Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[S:21]([NH-:24])(=[O:23])=[O:22].C(O)(=O)C.C>C(#N)C.C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[NH:13][C:10]([NH:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:24][S:21](=[O:23])(=[O:22])[C:15]=2[CH:16]=1
Reactant: [NH-]S(=O)(=O)c1cc(Cl)ccc1N
Reactant: S=C=NCCc1ccccc1
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCO
Product: O=S1(=O)N=C(NCCc2ccccc2)Nc2ccc(Cl)cc21
Temperature: 90 °C

Procedure:
2-Phenylethyl isothiocyanate (0.36 g) was added to a stirred slurry of 2-amino-5-chlorobenzenesulfonamide sodium salt (0.50 g) in 5 ml of acetonitrile at 60° C. After 2½ h an additional amount of 2-phenylethyl isothiocyanate (0.18 g) was added, and the temperature was raised to 90° C. for 1½ h. The reaction mixture was treated with 1 ml of 4M acetic acid, 5 ml of ethanol and 0.1 g of charcoal and filtered through celite. The solvent was evaporated and the residue extracted with 10 ml of ethyl acetate. The solvent was evaporated and the oily residue was purified on a silica column eluted with ethyl acetate. The title compound was obtained as white crystals; m.p. 250-252° C.
Reaction SMILES: [OH-].[Na+].[S:3](Cl)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Br:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][C:20]=3[NH:21]2)=[CH:17][CH:16]=1.CCOC(C)=O>O.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][C:20]=3[N:21]2[S:3]([C:6]2[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=2)(=[O:5])=[O:4])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3cc(Br)ccc23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CCN(C(=O)OC(C)(C)C)C3)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.2 %

Procedure:
6 N NaOH solution (6 mL), (Bu4N)2SO4 (50% wt. solution in H2O, 0.20 mL), and TsCl (646 mg, 3.39 mmol) were added to a suspension of tert-butyl 7-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (991 mg, 2.82 mmol) in toluene (20 mL) and the resulting suspension was stirred at 25° C. for 1.5 h. H2O and EtOAc were added to the suspension and the phases were separated. The organic phase was washed with H2O, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (1.285 g, 90%) as a white foam: 1H NMR (300 MHz, CDCl3) δ 8.32 (d, J=1.5 Hz, 1H), 7.78-7.66 (m, 2H), 7.36 (dd, J=8.4, 1.5 Hz, 1H), 7.25-7.21 (m, 2H), 7.21-7.13 (m, 1H), 4.92-4.81 (m, 2H), 3.74-3.63 (m, 2H), 2.70-2.61 (m, 2H), 2.37 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [C:1](=[O:4])([O-])O.[Na+].I[C:7]1[C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]([CH3:28])[N:8]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:13][C:12]1[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH2:1][OH:4])=[CH:20][CH:19]=2)=[N:8][C:9]([CH3:28])=[CH:10][CH:11]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(CO)cc3)c2cc1OC
Temperature: 80 °C
Reaction time: 5 h
Yield: 24 %

