Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([N:19]3[C:31]4[CH:30]=[C:29]5[C:32]([CH3:69])([CH3:68])[C:33]6[C:38]([C:28]5=[CH:27][C:26]=4[C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:37][CH:36]=[CH:35][C:34]=6[C:39]3[CH:40]=[C:41]4[C:49](=[CH:50][CH:51]=3)[N:48](C(OC(C)(C)C)=O)[C:47]3[CH:46]=[C:45]5[C:59]([CH3:67])([CH3:66])[C:60]6[C:65]([C:44]5=[CH:43][C:42]4=3)=[CH:64][CH:63]=[CH:62][CH:61]=6)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.C1(OC)C=CC=CC=1>[C:13]1([C:11]2[N:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]([N:19]3[C:31]4[CH:30]=[C:29]5[C:32]([CH3:69])([CH3:68])[C:33]6[C:38]([C:28]5=[CH:27][C:26]=4[C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:37][CH:36]=[CH:35][C:34]=6[C:39]3[CH:40]=[C:41]4[C:49](=[CH:50][CH:51]=3)[NH:48][C:47]3[CH:46]=[C:45]5[C:59]([CH3:67])([CH3:66])[C:60]6[C:65]([C:44]5=[CH:43][C:42]4=3)=[CH:64][CH:63]=[CH:62][CH:61]=6)[N:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(-c3cccc4c3C(C)(C)c3cc5c(cc3-4)c3ccccc3n5-c3nc(-c4ccccc4)nc(-c4ccccc4)n3)cc2c2cc3c(cc21)C(C)(C)c1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(-c2cccc4c2C(C)(C)c2cc5c(cc2-4)c2ccccc2n5-c2nc(-c4ccccc4)nc(-c4ccccc4)n2)cc13
Temperature: 40 °C
Reaction time: 3 h

Procedure:
30.2 g (34.0 mmol) of tert-butyl 7-{10-(4,6-diphenyl-1,3,5-triazin-2-yl)-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorenyl}-12,12-dimethyl-12H-10-azaindeno[2,1-b]fluorene-10-carboxylate are dissolved in 900 ml of toluene and 200 ml of anisole, and 50 ml of trifluoroacetic acid are subsequently added. The mixture is stirred at 40° C. for 3 h and, when the reaction is complete, neutralised by means of ice-water and 20% NaOH solution. The mixture is extracted with dichloromethane, dried and recrystallised from toluene. The yield is 23.6 g (30 mmol, 88%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.CN(C)[CH:18]=[O:19]>O1CCCC1>[CH3:9][O:8][C:5]1[CH:4]=[C:3]([CH3:10])[C:2]([CH:18]=[O:19])=[CH:7][N:6]=1
Reactant: COc1cc(C)c(Br)cn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C)c(C=O)cn1

Procedure:
In Route C, commercially available 5-bromo-2-methoxy-4-methylpyridine in anhydrous tetrahydrofuran is metallated with n-BuLi and then treated with N,N-dimethylformamide to afford 6-methoxy-4-methylnicotinaldehyde. This was converted to the tert-butylimine with tert-butylamine in dichloromethane. Metallation with lithium 2,2,6,6-tetramethylpiperidide (Li-TMP) (cf. J. Org. Chem. 1993, 58, 2463-2467) and addition of N,N-dimethylformamide affords the iminoacetaldehyde which is reduced with sodium cyanoborohydride in methanol to give 2-tert-butyl-6-methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine. Cleavage of the methyl group with refluxing 48% hydrobromic acid and treatment with triflic anhydride in the presence of base gives (VIIb) protected as the tert-butylamine.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-].[CH3:11][C@@H:12]1[O:22][C:20](=[O:21])[C@@H:19]([NH:23][C:24]([C:26]2[C:31]([OH:32])=[C:30]([O:33][CH3:34])[CH:29]=[CH:28][N:27]=2)=[O:25])[CH2:18][O:17][C:15](=[O:16])[C@H:14]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:13]1[O:42][C:43]([CH:45]([CH3:47])[CH3:46])=[O:44].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(Cl)Cl>[CH3:46][CH:45]([CH3:47])[C:43]([O:42][C@@H:13]1[C@@H:14]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:15](=[O:16])[O:17][CH2:18][C@H:19]([NH:23][C:24]([C:26]2[C:31]([O:32][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:30]([O:33][CH3:34])[CH:29]=[CH:28][N:27]=2)=[O:25])[C:20](=[O:21])[O:22][C@H:12]1[CH3:11])=[O:44]
Reactant: BrCc1ccccc1
Reactant: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1OCc1ccccc1
Reaction time: 8 h
Yield: 81.4 %

