Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:24]2[C:19](=[C:20]([Br:26])[CH:21]=[C:22]([I:25])[CH:23]=2)[C:17](=[O:18])[C:15]1=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[Mg]Br>>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:24]2[C:19](=[C:20]([Br:26])[CH:21]=[C:22]([I:25])[CH:23]=2)[C:17]([OH:18])([C:29]2[CH:28]=[CH:27][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[C:15]1=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Br[Mg]c1ccc2ccccc2c1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCN1C(=O)C(=O)c2c(Br)cc(I)cc21
Product: CC(C)(C)[Si](C)(C)OCCCCCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c(Br)cc(I)cc21
Yield: 75 %

Procedure:
The title compound (463 mg, 75%) was prepared from 1-(5-t-butyldimethylsilyloxypentyl)-4-bromo-6-iodoisatin (500 mg, 0.923 mmol) and 2-naphthylmagnesium bromide by the procedure similar to that described in Example 1.
Reaction SMILES: [BH4-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)/[C:10](=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)/[C:9]([CH3:25])=[C:8]2[CH2:26][C:27](Cl)=[O:28]>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)/[C:10](=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:17][CH:16]=1)/[C:9]([CH3:25])=[C:8]2[CH2:26][CH2:27][OH:28]
Reactant: COc1ccc2c(c1)C(CC(=O)Cl)=C(C)/C2=C/c1ccc(S(C)(=O)=O)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CCO)=C(C)/C2=C/c1ccc(S(C)(=O)=O)cc1

Procedure:
Lithium borohydride (1.38 mmol) in THF (2 ml) is added to a solution of (Z)-5-methoxy-2-methyl-1-(4-methylsulfonylbenzylidene)-3-indenylacetyl chloride (2.78 mmol) in THF (20 ml) at 0° C. The reaction is quenched with HCl (10%, aqueous, 30 ml) after 5 minutes. Ethyl acetate (50 ml) is added to extract the product.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH:8]=[O:9].[CH2:10]=[O:11].[OH-].[Na+]>CO>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][C:2]2([CH2:10][OH:11])[CH2:8][OH:9]
Reactant: C=O
Reactant: O=CC1CC2C=CC1C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCC1(CO)CC2C=CC1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 364 g of 5-norbornene-2-carbaldehyde (which had been synthesized by Diels-Alder reaction of acrolein with cyclopentadiene) and 1500 ml of methanol under ice cooling, 560 g of a 37% formaldehyde aqueous solution was added and then 546 g of a 25% sodium hydroxide aqueous solution was added dropwise over 30 minutes. After the completion of dropwise addition, the ice bath was removed, and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated by distilling off methanol under a reduced pressure. The resulting solid was dissolved in tetrahydrofuran and washed with a sodium hydroxide aqueous solution. The organic layer was concentrated in vacuum, obtaining crude 5-norbornene-2,2-dimethanol. This crude product was combined with 500 ml of tetrahydrofuran and 10 g of 5% palladium on activated carbon as a hydrogenation catalyst. Hydrogenation was carried out under a hydrogen pressure of 1.4 MPa in an autoclave which was maintained at 30-40° C. by occasional placement in a water bath. The reaction mixture was filtered of the catalyst, combined with ethyl acetate, and washed with a saturated potassium carbonate aqueous solution. The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 435 g (yield 94%) of the target compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=O.[C:12]([NH:16][OH:17])([CH3:15])([CH3:14])[CH3:13]>C1C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[N+:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[O-:17]
Reactant: CC(C)(C)NO
Reactant: O=Cc1c(O)cc(O)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[N+]([O-])=Cc1c(O)cc(O)cc1O
Yield: 65.4 %