Procedure:
Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and (4-hydroxymethyl)phenylboronic acid (90 mg) under an argon atmosphere, and the mixture was stirred at 80° C. for 5 hr. The reaction solution was cooled to room temperature, an aqueous sodium hydroxide solution was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (11 mg, yield 24%).
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].CCN=C=NCCCN(C)C.Cl.[NH2:34][C:35]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)=[CH:52][C:36]=1[C:37]([NH:39][C:40]1[CH:41]=[N:42][C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[N:44][CH:45]=1)=[O:38]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][N:2]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3](=[O:4])[C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([NH:34][C:35]2[CH:55]=[CH:54][C:53]([N:56]3[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]3)=[CH:52][C:36]=2[C:37](=[O:38])[NH:39][C:40]2[CH:45]=[N:44][C:43]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)=[N:42][CH:41]=2)=[O:10])[CH:6]=1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3ccccc3)nc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.6 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (314 mg, 1.08 mmol, 2.00 equiv) in dichloromethane (10 mL), EDC.HCl (155 mg, 0.81 mmol, 1.50 equiv), 4-dimethylaminopyridine (99 mg, 0.81 mmol, 1.50 equiv), and 2-amino-N-(2-phenylpyrimidin-5-yl)-5-(piperidin-1-yl)benzamide (200 mg, 0.54 mmol, 1.00 equiv). The resulting solution was stirred for 4 h at 25° C. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 114 mg (28%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 10.98 (m, 2H), 9.70 (s, 1H), 9.29 (s, 2H), 8.35 (m, 2H), 8.01 (m, 3H), 7.63 (m, 2H), 7.52 (m, 4H), 7.28 (m, 1H), 4.03 (m, 2H), 3.82 (m, 2H), 3.61 (m, 4H), 3.43 (m, 2H), 3.24 (m, 6H), 2.95 (s, 3H), 1.59 (m, 6H). MS (ES, m/z): 648 [M+H]+.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:26]=[CH:25][C:22](C=O)=[C:21]([Cl:27])[CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C([C:35]([O:37]O)=[O:36])C=1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:35]([O:37][C:22]1[CH:25]=[CH:26][C:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:20][C:21]=1[Cl:27])=[O:36]
Reactant: CC(C)(C)[Si](Oc1ccc(C=O)c(Cl)c1)(c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1ccc(OC=O)c(Cl)c1)(c1ccccc1)c1ccccc1
Yield: 81.9 %

Procedure:
4-{[t-butyl(diphenyl)silyl]oxy}-2-chlorobenzaldehyde (11.00 g, 28 mmol) was dissolved in CHCl3 (150 ml). In one portion m-chloroperbenzoic acid (MCPBA) (7.21 g, 41.8 mmol) was added and the solution heated to reflux for 72 h. The solution was diluted with CH2Cl2, washed with sat. NaHSO3, sat. NaHCO3, brine and dried (MgSO4). The solvent was removed to provide 9.42 g of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][C:4]=1[F:20].[N-:21]=[N+:22]=[N-:23].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[N:21]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][C:4]=1[F:20])=[N+:22]=[N-:23]
Reactant: CC(=O)Nc1nc(CCc2ccc(CCl)c(F)c2)cs1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CCc2ccc(CN=[N+]=[N-])c(F)c2)cs1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 77.4 %

Procedure:
To a solution of N-(4-{2-[4-(chloromethyl)-3-fluorophenyl]ethyl}-1,3-thiazol-2-yl)acetamide (203.3 mg, 0.650 mmol) in anhydrous N,N-dimethylformamide (2 ml) was added sodium azide (233.7 mg, 3.595 mmol), and the mixture was stirred at room temperature for 3.5 hr. Water (20 ml) and ethyl acetate (20 ml) were added to the reaction mixture, and the mixture was stirred, stood still and then partitioned. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diisopropyl ether (10 ml) was added to the residue, and the mixture was filtered and dried under reduced pressure to give N-(4-{2-[4-(azidomethyl)-3-fluorophenyl]ethyl}-1,3-thiazol-2-yl)acetamide (160.5 mg, 0.503 mmol, yield 77.3%) as a white solid.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][OH:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O>C(Cl)Cl>[C:1]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH:14]=[O:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCC[C@H]1CO
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C[C@@H]1CCCN1C(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of (2S)-1-benzoylpyrrolidine-2-methanol (24.1 g) in methylene chloride (120 ml) was added dropiwise to the solution at -70° C. The mixture was stirred for 30 mins. Triethylamine (89.5 ml) was added dropwise to the reaction solution at -70° C. The mixture was stirred for 50 mins at the same temperature, and then rised to 0° C. gradually. Water was added to the solution.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:11]([F:14])([F:13])[F:12])[N:5]=[CH:4][CH:3]=1.[N+](=[CH2:17])=[N-].N(N(C)C(N)=O)=O.C(O)(=O)C>C(OCC)(=O)C.C(OCC)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:17])=[O:9])=[C:6]([C:11]([F:14])([F:12])[F:13])[N:5]=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1c(Cl)ccnc1C(F)(F)F
Agent: CN(N=O)C(N)=O
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Cl)ccnc1C(F)(F)F
Reaction time: 0.25 h
Yield: 104.9 %

