Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]1[C:18]2=[N:19][C:20]3[C:21](=[C:22]([C:26]#N)[CH:23]=[CH:24][CH:25]=3)[N:17]2[CH2:16][CH2:15][CH2:14]1.[O:28]1CCCC1>>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]1[C:18]2=[N:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[O:28])[CH2:1][CH3:2])[C:21]=3[N:17]2[CH2:16][CH2:15][CH2:14]1
Reactant: C1CCOC1
Reactant: N#Cc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC[Mg]Br
Product: CCC(=O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 14.6 mL, 43.7 mmol) was added to a stirred solution of 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbonitrile (5.00 g, 14.6 mmol) in tetrahydrofuran (50 mL) at 0° C., and the mixture was stirred at 50° C. for 2 hr. The reaction was quenched by methanol, and the mixture was diluted with aqueous saturated ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. A mixture of the resulting imine, acetic acid (10 mL) and 1N hydrochloric acid (20 mL) was stirred at 50° C. for 2 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ethyl acetate/diisopropyl ether to give the title compounds as a colorless crystal (3.04 g, 8.12 mmol, 56%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[F:23])=[N:13][N:12]3[CH:24]=2)=[CH:5][C:4]=1[N+:25]([O-])=O)#[CH:2].CC(O)=O>C(O)C.O.[Fe]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[F:23])=[N:13][N:12]3[CH:24]=2)=[CH:5][C:4]=1[NH2:25])#[CH:2]
Reactant: C#Cc1ccc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: C#Cc1ccc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1N
Temperature: 80 °C
Yield: 72.3 %

Procedure:
To a solution of 2-(4-ethynyl-3-nitrophenyl)-6-(2-fluorophenyl)imidazo[1,2-b]pyridazine (0.050 g, 0.139 mmol) in ethanol (3 mL) and water (1 mL) containing AcOH (0.834 mmol) is added iron (0.038 g, 0.695 mmol). The mixture is stirred and heated at 80° C. for 2 hours, then concentrated under reduced pressure and sat. aqueous NaHCO3 (20 mL) is added. The mixture is extracted with EtOAc (3×20 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography using a gradient of hexanes to EtOAc to afford the title compound (0.033 g, 73%) as a yellow solid: Rf 0.30 (1:1 EtOAc:hexanes); LCMS (m/z)=329.4 [M+H]+, tR=2.65 min. (compound same as Example 320)
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13]([CH3:15])=O.[Si]([C:20]#[N:21])(C)(C)C>CCO>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][C:13]([C:20]#[N:21])([CH3:15])[CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: C[Si](C)(C)C#N
Solvent: CCO
Product: CC(C)(C#N)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.1 %

Procedure:
(2-Aminoethyl)carbamic acid tert-butyl ester (25.07 g, 156.5 mmol) was dissolved in EtOH (500 mL), treated with acetone (13.75 mL, 187 mmol), and the stirred solution was cooled in an ice bath. After stirring for 30 min, TMS-CN (62 mL, 465 mmol; CAUTION—toxic) was added dropwise over 1 h. The solution was stirred for 16 h, allowing to warm gradually to room temperature. The solution was concentrated in vacuo [caution: HCN gas evolved: a dry pump venting to the back of the fume hood was used]resulting in a pale yellow solid. This was dissolved in EtOAc (100 mL) and concentrated to a viscous oil. Hexane (500 mL) was added rapidly and the resulting mixture was swirled vigorously until a thick white crystalline precipitate formed. The mixture was allowed to stand for 30 min, and the crystallized product (30.0 g) was collected by filtration, washing with a small amount of hexane to give a white crystalline solid. The filtrate was concentrated in vacuo to give a viscous gum (5 g). This was quickly purified by flash chromatography eluting with EtOAc [N.B. the product is somewhat unstable to silica gel and decomposes if allowed to stay on the column for a long time]resulting in an additional 1.7 g of product, which was combined with the recrystallized material. Total yield=31.7 g, 89%. 1H NMR: δ (d6-DMSO, 400 MHz) 6.64 (1 H, t), 2.83 (2 H, m), 2.60 (1 H, t), 2.41 (2 H, m), 1.21 (9 H, s), 1.17 (6 H, s).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[C:22]([Cl:25])(Cl)=[O:23]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[Cl:25][C:22]([O-:23])=[O:11]
Reactant: O=C(Cl)Cl
Agent: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C([O-])Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Testosterone chloroformate was prepared as follows. To a solution of testosterone (2 g, 7.0 mmol) dissolved in tetrahydrofuran (50 ml) was added a 1.93M solution of phosgene in toluene (33 ml). The resulting solution was stirred for 4 h at room temperature, concentrated under vacuum, and the resulting residue vacuum dried for approximately 30 minutes (2.88 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[N:12]([CH2:19][CH3:20])[C:11]3=[O:21])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:23]1[N:27]([CH2:28]OCC[Si](C)(C)C)[C:26]2[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=2[N:24]=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[CH2:19]([N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([C:23]2[N:27]([CH3:28])[C:26]4[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=4[N:24]=2)[CH2:2][CH2:3]3)[C:11]1=[O:21])[CH3:20]
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: CCn1c(=O)n(-c2ccc3c(c2)CCN3)c2ncccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCn1c(=O)n(-c2ccc3c(c2)CCN3c2nc3ccccc3n2C)c2ncccc21
Temperature: 120 °C
Reaction time: 10 h
Yield: 8.2 %