Procedure:
2,4,6-Trihydroxybenzaldehyde (17.69 g, 0.115 mole) was added to a solution of N-tert-butyl hydroxylamine (14.32 g, 0.161 mole) in benzene (250 mL). p-Toluenesulfonic acid (15 mg) was added and the reaction vessel fitted with a Dean-Stark trap. The reaction was heated at reflux for 88 hours under nitrogen and then diluted with 500 mL of ethyl acetate. The solution was washed with water, brine and dried over sodium sulfate. The product was recrystallized from ethanol/water and then dried in vacuo for 2 hr at 35° C. to provide 16.95 g (65.5% yield) of the title compound. The product had a melting point of 189.9-190.3° C. and an Rf on silica gel TLC (50% hexane, 45% ethyl acetate, 5% methanol) of 0.31 (2,4,6-trihydroxybenzaldehyde Rf=0.47).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C.Cl.O>[NH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:4][CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1OCc1ccccn1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(N)cnc1OCc1ccccn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
3-Methyl-5-nitro-2-(pyridin-2-ylmethyloxy)pyridine (D14, 1.42 g, 5.8 mmol) in ethanol (100 ml) was treated dropwise with a solution of tin (II) chloride (5.68 g) in conc. HCl (10 ml) at 60° C. The mixture was stirred at 60° C. for one hour, then cooled, diluted with water and basified with 40% aqueous sodium hydroxide solution. The aqueous solution was extracted with dichloromethane (3×100 ml), dried (Na2SO4) and evaporated in vacuo to afford the title compound (1.24 g, 100%) as a brown liquid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:17]([CH:18]=[CH:19][CH:20]=[O:21])=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[OH:21][CH:20](/[CH:19]=[CH:18]/[C:17]1[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:23][CH:22]=1)[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: COc1ccc(C=CC=O)cc1
Reactant: C#CC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)/C=C/c1ccc(OC)cc1
Reaction time: 0.17 h

Procedure:
A solution of 5 ml (60 mmol) of methyl propiolate in 100 ml of tetrahydrofuran was treated at -78° under argon with 41.3 ml of n-butyllithium solution (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 9.73 g (60 mmol) of 4-methoxycinnamaldehyde in 100 ml of tetrahydrofuran was added. The reaction mixture was stirred at -78° for 20 minutes, then warmed to -20° and treated with 100 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed with water, dried over sodium sulphate and concentrated. Flash chromatography of the residue on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1) yielded methyl (E)-4-hydroxy-6-(4-methoxyphenyl)-5-hexen-2-ynoate as a yellow oil.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[C:7](=[O:19])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.Cl.ClCCl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[O:3]=[CH:4][CH2:5][N:6]([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[C:7](=[O:19])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(CN(Cc1cccnc1)C(=O)CCOCCc1ccccc1)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=CCN(Cc1cccnc1)C(=O)CCOCCc1ccccc1

Procedure:
N-(2,2-Diethoxyethyl)-3-phenethyloxy-N-(3-pyridylmethyl)propanamide (Example 5a), 0.086 g) was dissolved in anhydrous dioxane (3 mL) and treated with concentrated hydrochloric acid (0.6 mL) at ambient temperature. The resultant solution was stirred at ambient temperature for 2.5 hours. The reaction mixture was then poured into dichloromethane (10 mL) and basified with saturated sodium bicarbonate. The organic layer was isolated, washed with water (2×10 mL), washed with brine (10 mL), dried over anhydrous magnesium sulphate, filtered and concentrated to give the sub-titled compound that was used in the next step without further purification.
Reaction SMILES: F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+:12]1[C:20]2[C:15](=NC=C[CH:19]=2)[N+]([O-])=N1)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:40]3[CH:39]=[C:38]4[CH2:41][CH2:42][CH2:43][CH:44]5[CH2:49][C:48]([O:54][Si:55]([CH2:60][CH3:61])([CH2:58][CH3:59])[CH2:56][CH3:57])([C:50]([F:53])([F:52])[F:51])[CH2:47][CH2:46][C:45]5([C:62]([OH:64])=O)[C:37]4=[CH:36][C:35]=3[CH:34]=[N:33]2)=[CH:28][CH:27]=1.C1(N)CC1.C(Cl)Cl>CN(C=O)C>[CH:20]1([NH:12][C:62]([C:45]23[CH2:46][CH2:47][C:48]([O:54][Si:55]([CH2:60][CH3:61])([CH2:56][CH3:57])[CH2:58][CH3:59])([C:50]([F:52])([F:51])[F:53])[CH2:49][CH:44]2[CH2:43][CH2:42][CH2:41][C:38]2[C:37]3=[CH:36][C:35]3[CH:34]=[N:33][N:32]([C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=4)[C:40]=3[CH:39]=2)=[O:64])[CH2:15][CH2:19]1
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)CCC2(C(=O)O)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCCC2C1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC1(C(F)(F)F)CCC2(C(=O)NC3CC3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCCC2C1
Reaction time: 24 h
Yield: 92 %