Procedure:
Benzyl bromide (0.233 mol, 27.7 mL) was added to a solution of NaI (0.097 mol, 14.5 g) in acetone (1 L). Natural product UK-2A (1) (0.194 mol, 100 g) was added followed by powdered K2CO3 (0.388 mol, 53 g) and the mixture stirred vigorously overnight. The mixture was diluted with CH2Cl2 (500 mL) and washed with H2O (2×500 mL). The organic layer was dried (MgSO4), and concentrated in vacuo. Recrystallization (EtOAc/hexane) gave 95.5 g (79%) of 2 as an off-white solid (m.p. 169-170° C.) which contained ˜6.5% N-benzylated product (LC-MS). 1H-NMR and MS (M+1 605) were consistent for the title compound (2). The compound was used in the next step without further purification. The N-benzylated by-product could be removed from the mixture prior to recrystallization by filtration of the crude reside through a plug of silica gel (30% acetone/hexane as the eluent).
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]([C:14]([OH:16])=O)=[CH:6][CH:5]=1.[CH3:18][C:19]1([CH3:30])[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[C:22](=[O:28])[CH2:21][C:20]1=[O:29].C(N(CC)CC)C>C(#N)C.C[Si](C#N)(C)C>[F:17][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:14]([CH:21]2[C:20](=[O:29])[C:19]([CH3:30])([CH3:18])[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[C:22]2=[O:28])=[O:16])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Reactant: O=C(O)c1ccc(OC(F)F)c2ncccc12
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)C(C(=O)c2ccc(OC(F)F)c3ncccc23)C(=O)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.4 g (1.7 mmol) of 8-difluoromethoxy-5-quinolinecarboxylic acid was dissolved in 20 ml of acetonitrile, 0.4 g (1.9 mmol) of N,N-dicyclohexylcarbodiimide and 0.3 g (1.7 mmol) of 2,2,4,4-tetramethylcyclohexane-1,3,5-trione were added and the mixture was stirring at 25° C. for 20 hours. 0.4 g (4.0 mmol) of triethylamine and 2 drops of trimethylsilyl cyanide were then added, and stirring was continued at 30–35° C. for a further 3 hours. The precipitate was filtered off, and the filtrate was concentrated, 20 ml of 5% strength potassium carbonate solution were added and the mixture was washed with methyl tert-butyl ether. The aqueous phase was subsequently adjusted to pH 3 using concentrated hydrochloric acid and extracted with ethyl acetate. The solvent was removed and the residue was chromatographed over silica gel (mobile phase: methylene chloride/methanol). This gave 0.2 g of a colorless powder;
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13]CC)=[O:12])=[CH:4][CH:3]=1.Br[CH2:17][C:18]1[CH:37]=[CH:36][C:21]([O:22][CH2:23]/[C:24](/[C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)=[N:25]\[O:26][CH3:27])=[CH:20][CH:19]=1>>[C:32]([C:31]1[CH:30]=[CH:29][C:28](/[C:24](=[N:25]/[O:26][CH3:27])/[CH2:23][O:22][C:21]2[CH:36]=[CH:37][C:18]([CH2:17][O:1][C:2]3[CH:3]=[CH:4][C:5]([CH:8]4[CH2:10][CH:9]4[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=3)=[CH:19][CH:20]=2)=[CH:35][CH:34]=1)#[N:33]
Reactant: CCOC(=O)C1CC1c1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CBr)cc1)c1ccc(C#N)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(C3CC3C(=O)O)cc2)cc1)c1ccc(C#N)cc1

