Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]1([SH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[CH2:12]([O:19][N:20]=[C:21](Br)[CH:22]=[CH:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH2:12]([O:19][N:20]=[C:21]([S:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:22]=[CH:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrC(C=CSc1ccccc1)=NOCc1ccccc1
Reactant: Sc1ccccc1
Agent: [Na]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C(=CC(=NOCc1ccccc1)Sc1ccccc1)Sc1ccccc1
Yield: 43 %

Procedure:
Sodium salt of thiophenol (0.14 g) was added to ethanol (5 ml) solution of N-benzyloxy-3-phenylthioacrylimidoyl bromide (0.30 g) at room temperature, then it was heat refluxing for three hours. It was cooled, and chloroform (50 ml) was added to the reaction mixture. It was successively washed with 1N aqueous sodium hydroxide solution, pure water, aqueous saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain phenyl N-benzyloxy-3-(phenylthio)thioacrylimidate (0.14 g) as colorless oil.
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].C1(C)C=CC=CC=1.[OH-].[Na+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>CN(C)C=O>[CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([O:7][CH2:20][CH:22]1[O:24][CH2:23]1)=[O:6])[CH2:2][CH3:3]
Reactant: ClCC1CO1
Reactant: CCCC(CCC)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCC(CCC)C(=O)OCC1CO1
Reaction time: 6 h

Procedure:
Into a flask were introduced 70 g (0.48 mol) of di-n-propylacetic acid, 250 ml of toluene and 30 ml of N,N-dimethylformamide. After this operation, 40 g of 50%-aqueous solution of sodium hydroxide were added. This mixture was heated to 60°-80° C. and 138.7 g (1.5 mol) of epichlorhydrine were introduced. The reaction medium was maintained under stirring for 6 hours at 70°-80° C. and then concentrated in a rotary evaporator. After extraction with ethyl ether, the organic fractions were collected and distilled under 1 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li+].CCC[CH2-].[Cl-].[CH3:17][SiH:18]([C:20]1[C:27]2[C:23]([CH:24]=[CH:25][CH:26]=2)=[CH:22][C:21]=1[S:28][CH3:29])[CH3:19]>C1COCC1.CCCCCC>[CH3:19][SiH:18]([C:20]1[C:21]([S:28][CH3:29])=[C:22]([CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[C:23]2[C:27]=1[CH:26]=[CH:25][CH:24]=2)[CH3:17]
Reactant: CC1=Cc2ccccc2C1
Reactant: CSC1=C([SiH](C)C)C2=CC=CC2=C1
Agent: [CH2-]CCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSC1=C(C2C(C)=Cc3ccccc32)C2=CC=CC2=C1[SiH](C)C
Reaction time: 1 h

Procedure:
In a 250 mL round bottom flask with sidearm, stirring bar, and 60 mL dropping funnel was added 2-methylindene (13 g, 100 mmol, product made by Boulder) dissolved in THF (20 mL). N-Butyllithium (100 mmol, 40 mL of a 1.6 M solution in hexane) was added dropwise at room temperature. After addition was complete, the flask and contents were stirred an additional 2 h. A solution containing dimethylsilyl(2-methylthiopentalene)chloride in THF (30 mL) was added dropwise at room temperature. Stirring was continued for 1 hour, after which time the reaction was quenched with 30 mL of a 30% water/THF mixture, concentrated on a rotary evaporated, and a sample submitted for analysis.
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]4[CH2:20][CH2:19]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C@:29]([OH:33])([C:31]#[CH:32])[CH3:30])[CH:25]=1>>[CH:18]1([C:12]2[N:8]3[CH2:9][CH2:10][O:11][C:5]4[CH:4]=[C:3]([F:22])[C:2]([C:32]#[C:31][C@@:29]([OH:33])([C:26]5[CH:25]=[C:24]([CH3:23])[O:28][N:27]=5)[CH3:30])=[CH:21][C:6]=4[C:7]3=[N:14][C:13]=2[C:15]([NH2:17])=[O:16])[CH2:20][CH2:19]1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: NC(=O)c1nc2n(c1C1CC1)CCOc1cc(F)c(Br)cc1-2
Product: Cc1cc([C@](C)(O)C#Cc2cc3c(cc2F)OCCn2c-3nc(C(N)=O)c2C2CC2)no1

