Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.C[OH:17].[CH2:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1>[CH2:18]([O:20][C:6]1[C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH:5]=1)[CH3:19]
Reactant: CCO
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC1=CCCCC1=O
Yield: 66 %

Procedure:
50 g (0.45 mol) of 1,2-dicyclohexandione were dissolved in a mixture of 1 L of toluene and 0.5 L of ethanol. 10 g of p-toluenesulfonic acid were added and the solution heated at reflux for 2 days. (TLC chloroform/methanol 6/1). The solvent was then evaporated, the residue redissolved with dichloromethane and washed with a saturated solution of NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The crude was purified by chromatography on a silica gel column by eluting with a mixture of cyclohexane/ethyl acetate 98/2 (66% yield as an oil).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C@@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1.Cl[CH2:21][CH:22]=O.C([O-])(O)=O.[Na+].CCOC(C)=O>CO>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]3[CH:21]=[CH:22][N:12]=[C:7]3[C@@H:6]([CH2:13][CH3:14])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1
Reactant: O=CCCl
Reactant: CC[C@@H]1C(N)=Nc2cnc(Cl)nc2N1C1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC[C@@H]1c2nccn2-c2cnc(Cl)nc2N1C1CCCC1
Temperature: 68 °C

Procedure:
(R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydropteridin-6-amine (177 mg, 0.64 mmol) in MeOH (1.5 mL) treated with 50% aqueous chloroacetaldehyde (131 μL, 1.3 Eq.) and the reaction mixture heated to reflux for 6 hours. A further portion of 50% aq. chloroacetaldehyde (400 μL, 3.0 Eq.) was added, and the reaction mixture heated to 68° C. overnight. NaHCO3 (aq. sat.) and EtOAc was added, and the aqueous was further extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo.
Reaction SMILES: COC1C=CC(C[O:8][C@@H:9]2[C@@H:17]([CH:18]=[CH2:19])[O:16][C@H:15]3[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]3)[C@H:10]2[O:23]CC2C=CC(OC)=CC=2)=CC=1.C(O)(C(F)(F)F)=O.[NH4+].[OH-]>ClCCl>[CH3:22][N:20]([CH3:21])[C:13]1[S:14][C@H:15]2[O:16][C@H:17]([CH:18]=[CH2:19])[C@@H:9]([OH:8])[C@H:10]([OH:23])[C@H:11]2[N:12]=1
Reactant: C=C[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2[C@@H](OCc2ccc(OC)cc2)[C@@H]1OCc1ccc(OC)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2[C@@H](O)[C@@H]1O
Reaction time: 0.17 h
Yield: 32.2 %

Procedure:
A solution of above crude product 40 (220 mg, purity 57% by LC-MS) in dichloromethane (10 mL) was treated with TFA (1 mL) for 4 hours at room temperature. The solution was adjusted to pH at 8 with NH4OH, and then condensed to give a crude product, which was purified by Prep-HPLC with the following conditions (Agilent 1200 prep HPLC: Column, SunFire Prep C18, 19*50 mm 5 um; mobile phase, WATER with 0.03% NH4OH and CH3CN (10% CH3CN up to 45% in 10 min; Detector, UV 220 nm) to provide compound 43 (Example 7) as a white solid (35.7 mg). (ES, m/z): 245.0. 1H NMR (300 MHz, D2O) δ 6.20-6.22 (d, J=6.3 Hz, 1H), 5.79-5.87 (m, 1H), 5.30-5.38 (m, 2H), 3.98-4.08 (m, 2H), 3.87-3.91 (t, J=6.0 Hz, 1H), 3.46-3.52 (m, 1H), 2.93 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18].C(O)(C)C>[Pt].C1(C)C=CC=CC=1>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][CH2:16][C:17]([CH3:18])([OH:19])[CH3:20])=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2ccc(Br)cc12
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC(C)(O)CNc1c(N)cnc2ccc(Br)cc12
Reaction time: 72 h

