Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])[CH:17]=2)[CH:9]=1.[CH3:31][C:32]([CH3:34])=O.CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:32]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])[CH:17]=2)[CH:9]=1)([CH3:34])[CH3:31]
Reactant: CSc1nc(-c2ccnc(NC(C)c3ccccc3)c2)cc(N2CC3CC2CN3)n1
Reactant: CC(C)=O
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CSc1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc(N2C[C@@H]3C[C@H]2CN3C(C)C)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of 0.13 g (0.31 mmol) {4-[6-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-methylsulfanyl-pyrimidin-4-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 5 mL chloroform was treated with 0.2 mL (3.1 mmol) acetone, 0.19 g (3.1 mmol) NaBH3(CN) and 1 mL methanol. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a yellow solid. MS (ES+): 461 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]([NH2:1])[CH:3]=1
Reactant: CO
Reactant: Nc1cc(Cl)cc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)cc(Cl)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-amino-5-chloro-benzoic acid (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropewise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-5-chloro-benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8ClNO2 (M+H)+: 186.61, observed: 185.9.
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([OH:12])[CH2:10][C@H:9]2[N:13]([CH3:14])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>CN(C=O)C>[Si:20]([O:12][C@H:11]1[CH2:10][C@H:9]2[N:13]([CH3:14])[C@H:6]([CH2:7][CH2:8]2)[C@H:5]1[C:1]([O:3][CH3:4])=[O:2])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1[C@H]2CC[C@@H](C[C@@H]1O)N2C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2CC[C@H]1N2C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
2β-Carbomethoxy-3β-hydroxytropane (304 mg, 1.43 mmol) was dissolved in 4 mL of dry DMF. Imidazole (208 mg, 3.01 mmol) and tert-butyldimethylsilyl chloride (345 mg, 2.29 mmol) were added, and the reaction mixture was stirred overnight. Water was then added, and the mixture was extracted with ether. The combined organic layers were washed with water and brine and dried over MgSO4. The solvent was evaporated in vacuo, and the residue was chromatographed on silica gel half-saturated with ammonia using ethyl acetate as eluent to give 265 mg of the title compound (55% yield): IR (thin film) 2951, 2897, 2857, 1790, 1716, 1497, 1271, 1144, 1107, 837 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ 3.91 (dt, 1H, J=11.1, 6.1 Hz), 3.67 (s, 3H), 3.45-3.35 (m, 1H), 3.25-3.17 (m,1H), 2.75-2.68 (m,1H), 2.18 (s, 3H), 2.35- 1.42 (m, 6H), 0.84 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 75.46 MHz) δ 171.4, 64.6, 64.4, 61.6, 54.0, 51.1, 41.2, 39.5, 28.2, 25.8, 25.2, 18.1, 6.6, 6.3; mass spectrum m/z 313 (M+), 256, 242, 182, 97, 82; HRMS (FAB) calcd for C16H32NO3Si (MH ) 314.2143, found 314.2145.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]1[CH3:12].[Na].[C:14]1([C:20]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)C=O>CCOCC.C1(C)C=CC=CC=1.CO>[CH3:12][C:5]1[N:4]([CH2:3][CH2:2][N:22]2[C:21](=[O:26])[C:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:24][C:23]2=[O:25])[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCCl
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ncc([N+](=O)[O-])n1CCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O
Reaction time: 4 h

