloric acid and the mixture was maintained at reflux for 1/2 hour. The mixture was cooled, treated with excess of 10MKOH and extracted with two one liter portions of ether. The extracts were combined, dried (K2CO3) and filtered. Hydrogen chloride gas was bubbled into the ether solution until complete precipitation of the white salt; wt. 4.5 g (67.2%), mp 303°-305° C. Recrystallization from methanol-ether afforded pure white crystals, mp 303°-305° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([OH:17])=[O:16]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:13]=[C:14]([C:15]([OH:17])=[O:16])[N:11]=2)=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ccc(Cl)cc1
Reactant: O=C(O)C(=O)CBr
Solvent: CO
Product: O=C(O)c1csc(Nc2ccc(Cl)cc2)n1
Yield: 94.6 %

Procedure:
2-(4-Chloro-phenylamino)-thiazole-4-carboxylic acid (240 mg) was prepared according to General Procedure B using (4-chloro-phenyl)-thiourea (186 mg) and 3-bromo-2-oxo-propionic acid (200 mg) in methanol (2 mL). The crude product was used in a subsequent step without further purification.
Reaction SMILES: [BrH:1].N[C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10]CC)=[O:9])[N:7]=1.N([O-])=O.[Na+].[OH-].[Na+]>Br.O.CCO>[Br:1][C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1csc(Br)n1
Temperature: 0 °C

Procedure:
To a well stirred suspension of ethyl 2-aminothiazole-4-carboxylate hydrobromide (29.99 g, 0.17 mol) in 16% HBr(aq) (400 mL) at 0° C., a solution of NaNO2 (12.49 g, 0.18 mol) in H2O (22 mL) was added dropwise. The mixture was maintained at 0° C. for an additional 35 min then CuBr (28.23 g, 0.20 mol) and an additional volume of 16% HBr(aq) (150 mL) were added. The ice bath was removed and the suspension heated to 70° C. for 1 hr. The mixture was filtered hot. The filtrate was saturated with NaCl then extracted with EtOAc (2×400 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude brown oil/solid residue was used directly in the next step. A solution of the brown residue in EtOH (100 mL) and 1M NaOH (aq) (367 mL, 0.36 mol) was stirred and heated at reflux for 1 h. The reaction mixture was filtered then extracted with EtOAc (100 mL). The aqueous layer was separated and concentrated under reduced pressure to remove the remaining EtOH. The aqueous solution was acidified to pH 1 with 2N HCl(aq). The solid was filtered off and air dried to yield the title compound as a beige amorphous solid. MS m/z: 208 (M+H) 210 (M+3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([C:14](=[O:27])[C@@H:15]([NH:19][C:20]([O:22]C(C)(C)C)=O)[CH:16]([CH3:18])[CH3:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].CCN(C(C)C)C(C)C.C(Cl)(=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CCOC(C)=O.Cl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([C:14](=[O:27])[C@@H:15]([NH:19][C:20](=[O:22])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:16]([CH3:17])[CH3:18])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a solution of compound 702 (3.45 g, 8.8 mmol) in EtOAc at 0° C. was bubbled in gaseous HCl until saturated. The reaction was warmed to rt and stirred for 3 hr. Nitrogen was bubbled through the reaction to remove excess HCl, followed by concentration in vacuo. The residue suspended in CH2Cl2 (50 mL), treated with DIEA (3.4 mL, 19.5 mmol) followed by benzoyl chloride (1.2 mL, 10.3 mmol) and the reaction allowed to stir overnight. The reaction was concentrated in vacuo and the residue taken up into EtOAc and H2O. The layers were separated and the organic phase washed with sat. aq. NaHCO3, sat. aq. KHSO4, brine, dried over MgSO4, filtered and concentrated in vacuo to provide 3.45 g of compound 703. ##STR82##
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[O-]S(C(F)(F)[F:22])(=O)=O.F[N+]1C=CC=CC=1>C(Cl)Cl>[F:22][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]#[N:16])[C:8]=2[C:11]([F:12])([F:14])[F:13])[NH:3][C:2]=1[CH3:1]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1ccccc1
Solvent: ClCCl
Product: Cc1[nH]c2ccc(C#N)c(C(F)(F)F)c2c1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.1 %