Procedure:
1-[(6-Bromo-3-nitroquinolin-4-yl)amino]-2-methylpropan-2-ol (17.2 g, 50.5 mmol), toluene (150 mL) and isopropanol (20 mL) were added to a Parr flask containing 5% platinum on carbon (1.7 g) wetted with toluene. The flask was evacuated three times, charged with hydrogen to 30 psi, and shaken for 72 hours. The reaction mixture was filtered through a pad of CELITE filter agent. The CELITE was washed with several portions of dichloromethane followed by methanol. The filtrate was concentrated to provide crude 1-[(3-amino-6-bromoquinolin-4-yl)amino]-2-methylpropan-2-ol as a brown oil.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7](=[O:26])[C:8](=[N:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)=[CH:16][C:15]=1[F:25])[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:9]([C:8]1[C:7](=[O:26])[C:3]2[O:4][CH:5]=[CH:6][C:2]=2[N:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][C:15]=2[F:25])[N:12]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)C(=NNc1ccc(-n2cccn2)cc1F)C(=O)c1occc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1nn(-c2ccc(-n3cccn3)cc2F)c2ccoc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
A suspension of 1-(3-bromofuran-2-yl)-2-{[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]hydrazono}butane-1,3-dione (5.3 g) and potassium carbonate (3.5 g) in DMF (40 mL) was stirred at 90° C. for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was suspended in diisopropylether, and the precipitate was collected by filtration to give the title compound (2.56 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[C:9]1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)[CH:14]=CC=C[CH:10]=1.[C:38](=O)([O-:40])[O-:39].[K+].[K+]>C(O)CC.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:10]([O:40][C:38]([C:2]1[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=1)=[O:39])[CH2:9][CH3:14]
Reactant: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(Cl)ncn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCO
Product: CCCOC(=O)c1cc(N)ncn1
Temperature: 90 °C
Yield: 677.6 %

Procedure:
A mixture of 6-chloro-4-aminopyrimidine (2.00 g, 15.4 mmol), palladium acetate (361 mg, 1.61 mmol), 1,3-bis(diphenylphosphino)propane (631 mg, 1.52 mmol), and potassium carbonate (2.55 g, 18.5 mmol) in n-propanol (45 mL) and DMF (15 mL) was stirred at 90° C. under carbon monoxide atmosphere. The mixture was allowed to stand and cool to room temperature, and then filtered through Celite. Aqueous sodium bicarbonate solution was added to the filtrate, which was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated off in vacuo. The residue was purified by column chromatography on silica gel (chloroform/methanol=100/1 to 50/1) to give the title compound (1.86 g, 10.3 mmol, yield 67%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:7]=1[NH2:8].C1(P([C:33]2[CH:38]=[CH:37]C=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:40](Cl)(Cl)C#N>C(#N)C>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[C:7]3[N:8]=[C:40]([CH:38]([CH3:37])[CH3:33])[NH:1][C:2]=3[CH:3]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:5]=2)=[CH:14][CH:13]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cc(N)c(N)c(-c2ccc(F)cc2)c1
Reactant: N#CC(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2nc(C(C)C)[nH]c2c1
Temperature: 150 °C
Yield: 81.6 %

Procedure:
To a solution of methyl 5,6-diamino-4′-fluorobiphenyl-3-carboxylate (0.19 g, 0.73 mmol) and solid support triphenylphosphine (75% by weight; 0.77 g, 2.2 mmol) in acetonitrile (2.4 mL) was added trichloroacetonitrile (0.15 mL, 1.46 mmol). The mixture was heated in a microwave reactor for 10 min at 150° C. The mixture was cooled to ambient temperature, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (186 mg): LC-MS [M+1]=313.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:16]1[C:17](=[O:20])[CH2:18][CH2:19][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:15]1)[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Product: CCOC(=O)CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Yield: 51 %

Procedure:
In analogy to the procedure described in intermediate 5B, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 5A) and ethyl bromoacetate gave, after purification on a SiO2-column (n-heptane/EtOAc 1:2 to 100% EtOAc), the titled compound in 51% yield as white foam. MS: 399.1 (MH+, 2Cl).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[C:7]([CH:20]([OH:26])[C:21]([CH3:25])([CH3:24])[CH:22]=[CH2:23])[CH:6]=1)=[O:4].[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[C:7]([CH:20]([O:26][CH3:29])[C:21]([CH3:25])([CH3:24])[CH:22]=[CH2:23])[CH:6]=1)=[O:4]
Reactant: CI
Reactant: C=CC(C)(C)C(O)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(C)(C)C(OC)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.2 %

