Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([OH:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.CCN=C=NCCCN(C)C.[CH3:31][O:32][C:33](=[O:55])[C@@H:34]([NH:38][S:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH:35]([CH3:37])[CH3:36].CN(C=O)C>[Cl-].[Na+].O>[CH3:31][O:32][C:33](=[O:55])[C@@H:34]([NH:38][S:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:49]=[CH:50][C:51]([NH:54][C:4]([C:6]3[O:7][C:8]4[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([OH:19])[C:9]=4[C:10]=3[CH3:11])=[O:5])=[CH:52][CH:53]=2)=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH:35]([CH3:37])[CH3:36]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Reactant: CCOC(=O)c1oc2ccc(C(C)=O)c(O)c2c1C
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(C(C)=O)c(O)c4c3C)cc2)cc1)C(C)C
Temperature: 65 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
To 70 mg (0.3 mmol) of 5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 115 mg (2 eq) EDCI, 109 mg (1 eq) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester and 2 mL of DMF. The mixture was stirred at 65° C. overnight. The reaction mixture was poured into brine, and extracted with dichloromethane. The organic solution was washed with 2N HCl and water. Removal of the solvents under vacuum gave crude product, which was purified by column chromatography on silica gel to give 20 mg (10% yield) of (S)-2-{4′-[(5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as a white solid.
Reaction SMILES: Cl.CO[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:15])[CH3:14]>C(O)C.O>[CH2:13]([NH:15][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])[CH3:14]
Reactant: CCN
Reactant: COc1ccncc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCNc1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 96 %

Procedure:
4Methoxy-3-nitropyridine hydrochloride (11.2 g, 58.9 mmol) in ethanol (75 ml) was treated with a 70% solution of ethylamine in water (64 ml) and heated under reflux for 2 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue dissolved in ethyl acetate and water. The mixture was extracted (×3) with ethyl acetate, washed with water and saturated aqueous sodium chloride solution before drying over magnesium sulfate. Evaporation of the solvent afforded the title compound (11.7 g, 96%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34]1[NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=2[N:35]=1>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:35]1[C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=[C:34]1[C@@H:30]1[CH2:31][CH2:32][CH2:33][O:29]1)=[N:3][C:4]=2[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: c1ccc2[nH]c(C3CCCO3)nc2c1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c([C@@H]4CCCO4)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and racemic 2-(tetrahydrofuran-2-yl)-1H-benzimidazole were reacted to give a racemic mixture. The enantiomers were separated by SFC to give 253. LCMS m/z: 561.3 (MH+)
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)=O.[NH3:14]>CO>[C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)(=[O:2])[NH2:14]
Reactant: COC(=O)C1Cc2ccccc2N1
Reactant: N
Solvent: CO
Product: NC(=O)C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
To a solution of 2-methoxycarbonylindoline (22.733 g, 0.128 mmol) in methanol (230 mL) was introduced gaseous NH3 at room temperature until the solution was saturated with NH3. The mixture was stirred for 6 h at room temperature. The precipitates formed were collected, washed with methanol, and dried in vacuo to give 17.78 g of 2-carbamoylindoline (85%): 1H NMR (270 MHz, CDCl3) δ7.30 (bs, 1H), 7.11 (bs, 1H), 7.01 (d, 1H, J=7 Hz), 6.93 (dt, 1H, J=1, 7 Hz), 6.56 (m, 2H), 5.87 (bs, 1H), 4.12 (dd, 1H, J=10, 8 Hz), 3.25 (dd, 1H, J=16, 10 Hz), 2.93 (dd, 1H, J=16, 8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.4 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide as a yellow solid (54 mg, 44%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:9]2[CH2:8][CH2:7][C:6]3[CH:22]=[CH:23][CH:24]=[CH:25][C:5]=3[C:4]=2[N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.C(OCC)(=O)C>C1COCC1>[NH2:13][CH2:12][C:11]1[C:2]([NH2:1])=[N:3][C:4]2[C:5]3[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=3[CH2:7][CH2:8][C:9]=2[C:10]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21]
Reactant: N#Cc1c(N)nc2c(c1-c1ccc(Cl)cc1Cl)CCc1ccccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: NCc1c(N)nc2c(c1-c1ccc(Cl)cc1Cl)CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, a solution of 2-amino-4-(2,4-dichloro-phenyl)-5,6-dihydro-benzo[h]quinoline-3-carbonitrile (200 mg, 0.58 mmol) in THF (1 ml) is added slowly to a suspension of LiAlH4 (162 mg, 4.26 mmol) in THF (1 ml). After stirring for 2 h at room temperature, the reaction mixture is cooled to −20° C. and water (0.2 ml) is added. After 15 min, ethyl acetate is added and the mixture is filtered through Decalite. The organic phase is then separated, washed with water, and dried over sodium sulfate. Purification by flash chromatography (silica gel, methanol, dichloromethane) affords the title compound, MS: m/e=369.9 (M+H+), as a light yellow solid (53 mg, 26%).