Procedure:
1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.201 g, 0.530 mmol) was added to a solution of rac-(3R,4aR,12bS)-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carb oxylic acid (43, R1=4-Fluorophenyl, R3=Trifluoromethyl) (0.235 g, 0.407 mmol), cyclopropanamine (0.093 g, 1.6 mmol), N-ethyl-N,N-diisopropylethylamine (0.285 mL, 1.63 mmol), DCM (5 mL), and DMF (1 mL). After about 24 h, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.020 g, 0.053 mmol) was added. After about 24 h, the reaction mixture was partitioned between DCM (50 mL) and sat. aq. NaHCO3 (10 mL). The organic layer was washed with water (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (40 g) using a gradient of 0-17% EtOAc in heptane. The product fractions were combined and concentrated under reduced pressure to give rac-(3R,4aR,12bS)—N-cyclopropyl-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carboxamide (44, R1=4-Fluorophenyl, R2′=Cyclopropyl, R3=Trifluoromethyl) (0.230 g. 92% yield); LC/MS, method 4, Rt=2.65 min.; MS m/z: 616 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=0.9 Hz 1H), 7.86 (s, 1H), 7.73-7.65 (m, 2H), 7.45 (s, 1H), 7.29-7.22 (m, 2H), 4.99 (s, 1H), 2.93-2.72 (m, 2H), 2.72-2.46 (m, 4H), 2.26-2.08 (m, 2H), 2.08-1.87 (m, 3H), 1.75-1.63 (m, 2H), 1.42-1.29 (m, 1H), 1.05-0.96 (m, 9H), 0.78-0.60 (m, 8H), 0.32-0.15 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=[O:2].[CH3:12]OS(OC)(=O)=O.C(N(CC)CC)C>[Au].C(Cl)Cl>[C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O:3][CH3:12])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: O=Cc1ccccc1C(=O)O
Agent: [Au]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1C=O
Temperature: 25 °C
Yield: 103.1 %

Procedure:
Into a 3-neck 1 liter round bottom flask equipped with a magnetic stirrer, reflux condenser fitted with a drying tube, addition funnel with a septum and a nitrogen inlet, 100 g (0.659 mole) 2-carboxybenzaldehyde, about 140 ml methylene chloride and 162.8 g [122.2 ml (1.291 moles)] dimethylsulfate were placed. The mixture was heated to reflux 135.89 g [187.2 ml (1.343 moles)] triethylamine was added dropwise, maintaining a brisk reflux. After the addition was complete, the resulting gold-colored solution was allowed to cool to room temperature, and then washed with 400 ml water. After the layers were separated, the aqueous phase was extracted with 400 ml methylene chloride. The organic layers were combined and washed with 500 ml of a saturated aqueous sodium bicarbonate solution and with 500 ml water. The organic phase was dried over magnesium sulfate and then concentrated to give 111.5 g of the product as a gold liquid.
Reaction SMILES: [C:1]([C@H:4]([N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2].[CH:24]1([NH2:27])[CH2:26][CH2:25]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CCOC(C)=O.O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([N:9]([C@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:1]([NH2:2])=[O:3])[CH2:20][C:21](=[O:23])[NH:27][CH:24]2[CH2:26][CH2:25]2)(=[O:11])=[O:12])=[CH:14][CH:15]=1
Reactant: NC1CC1
Reactant: CC(C)C[C@H](C(N)=O)N(CC(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](C(N)=O)N(CC(=O)NC1CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28 %

