Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.F[C:23]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>>[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:23]2[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=2[C:25]([OH:27])=[O:26])=[CH:17][CH:16]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: COc1ccc(Nc2cc(F)c(F)cc2C(=O)O)cc1
Yield: 120.5 %

Procedure:
Using General Method 1, the reaction of 2.5 M solution of n-BuLi in hexanes (26 mL, 64 mmol), diisopropylamine (8.7 mL, 62 mmol), 4-methoxy-aniline (2.6 g, 17 mmol), and 2,4,5-trifluorobenzoic acid (3.6 g, 20.7 mmol) provided 5.72 g of the crude title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[N:21]4[CH2:22][CH2:23][CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][C:20]4=[N:19][C:14]=3[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:46].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[NH2:46][C:15]1[C:14]2[N:19]=[C:20]3[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:23][CH2:22][N:21]3[C:13]=2[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c(nc3cnc4cc(OCc5ccccc5)ccc4c32)C1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1

Procedure:
The methods described in Part I of Example 368 were used to treat tert-butyl 3-benzyloxy-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate (5.52 g, 12.4 mmol, Example 369 Parts A through D) with mCPBA (4.17 g of 77% purity, 18.6 mmol) followed by ammonium hydroxide (25 mL) and p-toluenesulfonyl chloride (2.6 g, 13.7 mmol) and purify the final compound to provide 2.07 g of tert-butyl 6-amino-3-benzyloxy-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:19]([O:21]CC=C)=[O:20])=[C:8]([C:11]3[N:12]=[CH:13][N:14]4[CH:18]=[CH:17][S:16][C:15]=34)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[K+:59]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:19]([O-:21])=[O:20])=[C:8]([C:11]3[N:12]=[CH:13][N:14]4[CH:18]=[CH:17][S:16][C:15]=34)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[K+:59]
Reactant: C=CCOC(=O)C1=C(c2ncn3ccsc23)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd]
Agent: CCCCC(CC)C(=O)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ncn4ccsc34)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 117 mg of allyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in a mixed solvent of 2.5 ml of dichloromethane and 2.5 ml of ethy acetate were added 8.1 mg of triphenylphosphine, 56.5 mg of potassium 2-ethylhexanoate, and 11.8 mg of tetrakis(triphenylphosphine)palladium (0), and the mixture was stirred under the atmosphere of argon at room temperature for 20 minutes. After confirming the exhaustion of the starting materials, the reaction mixture was diluted with 10 ml of ethyl acetate, extracted three or four times with water, and the aqueous layer was concentrated under reduced pressure. The concentrate was purified by column chromatography on COSMOSEAL 40C18-PREP to give the title compound in a yield of 55 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([NH:10][C@H:11]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]4[N:18]([CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:20][N:21]=3)[CH2:12]2)=[O:9])=[N:6][CH:7]=1.[CH3:25][C:26]1(C)[C:30](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:25]=[C:26]([C:2]1[CH:3]=[N:4][C:5]([C:8]([NH:10][C@H:11]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]4[N:18]([CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:20][N:21]=3)[CH2:12]2)=[O:9])=[N:6][CH:7]=1)[CH3:30]
Reactant: O=C(N[C@H]1CCN(c2nccn3cccc23)C1)c1ncc(Br)cn1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1cnc(C(=O)N[C@H]2CCN(c3nccn4cccc34)C2)nc1
Temperature: 120 °C

Procedure:
To a solution of (S)-5-bromo-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (0.075 g, 0.19 mmol, 1 eq) in 1.8 mL of DMF was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.10 g, 0.6 mmol, 3 eq), followed by K2CO3 (0.14 g, 0.99 mmol, 5 eq) in 0.2 mL of H2O and Pd(dppf)Cl2 (0.02 g, 0.02 mmol, 0.1 eq). After heating for 2 h at 120° C. the mixture was filtered, concentrated and carried forward to the next step.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:9]2[CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:17]I>CN(C=O)C>[CH3:17][O:3][C:4]1[C:9]2[CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: COC(=O)c1cc2c(O)cccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(OC)cccc2o1
Reaction time: 1 h
Yield: 100 %

