Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[I:10][C:11]1[CH:12]=[C:13]([C:18]([F:21])([F:20])[F:19])[C:14](O)=[N:15][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>O1CCCC1>[F:1][C:2]1([CH2:8][O:9][C:14]2[C:13]([C:18]([F:19])([F:21])[F:20])=[CH:12][C:11]([I:10])=[CH:16][N:15]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: Oc1ncc(I)cc1C(F)(F)F
Reactant: OCC1(F)CCOCC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC1(COc2ncc(I)cc2C(F)(F)F)CCOCC1
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 37C (0.537 g), 5-iodo-3-(trifluoromethyl)pyridin-2-ol (1.156 g), and triphenylphosphine (1.574 g) in tetrahydrofuran (20 mL) was cooled to 0° C. To this solution was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (0.921 g). The reaction mixture was stirred overnight. The solvent was removed, and the residue was purified with column flash chromatography on silica gel eluting with 4:1 hexanes/ethyl acetate to give the desired product.
Reaction SMILES: Cl.O1CCOCC1.[OH:8][C@@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][O:29]2)[CH:21]=1)[CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C>C(Cl)Cl>[NH2:12][CH2:11][CH2:10][C@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][O:29]2)[CH:21]=1)[OH:8]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCCO2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCC[C@@H](O)c1cccc(OCC2CCCO2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl/dioxane (4M, 2.5 mL) was added at 0° C. to a solution of tert-butyl ((3R)-3-hydroxy-3-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)propyl)carbamate (0.25 g, 0.71 mmol) in DCM (10 mL) and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction the solvent was removed under reduced pressure. Purification by column chromatography (MeOH:DCM with 1% aq. NH4OH, 1-10% gradient) gave Example 14 as a mixture of diastereomers as an off white semi-solid. Yield (0.22 g, 95%); 1H NMR (400 MHz, DMSO-d6): δ 7.20 (t, J=8.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 2H), 6.78-6.76 (m, 1H), 4.64-4.61 (m, 1H), 4.15-4.11 (dd, 1H), 3.93-3.87 (m, 2H), 3.78-3.75 (m, 1H), 3.70-3.64 (m, 1H), 2.69-2.66 (m, 2H), 2.01-1.95 (m, 1H), 1.88-1.79 (m, 2H), 1.70-1.65 (dd, J=6.8 Hz, 3H); MS: m/z 252.14 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][O:36][C:37]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:38]=1[NH2:39].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:35][O:36][C:37]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:38]=1[NH:39][C:24]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:26]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(N)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c(OC)c1
Yield: 53.8 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (72 mg) was added, and the admixture was refluxed with heat for 3 minutes. 2,4-Dimethoxyaniline (60 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 11 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 44 mg of the title compound (yield: 53%).
Reaction SMILES: ClC1[C:3](F)=[CH:4][C:5](F)=[C:6]([CH:14]=1)[C:7](NS(C)(=O)=O)=[O:8].[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.C1(CO)CCCC1>>[Cl:17][C:18]1[C:19]([O:8][CH2:7][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:14]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Agent: OCC1CCCC1
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with cyclopentylmethanol, the title compound was obtained as a colorless solid (0.12 g, 32%): 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.73 (d, J=7.4 Hz, 1H), 7.24 (d, J=12.4 Hz, 1H), 4.03 (d, J=6.8 Hz, 2H), 2.87 (s, 6H), 2.39-2.29 (m, 1H), 1.82-1.72 (m, 2H), 1.65-1.51 (m, 4H), 1.38-1.30 (m, 2H); MS (ES−) m/z 377.1, 379.1 (M−1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[CH2:19])=[CH:14][CH:13]=1.CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][OH:10])=[C:2](/[CH:19]=[CH:18]/[C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: OCc1ccc(F)cc1Br
Reactant: C=Cc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OCc1ccc(F)cc1/C=C/c1ccc(F)cc1
Temperature: 150 °C
Yield: 49.7 %