Procedure:
1.4 Parts of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole is mixed with 2.5 parts of the sodium salt of 5,5-diphenylhydantoin and 75 parts of dimethylformamide is added under nitrogen. The mixture is heated on a steam bath for 1 hour and then 10 parts of methanol is added and heating is continued for an additional 4 hours. The solvent is then evaporated on the steam bath under a stream of nitrogen to leave a residual mixture of solid and oil. The residue is mixed with toluene and filtered to remove some insoluble material. The toluene solution is diluted to a volume of 250 parts and washed with a mixture of 25 parts of sodium bicarbonate and 120 parts of water. The toluene solution is then washed with water and dried over magnesium sulfate and the solvent is evaporated to leave a solid residue. This is digested in warm ether and then cooled and the solid is separated by filtration. The solid is recrystallized from ethanol to give 3-[2-(2-methyl-5 -nitro-1-imidazolyl)ethyl]-5,5-diphenylhydantoin melting at about 209°-210.5° C. This compound has the following formula ##STR8##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([C:34]5[NH:35][C:36]6[C:41]([CH:42]=5)=[CH:40][CH:39]=[CH:38][CH:37]=6)[CH:28]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[CH3:43][C:44]1[CH:45]=[CH:46][C:47](S(O)(=O)=O)=[CH:48][CH:49]=1.C(=O)C1C=CC=CC=1.O>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:23])=[O:24])[C:18]([C:27]4[CH:28]=[C:29]5[C:34]6[NH:35][C:36]7[C:41]([C:42]=6[CH:43]([C:44]6[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=6)[O:33][C:30]5=[CH:31][CH:32]=4)=[CH:40][CH:39]=[CH:38][CH:37]=7)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(-c4cc5ccccc5[nH]4)c3)cc12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Solvent: O=Cc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(c3)-c3[nH]c5ccccc5c3C(c3ccccc3)O4)cc12
Temperature: 130 °C
Reaction time: 2 h
Yield: 175.1 %

Procedure:
A mixture of 2-(4-fluorophenyl)-5-(4-hydroxy-3-(1H-indol-2-yl)phenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 g, 0.08 mmol), PTSA (3.0 mg, 0.017 mmol), and benzaldehyde (42 mg, 0.41 mmol) in xylene (2 mL) was stirred at 130° C. for 2 h under microwave. Water was added, extracted with EtOAc, the organic layer was washed with brine, dried over Na2SO4. After concentrated, the resulting residue was purified using prep-TLC to provide the product of compound 63 (20 mg, yield: 38%). 1H-NMR (CDCl3, 400 MHz) δ 8.96 (s, 1H), 7.88˜7.92 (m, 2H), 7.76 (s, 1H), 7.65 (s, 1H), 7.50 (s, 1H), 7.32˜7.47 (m, 6H), 7.14˜7.17 (m, 4H), 6.96˜6.99 (m, 2H), 6.86 (s, 1H), 6.55 (s, 1H), 5.91 (d, J=4.8 Hz, 1H), 3.02 (s, 3H), 2.98 (d, J=4.8 Hz, 3H), 2.94 (s, 3H). MS (M+H)+: 672.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4]3[N:5]([N:13]=[C:14]([CH2:16][OH:17])[CH:15]=3)[C:6](=[O:12])[NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.[CH3:18]I.Cl>[Na].CO>[OH:17][CH2:16][C:14]1[CH:15]=[C:4]2[N:5]([C:6](=[O:12])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:2]([O:1][CH3:18])[C:3]=32)[N:13]=1
Reactant: CI
Reactant: O=c1[nH]c2cccc(O)c2c2cc(CO)nn12
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COc1cccc2[nH]c(=O)n3nc(CO)cc3c12
Reaction time: 3 h

Procedure:
To 4.2 g of 10-hydroxy-2-(hydroxymethyl)pyrazolo[1,5-c]-quinazoline-5(6H)-one in a solution of 0.58 g sodium dissolved in 100 ml dry methanol is added 2.9 g of methyl iodide. After stirring for 3 hours at 50°, the reaction is neutralized with one equivalent of 1N hydrochloric acid, evaporated and the residue recrystallized from absolute ethanol to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl[C:16]1[N:17]=[CH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=3)[NH:22][C:20]=2[N:21]=1.CN(C=O)C>C(O)CCC>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)=[CH:3][C:2]([NH:1][C:18]2[C:19]3[CH:24]=[C:23]([C:25]4[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=4)[NH:22][C:20]=3[N:21]=[CH:16][N:17]=2)=[CH:7]1
Reactant: Cn1cc(N)cc(-c2cncs2)c1=O
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3cnc(Cl)nc3[nH]2)CC1
Solvent: CCCCO
Solvent: CN(C)C=O
Product: Cn1cc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)cc(-c2cncs2)c1=O
Temperature: 120 °C
Reaction time: 15 h