Reaction SMILES: [K+].[Br-].CC1OC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCCC(C)=CC2)\C)N=1.CC1SC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCCC=CC2)\C)N=1.C[CH2:70][C:71]1[S:75][CH:74]=[C:73](/[CH:76]=[C:77](/[C@H:79]2[O:97][C:95](=[O:96])[CH2:94][C@H:93]([OH:98])[C:92]([CH3:100])([CH3:99])[C:90](=[O:91])[C@H:89]([CH3:101])[C@@H:88]([OH:102])[C@@H:87]([CH3:103])[CH2:86][CH2:85][CH2:84][C@H:82]3O[C@H:81]3[CH2:80]2)\[CH3:78])[N:72]=1.CC1SC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)[C@H](C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCCC=CC2)\C)N=1.CC1SC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCCC(C)=CC2)\C)N=1>CO>[CH3:70][C:71]1[S:75][CH:74]=[C:73](/[CH:76]=[C:77](/[C@H:79]2[O:97][C:95](=[O:96])[CH2:94][C@H:93]([OH:98])[C:92]([CH3:100])([CH3:99])[C:90](=[O:91])[C@H:89]([CH3:101])[C@@H:88]([OH:102])[C@@H:87]([CH3:103])[CH2:86][CH:85]=[CH:84][CH:82]=[CH:81][CH2:80]2)\[CH3:78])[N:72]=1
Reactant: CCc1nc(/C=C(\C)[C@@H]2C[C@@H]3O[C@@H]3CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O2)cs1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C/C=C\C=C\C[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C/C=C\CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@@H](C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C/C=C\CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)CC(=O)O1
Solvent: CO
Product: C/C(=C\c1csc(C)n1)[C@@H]1CC=CC=CC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1

Procedure:
colorless amorphous solid; [α]22D −205.2 (c 1.0, MeOH); UV (MeOH) λmax nm (ε) 218 (24600), 237 (28800); IR (KBr) νmax 3435, 2967, 2927, 2882, 1732, 1688, 1465, 1258, 988 cm−1; 1H NMR (CDCl3, 300 MHz) δ 6.97 (1H, s, H-19), 6.58 (1H, bs, H-17), 6.43 (1H, dd, 15.5, 10.8 Hz, H-11), 6.11 (1H, dd, J=10.8, 10.6 Hz, H-12), 5.75 (1H, ddd, J=15.5, 8.3, 5.6 Hz, H-10), 5.34 (1H, m, H-13), 5.34 (1H, dd, J=9.7, 2.4 Hz, H-15), 4.16 (1H, ddd, J=9.2, 4.9, 4.3 Hz, H-33), 3.74 (1H, ddd, J=2.2, 2.1, 1.7 Hz, H-7), 3.24 (1H, dq, J=2.1, 6.9 Hz, H-6), 3.06 (1H, d, J=2.2 Hz, 7-OH), 2.93 (1H, d, J=4.9 Hz, 3-OH), 2.78 (1H, dddd, J=14.1, 9.9, 9.7, 0.7, H-14a), 2.71 (3H, s, H-21), 2.48 (1H, m, H-9a), 2.47 (1H, dd, J=15.5, 9.2 Hz, H-2a), 2.40 (1H, dd, J=15.5, 4.3 Hz, H-2b), 2.38 (1H, bdd, J=14.1, 7.8 Hz, H-14b), 2.11 (3H, d, J=1.3 Hz, H-27), 1.96 (1H, m, H-8), 1.33 (3H, s, H-23), 1.11 (3H, d, J=6.9 Hz, H-24),1.06 (3H, s, H-22),1.05 (3H, d, J=6.8 Hz, H-25); 13C NMR, see Table 1; EIMS m/z 475 [M]+ (13), 387 (2), 316 (4), 288 (15), 230 (16), 204 (9), 171 (18), 168 (100), 164 (14), 151 (17); HREIMS m/z 475.2361 (calcd. for C26H37NO5S, 475.2392).