Procedure:
10-Bromo-3-cyclopropyl-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (62 mg) was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure E to afford 39.2 mg of 3-cyclopropyl-9-fluoro-10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 437 (M)+. 1H NMR (400 MHz, DMSO) δ 8.53 (d, J=18.5 Hz, 1H), 7.44 (s, 1H), 6.99 (d, J=10.5 Hz, 1H), 6.92 (s, 1H), 6.51 (s, 1H), 6.34 (s, 1H), 4.64-4.37 (m, 4H), 2.40 (s, 3H), 1.81 (s, 2H), 1.79-1.71 (m, 1H), 1.03-0.93 (m, 2H), 0.86-0.77 (m, 2H).
Reaction SMILES: CO.[CH:3]([O:8][CH3:9])([O:6][CH3:7])OC.[C:10]([C:14]1[CH:15]=[C:16](C(=O)C)[CH:17]=[C:18]([Cl:22])[C:19]=1[O:20][CH3:21])([CH3:13])([CH3:12])[CH3:11].[C:26](=O)([O-])[O-].[K+].[K+]>C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CCCCCCC.O>[C:10]([C:14]1[C:19]([O:20][CH3:21])=[C:18]([Cl:22])[CH:17]=[C:16]([C:3]([O:6][CH3:7])([O:8][CH3:9])[CH3:26])[CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: COc1c(Cl)cc(C(C)=O)cc1C(C)(C)C
Reactant: COC(OC)OC
Reactant: O=C([O-])[O-]
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCCCCCC
Product: COc1c(Cl)cc(C(C)(OC)OC)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 485.3 %

Procedure:
Methanol (1.4 mL), and trimethyl orthoformate (1.79 g, 16.95 mmol) were added to 1-(3-tert-butyl-5-chloro-4-methoxyphenyl)ethanone (1.36 g, 5.65 mmol), followed by stirring at room temperature. In addition, (±)-10-camphorsulfonic acid [(±)-CSA] (65 mg, 0.282 mmol, 5 mol %) was added, followed by 2 hours of stirring. Potassium carbonate (156 mg, 1.128 mmol) was added. After 40 minutes of stirring, water (10 mL) and n-heptane (10 mL) were added, and the solution was separated. After washing the organic layer with water (10 mL), the solvent was evaporated (50° C.) to obtain 1.57 g of the subject compound as a yellow oily substance (yield: 96.9%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([OH:10])=O.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([CH:20]([NH2:22])[CH3:21])=[CH:12]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([CH:20]([NH:22][C:8](=[O:10])[CH2:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH3:21])=[CH:12]1
Reactant: CC(N)c1csc2ccccc12
Reactant: O=C(O)CCc1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)CCc1ccco1)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.9 %

Procedure:
3-(2-Furyl)propionic acid (368 mg), 1-(benzothiophen-3-yl)ethylamine (443 mg), N-ethyl-N′-dimethylaminopropylcarbodiimide hydrochloride (575 mg), 1-hydroxybenzotriazole (405 mg), and triethylamine (304 mg) were added to dehydrated dimethylformamide (DMF, 15 mL), and stirred at room temperature for 12 hours. The reaction mixture was added with water, and extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 628 mg of the title compound.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C1(C)C=CC=CC=1>[CH:25]1([C:2]2[C:7]3[N:8]([C:15]4[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=4)[C:9](=[O:14])[C:10]([CH3:12])([CH3:13])[O:11][C:6]=3[CH:5]=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=2)[CH2:27][CH2:26]1
Reactant: CC1(C)Oc2cc([N+](=O)[O-])cc(Br)c2N(c2ccc(F)cc2)C1=O
Reactant: OB(O)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)Oc2cc([N+](=O)[O-])cc(C3CC3)c2N(c2ccc(F)cc2)C1=O
Temperature: 100 °C
Yield: 81 %