Procedure:
5-Amino-1-methyl-3-thiazol-5-yl-1H-pyridin-2-one (99.0 mg, 0.478 mmol) was added to a solution of tert-butyl 4-(chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (133 mg, 0.398 mmol) in 1-butanol (2.0 L). The reaction was stirred at 120° C. for 15 h. DMF (1.5 mL) was added and the mixture was filtered. The filtrate was purified by HPLC to yield the title compound. 1H-NMR (CD3OD, 400 MHz): δ=1.50 (s, 9H), 2.57 (m, 2H), 3.67 (m, 2H), 3.73 (s, 3H), 4.13 (m, 2H), 6.30 (s, br, 1H), 6.62 (s, 1H), 8.21 (s, 1H), 8.33 (d, J=2.4 Hz, 1H), 8.34 (d, J=2.4 Hz, 1H), 8.47 (s, 1H), 8.99 (s, 1H). MS (ES+): m/z 506.08 [MH+]. HPLC: tR=2.62 min (ZQ2000, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH2:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12].[O-]CCCC.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH2:11]([N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1)[CH3:12]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: CCNc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: CCCC[O-]
Solvent: Cc1ccccc1
Product: CCN(c1ccccc1)c1cccc([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
1-Bromo 3-nitrobenzene (500 mg, 2.5 mmol) and N-ethylaniline (375 μL, 3.0 mmol) were dissolved in toluene (15 ml) and sodium butoxide (193 mg, 2.0 mmol), Xantphos (143 mg, 0.25 mmol) and tris (dibenzylideneacetone) dipalladium (57 mg, 0.06 mmol) were added. The reaction mixture was stirred at 110° C. for 16 hours. The mixture was filtered through celite and the filtrate was concentrated to give crude product, which was purified by column chromatography (9:1 hexanes-ethyl acetate) to give N-ethyl-3-nitro-N-phenylaniline as colorless oil (400 mg, 1.65 mmol, 67% yield). 1H NMR (400 MHz, CDCl3): 6.99-7.59 (m, 8H), 6.58-6.69 (m, 1H), 3.79 (q, 2H), 1.25 (t, 3H); MS (EI) for C14H14N2O2: 242 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[C:13]([O:17][CH2:18][C:19]([NH2:22])([CH3:21])[CH3:20])[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[C:13]([O:17][CH2:18][C:19]([NH:22][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)([CH3:20])[CH3:21])[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)c3ccncc3)c2c1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
To a solution of ethyl-4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b, 1.0 g, 3.15 mmol) in dry DMF (20 mL) was added isonicotinic acid (504 mg, 4.10 mmol), followed by EDCI (783 mg, 4.10 mmol), HOBt (554 mg, 4.10 mmol), and triethylamine (414 mg, 4.10 mmol) at room temperature under nitrogen. After it was stirred at room temperature for 12 hrs, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, and extracted with EtOAc (3×). The aqueous layer was basified with 2N NaOH to pH 8 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified by chromatography on silica gel eluting with 10% MeOH in dichloromethane to give the title compound as a yellow solid (1.1 g, 83%). 1H NMR (400 MHz, DMSO-d6) δ 1.29 (t, J=4 Hz, 3H), 1.51 (s, 6H), 2.94 (s, 3H), 4.28 (q, J=4 Hz, 2H), 4.42 (s, 2H), 6.93 (dd, J=1, 8 Hz, 1H), 7.24 (dd, J=1, 8 Hz, 2H), 7.52 (t, J=8 Hz, 1H), 7.69 (dd, J=2, 4 Hz, 2H), 8.14 (s, 2H), 8.37 (s, 1H), 8.67 (dd, J=2, 4 Hz, 2H). MS 423 (MH+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[O:11]=[C:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([NH:30][C:31]([C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)=[O:32])[CH:24]=[CH:23]4)=[CH:3][CH:4]=2)[NH:8]1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1Cc2ccc(-c3ccc4cc(NC(=O)c5ccsc5)ccc4c3)cc2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.5 %