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (101 mg) in NMP (2 ml) was stirred at 120° C. for 10 h, treated with saturated NaHCO3 solution and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DMF (2 mL), and then iodomethane (0.022 mL) and Cs2CO3 (0.176 g) were added. The mixture was stirred at room temperature for 3 h, treated with water and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in CH3CN and the precipitate was filtered off. The residue was purified by prep. HPLC, and then chromatographed on silica gel eluting with AcOEt/Hexane. Crystallization from AcOEt/Hexane gave the title compound (12 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>ClCCl>[CH2:39]([O:38][C:36](=[O:37])[NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OCc3ccccc3)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl), phenyl)-3-methoxybenzamide (50 mg, 136 μmol) and triethylamine (0.038 mL, 0.27 mmol) in dichloromethane was added benzyl chloroformate (26 mg, 150 μmol), dropwise at room temperature. The mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with dichloromethane (3×20 mL) and dried over anhydrous MgSO4. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography. (EtOAc/Hexane=50-90%). {2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]ethyl}-carbamic acid benzyl ester was obtained as white solid in 37% yield. LCMS m/z (%)=501 (M+H, 100) 1H NMR (400 MHz, CDCl3) δ ppm 3.5 (q, J=5.4 Hz, 2 H), 3.7 (s, 3H), 3.9 (s, 3 H), 4.0 (t, J=5.1 Hz, 2 H), 4.9 (t, J=5.8 Hz, 1 H), 5.1 (s, 2 H), 6.3 (d, J=2.0 Hz, 1 H), 7.0 (d, J=8.6 Hz, 1 H), 7.1 (m, 1 H), 7.3 (m, 5 H), 7.4 (m, 1 H), 7.5 (m, 2 H), 7.7 (dd, J=8.8, 2.8 Hz, 1 H), 7.8 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]>>[Br-:8].[CH3:13][O:12][C:10]([CH2:9][N+:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:11]
Reactant: Clc1ccccn1
Reactant: COC(=O)CBr
Product: COC(=O)C[n+]1ccccc1Cl
Product: [Br-]
Temperature: 60 °C
Yield: 46.4 %

Procedure:
A mixture of 2-chloropyridine (16 g) and methyl bromoacetate (72 g) was allowed to stand for one week at room temperature and then heated for 7 hours at 60° C. The resulting precipitates were collected by filtration and washed with diethyl ether to give 1-methoxycarbonylmethyl-2-chloropyridinium bromide (17.43 g), mp. 163° to 165° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C@H:18]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH2:23][CH2:22]1)=[O:20]>>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][C@@H:18]([NH:17][C:14]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[CH2:23][CH2:22]2)=[O:20])=[CH:40][CH:41]=1.[Cl:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][C@@H:18]([NH:17][C:14]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[CH3:6])=[O:15])[C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[CH2:25][CH2:26]2)=[O:20])=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Product: CN1CCCCC1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1

Procedure:
tert-Butyl 2-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}piperidinecarboxylate was prepared according to the procedure described in Preparation V by using piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (Aldrich) (82 mg, 0.36 mmol) and (2R)-2-Amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl}-amino]phenyl}piperazinyl)propan-1-one. The desired compound was isolated as a white solid (106 mg). MS (ESI, pos. ion) m/z: 648 (M+H); (ESI, neg. ion) m/z: 646 (M−H). Calc'd for C31H42ClN5O6S: 647.25.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:4][CH:3]=1.[CH:15](=O)[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH2:15]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1)[CH3:16]
Reactant: Fc1ccc(NCc2c[nH]cn2)cc1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN(Cc1c[nH]cn1)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
To a solution of (4-fluoro-phenyl)-(1H-imidazol-4-ylmethyl)-amine (0.20 g, 1.05 mmol) in 1,2-dichloroethane (6 ml) were added acetaldehyde (0.30 ml, 5.23 mmol), sodium triacetoxyborohydride (0.67 g, 3.14 mmol) and acetic acid (0.06 ml). The reaction mixture was stirred at 40° C. for 16 h. The reaction mixture was then concentrated in vacuo and the residue was purified using flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: methanol/ethyl acetate/heptane gradient) to yield a white solid (131 mg, 57%); MS (ISP): 220.4 ((M+H)+.).
Reaction SMILES: [NH2-].[Na+].[F:3][C:4]([F:20])([F:19])[C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=1.N.Cl[CH2:23][CH:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1>C1(C)C(C)=CC=CC=1.CN(P(N(C)C)(N(C)C)=O)C>[F:20][C:4]([F:3])([F:19])[C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:23][CH:24]3[CH:29]4[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]4)[CH2:25]3)[C:7]=2[CH:6]=1
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1S2
Reactant: ClCC1CN2CCC1CC2
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1C
Product: FC(F)(F)c1ccc2c(c1)N(CC1CN3CCC1CC3)c1ccccc1S2
Reaction time: 18 h