Procedure:
Sodium hydride (32.5 mg, 1.35 mmol) was added to a solution of methyl 4-hydroxy-benzofuran-2-ylcarboxylate (240 mg, 1.25 mmol) in DMF (5 ml). After stirring for 10 min methyl iodide (888 mg, 6.25 mmol) was added and stirring was continued for an additional 1 h. The reaction was carefully quenched with water (30 ml) and diluted with ethyl acetate (50 ml). The separated organic layer was washed with 0.5M aqueous HCl, saturated aqueous sodium bicarbonate solution (50 ml), dried over sodium sulfate, and concentrated in vacuo to give pure methyl 4-methoxy-benzofuran-2-ylcarboxylate (257 mg, 1.25 mmol) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[C:8]2[CH:9]=[CH:10][CH:11]([CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[O:12][C:7]=2[C:6]([O:20][CH3:21])=[C:5]([O:22][CH3:23])[CH:4]=1)=[O:2].[OH-].[Na+].Cl.[Na+].[Cl-]>O1CCCC1>[CH:1]([C:3]1[C:8]2[CH:9]=[CH:10][CH:11]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[O:12][C:7]=2[C:6]([O:20][CH3:21])=[C:5]([O:22][CH3:23])[CH:4]=1)=[O:2]
Reactant: COC(=O)CCCC1C=Cc2c(C=O)cc(OC)c(OC)c2O1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C=O)c2c(c1OC)OC(CCCC(=O)O)C=C2
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
1.5 g of methyl (RS)-4-(5-formyl-7,8-dimethoxy-2H-1-benzopyran-2-yl)-butyrate were dissolved in 10 ml of tetrahydrofuran under argon and then treated with 1 ml of 1N NaOH and stirred at 20° C. for 1.5 hrs. The reaction mixture was acidified with 9 ml of 1N HCl, saturated with NaCl and extracted with 2×20 ml of ethyl acetate. The crude product was chromatographed on silica gel in ethyl acetate and chromatographed from toluene/hexane 1:1 There was obtained (RS)-4-(5-formyl-7,8-dimethoxy-2H-1-benzopyran-2-yl)-butyric acid as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](O)[CH2:6][CH2:5]2.N1C=CC=CC=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([Cl:20])[CH2:6][CH2:5]2
Reactant: OC1CCc2cc(Br)ccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: ClC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-indan-1-ol (2.0 grams, 9.38 mmol) and pyridine (1.6 mL, 20 mmol)in CH2Cl2 (20 mL) at 0° C. was added thionyl chloride (2.2 grams, 1.30 mL, 18.7 mmol). The reaction mixture was allowed to warm slowly to room temperature. After 1 hour, the reaction mixture was cooled to 0° C., quenched with saturated aqueous NaHCO3 (10 mL) and diluted with CH2Cl2 (100 mL). The organic layer was separated and washed with saturated NaHCO3 (1×25 mL) and saturated aqueous NaCl (1×25 mL), dried over magnesium sulfate (MgSO4) and concentrated in vacuo to give a yellow oil. 1H NMR (250 MHz, CDCl3): d 7.4 (s, 1 H), 7.36 (d, 1 H), 7.20 (d, 1 H), 5.35 (dd, 1 H), 3.15 (m), 2.84 (m), 2.55 (m), 1.83 (m).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)[CH:3]=1.B(Br)(Br)Br.Cl.O>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: COc1ccc(Cc2cc(Br)sc2Cl)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Cc2cc(Br)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of thiophene 3 (5.44 g, 17.1 mmol) in CH2Cl2 (50 mL) was added boron tribromide (20 mL, 1M in CH2Cl2) at 0° C. The mixture was warmed up to room temperature slowly and stirred at room temperature for 3 hours. To the mixture was added aq. 1N HCl solution (35 mL) dropwise at 0° C. and H2O was added to the mixture. The mixture was extracted with EtOAc (50 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 4 was dried under high vacuum and used without further purification. (5.1 g, 99%)
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][NH2:20]>C(Cl)Cl>[CH2:19]1[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][N:13]2[C:6](=[O:7])[NH:20]1
Reactant: NCC1CCCCN1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C1NCC2CCCCN12

Procedure:
A solution of CDI (830 mg, 5.1 mmol) and piperidin-2-ylmethanamine (520 mg, 4.6 mmol) in DCM (20 mL) was stirred at room temperature overnight. After the solvent was removed, the residue was directly used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.CCN(C(C)C)C(C)C.Br[C:19]1[C:28]2[C:23](=C[CH:25]=[C:26](OC)[N:27]=2)[N:22]=[CH:21]C=1N>CN(C)C=O>[CH3:19][C@@H:28]1[CH2:23][N:22]([CH3:21])[CH2:25][CH2:26][N:27]1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: COc1ccc2ncc(N)c(Br)c2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C)CCN1c1cc(N)ncn1
Temperature: 220 °C
Yield: 23.8 %