Procedure:
6-bromoindolin-2-one (25.2 mg, 0.119 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (72.1 mg, 0.190 mmol), Fibercat palladium catalyst (Johnson-Matthey, 35.4 mg), and K2CO3 (2 M in water, 0.25 ml, 0.5 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.1 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C, first for 10 minutes, and then for 20 minutes. The reaction was cooled to room temperature, diluted with water (5 ml), and extracted with dichloromethane (3×10 ml) and EtOAc (6×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (7.1 mg, 16%). MS (ESI pos. ion) m/z: 385 (M+H). Calc'd Exact Mass for C23H16N2O2S: 384.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27](F)[CH:28]=3)[C:23](=[O:32])[C:22]([C:33]([OH:35])=[O:34])=[CH:21]2)[CH2:19][CH2:18]1>>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:11]2([CH2:12][CH2:13][N:14]([C:27]3[CH:28]=[C:29]4[C:24]([C:23](=[O:32])[C:22]([C:33]([OH:35])=[O:34])=[CH:21][N:20]4[CH:17]4[CH2:19][CH2:18]4)=[CH:25][C:26]=3[F:31])[CH2:15][CH2:16]2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC1CC12CCNCC2
Product: CC(C)(C)OC(=O)NC1CC12CCN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)CC2
Yield: 96.3 %

Procedure:
According to the procedure of example 1A, 1-tert-butoxycarbonylamino-6-azaspiro[2.5]octane (260.0 mg, 1.15 mmol ) and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (274 mg, 1.04 mmol) were reacted to generate the title product (472 mg, 1.00 mg, 97% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([SH:26])[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.CCN(C(C)C)C(C)C.I[CH:41]1[CH2:44][N:43]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:42]1.[NH4+].[Cl-]>C(#N)C.CCOC(C)=O>[C:48]([O:47][C:45]([N:43]1[CH2:44][CH:41]([S:26][C:18]2[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=[C:16]([C:15](=[O:27])[N:14]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:29][CH3:30])[CH3:28])[CH:17]=2)[CH2:42]1)=[O:46])([CH3:51])([CH3:49])[CH3:50]
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(S)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SC2CN(C(=O)OC(C)(C)C)C2)cc(C(F)(F)F)c1