Procedure:
Compound 45 was prepared from ethyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.1 g, 0.48 mmol), and 4-{(1Z)-2-[4-(bromomethyl) phenoxy]-N-methoxyethanimidoyl}benzonitrile (0.175 g, 0.48 mmol) by following the procedure described in scheme 17.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:23])[CH2:10][C:11]1[C:19]2[O:18][CH:17](Cl)[CH:16]([Cl:21])[C:15]=2[CH:14]=[C:13]([F:22])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.O.[Cl-].[NH4+]>CC(C)([O-])C.[K+].C(O)(C)(C)C.C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:23])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[C:16]([Cl:21])[C:15]=2[CH:14]=[C:13]([F:22])[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Cc1cc(F)cc2c1OC(Cl)C2Cl)NC(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CC(Cc1cc(F)cc2c(Cl)coc12)NC(=O)OC(C)(C)C
Temperature: 35 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
A mixture of 0.30 gm (0.82 mMol) N-tert-butoxycarbonyl 1-(2,3-dichloro-2,3-dihydro-5-fluorobenzofur-7-yl)-2-aminopropane and 0.135 gm 18-crown-6 in 6.5 mL 1M potassium tert-butoxide in tert-butanol was stirred at 35° C. for 1 hour. The reaction mixture was diluted with 4 mL tert-butanol was continued for an additional 2.5 hours. The reaction mixture was cooled to room temperature and diluted with 50 mL diethyl ether followed by 5 mL water and 20 mL saturated aqueous ammonium chloride. The phases were separated and the aqueous phase was extracted with 25 mL diethyl ether. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure to provide an off-white solid. This solid residue was subjected to silica gel chromatography, eluting with hexane containing 7% ethyl acetate. Fractions containing the desired compound were combined and concentrated under reduced pressure to provide 0.151 gm (56%) of the desired compound as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH2:12]1[O:15][CH:13]1[CH3:14]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH3:14][CH2:13][O:15][CH2:12][CH3:1]
Reactant: CC1CO1
Agent: Oc1ccc2ccccc2c1
Solvent: Cc1ccccc1
Product: CCOCC
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a clean, dry stirred tank pressure vessel with nitrogen inlet is charged 1434.05 g (9.95 moles) of 2-Naphthol and 1445 mLs of Toluene. The vessel is purged with nitrogen and a catalytic amount (4.97 g) of BF3/Etherate Solution is charged. The temperature is raised to 110° C. and 2310.86 g (39.79 moles) of Propylene Oxide is added at a constant rate to keep the pressure inside the vessel below 50 psig. After all Propylene Oxide is added, the reaction mixture is allowed to react for an additional 3 hours after which the temperature is raised to 150° C. and the toluene is distilled off under nitrogen sparge. After the distillation of Toluene, the temperature is cooled to 110° C. and vacuum is applied for 1 hour.
Reaction SMILES: [O:1]=[C:2]1[NH:7]C2C=C([N+]([O-])=O)C=CC=2O[CH2:3]1.N[C:16]1[CH:21]=[C:20]([N+]([O-])=O)[CH:19]=[CH:18][C:17]=1[OH:25].C(=O)(O)[O-].[Na+]>C(C(C)=O)C(C)C>[O:25]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:3][C:2](=[O:1])[NH:7]1
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1Cc2ccccc2ON1
Temperature: 5 °C