Procedure:
To a solution of {N-[(1R)-1-carbamoyl-3-methyl-butyl]-N-(4-chlorobenzenesulfonyl)amino}acetic acid (Example 59, 175 mg, 0.480 mmol), cyclopropylamine (41 uL, 0.58 mmol)in CH2Cl2 (3 mL) was added 1-hydroxybenzotriazole (47 mg, 0.72 mmol), and 1,3-dicyclohexylcarbodiimide (144 mg, 0.720 mmol). The reaction was stirred for 18 h at rt, and then was poured into an EtOAc/water mixture. The organic layer was separated, dried over MgSO4, and concentrated to a clear oil residue. The residue was further purified by Biotage 40S (eluted in 40% EtOAc in hexanes) to afford a white solid (54 mg, 29%). MS(ESI), (M+H)+402.2; 1H NMR (CDCl3, 500 MHz) δ7.85 (dd, 2H, J=1.9, 8.9), 7.50 (dd, 2H, J=2.0, 8.7), 7.40 (br s, 1H), 6.55 (br s, 1H), 6.30 (br s, 1H), 4.23 (dd, 1H, J=2.9, 8.9), 3.92 (d, 1H, J=17), 3.83 (d, 1H, J=17), 2.68-2.73 (m, 1H), 1.75-1.83 (m, 1H), 1.50-1.57 (m, 1H), 1.40-1.49 (m, 1H), 0.88 (d, 3H, J=6.4), 0.87 (d, 3H, J=6.7), 0.80 (d, 2H, J=7.0), 0.51 (t, 2H, J=4.0).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].CC1[N+](CC2C=NC(C)=NC=2N)=CSC=1CCO.Cl.[Cl-].OC(CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=O.[NH2:55][C@H:56]([C:64]([OH:66])=[O:65])[CH2:57][CH2:58][CH2:59][NH:60]C(=N)N.C(=O)([O-])[O-].[Ca+2]>[Pt]>[NH2:55][C@H:56]([C:64]([OH:66])=[O:65])[CH2:57][CH2:58][CH2:59][NH2:60]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: [Pt]
Agent: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Agent: Cl
Product: NCCC[C@H](N)C(=O)O
Reaction time: 96 h

Procedure:
Media containing 10 g/dl of glucose, 7 g/dl of (NH4)2SO4, 0.15 g/dl of KH2PO4, 0.04 g/dl of MgSO4.7H2O, 1 mg/dl of FeSO4.7H2O, 1 mg/dl of MnSO4.4H2O, 100 μg/1 of thiamine hydrochloride, 100 μg/1 of biotin, 60 mg of soybean protein acid hydrolysate (calculated as total nitrogen) and 15 mg/dl of L-arginine and 5 g/dl of calcium carbonate (independently sterilized) was adjusted to pH 7.2 and 25 ml of the media was charged into a 500 ml flask equipped with a shoulder followed by sterilization with heating. One platinum loop of the strain shown in Table 2 was inoculated on the medium and shaken for 4 days while keeping at 31.5° C. L-Ornithine was produced and accumulated in the culture solution of each strain in the amount shown in Table 2.
Reaction SMILES: C1N[C:4](=[O:5])NC1.[NH2:7][C:8]1[C:13]([OH:14])=[CH:12][C:11]([C:15]2[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=2[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:10][C:9]=1[OH:26].[Cl-].[Na+]>>[C:22]([C:16]1[C:17]([CH3:20])([CH3:21])[CH2:18][O:19][C:15]=1[C:11]1[CH:10]=[C:9]([OH:26])[C:8]2[N:7]=[C:15]([C:11]3[CH:12]=[CH:13][C:8]([O:5][CH3:4])=[CH:9][CH:10]=3)[O:14][C:13]=2[CH:12]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C1NCCN1
Reactant: CC(C)(C)C1=C(c2cc(O)c(N)c(O)c2)OCC1(C)C
Agent: [Cl-]
Agent: [Na+]
Product: COc1ccc(-c2nc3c(O)cc(C4=C(C(C)(C)C)C(C)(C)CO4)cc3o2)cc1
Temperature: 150 °C
Yield: 81.9 %