Procedure:
To a suspension of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-3-mercapto-N-methyl-5-(trifluoromethyl)benzamide (0.35 g, 802 μmol, example 216, intermediate a) in acetonitrile (4 mL) was added DIPEA (259 mg, 350 μL, 2.00 mmol). The instantly formed yellow solution was treated with tert-butyl 3-iodoazetidine-1-carboxylate (284 mg, 1.0 mmol) and heated to reflux for 75 minutes. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless foam (0.405 g; 85%). MS (ESI): m/z=592.19 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH2:21][CH:22]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][PH3+].C1CCN2C(=NCCC2)CC1>O1CCCC1.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH2:21][CH:22]=[CH:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [PH3+]Cc1cccs1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CC=O)C1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CC=Cc2cccs2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In tetrahydrofuran (50 ml) was dissolved 1,4-bis(tert-butoxycarbonyl)-2-formylmethylpiperazine (1.01 g). Under ice cooling, a solution of [(thien-2-yl)methyl]phosphonium (1.62 g) in chloroform (100 ml) was added to the resulting solution, followed by the dropwise addition of 1,8-diazabicyclo[5.4.0]-7-undecene (620 μl). The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was distilled under reduced pressure. The residue was subjected to chromatography on a silica gel column (hexane:ethyl acetate=9:1 to 2:1), whereby the title compound (1.13 g) was obtained as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[OH:12]O>C(Cl)Cl.C[Re](=O)(=O)=O>[F:1][C:2]1[CH:3]=[N+:4]([O-:12])[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: OO
Reactant: Fc1cnccc1C(F)(F)F
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: [O-][n+]1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-fluoro-4-(trifluoromethyl)pyridine (5.00 g; 30.3 mmol) in CH2Cl2 (10 mL) was cooled to 0° C., then methyltrioxorhenium(VII) (0.062 g; 0.249 mmol) and hydrogen peroxide (30%; 6.2 mL; 61 mmol) were added and the mixture was warmed to room temperature. After stirring for 2 hours, the reaction was quenched by the addition of MnO2 (5 mg) and 30 minutes additional stirring. After dilution with additional CH2Cl2, the mixture was filtered through Solka Floe, dried (MgSO4) and concentrated in vacuo to provide 3-fluoro-4-(trifluoromethyl)pyridine 1-oxide of sufficient purity to be used directly. The N-oxide (3.70 g; 20.4 mmol) was dissolved in trifluoroacetic anhydride (21.6 mL; 153 mmol) in a hydrogenation bomb and heated to 85° C. for 15 hours. After cooling to 0° C., water was added, followed by solid K2CO3 until pH 9. The aqueous fraction was extracted with EtOAc and Me-THF, and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification by ISCO CombiFlash (70:30 to 0:100 hexanes:EtOAc) provided the title compound as a pink solid. 1H NMR (400 MHz, Acetone): δ 11.48 (s, 1 H); 7.55 (d, J=7.1 Hz, 1 H); 6.39 (t, J=6.2 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:24]([Cl:25])=[CH:23][C:22]([C:26]([O:28]CC)=[O:27])=[CH:21][N:20]=3)[CH2:15][CH2:14]2)[CH2:10][C@H:9]1[C:31]([N:33]1[CH2:37][CH2:36][S:35][CH2:34]1)=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.Cl.ClC1C(N2CCN([C@@H]3CN[C@H](C(N4CCSC4)=O)C3)CC2)=NC=C(C(OCC)=O)C=1.[OH-].[Li+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[C:24]([Cl:25])=[CH:23][C:22]([C:26]([OH:28])=[O:27])=[CH:21][N:20]=3)[CH2:17][CH2:18]2)[CH2:10][C@H:9]1[C:31]([N:33]1[CH2:37][CH2:36][S:35][CH2:34]1)=[O:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(N2CCN([C@H]3C[C@@H](C(=O)N4CCSC4)N(C(=O)OC(C)(C)C)C3)CC2)c(Cl)c1
Agent: CCOC(=O)c1cnc(N2CCN([C@@H]3CN[C@H](C(=O)N4CCSC4)C3)CC2)c(Cl)c1
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@@H](N2CCN(c3ncc(C(=O)O)cc3Cl)CC2)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 42.8 %

Procedure:
3-{(2S,4S)-1-tert-Butoxycarbonyl-4-[4-(3-chloro-5-ethoxycarbonyl-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [product of Example 216 (3), 6.49 g] was dissolved in ethanol (30 mL), and aqueous solution (30 mL) of lithium hydroxide (0.59 g) was added thereto. The mixture was stirred at room temperature for 19 hr and ethanol was evaporated under reduced pressure. The concentrate was washed with ethyl acetate, and 1 mol/L hydrochloric acid was added thereto. The precipitated solid was collected by filtration to give 3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-carboxy-3-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (2.64 g) as a white solid.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:41])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][C@@H:27]1[C:31]([O:33]CC1C=CC=CC=1)=[O:32])=[O:25])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:31]([C@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:41])([OH:33])=[O:32]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)CCCCCCCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CCCN1C(=O)CCCCCCCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 87.2 %

Procedure:
100 mg (0.18 mmol) (R)-1-[9-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-9-oxo- nonanoyl]-pyrrolidine-2-carboxylic acid benzyl ester in 20 ml ethanol were hydrogenated in the presence of 20 mg 5% Pd on carbon for two hours at room temperature. Filtration and evaporation gave 60 mg (R)-1-[9-[(R)-2- carboxy-pyrrolidin-1-yl]-9-oxo-nonanoyl]pyrrolidine-2-carboxylic acid, as a colorless oil. ISP-MS: 383 (MH+).