Procedure:
To a stirred solution of 4-chloro-2-(trifluoromethyl)nicotinic acid (8.75 g, 38.8 mmol) in ethyl acetate (100 mL) in an ice bath is added a solution of diazomethane [generated from 12 g (116 mmol) of N-nitroso-N-methylurea] in diethyl ether (200 mL). The solution is stirred for 15 minutes, followed by the addition of acetic acid (until effervescence stops). The solution is concentrated in vacuo to afford 9.75 g (99%) of the title compound as a brown oil: 1H NMR (400 MHz, CD3OD), 8.686 (d, 1H), 7.828 (d, 1H), 3.937 (s, 3H). LC/MS (M+1)=240.1
Reaction SMILES: C[C:2]1[C:10]([C:11](=[O:13])[CH3:12])=[CH:9][C:8]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:51][O:52][C:53]1[CH:54]=[C:55]([CH:79]=[CH:80][CH:81]=1)[CH2:56][N:57]([CH2:65][C@@H:66]([OH:78])[C@@H:67]([NH2:77])[CH2:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=1)[C:58](=[O:64])[O:59][C:60]([CH3:63])([CH3:62])[CH3:61]>CN(C=O)C.C(OCC)(=O)C>[CH3:51][O:52][C:53]1[CH:54]=[C:55]([CH:79]=[CH:80][CH:81]=1)[CH2:56][N:57]([CH2:65][C@@H:66]([OH:78])[C@@H:67]([NH:77][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:9]=[C:10]([C:11](=[O:13])[CH3:12])[CH:2]=1)[CH2:68][C:69]1[CH:70]=[C:71]([F:76])[CH:72]=[C:73]([F:75])[CH:74]=1)[C:58](=[O:64])[O:59][C:60]([CH3:63])([CH3:61])[CH3:62]
Reactant: CC(=O)c1cc(S(C)(=O)=O)cc(C(=O)O)c1C
Reactant: COc1cccc(CN(C[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)C(=O)OC(C)(C)C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(C)=O)cc(S(C)(=O)=O)c2)C(=O)OC(C)(C)C)c1
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
A mixture of methyl 3-acetyl-5-(methylsulfonyl)benzoic acid (52 mg, 0.215 mmol), HATU (98 mg, 0.258 mmol) and Hunig's base (111.1 mg, 0.15 mL, 0.86 mmol) in DMF (1.0 mL) was stirred for 10 min and then tert-butyl 3-methoxybenzyl((2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl)-carbamate (94 mg, 0.215 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with H2O 3 times and concentrated under vacuum. The crude mixture was purified by reverse phase prep HPLC to give the title compound (70 mg): 1H NMR (CD3OD, 500 MHz) δ ppm 1.48 (9H, s), 2.70 (3H, s), 2.87-2.90 (1H, m), 3.11-3.15 (2H, m), 3.20 (3H, s), 3.37 (1H, m), 3.76 (3H, s), 3.79-3.80 (1H, m), 3.99 (1H, m), 4.33-4.39 (1H, m), 4.43-4.47 (1H, m), 6.73 (1H, m), 6.80-6.83 (3H, m), 6.91 (2H, m), 7.21-7.25 (1H, m), 8.45 (1H, m), 8.54 (1H, m), 8.61 (1H, m). HPLC retention time: 2.022 min (method B). MS (ESI) (M+H)+ 661.14.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[NH2:17][CH2:18][C:19]([N:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][O:31][C:32]2[C:40]3[N:39]=[C:38]([O:41][CH3:42])[N:37]([CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=4)[C:36]=3[CH:35]=[CH:34][CH:33]=2)[C:24]=1[Cl:50])[CH3:22])=[O:20].ClC1C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[Cl:50][C:24]1[C:25]([CH2:30][O:31][C:32]2[C:40]3[N:39]=[C:38]([O:41][CH3:42])[N:37]([CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=4)[C:36]=3[CH:35]=[CH:34][CH:33]=2)=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[N:21]([CH3:22])[C:19](=[O:20])[CH2:18][NH:17][C:14](=[O:16])[CH2:13][CH2:12][C:9]1[CH:10]=[N:11][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][CH:8]=1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Reactant: CS(=O)(=O)Nc1ccc(CCC(=O)O)cn1
Agent: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CCc4ccc(NS(C)(=O)=O)nc4)c3Cl)cccc2n1Cc1ccccn1