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([N:23]([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)C=CC=CC=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:28]1>O1CCOCC1>[CH3:25][N:23]([CH3:24])[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:8]([N:27]2[CH2:32][CH2:31][CH2:30][CH:29]([C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][CH:34]=3)[CH2:28]2)=[O:7])[CH2:12][CH2:13]1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Reactant: c1ccc2c(C3CCCNC3)c[nH]c2c1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CCCC(c3c[nH]c4ccccc34)C2)CC1
Yield: 20.6 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (529 mg, 1.5 mmole) was added to a solution of 3-piperidine-3-yl-1H-indole (300 mg, 1.5 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 20 hours. The reaction mixture was worked up by distilling off the solvent. The residue contained, in addition to phenol, also the two diastereoisomers of 3-(1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (50 g). Methanol/EE (1:1; 900 ml) was used as eluent. The non-polar diastereoisomer of 3-(1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (220.6 mg, m.p. 165°-170° C., 32%) and the polar diastereoisomer of 3-(1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (142 mg, m.p. 95°-99° C., 31%) were thereby obtained in pure form.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[CH:4]=1)=O.C([BH3-])#N.[Na+].B(F)(F)F.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OC)(C)(C)C>[CH3:1][C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[CH:4]=1
Reactant: O=Cc1ccn(-c2ccccc2O)c1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccn(-c2ccccc2O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
To 2-(3-formyl-1-pyrrolyl)phenol (2.9 g, 15.5 mmol) in 50 ml dry tetrahydrofuran are added sodium cyanoborohydride (1.94 g, 31 mmol) and boron trifluoride diethyletherate (5.7 ml, 47 mmol). The resulting solution is stirred for 3 hours at ambient temperature. Saturated sodium bicarbonate (100 ml) is added and the resulting mixture is stirred for 1 hour before extraction with t-butylmethylether. The organic layer is dried and concentrated and the residue is purified by chromatography (toluene/ethanol 9:1) to yield 2-(3-methyl-1-pyrrolyl)phenol (300 mg, 11%). This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH2:11][CH:12]([CH2:25][OH:26])[CH2:13][CH2:14][N:15]1[CH:22]=[C:21]([CH:23]=[CH2:24])[C:19](=[O:20])[NH:18][C:16]1=[O:17]>N1C=CC=CC=1>[C:1]([O:10][CH2:11][CH:12]([CH2:25][O:26][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:14][N:15]1[CH:22]=[C:21]([CH:23]=[CH2:24])[C:19](=[O:20])[NH:18][C:16]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1cn(CCC(CO)CO)c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: C=Cc1cn(CCC(COC(=O)c2ccccc2)COC(=O)c2ccccc2)c(=O)[nH]c1=O
Reaction time: 48 h
Yield: 65.6 %

Procedure:
Benzoylchloride (600 mg, 4.2 mmol) was added to a solution of 20 (450 mg, 1.87 mmol) in dry pyridine (50 ml) and the reaction was allowed to proceed at 25° C. with stirring for 48 h. The reaction mixture was poured onto ice water (50 ml) and extracted with dichloromethane (3×50 ml). The dichloromethane extract was dried over sodium sulfate, the solvent was removed in vacuo and the residue obtained was purified by elution from a silica gel column using chloroform-methanol (97:3, v/v) as eluent to yield 22 as a viscous oil (550 mg, 65.4%) which was used directly in the next reaction step.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[F:13][B-](F)(F)F.F[B-](F)(F)F.F[N+]12CC[N+](O)(CC1)CC2.C(#N)C.NC1C=CC=CC=1>C(OCC)(=O)C>[Cl:9][C:8]1[C:7]([F:13])=[C:5]([C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]=1[Cl:1])[NH2:6]
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: F[B-](F)(F)F
Agent: O[N+]12CC[N+](F)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: Nc1ccccc1
Product: Nc1c([N+](=O)[O-])cc(Cl)c(Cl)c1F
Temperature: 25 °C
Yield: 36.6 %

Procedure:
4,5-Dichloro-2-nitroaniline (9.8 g, 47.4 mmol), 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (18.5 g, 57.4 mmol, Allied Signal, Buffalo), and acetonitrile (300 mL) were combined and the mixture was heated to reflux for several hours. After thin-layer chromatography showed that no starting aniline remained, the mixture was allowed to cool to rt and was poured into ethyl acetate, causing a precipitate to form. The mixture was filtered through a pad of Celite, purified by silica gel and the solvents were removed in vacuo to provide a brown solid (3.9 g, 37%); 1H NMR (DMSO-d6) δ: 8.11 (d, J=2.2 Hz, 1H, Ar—H), 7.67 (br s, 2H, NH2).