Procedure:
To a solution of T21.4 (1530 mg, 4269 μmol) in DMF (40 mL), was added sodium hydride (60% in oil) (213 μL, 8538 μmol). The mixture was stirred at room temperature for 10 minutes and then methyl iodide (530 μL, 8538 μmol) was added in one portion and the mixture was stirred at room temperature for 30 minutes. Water was added and the mixture was, extracted with EtOAc. The organic phase was washed with water and brine and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to give the product as a residue which was purified by chromatography to give the product as an oil (0.75 g, 47%). MS ESI m/e: 373.2 (M+18)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](O)=[O:8])(=O)[CH3:2].[NH2:14][N:15]1[C:27](=[O:28])[C:25]2[C:26]3[N:18]([C:19]([O:29][CH3:30])=[CH:20][C:21]=3[CH2:22][CH2:23][CH:24]=2)[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:16]1.P(Cl)(Cl)Cl.[P].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:30][O:29][C:19]1[N:18]2[C:17]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:16][N:15]([N:14]3[C:7](=[O:8])[C:6]4[C:5](=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:4]=[C:1]3[CH3:2])[C:27](=[O:28])[C:25]3=[CH:24][CH2:23][CH2:22][C:21]([CH:20]=1)=[C:26]23
Reactant: COc1cc2c3n1C(c1ccccc1)=CN(N)C(=O)C3=CCC2
Reactant: CC(=O)Nc1ccccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [P]
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c3n1C(c1ccccc1)=CN(n1c(C)nc4ccccc4c1=O)C(=O)C3=CCC2
Temperature: 25 °C
Yield: 17.3 %

Procedure:
0.834 g (4.65 mmol) of acetylanthranilic acid and 1.3 g (4.23 mmol) of 3-amino-9-methoxy-1-phenyl-6,7-dihydro-3H-[1,4]diazepino[6,7,1-hi]indol-4-one are dissolved in 13 ml of CH2Cl2, the mixture is stirred at room temperature and 0.7 g (5 mmol) of phosphorus trichloride is added. The mixture is stirred for 20 h and 0.35 g of phosphorus trichlonrde is added, followed by a fuirther 0.35 g 8 h later. The mixture is cooled, 50 ml of saturated NaHCO3 solution and 100 ml of CH2Cl2 are added and the organic phase is separated out after settling has taken place and washed with water. This solution is dried, evaporated and purified by chromatography in the mixture DM1. 0.33 g of yellow powder is obtained. M.p.=277° C.—Yld 17%.—TLC (DM3): Rf=0.47.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:24])[CH2:9][N:10]2[CH2:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:32][C:33]1([C:39]([Cl:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([NH:24][C:39]([C:33]2([CH3:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:9][N:10]2[CH2:11][CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:41]
Reactant: COc1ccccc1C1=CCN(C[C@H](N)CC2CCCCC2)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C1=CCN(C[C@@H](CC2CCCCC2)NC(=O)C2(C)CCCCC2)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.25 g (0.76 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-amine and 0.21 mL (1.52 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.13 g (0.84 mmol) of 1-methyl-cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane. The reaction mixture was allowed to stir under nitrogen at 0° C. for one hour, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted to the hydrochloride.hemihydrate salt of the title compound with ethanolic HCl to yield 0.15 g (41%) of yellow solid; mp=93-95° C.; MS(+)ESI m/z=453 (M+H)+.
Reaction SMILES: [C:1]1(OB(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[F:24][C:25]([F:54])([F:53])[C:26]1[CH:27]=[C:28]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:29][N:30]1[CH2:37][CH2:36][CH2:35][NH:34][C:33]2[N:38]=[C:39]([S:43][CH3:44])[N:40]=[C:41](Cl)[C:32]=2[C:31]1=[O:45]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:24][C:25]([F:54])([F:53])[C:26]1[CH:27]=[C:28]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:29][N:30]1[CH2:37][CH2:36][CH2:35][NH:34][C:33]2[N:38]=[C:39]([S:43][CH3:44])[N:40]=[C:41]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:32]=2[C:31]1=[O:45]
Reactant: OB(O)Oc1ccccc1
Reactant: CSc1nc(Cl)c2c(n1)NCCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CSc1nc2c(c(-c3ccccc3)n1)C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 99.7 %