Procedure:
Compound 5 was prepared from 3-(6-(methylsulfonamido)pyridin-3-yl)propanoic acid and 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide described for compound 1. MS (APCI) 737(M+), 1H NMR (CDCl3) 2.41-2.51 (m, 2H), 2.65 (s, 3H), 2.81-2.92 (m, 2H), 3.05 (s, 3H), 3.22 (s, 3H), 3.33-3.52 (m, 1H), 3.37-3.90 (m, 1H), 5.40 (s, 2H), 5.61 (s, 2H), 6.50-6.61 (m, 1H), 6.71 (s, 1H), 7.17-7.3 (m, 4H), 7.34-7.42 (m, 1H), 7.42-7.52 (m, 1H), 7.55-7.63 (m, 2H), 7.70-7.80 (m, 1H), 7.82-7.95 (m, 1H), 8.04 (s, 1H), 8.61-8.68 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([NH:9][CH2:10][CH3:11])[CH:8]=1)#[N:2].Cl.[CH2:13]([OH:16])[CH2:14][CH3:15]>>[CH2:10]([NH:9][C:7]1[CH:8]=[C:3]([C:1](=[NH:2])[O:16][CH2:13][CH2:14][CH3:15])[CH:4]=[N:5][CH:6]=1)[CH3:11]
Reactant: CCNc1cncc(C#N)c1
Reactant: CCCO
Agent: Cl
Product: CCCOC(=N)c1cncc(NCC)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Into a solution of 3-cyano-5-ethylaminopyridine (380 mg, 2.59 mmol) in 1-propanol (40 ml) was passed hydrogen chloride gas under ice-cooling for 30 minutes. The reactor was tight sealed, and the mixture was stirred at room temperature for 20 hours and concentrated under reduced pressure. After the residue was neutralized with a saturated aqueous sodium carbonate solution and extracted with chloroform (50 ml×3). The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product of propyl 5-ethylamino-3-pyridinecarboximidate. The crude product was then dissolved in acetonitrile (5 ml) and an aqueous solution (18 ml) of cyanamide (210 mg, 5.0 mmol), Na2HPO4 (355 mg, 2.5 mmol) and NaH2PO4 ·2H2O (1.56 g, 10 mmol) was added to the solution, and the mixture was stirred at room temperature over night. After the reaction was completed, the reaction mixture was extracted with chloroform (30 ml×3), and the chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (Wako Gel C-200, 30 g; eluted with hexane/ethyl acetate) to give propyl N-cyano-5-ethylamino-3-pyridinecarboximidate (322 mg, 1.38 mmol) as a colorless oil (Yield 54%).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[O:8][CH:9]1[N:17](CC2C=CC(C(O)(C)C)=CC=2)[CH:16]=[CH:15][CH:14]=[C:10]1[C:11]([OH:13])=O)=[O:4].[NH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C>CN(C)C=O.O>[CH3:32][N:2]([CH3:1])[C:3]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[O:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([OH:44])([CH3:42])[CH3:43])=[CH:37][CH:36]=1)=[O:13])=[O:4]
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: CN(C)C(=O)c1cccc(OC2C(C(=O)O)=CC=CN2Cc2ccc(C(C)(C)O)cc2)c1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc(C(C)(C)O)cc2)c1

Procedure:
To a stirred solution of 2-(3-Dimethylcarbamoyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinic acid (0.300 grams, 1.05 mmole), 2-(4-Aminomethyl-phenyl)-propan-2-ol (0.190 grams, 1.15 mmole), and 1-hydroxybenzotriazole hydrate (0.155 grams, 1.15 mmole) in dry dimethylformamide (5 ml) was added 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (0.242 grams, 1.26 mmole) and stirred over night. The mixture poured into 100 ml water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgSO4, filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 2.5% methanollmethylene chloride (0.360 g). 1H NMR (CDCl3) d 1.54 (6H, s), 3.00 (3H, s), 3.08 (3H, s), 4.66 (2H, d), 7.20 (3H, m), 7.29 (4H, m), 7.43 (2H, m) 8.08 (1H, m), 8.18 (1H, dd), 8.63 (1H, dd); MS: m/e 433 (M+).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C@@H:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])[C:8](=O)[CH2:9][C@H:5]12)[CH3:3].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:34]2[N:35]=[CH:36][N:37]3[CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[S:39][C:38]=23)=[O:33])[CH:27]=1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:8]([C:40]3[S:39][C:38]4=[C:34]([C:32]([C:28]5[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=5)=[O:33])[N:35]=[CH:36][N:37]4[CH:41]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cccnc3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cccnc5)c4s3)C[C@H]12
Yield: 73 %