Procedure:
A mixture of 5-bromo-4-(4-fluorophenyl)-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 53(6), 200 mg), cyclopropylboronic acid (65 mg), potassium phosphate (410 mg), tetrakis-(triphenylphosphine)palladium(0) (66 mg), water (0.1 mL) and toluene (5 mL) was heated at 100° C. under argon atmosphere for 4 hours. After cooling, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent; n-hexane/ethyl acetate=95/5→65/35) to give 5-cyclopropyl-4-(4-fluorophenyl) -2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (146 mg) as a pale yellow powder.
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)C(C)C)(C)C.Cl[C:38]([O:40][CH2:41][CH2:42][Cl:43])=[O:39]>>[Cl:43][CH2:42][CH2:41][O:40][C:38](=[O:39])[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
Reactant: O=C(Cl)OCCCl
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OCCCl)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a solution of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (0.5000 g, 1.365 mmol) and N,N-Diisopropylethylamine (0.2383 mL, 1.365 mmol) in 1 mL of was added dropwise, 2-Chloroethyl chloroformate (0.1951 g, 1.365 mmol). The reaction mixture was stirred overnight at ambient temperature. Ethanol was removed under vacuum and the crude was purified by preparative LCMS (m/z=472). The proper fractions were collected and lyophilized to afford the title compound as an off-white solid in 38% yield. LCMS m/z (%)=472 (M+H 35Cl, 100), 474 (M+H 37Cl, 40). 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.71 (d, J=2.16 Hz, 1H), 7.68 (d, J=2.01 Hz, 1H), 7.45-7.34 (m, 3H), 7.08 (d, J=8.08 Hz, 1H), 6.98 (d, J=8.08 Hz, 1H), 6.31 (bs, 1H), 7.19-7.13, (m, 2H), 5.18 (bt, J=5.80 Hz, 1H), 4.28 (t, J=6.01 Hz, 2H), 4.03 (t, J=4.80 Hz, 2H), 3.85 (s, 3H), 3.78 (s, 3H), 3.65 (t, J1=5.80 Hz, 2H), 3.45 (q, J=11.10 Hz, 2H).
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.NC1[N:20]=[CH:21][NH:22][C:23]=1[Cl:24]>C(O)(=O)C>[F:16][C:13]([F:14])([F:15])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:20]3[CH:21]=[N:22][C:23]([Cl:24])=[C:17]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: Nc1nc[nH]c1Cl
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2ccnc3c(Cl)ncn23)c1

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone, 40 ml. of glacial acetic acid and 0.01 mole of 4-amino-5-chloroimidazole is refluxed for 6 hours. The solvent is removed under reduced pressure and the residue worked up as for Example 29 to give the product of the example.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]1[N:32]=[C:33]([NH2:36])[S:34][CH:35]=1.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:30][C:31]2[N:32]=[C:33]([NH2:36])[S:34][CH:35]=2)[N:3]=1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Reactant: Nc1nc(CCl)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3csc(N)n3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 68.3 mg (0.46 mmol) of 4-chloromethyl-2-amino-1,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40° C. under reduced pressure. This gives 115.9 mg (86.2% of theory) of product.
Reaction SMILES: C(O[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([OH:14])=[CH:11]2)=[CH:6][CH:5]=1)C>C1C2C(=CC=CC=2)C=CC=1O.C(Cl)(Cl)(Cl)Cl>[CH:5]1[CH:6]=[C:7]2[CH:8]=[CH:9][C:10]([OH:14])=[C:11]([C:11]3[C:12]4[C:7](=[CH:6][CH:5]=[CH:4][CH:13]=4)[CH:8]=[CH:9][C:10]=3[OH:14])[C:12]2=[CH:13][CH:4]=1
Reactant: CCOc1ccc2ccc(O)cc2c1
Agent: Oc1ccc2ccccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A reaction flask described in example 9 was charged with a solution of catalyst 1c (12.2 mg, 0.02 mmol) in anhydrous CCl4 (1 mL). The solution was stirred for 10 min under an oxygen atmosphere and then treated with a solution of 7-ethoxy-2-naphthol (38 mg, 0.2 mmol) in anhydrous CCl4 (1 mL) under 0° C. The reaction mixture was stirred at 0° C. until the reaction was complete (monitored by TLC). The crude mixture was concentrated under reduced pressure, and purified by column chromatography (Ethyl acetate/Petroleum ether=⅓) to give (R)-BINOL 3e, Yield 99%. [α]D25=−154.0 (c=0.4 in EtOAc), 1HNMR (300 MHz, CDCl3) δ (ppm) 7.87 (d, J=9.0 Hz, 2H, 2×HC (5)), 7.78 (d, J=9.0 Hz, 2H, 2×HC (4)), 7.21 (d, J=9.0 Hz, 2H, 2×HC (3)), 7.03 (dd, J=9.0 Hz, 2.4 Hz, 2H, 2×HC (6)), 6.49 (d, J=2.1 Hz, 2H, 2×HC (8)), 5.06 (s, 2H, 2×OH), 3.78 (m, 4H, 4×OCH2), 1.28 (t, 6H, 6×CH3). e.e. 96%.
Reaction SMILES: [NH2:1][CH2:2][C:3](N)([CH3:5])[CH3:4].O[C:8]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[OH2:15]>>[CH3:4][C:3]1([CH3:5])[NH:14][C:13](=[O:15])[C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[NH:1][CH2:2]1
Reactant: N#CC1(O)CCCC1
Reactant: CC(C)(N)CN
Reactant: O
Product: CC1(C)CNC2(CCCC2)C(=O)N1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 6.1 ml of 1,2-diamino-2-methylpropane in 17 ml water 5.7 ml of 1-hydroxycyclopentane-1-carbonitrile was slowly added. The reaction was kept at reflux for 48 h, and the cooled to r.t. The precipitated product was isolated by suction and washed with water. From the filtrate additional solid could be obtained. The combined solids were freeze-dried and 9.32 g (90%) of the title compound were obtained, which could be used in the next step without further purification.
Reaction SMILES: [Cr]([O-])(OCl)(=O)=O.[NH+]1C=CC=CC=1.[CH2:13]([O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:17]=1[CH2:18][OH:19])[CH3:14].CCOCC>ClCCl>[CH2:13]([O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:17]=1[CH:18]=[O:19])[CH3:14]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1CO
Agent: O=[Cr](=O)([O-])OCl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1C=O
Yield: 83.2 %