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1)(=[O:10])[CH3:9].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[N+:35]([O-:37])=[O:36])[CH:30]=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[C:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[CH:30][C:29]2[CH:32]=[CH:33][C:34]([N+:35]([O-:37])=[O:36])=[C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:28]=2)[N:13]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1cccc(C)n1
Reactant: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc(C=Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)n1
Temperature: 180 °C
Yield: 23.1 %

Procedure:
A mixture of acetic anhydride (6 ml), 2-acetamido-6-methylpyridine (8.00 g) and 3-benzyloxy-4-nitrobenzaldehyde (13.7 g), was heated at 180° C. for 22 hours with stirring. After cooling, the reaction mixture was dissolved in chloroform (150 ml). The solution was washed with aqueous potassium carbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (640 g) by eluting with chloroform and washed with a mixture of ethyl acetate and diisopropyl ether to give 2-acetamido-6-[2-(3-benzyloxy-4-nitrophenyl)vinyl]pyridine (4.80 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C@H:11]1[N:19]([C:20](=[O:39])[C@@H:21]([NH:25][C:26](=[O:38])[C@@H:27]([N:29](C)[C:30](=O)OC(C)(C)C)[CH3:28])[CH:22]([CH3:24])[CH3:23])[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH2:12]1)=[O:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C@H:11]1[N:19]([C:20](=[O:39])[C@@H:21]([NH:25][C:26](=[O:38])[C@@H:27]([NH:29][CH3:30])[CH3:28])[CH:22]([CH3:23])[CH3:24])[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH2:12]1)=[O:10]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1F)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
In a 50 mL round-bottomed flask, tert-butyl (S)-1-((S)-1-((S)-2-(2-fluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (39 mg, 72.0 μmol, Eq: 1.00) was combined with DCM (3.00 mL) to give a colorless solution. TFA (1.00 mL, 13.0 mmol, Eq: 180) was added the reaction was stirred at rt for 30 min and then concentrated in vacuo. The residue was taken up in DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo to give (S)—N-(2-fluorophenyl)-1-((S)-3-methyl-2-((S)-2-(methylamino)propanamido)butanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide as an off-white solid (25 mg), m/z=442 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[C:17]([F:35])[CH:16]=2)=[N:6][C:7]([S:12][CH3:13])=[N:8][C:9]=1[NH:10][NH2:11])(=[O:3])[NH2:2].[CH:36]([O-])([O-])OC>CC(N(C)C)=O>[C:1]([C:4]1[C:9]2[N:8]([CH:36]=[N:11][N:10]=2)[C:7]([S:12][CH3:13])=[N:6][C:5]=1[NH:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([N:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:26][CH2:27]2)=[C:17]([F:35])[CH:16]=1)(=[O:3])[NH2:2]
Reactant: CSc1nc(NN)c(C(N)=O)c(Nc2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Reactant: COC([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CSc1nc(Nc2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)c(C(N)=O)c2nncn12
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 15E (281 mg, 0.55 mmol) in dimethylacetamide (5 mL) was added methyl orthoformate (2 mL). The mixture was stirred at ambient temperature for 1 hour and at 60° C. for 4 hours. After cooling to ambient temperature, 9/1 petroleum ether/ethyl acetate (50 mL) was added and the precipitate was filtered. The solid was washed with petroleum ether and dried under vacuum to give the title compound. MS: 521 (M+H+).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]1[CH:32]=[CH:31][C:30]([S:33][C:34]2[N:35]=[CH:36][N:37]3[CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[S:39][C:38]=23)=[CH:29][CH:28]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:40]3[S:39][C:38]4=[C:34]([S:33][C:30]5[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=5)[N:35]=[CH:36][N:37]4[CH:41]=3)[C@H:9]([CH3:10])[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@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(Sc3ccncc3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(Sc5ccncc5)c4s3)[C@H](C)[C@H]12