Procedure:
Charged (2-bromo-4-fluorophenyl)methanol (954 mg, 4.65 mmol), 4-fluoro-1-vinylbenzene (1.14 g, 9.31 mmol), Pd(PPh3)2Cl2(49 mg, 0.07 mmol), Et3N (942 mg, 9.31 mmol) and DMF (5 mL) to a sealed tube, the mixture was then purged with nitrogen, heated to 150° C. for 3 h in microwave oven. The reaction mixture was filtered, the filtrate was then extracted with ethyl acetate, concentrated and purified by flash column chromatograph to give 569 mg of the title compound (50%). 1H NMR (400 MHz, CDCl3): δ 1.60 (1H, t, J=6.4 Hz), 4.78 (2H, d, J=6.4 Hz), 6.93-7.08 (4H, m), 7.31-7.35 (3H, m), 7.48-7.52 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([Br:15])[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([OH:16])[N:3]=1.S(=O)(=O)(O)N.N[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>>[Br:15][C:7]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([OH:16])[N:3]=[C:2]2[NH:1][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1
Reactant: Nc1nc(O)nc2c(Br)cc([N+](=O)[O-])cc12
Reactant: CN1CCN(CCCN)CC1
Agent: NS(=O)(=O)O
Product: CN1CCN(CCCNc2nc(O)nc3c(Br)cc([N+](=O)[O-])cc23)CC1
Temperature: 0 °C
Yield: 40 %

Procedure:
A mixture of 4-amino-8-bromo-6-nitro-quinazolin-2-ol (24.1 mg, 0.0845 mmol), sulfamic acid (16.4 mg, 0.169 mmol) and 1-(3-aminopropyl)-4-methylpiperazine (1 ml) was heated at reflux for 7 h. The cooled reaction mixture was poured into 10 ml ice water. The resulting precipitate was collected and purified by preparative HPLC. 19.2 mg product was obtained. Yield: 40%; 1H NMR (500 MHz, DMSO-d6): δ 1.91521–1.95482 (m, 2H), 2.78103(s, 8H), 3.16555(b, 4H), 8.68221–8.68666(d, J=2.225 Hz, 1H), 9.10824–9.11291(d, J=2.335 Hz, 1H); ESI-MS: 425, 427 (M++1)
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:27][C:28]1[CH:29]=[C:30]([C:35](=[O:63])[C:36](=[C:54]2[NH:58][C:57]3[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=3[NH:55]2)[C:37]([C:39]2[CH:40]=[C:41]([S:45]([NH:48][C:49](=[NH:53])[C:50]([OH:52])=O)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=2)=[O:38])[CH:31]=[C:32]([F:34])[CH:33]=1>O.CN(C=O)C.C(N(CC)CC)C>[F:34][C:32]1[CH:31]=[C:30]([C:35](=[O:63])[C:36](=[C:54]2[NH:58][C:57]3[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=3[NH:55]2)[C:37]([C:39]2[CH:40]=[C:41]([S:45]([NH:48][C:49](=[NH:53])[C:50]([N:3]([CH3:4])[CH3:2])=[O:52])(=[O:46])=[O:47])[CH:42]=[CH:43][CH:44]=2)=[O:38])[CH:29]=[C:28]([F:27])[CH:33]=1
Reactant: CNC
Reactant: N=C(NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(=N)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
Dimethylamine hydrochloride (31 mg), triethylamine (0.05 mL), HOBt (51 mg) and WSC.HCl (73 mg) were added to a DMF (5 mL) solution of [({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)amino](imino)acetic acid (40 mg), followed by stirring at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to obtain 2-[({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)amino]-2-imino-N,N-dimethylacetamide (28 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:24])=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)nc1
Reactant: Nc1ccc2cccnc2c1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2cccc(F)c2)nc1

Procedure:
Using the procedure outlined in Example 104, the title compound was prepared from 7-aminoquinoline (D55) (28 mg, 0.19 mmol) and 6-(3-fluorophenyl)-nicotinic acid (D73) (50 mg, 0.23 mmol) as a yellow solid. MS(ES): MH+ 344, M-H+ 342
Reaction SMILES: [Cl-:1].[Cl:2]C1N(C)CC[NH+]1C.[NH2:10][C:11]1[C:12]([I:25])=[C:13]([C:22](O)=[O:23])[C:14]([I:21])=[C:15]([C:19]=1[I:20])[C:16](O)=[O:17].C1(C)C=CC=CC=1>CCCCCC>[NH2:10][C:11]1[C:12]([I:25])=[C:13]([C:22]([Cl:2])=[O:23])[C:14]([I:21])=[C:15]([C:19]=1[I:20])[C:16]([Cl:1])=[O:17]
Reactant: [Cl-]
Reactant: CN1CC[NH+](C)C1Cl
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Yield: 94.8 %