Procedure:
To a 250 mL round bottom flask fitted with a reflux condenser, was added pyridinium chloro chromate (PCC) (16.1 g, 75 mmol) in anhydrous dichloromethane (100 mL). 2-Ethoxy-6-pentadecyl-benzyl alcohol (18.1 g, 50 mmol) in dichloromethane (10 mL) was added in one portion to the magnetically stirred solution. After 1.5 hr dry ether (100 mL) was added and the supernatant decanted from the black gum. The insoluble residue was washed thoroughly with diethyl ether (3×25 mL), where upon it became black granular solid. The organic solution was passed through a short pad of celite, and the solvent was removed by distillation to obtain brownish low melting solid (Yield: 15 g).
Reaction SMILES: [OH:1][CH:2]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>>[CH3:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6]2)=[CH:31][CH:30]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCN(Cc2ccc(C)cc2)CC1

Procedure:
Following the procedure of Example 5, 1-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine was reacted with 4-methylbenzyl chloride to form 1-(4-methylbenzyl)-4-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine, mp 238°-239° C.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C:8](=[O:9])[NH:7][C@H:6]1[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2].[NH2:13][C@H:14]([C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH2:27])=[O:26])=[O:22])[CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1>>[C:1]([NH:4][C@@H:5]1[C:8](=[O:9])[NH:7][C@@H:6]1[C:10]([NH:13][C@H:14]([C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH2:27])=[O:26])=[O:22])[CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1)=[O:12])(=[O:3])[CH3:2].[C:1]([NH:4][C@H:5]1[C:8](=[O:9])[NH:7][C@H:6]1[C:10]([NH:13][C@H:14]([C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH2:27])=[O:26])=[O:22])[CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: CC(=O)N[C@H]1C(=O)N[C@H]1C(=O)O
Product: CC(=O)N[C@@H]1C(=O)N[C@@H]1C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(N)=O
Product: CC(=O)N[C@H]1C(=O)N[C@H]1C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(N)=O