Procedure:
0.9 ml of a 65% suspension of sodium amide in xylene and then 25 ml of hexamethylphosphotriamide were added to a suspension of 5.3 g of 2-trifluoromethyl-phenothiazine in 25 ml of xylene. The mixture was agitated and heated to reflux. When the evolution of ammonia ceased (2 hours), 16.3 ml of a 9.8% solution of 3-chloromethyl-quinuclidine in xylene were added to the reaction mixture over a period of 30 minutes and refluxing was continued for 18 hours. After cooling, the xylene was evaporated off under reduced pressure and the residual solution was poured into 250 ml of distilled water. The precipitate obtained was separated on Clarcel filter medium, washed with 50 ml of distilled water, and then suspended in 100 ml of ethyl acetate. The insoluble portion was filtered off and the filtrate was washed with 30 ml of distilled water, and then extracted three times with a total of 150 ml of N.aqueous acetic acid. The combined acid extracts were rendered alkaline on an ice bath with 25 ml of ION aqueous sodium carbonate and the oil which separated was extracted twice with a total of 200 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulphate and evaporated. The residue was recrystallised in acetonitrile; 2-trifluoromethyl-10-(3-quinuclidinyl-methyl)-phenothiazine, m.p. 150° C, was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][N:24](/[C:27](/[NH:36]C(=O)OC(C)(C)C)=[N:28]\C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:50][C:47]1[CH:48]=[CH:49][C:44]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27](=[NH:28])[NH2:36])[CH2:23][CH2:22]2)=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)N1CCC(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)N1CCC(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Reaction time: 0.5 h