Procedure:
To a reaction flask, 4.23 g (0.025 mole) of 2-chloro-1,3-dimethylimidazolinium chloride, 5.58 g (0.01 mole) of 5-amino-2,4,6-triiodoisophthalic acid and 80 g of toluene were charged and reacted at 105°-110° C. for 4 hours. Thereafter, the reaction mass was cooled and toluene was removed under reduced pressure. To the concentrate thus obtained, 100 ml of hexane was added to crystallize 5-amino-2,4,6-triiodoisophthaloyl dichloride. The precipitate was filtered and dried under reduced pressure to obtain 5.65 g (95% yield) of 5-amino-2,4,6-triiodoisophthaloyl dichloride as white crystals.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[CH3:10][C:11]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24](OCC)=[O:25])=S)=[CH:16][C:15]=1[F:29].[NH:35]1[CH:39]=[C:38]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:37]=[N:36]1.C(Cl)Cl>ClCCCl.Cl[Ti](Cl)(Cl)Cl.CCO>[CH3:10][C:11]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:12]=1[O:13][C:14]1[CH:19]=[C:18]2[C:17](=[CH:16][C:15]=1[F:29])[N:20]=[C:21]([N:35]1[CH:39]=[C:38]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:37]=[N:36]1)[NH:23][C:24]2=[O:25]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2c(C)cccc2C)c(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CCO
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2nc3cc(F)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 3.3 %

Procedure:
Neat diisopropylcarbodiimide (45.4 g, 290 mmol) was added to a solution of 1-(4-(2,6-dimethylphenoxy)-3-fluorophenyl)-3-ethoxycarbonylthiourea (100 g, 276 mmol), ethyl pyrazole-4-carboxylate (45.4 g, 290 mmol), and DCM (1 L). The solution was maintained at rt for 24 h, then concentrated. The residue was stirred with ether (500 mL) for 3 h in an ice bath, then filtered. The filtrate was concentrated to a thick orange oil (180 g, ca. 70% purity, 97%). A portion of this material (20 g, ca. 30 mmol) was dissolved in DCE (150 mL), then neat TiCl4 was added. The mixture was then heated to reflux for 6 h, then cooled in an ice bath. EtOH (750 mL) was added, and the mixture was stirred for 3 h. The resulting precipitate was collected by filtration, washed with cold EtOH, and dried to provide the titled compound (3.9 g, 31%). 1H NMR (500 MHz, DMSO): 13.03 (s, 1H), 8.95 (d, J=0.6 Hz, 1H), 8.29 (s, 1H), 7.75 (d, J=11.5 Hz, 1H), 7.31-7.24 (m, 2H), 7.22 (dd, J=8.5, 6.4 Hz, 1H), 6.96 (d, J=9.1 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 2.11 (s, 6H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.FC(F)(F)S(O[C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[O:17][CH:2]3[CH:3]=[CH:4][C:5]4[C:10]([N:1]3[C:27]3[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:26]2=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)c1cc(F)c(F)cc1OS(=O)(=O)C(F)(F)F
Reactant: c1ccc2ncccc2c1
Reactant: O=Cc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1cc2c(cc1F)N1c3ccccc3C=CC1OC2c1ccc(Cl)cc1
Yield: 68 %

Procedure:
Following the general procedure, treatment of quinoline (0.064 g, 59 μL, 0.50 mmol) and 4-chlorobenzaldehyde (0.105 g, 0.75 mmol) with 4,5-difluoro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.201 g, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=75/25) of the crude reaction mixture afforded 5-(4-chlorophenyl)-2,3-difluoro-5H,6aH-benzo[4,5][1,3]oxazino[3,2-a]quinoline as inseparable mixture of diastereomers as a white solid (0.118 g, 68% yield, dr determined by 1H NMR analysis of crude reaction mixture is 10:1).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:20]([NH2:21])[C:19](=[O:22])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].C(O[CH:26](OCC)[CH2:27][N:28]=[C:29]=[N:30][Si](C(C)(C)C)(C)C)C.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:20]([NH:21][C:29]3[NH:28][CH:27]=[CH:26][N:30]=3)[C:19](=[O:22])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: CCOC(CN=C=N[Si](C)(C)C(C)(C)C)OCC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(Nc3ncc[nH]3)[C@H]2SC1
Reaction time: 1.5 h