Procedure:
3-Oxo-6-nitro-3,4-dihydro-2H-1,4-benzoxazine. A solution of 2-amino-4-nitrophenol (8.80 g), in methyl isobutyl ketone (30 mL) was treated with sodium bicarbonate (11.5 g) and distilled water (35 mL). The mixture was cooled to 5° C. under a nitrogen atmosphere, treated dropwise with chloroacetyl chloride (5.0 mL) and then heated to reflux for 18 hours. A brown solid was collected from the cooled mixture by filtration. The solid was dried under vacuum at 50° C. for 24 hours yielding benzoxazinone (10.5 g) as a brown solid; mp 235°-236° C.; MS: m/z=195(M+1); NMR: 4.76 (s,2), 7.14 (d,1), 7.74 (d,1), 7.82 (dd,1), 11.07 (broad s,1).
Reaction SMILES: C([Si]([O:8][C:9](=O)[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])(C)C)(C)(C)C.C(Cl)(=O)C([Cl:30])=O>ClCCl.CN(C)C=O>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:11]=[CH:10][C:9]([Cl:30])=[O:8])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC(=O)C=Cc1ccccc1O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1C=CC(=O)Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 10.01 g 3-[2-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acrylic acid tert-butyl-dimethyl-silanyl ester in 25 ml of dichloromethane, three drops of dimethylformamide were added and 4.14 g oxalyl chloride was dropped in at 0° C. After stirring at 0° C. for 90 minutes and then at room temperature overnight, the mixture was evaporated to dryness. The resulting brown solid (7.52 g) was not further purified.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:29]=2[C:28]2[CH2:27][NH:26][CH2:25][CH2:24][C:23]=2[S:22]3)[CH2:12][CH2:11]1.C(Cl)(=O)C>ClCCl>[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:29]=2[C:28]2[CH2:27][N:26]([C:3](=[O:5])[CH3:2])[CH2:25][CH2:24][C:23]=2[S:22]3)[CH2:12][CH2:11]1
Reactant: CN(C)C1CCC(Oc2cccc3sc4c(c23)CNCC4)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCc2sc3cccc(OC4CCC(N(C)C)CC4)c3c2C1
Reaction time: 2 h

Procedure:
To a solution of N,N-dimethyl-4-[8-thia-4-azatricyclo[7,4,0,0-[2,7]]trideca-1(13),2(7),9,11-tetraen-13-yloxy]cyclohexan-1-amine trifluoroacetate (43 mg) and TEA (50 mg, 0.49 mmol, 3.80 equiv) in 10 mL of dichloromethane at 0° C. was added acetyl chloride (20 mg, 0.25 mmol, 1.96 equiv) at 0° C. The resulting solution was stirred for 2 hours at this temperature under nitrogen. The reaction was then quenched with CH3OH and concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions (Waters): Column: Xbridge Prep C18, 5 μm, 19*50 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (10% CH3CN up to 35% in 11 min, up to 95% in 1.5 min, down to 10% in 1.5 min); flow rate: 20 mL/min; UV detection at 254/220 nm. This resulted in 12.6 mg (26%) of 1-(13-[[4-(dimethylamino)cyclohexyl]oxy]-8-thia-4-azatricyclo[7.4.0.0-[2,7]]trideca-1(13),2(7),9,11-tetraen-4-yl)ethan-1-one as a white solid. MS (ES): m/z 375 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 1.30-1.65 (m, 4H), 1.94 (d, 2H), 2.13 (s, 3H), 2.20-2.32 (m, 9H), 2.81, 2.91 (t, t, 2H, J=5.7 Hz), 3.77, 3.84 (t, t, 2H, J=5.7 Hz), 5.02-5.18 (m, 1H), 8.38, 8.39 (s, s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[NH:12][C:11]2[C:13]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=3)=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:10]=2[N:9]=1>>[N:1]1([C:8]2[NH:9][C:10]3[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[C:13]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=4)[C:11]=3[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3nc(Cl)[nH]c23)cc(F)c1F
Reactant: C1CNCCN1
Product: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(N4CCNCC4)nc23)cc(F)c1F