Procedure:
In nitrogen atmosphere at a room temperature, to 310 mg (1.46 mmol) of trimethyl 4-methoxy-1-orthobenzoate was added 1 ml of ethyleneurea dissolving 133 mg (0.48 mmol) of 5-(4-amino-3,5-dihydrophenyl)-4-t-butyl-3,3-dimethyl-2,3-dihydrofuran (Compound [8]), and the mixture was heated for 1.0 hours at 150° C. The resulting mixture was poured in saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried with magnesium sulfate anhydride, and concentrated. The residue was applied to a silica gel column and the elution was carried out with the mixture of hexane and ethyl acetate (hexane: ethyl acetate=3:1), and then followed by recrystallization from the mixture of methylene chloride and hexane to obtain 155 mg of 4-t-butyl-5-(4-hydroxy-2-(p-methoxyphenyl)benzo[d]-oxazol-6-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [67]) as a colorless granular micro-crystal. Yield 81.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.[CH3:10][O:11][CH2:12][CH2:13][NH:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([CH2:8][N:14]([CH2:13][CH2:12][O:11][CH3:10])[CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(CBr)n1
Reactant: CNCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN(C)Cc1cccc(Cl)n1
Temperature: 80 °C
Yield: 93.9 %

Procedure:
To a solution of 2-chloro-6-(bromomethyl)pyridine (490 mg, 2.37 mmole) in 5 mL of dry acetonitrile is added 0.51 mL (4.74 mmol) of 2-methoxy-N-methylethylamine and 328 mg (2.37 mmol) of potassium carbonate. The reaction is heated at 80° C. for 2 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 478 mg (94% yield) of (6-Chloro-pyridin-2-ylmethyl)-(2-methoxy-ethyl)-methyl-amine. Diagnostic 1H NMR (400 MHz, CDCl3) 2.34 (s, 3h), 2.67 (t, 2H, J=5.9 Hz), 3.34 (s, 3H), 3.52 (t, 2H, J=5.8 Hz), 3.71 (s, 3H), 7.19 (d, 1H, J=7.9 Hz), 7.54 (d, 1H, J=7.9 Hz), 7.60–7.64 (m, 1H); MS 215.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][N:16]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]1[CH3:22].C(N(CC)CC)C.CP(OP(CC)(C)=O)(CC)=O>CN(C)C=O>[CH3:22][C:17]1[N:16]([CH2:15][CH2:14][NH:13][C:8](=[O:10])[CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=2)[C:20]([CH3:21])=[CH:19][CH:18]=1
Reactant: Cc1ccc(C)n1CCN
Reactant: O=C(O)COc1ccc(Cl)cc1
Agent: CCP(C)(=O)OP(C)(=O)CC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C)n1CCNC(=O)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9.3 g (0.05 mol) of 4-chlorophenoxyacetic acid, 6.9 g (0.05 mol) of 1-(2-aminoethyl)-2,5-dimethylpyrrole and 35 ml of triethylamine are dissolved in 50 ml of dimethylformamide. At -5° to 0° C., 20 ml of methylethylphosphinic anhydride are added dropwise, and the mixture is then stirred at room temperature for 3 h. The reaction mixture is poured into ice-cold aqueous sodium bicarbonate solution, and the mixture is extracted with methylene chloride and the extract is concentrated. The residue is chromatographed over a 20 cm silica gel column using a 1:1 methylene chloride/ethyl acetate mixture as the mobile phase, and the product is crystallized using ligroin. Yield: 10.5 g (69% of theory), Melting point: 75°-77° C. Elemental analysis: C16H19CLN2O2 (306.80) calculated: C 62.6 H 6.2 CL 11.6 N 9.1 0 10.4 found: C 62.7 H 6.4 CL 11.7 N 9.2 0 10.4
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:29]([O:31]CC(Cl)(Cl)Cl)=[O:30])=[C:15](OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)=O.[Zn]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:29]([OH:31])=[O:30])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OCC(Cl)(Cl)Cl)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3SC2)cc1
Agent: [Zn]