Procedure:
To a mixture of t-butyl 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylate (3.3 g.) and 1-(2,2-diethoxyethyl)-3-t-butyldimethylsilylcarbodiimide (2.0 g.) in CH2Cl2 (50 ml.) at room temperature was added trifluoromethanesulphonic acid (0.89 ml.) over 2 minutes. The mixture was evaporated to dryness and the residue, t-butyl 3-acetoxymethyl-7-[2-(2,2-diethoxyethyl)-3-t-butyldimethylsilyl]guanidinoceph-3-em-4-carboxylate, was dissolved in acetonitrile (50 ml.) and the mixture treated first with 50% w/v aqueous HF (0.8 ml.) at room temperature for 15 minutes and then with 12N aqueous HCl (1.0 ml.) for 1.5 hours at room temperature. The reaction mixture was evaporated to dryness and the residue triturated with ether to give t-butyl 3-acetoxymethyl-7-(imidazol-2-yl)aminoceph-3-em-4-carboxylate as a mixture of salts. This powder was dissolved in TFA (5 ml.) and this solution allowed to stand for 15 minutes at room temperature. The solvent was evaporated and the residue triturated with ether (yield from 7-amino derivative 41%) and then purified by chromatography on "Dowex" 1 resin (acetate form) using 0.1% v/v aqueous HOAc as eluant to give 3-acetoxymethyl-7-(imidazol-2-yl)aminoceph-3-em-4-carboxylic acid (yield from 7-amino derivaive 34%) having the following n.m.r. in d6DMSO: 2.1 (s, 3H); 3.45 (d, 1H); 3.7 (d, 1H); 4.8 (d, 1H); 5.15 (d, 1H); 5.3 (d, 1H); 5.7 (d, 1H); 7.1 (s, 2H); 9.4 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=O)[CH:22]([CH3:29])[CH2:23][C:24](OCC)=[O:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:32][NH2:33]>C(O)(C)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]([CH3:29])[CH2:23][C:24](=[O:25])[NH:33][N:32]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(C)C(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: NN
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 90 °C
Yield: 53.1 %

Procedure:
A mixture of crude 4-[4-(3-ethoxycarbonyl-2-methyl-propionyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (9 g, 21.4 mmol) and hydrazine monohydrate (3.58 ml, 71.6 mmol) in isopropanol (70 mL) was heated at 90° C. for 2 days and concentrated at reduced pressure to give a crude residue. The crude reside was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4), filtered, and concentrated to give a crude product. The crude product was purified by ISCO (120 g silica gel column) chromatography using 2 to 5% methanol in methylene chloride to obtain 4-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (4.4 g, 53%), MS m/z 388 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([C:15]#[C:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[BrH:26].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[Br:26][C:16]1[CH:15]=[C:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:17]=1
Reactant: COc1cc(C(=O)C#CCNC(=O)OC(C)(C)C)cc(OC)c1OC
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(-c2cc(Br)cn2C(=O)OC(C)(C)C)cc(OC)c1OC
Temperature: 4 °C
Reaction time: 0.75 h
Yield: 89.9 %

Procedure:
To a stirred solution of 3-(tert-butoxycarbonylamino)-1-propinyl 3,4,5-trimethoxyphenyl ketone (1.0 g, 2.78 mmol, Example 76c) in CH2Cl2 (10 ml) a solution of HBr (732 μl, 1.5 equiv., 33% in acetic acid) is added at 4° C. The reaction mixture is stirred for 45 min at 4° C., and poured onto ice, saturated aqueous NaHCO3 solution and ethyl acetate. The organic layer is dried (MgSO4), the solvents are evaporated and the residue chromatographed on SiO2 with ethyl acetate/hexane (1:3) to yield the title compound (1.0 g, 89.9%) as a white solid. 1H-NMR (300 MHz, DMSO-d6): 7.45 (d, J=2.0, 1H); 6.66 (s, 2H); 6.38 (d, J=2.0, 1H); 3.77 (s, 2MeO); 3.67 (s, MeO); 1.33 (s, tBu).
Reaction SMILES: [CH2:1](OC(=O)O[C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3Cl)C=C1)C.[Cl:23][C:24]1[N:32]=[C:31]2[C:27]([N:28]=[CH:29][N:30]2[C@@H:33]2[CH2:37][C@H:36]([N:38]3[N:42]=[N:41][C:40]([CH2:43][CH3:44])=N3)[C@@H:35]([OH:45])[C@H:34]2[OH:46])=[C:26]([NH:47][CH2:48][CH:49]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[N:25]=1.C(C1C=NNN=1)C>>[Cl:23][C:24]1[N:32]=[C:31]2[C:27]([N:28]=[CH:29][N:30]2[CH:33]2[CH2:37][CH:36]([N:38]3[CH:1]=[C:40]([CH2:43][CH3:44])[N:41]=[N:42]3)[CH:35]([OH:45])[CH:34]2[OH:46])=[C:26]([NH:47][CH2:48][CH:49]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[N:25]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Agent: CCc1cn[nH]n1
Product: CCc1cn(C2CC(n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C(O)C2O)nn1