Procedure:
Piperazine (429 mg, 4.99 mmol, Aldrich) and 2-chloro-5-trifluoromethyl-7-(3,4,5-trifluoro-phenyl)-1H-benzoimidazole (582 mg, 1.66 mmol, Example 51b) reacted under the conditions of Example 100e to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 401 (M+1).
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11](=[CH2:22])[CH2:12][CH2:13][O:14][Si](C(C)(C)C)(C)C)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[CH2:6]([O:5][P:4](/[CH:9]=[CH:10]/[C:11](=[CH2:22])[CH2:12][CH2:13][OH:14])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: C=C(/C=C/P(=O)(OCC)OCC)CCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(/C=C/P(=O)(OCC)OCC)CCO
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of E-5-t-butyldimethylsilyloxy-3-methylidene-1-pentenyl-phosphonic acid diethyl ester (1.7 g, 4.86 mmol) and 1M tetrabutylammonium fluoride in tetrahydrofuran (8 ml, 8 mmol) is stirred 2 hours at 20° C. Then the reaction mixture is concentrated in vacuo and the title product is purified by flash chromatography on silica gel (1.1 g, 94%).
Reaction SMILES: C1(OC)C=CC=CC=1.[CH3:9][O:10][N:11]=[C:12]([C:51]1[N:52]=[N:53][S:54][CH:55]=1)[C:13]([NH:15][C:16]1([O:49][CH3:50])[C:47](=[O:48])[N:18]2[C:19]([C:31]([O:33]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:32])=[C:20]([CH2:23][S:24][C:25]3[N:29]([CH3:30])[N:28]=[N:27][N:26]=3)[CH2:21][S:22][C@H:17]12)=[O:14].FC(F)(F)C(O)=O>ClCCCl>[CH3:9][O:10][N:11]=[C:12]([C:51]1[N:52]=[N:53][S:54][CH:55]=1)[C:13]([NH:15][C:16]1([O:49][CH3:50])[C:47](=[O:48])[N:18]2[C:19]([C:31]([OH:33])=[O:32])=[C:20]([CH2:23][S:24][C:25]3[N:29]([CH3:30])[N:28]=[N:27][N:26]=3)[CH2:21][S:22][C@H:17]12)=[O:14]
Reactant: CON=C(C(=O)NC1(OC)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nnnn3C)CS[C@@H]21)c1csnn1
Solvent: ClCCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)NC1(OC)C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@@H]21)c1csnn1
Reaction time: 2 h
Yield: 32.1 %

Procedure:
Anisole (0.86 ml.) was added at ambient temperature to a solution of diphenylmethyl 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (0.86 g.) in dry 1,2-dichloroethane (10 ml.), and then trifluoroacetic acid (1.68 g.) was added dropwise thereto under ice-cooling. The resulting mixture was stirred for 2 hours under ice-cooling and the reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate (20 ml.) and water (20 ml.). After shaking the mixture, the ethyl acetate layer was separated. The remaining aqueous layer was further extracted with ethyl acetate (10 ml. and 5 ml.). The ethyl acetate layers were combined and 10% aqueous solution of dipotassium hydrogen phosphate (20 ml.) was added thereto. The mixture was shaken and the aqueous layer was separated. The ethyl acetate layer was further extracted with 10% aqueous solution of dipotassium hydrogen phosphate (10 ml. and 5 ml.). The aqueous layers were combined and washed in turn with ethyl acetate (10 ml. and 5 ml.) and ether (10 ml.). The remaining solvent in the aqueous layer was removed by bubbling of nitrogen gas. The resulting aqueous layer was adjusted to pH 2 with 10% hydrochloric acid under ice-cooling. Precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.21 g.).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.[CH3:44][N:45]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:44][N:45]1[CH2:51][CH2:50][CH2:49][N:48]([CH2:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([NH:27][C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:15]=2[C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=2)=[O:38])=[O:37])[CH2:47][CH2:46]1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Reactant: CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 38.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.15 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), 1-methyl-1,4-diazepane (65.4 mg, 0.57 mmol, 3.74 equiv), KI (12.7 mg, 0.08 mmol, 0.50 equiv), and potassium carbonate (42.4 mg, 0.31 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 70° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 40 mg (23%) of a yellow solid. 1H-NMR (400 MHz, CD3OD, ppm): δ 8.95-8.93 (d, J=4.2 Hz, 1H), 8.75-8.73 (d, J=6.6 Hz, 1H), 8.46 (s, 1H), 8.18-8.17 (d, J=4.2 Hz, 1H), 8.09 (s, 1H), 8.02-8.00 (d, J=8 Hz, 1H), 7.90-7.88 (m, 1H), 7.75-7.55 (m, 1H), 4.72 (s, 2H), 4.19 (s, 2H), 3.70-3.67 (t, J=5.6 Hz, 4H), 3.55-3.49 (m, 4H), 3.18-3.16 (t, J=5.6 Hz, 2H), 2.95 (s, 3H), 2.22-2.18 (m, 2H), 2.07-2.05 (t, J=5.2 Hz, 4H), 1.84-1.83 (d, J=5.2 Hz, 1H). MS (ES, m/z): 685 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[Br:11][CH2:12][CH2:13]Br>>[Br:11][CH2:12][CH2:13][O:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[Cl:10]
Reactant: Cc1cc(Cl)c(O)c(Cl)c1
Reactant: BrCCBr
Product: Cc1cc(Cl)c(OCCBr)c(Cl)c1
Yield: 61 %