Solvent: O=CO
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
Zinc powder (4.0 g.) was added portionwise to a stirred solution of 2,2,2-trichloroethyl 7-(2-phenylacetamido)-3-tosyloxy-3-cephem-4-carboxylate (0.8 g.) in formic acid (16 ml.) over 3 minutes under ice-cooling. The mixture was stirred at the same temperature for 5 minutes and then filtered. The remaining zinc powder was washed with ethyl acetate. The filtrate and washings were combined together, washed three times with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated to dryness in vacuo. The residue was pulverized by trituration with diisopropyl ether and the precipitates were collected by filtration to give 7-(2-phenylacetamido)-3-cephem-4-carboxylic acid (0.32 g.), Yield 78.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[F:36])[NH:5][C:6]1[C:15]2[CH:14]=[C:13]3[N:16]([C:20](=[O:30])[CH2:21][CH2:22][CH2:23]C(=O)CCCCl)[CH2:17][CH2:18][O:19][C:12]3=[CH:11][C:10]=2[N:9]=[CH:8][C:7]=1[C:31]#[N:32].[I-].[Na+].[CH3:39][NH:40][CH3:41].O1CCCC1.C(=O)(O)[O-].[Na+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[F:36])[NH:5][C:6]1[C:15]2[CH:14]=[C:13]3[N:16]([C:20](=[O:30])[CH2:21][CH2:22][CH2:23][N:40]([CH3:41])[CH3:39])[CH2:17][CH2:18][O:19][C:12]3=[CH:11][C:10]=2[N:9]=[CH:8][C:7]=1[C:31]#[N:32]
Reactant: N#Cc1cnc2cc3c(cc2c1Nc1ccc(F)c(Cl)c1)N(C(=O)CCCC(=O)CCCCl)CCO3
Reactant: CNC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [I-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCCC(=O)N1CCOc2cc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c3cc21
Temperature: 45 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
An amount of 500 mg (1.09 mmol) of 9-(3-chloro-4-fluoroanilino)-1-[4-(chlorobutyryl)butanoyl]-2,3-dihydro-1H-[1,4]oxazino[3,2-g]quinoline-8-carbonitrile was stirred in N,N-dimethylformamide (4.5 mL), and to this was added sodium iodide (0.163 g, 1.69 mmol), tetrabutylammonium iodide (0.80 g, 0.22 mmol), and dimethylamine solution in tetrahydrofuran 2M (11 mL, 21.8 mmol). The mixture was heated at 45° C. for 4 hours and stirred at room temperature for an additional 16 hours. To this was added ethyl acetate and sodium bicarbonate solution, and after separation of the layers, the organic phase was dried over sodium sulfate and evaporated to obtain the crude product. Purification of the crude product was carried out by flash chromatography (20% acetone in methanol), to give a tan solid (129 mg, 33% yield), m.p. 165° C.; 1H NMR (DMSO-d6) δ 9.78 (bs, 1H), 8.69 (bs, 1H), 8.39 (s, 1H), 7.39 (m, 2H), 7.26 (s, 1H), 7.21 (m, 1H), 4.39 (t, 2H), 3.98 (t, 2H), 2.64 (t, 2H), 2.20 (t, 2H), 2.07 (s, 6H), 1.71 (m, 2H); HRMS (EI) m/z 467.1514 (M+1). Analysis for C24H23ClFN5O2.0.3H2O.0.3C2H5CO2CH3: Found: C, 60.22; H, 5.16; N, 14.12. Calcd: C, 60.56; H, 5.24; N, 14.01.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].[BrH:15].Br.[NH+]1C=CC=CC=1.O>C(O)(=O)C>[NH2:9][C:7]1[S:8][C:4]([C:1](=[O:3])[CH2:2][Br:15])=[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:6]=1
Reactant: CCOC(=O)c1nc(N)sc1C(C)=O
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(N)sc1C(=O)CBr
Reaction time: 1 h

Procedure:
To a solution of ethyl 5-acetyl-2-amino-4-thiazolecarboxylate (12.9 g) in a mixture of 30% solution of hydrogen bromide in acetic acid (50 ml) and acetic acid (50 ml) was added pyridinium hydrobromide perbromide (21.1 g) at ambient temperature and stirred for one hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was washed with diisopropyl ether to give ethyl 2-amino-5-(2-bromoacetyl)-4-thiazolecarboxylate (14.86 g). mp 164°-166° C. (dec.).