Procedure:
Phenylboric acid (732 mg), tetrakis(triphenylphosphine)palladium (289 mg), toluene (15 ml), 1,4-dioxane (8 ml) and a 2 mol/L aqueous solution of sodium carbonate (15 ml) were added to 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 7; 2.43 g). While heated, the mixture was refluxed for 5 hours under a stream of argon gas. Subsequently, the reaction mixture was diluted with ethyl acetate, was washed with a 2 mol/L aqueous solution of sodium carbonate, and was then dried over anhydrous sodium sulfate. The solvent was removed and the resulting residue was purified on a silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxo-4-phenylpyrimido[4,5-b][1,5]diazocine (2.63 g, 100%).
Reaction SMILES: C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[OH:25][C@@H:26]([C@H:28]1[C:49](=[O:50])[N:30]2[CH:31]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])[C:32](=O)[C@H:33]([CH3:34])[C@H:29]12)[CH3:27].F[C:52](F)(F)[S:53](O)(=O)=O.FC(F)(F)S(O)(=O)=O.S[C@@H]1[CH2:72][N:71](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:70]([C:86]([N:88]2[CH2:93][CH2:92][N:91]([CH2:94][C:95]([O:97][CH2:98][C:99]3[CH:104]=[CH:103][C:102]([N+:105]([O-:107])=[O:106])=[CH:101][CH:100]=3)=[O:96])[CH2:90][CH2:89]2)=[O:87])[CH2:69]1>C(#N)C>[N+:105]([C:102]1[CH:101]=[CH:100][C:99]([CH2:98][O:97][C:95]([CH2:94][N:91]2[CH2:90][CH2:89][N:88]([C:86]([C@@H:70]3[CH2:69][C@H:52]([S:53][C:32]4[C@H:33]([CH3:34])[C@@H:29]5[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:49](=[O:50])[N:30]5[C:31]=4[C:36]([O:38][CH2:39][C:40]4[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=4)=[O:37])[CH2:72][NH:71]3)=[O:87])[CH2:93][CH2:92]2)=[O:96])=[CH:104][CH:103]=1)([O-:107])=[O:106]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: O=C(CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@@H]3CN[C@H](C(=O)N4CCN(CC(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 68 %