Procedure:
This compound is prepared from carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (Intermediate AC) using a procedure analogous to that of (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Intermediate BA6) by replacing 5-ethyl-2H-tetrazole with 4-ethyl-2H-[1,2,3]triazole (first step a). MS (ES+) m/e 545.24 (MH+)
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([NH2:9])=[CH:7][N:6]=[CH:5][N:4]=1.[CH2:10]([O:13][C:14]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17])[CH2:11][CH3:12]>>[NH2:2][C:3]1[C:8]([NH:9][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:14]=2[O:13][CH2:10][CH2:11][CH3:12])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: CCCOc1cc(OC)ccc1C(=O)Cl
Reactant: Nc1cncnc1N
Agent: Cl
Product: CCCOc1cc(OC)ccc1C(=O)Nc1cncnc1N

Procedure:
The above compound was prepared from 4.4 g of 4,5-diaminopyrimidine hydrochloride and 7.6 g of 2-n-propyloxy-4-methoxy-benzoylchloride using a procedure analogous to that of Example 11(a). The crude product obtained was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[CH:27]=[C:16]2[C:17]3[C:22]([CH2:23][CH2:24][N:15]2[C:14](=[O:28])[N:13]=1)=[CH:21][C:20]([O:25][CH3:26])=[CH:19][CH:18]=3>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][O:8][C:12]1[CH:27]=[C:16]2[C:17]3[C:22]([CH2:23][CH2:24][N:15]2[C:14](=[O:28])[N:13]=1)=[CH:21][C:20]([O:25][CH3:26])=[CH:19][CH:18]=3
Reactant: OCC1COCCO1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1)CCn1c-2cc(OCC2COCCO2)nc1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[1,4]Dioxan-2-yl-methanol (42 mg, 0.36 mmol, 2 eq.) was dissolved in DCM (3 mL) with NaH (14 mg, 0.36 mmol, 2 eq., 60% in mineral oil). After 30 min, intermediate 38 (50 mg, 0.18 mmol, 1 eq.) was added to the mixture and the reaction was stirred at RT for 16 h. The reaction mixture was evaporated to dryness and the crude product was purified by preparative HPLC-MS to provide compound 162.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([CH2:17][NH:18][CH3:19])[C:10]=1[O:11][C@H:12]1[CH2:16][CH2:15][O:14][CH2:13]1)[NH2:7].C(N(CC)C(C)C)(C)C.[CH2:29]([O:36][C:37]([O:39]N1C(=O)CCC1=O)=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[NH2:7][C:6]1[CH:5]=[C:4]([F:3])[C:10]([O:11][C@H:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[C:9]([CH:8]=1)[CH2:17][N:18]([CH3:19])[C:37](=[O:39])[O:36][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CNCc1cc(N)cc(F)c1O[C@H]1CCOC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cc(N)cc(F)c1O[C@H]1CCOC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To 39A (640 mg, 2.043 mmol), N,N-diisopropylethylamine (1.424 ml, 8.17 mmol) in DMF (10 ml), was added N-(benzyloxycarbonyloxy) succinimide (560 mg, 2.248 mmol). The mixture was stirred at rt for 1 h, quenched with water, extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography to give 39B (540 mg, 1.442 mmol, 70.6% yield). MS (ESI) m/z: 375.2 (M+H)+.