Procedure:
The residue containing compound (32) obtained in Reference Example 7 was reacted with L-histidyl-L-prolinamide (free base) in a similar manner as above. The thus obtained reaction mixture was purified by column chromatography using silica gel (150 g). The desired compound was eluted with ethyl acetate-methanol-ammonia water (20:10:1). After the solvent was removed, the product was lyophilized. Thus, 274 mg was obtained as a mixture of Nα -[(2S,3S)-3-acetylamino-4-oxo-2-azetidinylcarbonyl]-L-histidyl-L-prolinamide (34a) and Nα -[(2R,3R)-3-acetylamino-4-oxo-2-azetidinylcarbonyl]-L-histidyl-L-prolinamide (34b).
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([CH3:24])[N:3]=1.C(=O)(O)O.[NH2:29][C:30]([NH2:32])=[NH:31]>CN(C)C(=O)C>[NH2:31][C:30]1[N:32]=[C:8]([NH2:9])[C:7]2[C:2](=[N:3][C:4]([CH3:24])=[C:5]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:22])([F:21])[F:23])[CH:11]=3)[N:6]=2)[N:29]=1
Reactant: Cc1nc(N)c(C#N)nc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: Cc1nc2nc(N)nc(N)c2nc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
This compound is prepared in a manner analogous to that of Step B of Example 4, using 1.1 grams (0.003 mole) of 2-amino-3-cyano-5-[3,5-di(trifluoromethyl)phenyl]-6-methylpyrazine and 1.3 grams (0.007 mole) of guanidine carbonate in 10 mL of N,N-dimethylacetamide, yielding 2,4-diamino-6-[3,5-di(trifluoromethyl)phenyl]-7-methylpteridine.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([CH:12]2[N:17](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:16][CH2:15][N:14]([C:31]([C@@H:33]3[CH2:37][C@H:36]([S:38][C:39]4[C@H:40]([CH3:63])[C@@H:41]5[C@@H:58]([C@H:59]([OH:61])[CH3:60])[C:57](=[O:62])[N:42]5[C:43]=4[C:44]([O:46]CC4C=CC([N+]([O-])=O)=CC=4)=[O:45])[CH2:35][N:34]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:32])[CH2:13]2)=[O:11])=CC=1)([O-])=O>O1CCCC1.O>[C:10]([CH:12]1[NH:17][CH2:16][CH2:15][N:14]([C:31]([C@@H:33]2[CH2:37][C@H:36]([S:38][C:39]3[C@H:40]([CH3:63])[C@@H:41]4[C@@H:58]([C@H:59]([OH:61])[CH3:60])[C:57](=[O:62])[N:42]4[C:43]=3[C:44]([OH:46])=[O:45])[CH2:35][NH:34]2)=[O:32])[CH2:13]1)([OH:11])=[O:9]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCNC(C(=O)O)C4)C3)[C@H](C)[C@H]12

Procedure:
160 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[3-(4-nitrobenzyloxycarbonyl)-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 3 ml of a 1:1 by volume mixture of tetrahydrofuran and water, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 160 ml of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 7(b), to give 35 ml of the title compound, as a powder.
Reaction SMILES: O.[C@@H:2]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CO>[CH3:22][N:23]([CH:25]=[N:15][C:14]1[C:13]2[N:12]=[CH:11][N:10]([C:19]=2[N:18]=[CH:17][N:16]=1)[C@@H:2]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1)[CH3:24]
Reactant: COC(OC)N(C)C
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: CO
Solvent: O
Product: CN(C)C=Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 50 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a stirred solution of 2′-deoxyadenosine monohydrate 54 (1.00 g; 3.71 mmol) in methanol (43 mL), N,N-dimethylformamide dimethyl acetal (2.48 mL; 18.6 mmol) was added. The reaction was stirred at 50° C. for 16 h. After evaporation, CH2Cl2-hexane (1:1) was added. The white solid formed was then filtered, collected and washed by hexane to afford 55 as white solid (1.13 g; 99% yield): 1H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H, CHN(CH3)2), 8.44 (s, 1H, 2-H), 8.43 (s, 1H, 8-H), 6.48 (dd, J=6.2, 7.8 Hz, 1H, 1′-H), 4.59 (m, 1H, 3′-H), 4.07 (m, 1H, 4′-H), 3.86 (dd, J=3.1, 12.2 Hz, 1H, one of 5′-H), 3.76 (dd, J=3.5, 12.2 Hz, 1H, one of 5′-H), 3.25 (s, 3H, one of NCH3), 3.24 (s, 3H, one of NCH3), 2.80-2.88 (ddd, J=5.9, 7.8, 13.5 Hz, 1H, one of 2′-H), 2.40-2.47 (ddd, J=2.8, 6.1, 13.4 Hz, 1H, one of 2′-H); 13C NMR (100 MHz, CD3OD) δ 161.0, 159.9, 152.8, 151.1, 142.8, 127.0, 89.7, 86.9, 72.9, 63.5, 41.5 (N(CHO 2) 35.3; HRMS (FAB+) calcd for C33H19O3N6 (M+H+): 307.1519. found: 307.1511.