Procedure:
4-Nitrobenzyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (469 mg) was prepared in the same manner as in step a) of Example 1, except that 400 mg of 4-nitrobenzyl (3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate and 700 mg of 7-(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][C@H:8]2[CH2:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[C:3]1=[O:27].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34].C(N(C(C)C)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:25]([S:22]([CH2:21][C@H:8]1[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[C:30]([C:29]([F:28])([F:39])[F:40])[CH:31]=3)[C:3]2=[O:27])[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9]1)(=[O:24])=[O:23])[CH3:26]
Reactant: CCS(=O)(=O)C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCS(=O)(=O)C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A sample of tert-butyl (1R,3R,4S)-4-((S)-3-amino-2-oxopyrrolidin-1-yl)-3-(ethylsulfonylmethyl)cyclohexylcarbamate (100 mg, 0.25 mmol) in DMF (10 mL) was charged with 3-(trifluoromethyl)benzoic acid (57 mg, 0.29 mmol), N,N-diethylisopropylamine (0.05 mL, 0.29 mmol), and HATU (114 mg, 0.29 mmol). The reaction was stirred for 48 h at RT and then partitioned between EtOAc and sat. NaHCO3; the aqueous phase was back extracted with EtOAc (1×). The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford tert-butyl (1R,3R,4S)-3-(ethylsulfonylmethyl)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)cyclohexylcarbamate. MS found: (M+H)+=578.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[N:10]=[C:9]2[CH:20]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:22]1([CH2:27][C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[N:10]=[C:9]2[CH2:20][NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([CH2:27][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH:29]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1nc2ccc(F)cc2c(=O)n1-c1cccnc1Cl
Reactant: Nc1cccc(CN2CCCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=c1c2cc(F)ccc2nc(CNc2cccc(CN3CCCC3)c2)n1-c1cccnc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(2-chloro-pyridin-3-yl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.150 g, 0.49 mmol), 3-pyrrolidin-1-ylmethylaniline (0.044 g, 0.25 mmol), and acetic acid (0.14 mL, 2.45 mmol) in dichloroethane (10 mL) was chilled to 0° C. and sodium triacetoxyborohydride (0.312 g, 1.47 mmol) was added. The reaction was stirred for 1 hour at 0° C. and then allowed to warm to ambient temperature. The reaction was quenched by addition of saturated aqueous bicarbonate and continued stirring for 30 minutes. The phases were separated and the aqueous layer was extracted with methylene chloride. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (45 g) with elution proceeding as follows: 10% methanol/0.5% ammonium hydroxide/chloroform (200 mL), nil; (50 mL), unweighed impurity; (25 mL), nil; (75 mL), unweighed mixed fraction; (200 mL), 0.010 g (8%) of 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-[(3-pyrrolidin-1-ylmethyl-phenylamino)-methyl]-3H-quinazolin-4-one as a pale yellow solid which had: 1H NMR δ 8.60 (d, J=5 Hz, 1H), 7.80 (t, J=5 Hz, 1H), 7.76 (d, J=9 Hz, 1H), 7.71 (dd, J=3, 9 Hz, 1H), 7.58-7.50 (m, 2H), 7.35 (dd, J=5, 8 Hz, 1H), 7.14-7.08 (m, 2H), 6.80 (dd, J=4, 9 Hz, 1H), 4,44 (s, 1H), 3.90-3.65 (m, 4H), 2.79 (br s, 4H), 1.90 (br s, 4H); APCI MS m/z=464 (P+1)