Procedure:
To a solution of 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.063 g, 0.28 mmol) in CH2Cl2 (4 mL) was added 1-fluoropyridinium triflate (0.104 g, 0.42 mmol) and stirred at rt for 3 days. The mixture was partitioned between EtOAc and 0.1N HCl. The organic phase was washed with 0.1N HCl and sat'd brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (10-50% EtOAc-hexanes gradient) to afford the title compound as a white solid (0.015 g, 22% yield, 94% purity): MS (ES) m/z 243 (M+1).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15](=O)[CH2:16][CH3:17].[CH3:19][O:20][CH2:21][CH2:22][C@@H:23]1[NH:28][CH2:27][CH2:26][N:25]([C:29]2[C:38]3[N:37]=[C:36]([C:39]([F:42])([F:41])[F:40])[S:35][C:34]=3[NH:33][C:32]3[CH:43]=[CH:44][CH:45]=[CH:46][C:31]=3[N:30]=2)[CH2:24]1>ClC(Cl)C>[CH3:19][O:20][CH2:21][CH2:22][C@@H:23]1[N:28]([CH2:15][CH2:16][CH3:17])[CH2:27][CH2:26][N:25]([C:29]2[C:38]3[N:37]=[C:36]([C:39]([F:41])([F:42])[F:40])[S:35][C:34]=3[NH:33][C:32]3[CH:43]=[CH:44][CH:45]=[CH:46][C:31]=3[N:30]=2)[CH2:24]1
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCN1CCN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)C[C@@H]1CCOC
Yield: 73.8 %

Procedure:
Add sodium triacetoxyborohydride (0.273 g, 1.29 mmol), and then propionaldehyde (0.083 mL, 1.15 mmol) to (S)-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.353 g, 0.858 mmol) in anhydrous dichloroethane (15 mL) and stir at ambient temperature overnight. Add saturated aqueous sodium bicarbonate and extract aqueous phase with dichloromethane. Wash organics with saturated aqueous sodium chloride, and dry (sodium sulfate), filter, and concentrate under reduced pressure to a residue (0.29 g). Purify the residue by flash chromatography, eluting with a gradient of a 3% solution of 2M ammonia in methanol, in dichloromethane, (0-100%) to give the title compound (0.287 g, 74%): mass spectrum (APCI, m/e): 454 (M+1); NMR (1H, 300 MHz, DMSO-d6): δ 8.46 (s, 1H), 6.96-6.82 (m, 3H), 6.71 (m, 1H), 3.46 (br. m, 3H), 3.31-3.17 (m, 3H), 3.15 (s, 3H), 2.73 (m, 1H), 2.58-2.44 (m, 2H), 2.31 (m, 2H), 1.67 (m, 2H), 1.40 (m, 2H), 0.83 (t, 3H, J=7.5 Hz).
Reaction SMILES: N[CH2:2][CH2:3][C:4]([OH:6])=[O:5].C[N+](CC(O)=O)(C)C.[CH2:15]([C@H:18](N)[C:19](O)=O)[CH2:16][NH2:17].N1CCC=C(C(O)=O)C1.N1CCCC(C(O)=O)C1.O1C2CCNCC=2C(O)=N1>>[NH2:17][C@@H:16]1[CH2:15][CH2:18][CH2:19][C@H:3]([C:4]([OH:6])=[O:5])[CH2:2]1
Reactant: NCCC(=O)O
Reactant: NCC[C@H](N)C(=O)O
Agent: C[N+](C)(C)CC(=O)O
Agent: O=C(O)C1=CCCNC1
Agent: O=C(O)C1CCCNC1
Product: N[C@@H]1CCC[C@H](C(=O)O)C1

Procedure:
[3H]GABA3 (98.9 Ci/mmole) was obtained from New England Nuclear (Boston, Mass.). β-alanine, betaine and L-DABA (L-(2,4) diaminobutyric acid) were from Sigma Chemical Company (St. Louis, Mo.); guvacine, nipecotic acid, OH-nipecotic (hydroxynipecotic acid), and THPO (4,5,6,7-tetrahydroisoxazolo (4,5-c]pyridin-3-ol) were from RBI (Natick, Mass.). ACHC (cis-3-aminocyclohexanecarboxylic acid) was kindly provided by Drs. Richard Milius and William White of the NIgH Chemical Synthesis Program.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:22])[C:17]([CH3:21])([CH3:20])[CH2:18]Cl)[C:11]2=[O:23])[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+].O>C1COCC1>[F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:18][C:17]([CH3:21])([CH3:20])[C:16]3=[O:22])[C:11]2=[O:23])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(CCl)C(=O)NC1CCN(c2cccc(OC(F)(F)F)c2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CN(C2CCN(c3cccc(OC(F)(F)F)c3)C2=O)C1=O
Reaction time: 0.08 h
Yield: 71.4 %

Procedure:
A stirred solution of 1-(3-trifluoromethoxyphenyl)-3-(3-chloro-2,2-dimethylpropanoyl)amino-2-pyrrolidinone (0.31 g) in THF (5 ml) was treated with a 60% dispersion of sodium hydroxide in oil (0.036 g). Once the effervescence had ceased, the yellow mixture was stirred for 5 min then poured into water. The mixture was extracted with dichloromethane (x2), the combined extracts were washed with brine and dried (MgSO4). Evaporation of the solvent under reduced pressure left an oil, which was purified by chromatography on silica-gel, eluting with ethyl acetate/hexane mixtures, to give the title compound as a pale tan crystalline solid (0.20 g).