Procedure:
4-Methyl-2,6-dichlorophenol was reacted with 1,2-dibromoethane according to the procedure described in Step 2A to yield the titled compound (4.66 g, 61%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.29 (s, 3H) 3.70 (d, J=7.20 Hz, 2H) 4.29 (d, J=7.20 Hz, 2H) 7.11 (s, 2H).
Reaction SMILES: OP([O-])(O)=O.[K+].[CH3:7][CH:8]([CH2:14][C:15]([O:17]C)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11].C(=O)([O-])[O-].[K+].[K+].Cl>CO>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C@H:8]([CH3:7])[CH2:14][C:15]([OH:17])=[O:16]
Reactant: COC(=O)CC(C)CC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=P([O-])(O)O
Solvent: CO
Product: COC(=O)C[C@H](C)CC(=O)O

Procedure:
To a 5 1. four necked flask fitted with a stirred and pH electrode was added 2.5 1. of 0.1M potassium acid phosphate buffer pH 7.0 followed by 150 mg. of pig liver esterase and 150 g. of dimethyl 3-methylglutarate. The pH of the mixture was maintained at about 6.85 by periodic addition of a 10% potassium carbonate solution. After 2.5 hours the reaction was acidified with 10% hydrochloric acid to pH 2.0 and the product extracted with diethyl ether. The extracts were combined, dried over magnesium sulfate and concentrated in vacuo to give 114 g. of the desired product, [alpha]D =-1.48 (CH3OH C=0.086 g/ml).
Reaction SMILES: N#N.C(OC([NH:13][C@H:14]([C:22]([NH:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O)C1C=CC=CC=1.Cl>[Pd].C(O)C>[CH3:28][CH:27]([CH3:29])[CH2:26][CH2:25][NH:24][C:22](=[O:23])[C@H:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:13]
Reactant: CC(C)CCNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: N#N
Solvent: CCO
Product: CC(C)CCNC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 3 h
Yield: 60.4 %

Procedure:
A mixture of N2 -benzyloxycarbonyl-N-(3-methylbutyl)-L-phenylalaninamide (7.0 g.), ethanol (200 ml.) and palladium on carbon (10%, 250 mg.) was hydrogenated under pressure (40 p.s.i.g.) for three hours (10% uptake). Concentrated hydrochloric acid (1.65 ml.) was added and the hydrogenation was continued overnight. The mixture was filtered, and the filtrate was stripped of volatiles. A small amount of crystals separated from an ether-ethanol solution of the residue. The mother liquor was stripped of volatiles and purified by reverse phase high pressure liquid chromatography on octadecylsilated silica gel using ammonium acetate (0.2%) in methanol-water (65:35) as the eluant, affording N-(3-methylbutyl)-L-phenylalaninamide (2.5 g.) as a clear gum.