Procedure:
290 μl of diphenylphosphoryl chloride and 245 μl of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 500 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 5 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. 520 μl of diisopropylethyl-amine and a solution of 1.57 g of (2S,4S)-4-mercapto-2-[4-(4-nitrobenzyloxycarbonylmethyl)-1-piperazinyl-carbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine bis(trifluoromethanesulfonate) (prepared as described in Preparation 56) in 5ml of dry acetonitrile were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was allowed to stand overnight at the same temperature. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was subjected to column chromatography through a Lobar column (Merck, LiChroprep Si60, size B), using with a 5:1 by volume mixture of ethyl acetate and methanol as the eluent. Those fractions containing the title compound were combined and concentrated by evaporation under reduced pressure, to give 706 mg of the title compound, as a powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:18][CH3:19])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)#[N:21].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:18][CH3:19])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:29][NH:28][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:31][CH:30]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(C(=O)NN)cc1
Reactant: CCc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
(2R,3R)-2-(3-chloro-4-cyano-2-ethylphenylamino)-3-hydroxybutanoic acid (700 mg, 2.48 mmol), 4-cyanobenzohydrazide (439 mg, 2.73 mmol) and anhydrous THF (20 mL) were placed in a 50 mL round bottomed flask and the mixture was cooled to −15° C. 1-Hydroxybenzotriazole hydrate (335 mg, 2.48 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (589 mg, 3.07 mmol) at −15° C. followed by triethylamine (0.43 mL, 3.07 mmol). The reaction mixture was maintained at −15° C. and stirred for 1 h after which, stirring continued overnight while the mixture slowly warmed to room temperature. After 18 h, the mixture was filtered under vacuum and the residue washed with THF (30 mL). The THF solution was concentrated to ca. 10 mL, whereupon EtOAc (40 mL) was added followed by water (30 mL). The phases were partitioned and the organic phase washed with water (15 mL), brine (15 mL), dried (Na2SO4), filtered and concentrated to furnish a light brown solid. Purification by flash column chromatography [EtOAc-hexanes (4:1) as eluent] afforded the title compound as a white solid (890 mg, 62%). 1H NMR (500 MHz, acetone-d6, δ in ppm) δ 9.67 (br s, 2H), 8.11 (d, J=8.8 Hz, 2H), 7.96 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.8 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 5.66 (d, J=7.03 Hz, 1H), 4.62 (br s, 1H), 4.32-4.22 (m, 1H), 4.18 (dd, J=1.7 Hz, 7.4 Hz, 1H), 2.94-2.77 (m, 2H) 1.39 (d, J=6.2 Hz, 3H), 1.17 (t, J=7.6 Hz, 3H).
Reaction SMILES: C(O)C.CS[C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)=[CH:13][CH:14]=2)[CH2:9]1)=[NH:7].[ClH:32].[CH3:33][NH2:34].C([O-])(=O)C.[Na+]>O>[ClH:32].[ClH:32].[CH3:33][NH:34][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][CH:20]3[CH2:21][CH2:22][N:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH2:24][CH2:25]3)=[CH:13][CH:14]=2)[CH2:9]1)=[NH:7]
Reactant: CN
Reactant: CSC(=N)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNC(=N)N1CCc2ccc(OCC3CCN(c4ccncc4)CC3)cc2C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 119.4 %

Procedure:
To an ethanol solution (2 ml) of 7-[1-(pyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carbothioimidic acid methyl ester (100 mg) were added methylamine hydrochloride (20 mg) and sodium acetate (25 mg), and the mixture was stirred at 80° C. for 3 hours. After completion of the reaction, water was added and the mixture was washed with chloroform. Thereto was added aqueous sodium hydrogencarbonate solution and the mixture was washed with chloroform. To the aqueous layer was added 4N aqueous sodium hydroxide solution and the mixture was extracted with chloroform. The extract was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated and the obtained residue was treated with hydrogen chloride—ethanol solution and dried under reduced pressure to give the title compound (80 mg).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH2:21])[CH3:17].C1(C)C=CC=CC=1.C(N(CCCC)CCCC)CCC>O>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][N:21]=[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:17]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Temperature: 20 °C

Procedure:
To a 250 mL round bottom flask, was added 5.52 g of benzophenone (1 eq), 8.46 g of glycine ethyl ester hydrochloride (1, 2 eq), 67 mL of toluene, and a trace amount of BF3 Et2O. The slurry was heated to reflux (112˜113° C.). Tributylamine (11.2 g) was then added dropwise over 120 min. The reaction mixture was stirred at reflux (114-116° C.) until the area percent (AP) of benzophenone <9.0% by HPLC (22-29 h). The reaction mixture was cooled to 15-25° C. and water (35 mL) was added. After phase separation, the organic phase was concentrated to 50% (w/w) under reduced pressure at <40°. The concentrated solution was then cooled to 20° C., followed by addition of methanol (3 mL). The slurry was cooled to 10° C. and stirred for 30 min. The resultant slurry was filtered. The wet cake was washed with cold water/methanol (5:1 v/v, 2×20 mL), and dried under vacuum at 20° C. for 24 h to give N-(diphenylmethylene)glycine ethyl ester (2) as an off-white to yellow solid (5.5 g, 95% pure by HPLC, 65.6% isolated yield). 1H NMR (CDCl3): δ1.27 (t, J=7.25 Hz, 3H), 4.20 (s, 2H), 4.20 (q, J=7.07, 2H), 7.17-7.67 (m, 10H).