Procedure:
(Z)-tert-butyl ((4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)((tert-butoxycarbonyl)imino)methyl)carbamate was combined (154 mg, 0.21 mmol) with 30% TFA in CH2Cl2 (7 mL) at room temperature and the resulting mixture was stirred for 0.5 hr. The solvent was removed and the residue was triturated with diethyl ether. The white solid was collected and purified on a Gilson (20-90% CH3CN (0.1% TFA)/H2O) (0.1% TFA)) to yield 4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidine-1-carboximidamide as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([OH:12])=O)=[CH:3]1.[C:13]([O:17][C:18](=[O:35])[NH:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:21]=1)([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[C:13]([O:17][C:18](=[O:35])[NH:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:10]([C:4]2[CH:5]=[C:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:12])=[C:22]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:21]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1cc(C(=O)O)cn(C)c1=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(NCc2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(NC(=O)OC(C)(C)C)cc2NCc2ccccc2)cn(C)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,5-Dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D1 (5.000 g; 16 mmol) and (4-Amino-3-benzylamino-phenyl)-carbamic acid tert-butyl ester E-1.5 (3.200 g; 19 mmol) are dissolved in THF and and cooled to 0° C. DIPEA (6.186 g; 48 mmol) is then added, the mixture is stirred for 15 min Finally HATU (12.133 g; 32 mmol) is added. The mixture is stirred at room temperature for 1 hr. The reaction is diluted with water and extracted with MeOH/DCM. The combined organic layer is dried over Na2SO4 and concentrated in vacuum. The residue is used in the next step without further purification.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:25]([NH:27][C@@H:28]([C:30]([OH:32])=[O:31])[CH3:29])=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.C(O[C:38]([NH:40][C@@H:41]([C:51]([OH:53])=O)[CH2:42][O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:39])(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.[C:69]([O:73][C:74]([NH:76][C@H:77](C(O)=O)[CH2:78][C:79]1[C:87]2[C:82](=[CH:83][CH:84]=[CH:85][CH:86]=2)[NH:81][CH:80]=1)=[O:75])([CH3:72])([CH3:71])[CH3:70]>>[C:69]([O:73][C:74]([NH:76][C@H:77]([C:38]([NH:40][C@@H:41]([C:51]([NH:8][C@H:9]([C:25]([NH:27][C@@H:28]([C:30]([OH:32])=[O:31])[CH3:29])=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:53])[CH2:42][O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:39])[CH2:78][C:79]1[C:87]2[C:82](=[CH:83][CH:84]=[CH:85][CH:86]=2)[NH:81][CH:80]=1)=[O:75])([CH3:72])([CH3:70])[CH3:71]
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@@H](COCc1ccccc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
Nαt-Butoxycarbonyl-L-tryptophyl-O-benzyl-D-seryl-O-benzyl-L-tyrosyl-D-alanine resin is prepared from 8 g. of Nα-t-butoxycarbonyl-O-benzyl-L-tyrosyl-D-alanine resin by successive coupling, according to the general process for solid phase synthesis given in Example 1, with (13 g., 9.8 mmol, of Nα-t-butoxycarbonyl-O-benzyl-D-serine and 2 g., 9.7 mmol, of dicyclohexylcarbodiimide and (2) 3 g., 9.8 mmol, of Nα-t-butoxycarbonyl-L-tryptophan and 2 g. of dicyclohexylcarbodiimide. The resin is washed with ethanol and dried. It is then stirred for twenty-four hours at 25° C. with 200 ml. of methanol and 20 ml. of triethylamine. The mixture is filtered and the methanol solution evaporated. The residue is solidified from ether-petroleum ether; 2 g.; m.p. 155°-156° C.
Reaction SMILES: [C:1]1([C:7]([CH3:14])([CH3:13])[CH:8]([SH:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([O:26][CH3:27])[N:19]=1>CC(C)=O.O>[C:1]1([C:7]([CH3:14])([CH3:13])[CH:8]([S:12][C:18]2[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([O:26][CH3:27])[N:19]=2)[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(c1ccccc1)C(S)C(=O)O
Reactant: COc1nc(Cl)nc(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COc1nc(OC)nc(SC(C(=O)O)C(C)(C)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
1.9 g of 3-phenyl-3-methyl-2-mercaptobutyric acid was dissolved in 50 ml of acetone, and 1.2 g of potassium hydroxide dissolved in 5 ml of water was added thereto under cooling with ice. 1.5 g of 2-chloro-4,6-dimethoxy-S-triazine dissolved in 20 ml of acetone was added thereto. The mixture was stirred for 30 minutes. Then, the reaction solution was poured into water and extracted with 50 ml of ethyl acetate. The aqueous layer was acidified with a citric acid aqueous solution and extracted with 100 ml of chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain 2.2 g of the desired product.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13](O)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:26][CH2:27][C:28]1[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:34][C:33]1[CH:32]=[C:31]([CH3:35])[NH:30][C:29](=[O:36])[C:28]=1[CH2:27][NH:26][C:13]([C:12]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=2[N:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:11]=1)=[O:14]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccc(S(C)(=O)=O)cc3)nc21
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(S(C)(=O)=O)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 1-(1-methylethyl)-6-[4-(methylsulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (90 mg, 0.250 mmol), DMSO (2 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (70.9 mg, 0.376 mmol), N-methylmorpholine (0.110 mL, 1.002 mmol), 1-hydroxy-7-azabenzotriazole (68.2 mg, 0.501 mmol) and EDC (96 mg, 0.501 mmol). The final product was collected as 106 mg (85%). LCMS E-S (M+H)=494.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=5.6 Hz, 6H), 2.13 (br. s., 3H), 2.23 (br. s., 3H), 4.42 (m, 2H), 5.36 (br. s., 1H), 5.91 (br. s., 1H), 8.11 (d, J=7.3 Hz, 2H), 8.27 (br. s., 1H), 8.39-8.64 (m, 3H), 9.01 (br. s., 1H), 11.58 (br. s., 1H).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[O:24][C:23]([C:25]([NH2:27])=[O:26])=[N:22][N:21]=1.C(=O)(O)[O-].[Na+].Cl>CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[O:24][C:23]([C:25](=[O:26])[NH2:27])=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: NC(=O)c1nnc(S)o1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(=O)c1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)o1

Procedure:
7-Aminocephalosporanic acid (10.88 g, 40 mmole) and 5-mercapto-1,3,4-oxadiazol-2-ylcarboxamide (6.40 g, 44 mmole) in 50% aqueous acetone (500 ml) were treated with solid sodium bicarbonate to pH 7 then heated at 60° for 5 hours. The solution was acidified to pH 4.0 with 5 N hydrochloric acid, cooled in an ice bath for one hour and the precipitated solid collected, washed with water (100 ml) ethanol (200 ml) and ether (200 ml) and dried in vacuo, 5.87 g (41.1%), δ(CF3CO2H) 3.5-4.1 (2H,m, C2 methylene), 4.4-4.9 (2H,m, --CH2S--), 5.42 (2H,s, β-lactam protons), 7.89 (2H, d, J 28 Hz, --CONH2).