Procedure:
A mixture of 6-chloro-4-pyrimidinamine (200 mg, 1.544 mmol), Hunig's base (1.2 ml, 6.95 mmol) and (3R)-1,3-dimethylpiperazine (Ref.: WO2009061879 (A1)) (433 mg, 2.316 mmol) in N,N-dimethylformamide (DMF) (2 ml) was heated to 220° C. via a microwave reactor for 15 min. The reaction mixture was purified by RP-HPLC to yield 6-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinamine (76 mg, 0.367 mmol, 24% yield). MS (ES+) m/z 208.0 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17]O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][Br:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
To a solution of 4-hydroxymethylpiperidine-1-carboxylic acid benzyl ester (1.11 g), carbon tetrabromide (1.77 g) in methylene chloride (11 ml) was added triphenylphosphine (1.4 g) with ice-cooling, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:acetone=10:1) and dried under reduced pressure to give the title compound (1.25 g).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.C([Li])CCC.CCCCCC.CN([CH:29]=[O:30])C>C1COCC1.[Cl-].[Na+].O.O>[CH3:14][N:5]1[C:4]2[CH:3]=[C:2]([CH:29]=[O:30])[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: CN(C)C=O
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CN1c2cc(C=O)sc2C(=O)NC1(C)C
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
To a stirred suspension of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (259 mg, 0.941 mmol) in THF (10 mL) at −78° C. was added dropwise 1.6 M n-butyllithium in hexane (1.29 mL, 2.07 mmol). After 20 min, DMF (0.146 mL, 1.88 mmol) was added, and the mixture was allowed to −30° C. for 30 min. The mixture was poured into water (50 mL) and brine (50 mL). Extraction with EtOAc (100 mL), washing with brine, drying over MgSO4, filtration and concentration under reduced pressure gave the title compound (205 mg, 97%) as yellow solid:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Br)ccc1C(=O)O
Product: Cc1cc(Br)ccc1C(=O)N1CCCC1

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-methyl benzoic acid and pyrrolidine.
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[O:10]C1C=CC=CC=1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-]=C=O>>[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]=[O:10]
Reactant: COc1ccccc1OC(=O)NCc1ccccc1
Agent: [N-]=C=O
Product: O=C=NCc1ccccc1

Procedure:
6 grams of bis-methylsalicyl carbonate and 1.97 grams of benzylamine, corresponding to a 1:1 molar ratio, were dissolved in 20 milliliter of dichloromethane. The solution was stirred at room temperature under atmospheric conditions for 30 minutes to form 2-methoxyphenyl benzylcarbamate. (Isocyanatomethyl)benzene was prepared by pyrolysis of this carbamate as shown in FIG. 6 using the same procedure as in Example 45. The desired isocyanate was observed to be formed.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([S:47](Cl)(=[O:49])=[O:48])[CH:42]=1>O1CCCC1.O>[Cl:3][C:4]1[C:9]([C:10]2[N:14]([S:47]([C:43]3[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=3)(=[O:49])=[O:48])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate, 15-crown-5 (330 mg) and pyridine-3-sulfonyl chloride (266 mg) under ice-cooling and the mixture was stirred for 15 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to give the title compound as a pale-yellow oil (yield 465 mg, 97%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]([CH:15]1[CH2:19][C:18](=[O:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH2:16]1)=[O:14].[CH2:29](Cl)[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[NH4+].[Cl-]>C1COCC1>[CH3:11][O:12][C:13]([C:15]1([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:19][C:18](=[O:20])[N:17]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH2:16]1)=[O:14]
Reactant: ClCOCc1ccccc1
Reactant: COC(=O)C1CC(=O)N(c2c(C)cccc2C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(COCc2ccccc2)CC(=O)N(c2c(C)cccc2C)C1
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 22 %

Procedure:
LHMDS (1 M solution in THF, 9.72 mL, 9.72 mmol) was added slowly to a cooled (−50° C.) solution of 1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (2 g, 8.09 mmol) in THF (50 mL). The solution was stirred at −50° C. for 5 min then warmed to 0° C. and stirred for a further 5 min. After cooling back to −50° C., BOMCl (˜90% pure, 2.46 mL, 17.8 mmol) was added and the resulting reaction mixture was warmed to room temperature and stirred for 2 h. Saturated aqueous NH4Cl solution (25 mL) was added, and the aqueous solution was extracted with EtOAc (3×75 mL). The combined organic layer were washed with water (100 mL), brine (100 mL), dried (Na2SO4) and evaporated. The residue was purified by automated flash chromatography (SiO2, 10→50% EtOAc/hexanes) to give 3-benzyloxymethyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (653 mg, 22% yield). LC-MS: Rt (retention time): 2.72 min, MS: (ES) m/z 368.1 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([CH2:2][C:3]([NH:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([NH:14][CH2:15][CH2:16][O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Reactant: C1COCCN1
Product: O=C(CN1CCOCC1)Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Yield: 100.4 %