Yield: 4.9 %

Procedure:
The procedure of Example 1a) was repeated, except that 1.18 g of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.78 g of 7-(pyridin-4-yl)thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 93.1 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-4-yl)thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9](OCC)OCC)=[C:6]([Cl:16])[N:5]=[CH:4][N:3]=1.[NH2:17][C@H:18]1[CH2:22][C@H:21]([OH:23])[C@H:20]([CH2:24][OH:25])[CH2:19]1.Br.C(O)(C)C.C(N(CC)CC)C.Cl.C(=O)(O)[O-].[Na+]>O>[Cl:16][C:6]1[C:7]2[CH:8]=[CH:9][N:17]([C@H:18]3[CH2:22][C@H:21]([OH:23])[C@H:20]([CH2:24][OH:25])[CH2:19]3)[C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: N[C@@H]1C[C@@H](CO)[C@@H](O)C1
Reactant: CCOC(Cc1c(Cl)ncnc1Cl)OCC
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: OC[C@@H]1C[C@@H](n2ccc3c(Cl)ncnc32)C[C@@H]1O
Temperature: 85 °C
Reaction time: 3 h

Procedure:
To a slurry of 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (10.0 g, 0.0377 mol) and (1S,2S,4R)-4-amino-2-(hydroxymethyl)cyclopentanol.HBr (800 g) in isopropyl alcohol (82 mL, 1.1 mol) and water (11 mL, 0.59 mol), triethylamine (13 mL, 0.094 mol) was added. This mixture was then heated to 85° C. for 23 hours. The mixture was cooled to 50° C., at which point 4M hydrochloric acid in water (20 mL) was added slowly. The resulting mixture was then stirred at 50° C. for 3 hours. HPLC indicated that the reaction was complete. The reaction mixture was cooled to ambient temperature and sodium bicarbonate (10 g, 0.1 mol) was added portionwise. Excess solids were filtered; the bed washed with isopropyl alcohol (20 mL) and the filtrate concentrated to ˜70 mL. Ethyl acetate (150 mL) was added followed by a mixture of saturated NaHCO3 aq (35 mL) and water (35 mL). The layers were separated and the aqueous phases extracted with ethyl acetate (2×50 mL) and filtered. The organic layers were combined and washed with saturated NaCl aq (50 mL) and then concentrated to afford the title compound (90.3 g) as a brown solid. 1H NMR (300 MHz, CD3OD, δ): 8.56 (s, 1H), 7.67 (d, 1H), 6.65 (d, 1H), 5.52 (m, 1H), 4.50 (m, 1H), 3.79 (m, 1H), 3.66 (m, 1H), 2.63 (m, 1H), 2.25 (m, 3H) and 2.02 (m, 1H).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=O)[CH2:2]1)[CH2:8]2.Cl.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C(O)C>[CH2:13]([O:20][N:21]=[C:4]1[CH:5]2[CH2:10][N:1]3[CH2:8][CH:7]([CH2:9][CH:3]1[CH2:2]3)[CH2:6]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C2CC3CC1CN(C3)C2
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCO
Product: c1ccc(CON=C2C3CC4CC2CN(C4)C3)cc1
Reaction time: 8 h

Procedure:
A mixture of 1-azatricyclo[3.3.1.13,7]decan-4-one (45 mg, 0.30 mmol) (prepared as reported in Becker, D. P. and Flynn, D. L. Synthesis 1992, 1080-1082) and O-benzylhydroxylamine hydrochloride (Aldrich, 51 mg, 0.32 mmol) were combined in a test tube with ethanol (3 mL). Concentrated hydrochloric acid (12 M, 0.1 mL) was added, and the mixture was heated at reflux until the solids dissolved. The solution was allowed to stand at room temperature overnight, then concentrated under vacuum. The residue was dissolved in acetonitrile (0.7 mL), and the solution was diluted with ethyl acetate (5 mL). The resulting white precipitate was collected by filtration, washed with ethyl acetate (2 mL) and dried under vacuum to provide the title compound as the hydrochloride salt. 1H NMR (300 MHz, CD3OD) δ 1.89-2.07 (m, 2 H), 2.15-2.37 (m, 3 H), 2.85 (s, 1 H), 3.42-3.85 (m, 7 H), 5.08 (s, 2 H), 7.24-7.40 ppm (m, 5 H); MS (DCI/NH3) m/z 257 (M+H)+; Anal. C16H20N2O-2HCl requires C, 58.36; H, 6.73; N, 8.51; Found C, 58.61; H, 6.49; N, 8.48.