Procedure:
Prepared from 2-chloro-N-[2-(2-phenoxy-ethylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 122, step A) (180 mg, 0.50 mmol; HPLC 1.096 min) and morpholine (0.87 ml, 10 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (206 mg, 100%; HPLC 0.588 min), MS (ISP) m/e=411.2 [(M+H)+].
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[NH:16]1[C:24]2[C:19](=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:19]=2[CH:18]=[CH:17][NH:16]3)[C:11]=1[CH3:12]
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc3[nH]ccc23)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 19 h

Procedure:
To a stirred solution of 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.0 g, 4.03 mmol) in toluene (8.06 mL) was added 1H-indol-4-ylboronic acid (0.973 g, 6.05 mmol), potassium carbonate (1.671 g, 12.1 mmol) and palladium tetrakistriphenylphosphine (0.466 g, 0.403 mmol). The reaction was stirred at 100° C. and stirring continued for 19 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude product was placed in DCM and filtered to give the desired product. The filtrate was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-2-(1H-indol-4-yl)-3-methylquinoline as a yellow solid. Mass Spectrum (ESI) m/e=329.0 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([F:25])(=[O:24])=[O:23])=[CH:11][CH:10]=1)C1C=CC=CC=1.B(F)(F)F.CCOCC>C(S)(S)C.C(OCC)C.O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([F:25])(=[O:24])=[O:23])=[CH:13][CH:14]=1
Reactant: O=S(=O)(F)CCCCCCCc1ccc(OCc2ccccc2)cc1
Agent: CC(S)S
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Product: O=S(=O)(F)CCCCCCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 13.1 (0.182 g, 0.5 mmol) in ethanedithiol (10 mL), at room temperature, under an argon atmosphere was added BF3.Et2O (0.282 g, 2.0 mmol). The reaction mixture was stirred at room temperature for 1 hour and then diluted with diethyl ether (20 mL) and water (10 mL). The organic layer was separated and the aqueous phase extracted with diethyl ether. The combined organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue obtained was chromatographed through a column of silica gel eluting with 50% diethyl ether-hexane to give 14.1 (0.096 g, 70% yield) as a white solid (m p 47-51° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)[O:10][CH:11]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:12]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]2[C:18](=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:36](=[O:37])[C:35]3[C:30](=[N:31][C:32]([CH3:38])=[CH:33][CH:34]=3)[N:29]([CH2:39][CH3:40])[CH:28]=2)=[O:26])=[CH:5][CH:4]=1.[C:56]1(=[O:62])[O:61][C:59](=[O:60])[CH2:58][CH2:57]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:55][O:54][C:51]1[CH:50]=[CH:49][C:48]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:10][CH:11]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:12]2[N:13]([C:18](=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]3[C:36](=[O:37])[C:35]4[C:30](=[N:31][C:32]([CH3:38])=[CH:33][CH:34]=4)[N:29]([CH2:39][CH3:40])[CH:28]=3)=[O:26])[CH2:14][CH:15]([O:17][C:56](=[O:62])[CH2:57][CH2:58][C:59]([OH:61])=[O:60])[CH2:16]2)=[CH:53][CH:52]=1
Reactant: CCn1cc(C(=O)NCCCCCC(=O)N2CC(O)CC2C(OC(c2ccc(OC)cc2)c2ccc(OC)cc2)c2ccccc2)c(=O)c2ccc(C)nc21
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1cc(C(=O)NCCCCCC(=O)N2CC(OC(=O)CCC(=O)O)CC2C(OC(c2ccc(OC)cc2)c2ccc(OC)cc2)c2ccccc2)c(=O)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Referring to scheme 27, Compound 99 (1.48 g, 2 mmol) is mixed with succinic anhydride (0.200 g, 2 mmol) and DMAP (0.244 g, 13 mmol) and dried in a vacuum at 40° C. overnight. The mixture is dissolved in anhydrous dichloromethane (5 mL), triethylamine (0.606 g, 0.96 mL, 6 mmol) is added and the solution stirred at room temperature under argon atmosphere for 16 h. It is then diluted with dichloromethane (100 mL) and washed with ice cold aqueous citric acid (5% wt., 100 mL) and water (2×100 μL). The organic phase is dried over anhydrous sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography to afford compound 101.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([O-:26])=[O:25])=[O:3].[Na+].C(OCC)(=O)C.Cl>O>[C:2]([O:4][CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[CH:10]([NH:13][C:14](=[O:15])[CH2:16][C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([OH:26])=[O:25])(=[O:3])[CH3:1]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 99.7 %

Procedure:
21.6 g of sodium cephalothin was dissolved in 500 ml of water and layered with 500 ml ethyl acetate. The mixture was acidified to pH4 by addition of 6N HCl and the product was extracted into the ethyl acetate phase, which was dried (MgSO4) and evaporated in vacuo to yield 20.4 g of 3-acetoxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid, mp 152°-154°.