Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH3:22])[C:14]4=[O:23])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[OH-].[K+].[CH:26]1[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][CH:27]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:32]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH3:22])[C:14]4=[O:23])[CH2:12]3)[CH:6]=2)[C:2]([I:1])=[N:3]1)[C:29]1[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=1
Reactant: CN1C(=O)[C@@]2(C[C@H]2c2ccc3c(I)n[nH]c3c2)c2ccccc21
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CN1C(=O)[C@@]2(C[C@H]2c2ccc3c(I)nn(Cc4ccccc4)c3c2)c2ccccc21
Reaction time: 18 h

Procedure:
A round-bottom flask was charged with (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-1′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (200 mg, 0.482 mmol), tetrabutylammonium bromide (2.0 mg, 0.005 mmol), CH2Cl2 (3.5 mL), and KOH (1.0 mL, 50% wt aqueous solution). The mixture was then treated with BnBr (69 uL, 0.578 mmol) and the reaction stirred for 18 h at which time the product was extracted with CH2Cl2 (3×) and the combined organic layers washed with brine and dried over MgSO4. After removal of solvent, purification using a Biotage Isolera (silica gel, 1-5% MeOH in DCM) gave the title compound. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, 1H, J=8.2 Hz), 7.29-7.25 (m, 3H), 7.15-7.10 (m, 4H), 6.97 (d, 1H, J=8.3 Hz), 6.85 (d, 1H, J=8.0 Hz), 6.56 (t, 1H, J=7.3 Hz), 5.72 (d, J=7.5 Hz, 1H), 5.63-5.49 (m, 2H), 3.39 (t, J=8.8 Hz, 1H), 3.32 (s, 3H), 2.22-2.19 (m, 1H), 1.97-1.94 (m, 1H); MS ESI 506.1 [M+H]+, calcd for [C25H20IN3O+H]+ 506.07. Recrystallization from neat MeOH yielded clear, colorless crystals which were submitted for single crystal X-ray structure determination. The structure obtained (see FIGURE) confirmed the relative and absolute stereochemistry as (1R,2S), i.e. identical to that predicted by the “Sharpless mnemonic”. The crystallographic data is summarized in the table below.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH3:17][O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:25]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=2[O:23][CH2:22]1.[Br:32][C:33]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][C@@H:37]2O.C(P(CCCC)CCCC)CCC>O1CCCC1.O>[CH3:17][O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][C@H:37]3[C:38]4[C:34](=[C:33]([Br:32])[C:41]([C:42]([F:43])([F:44])[F:45])=[CH:40][CH:39]=4)[CH2:35][CH2:36]3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: O[C@H]1CCc2c1ccc(C(F)(F)F)c2Br
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reaction time: 2.5 h

Procedure:
A solution of di-tert-butyl azodicarboxylate (6.3 g) in tetrahydrofuran (20 mL) is added dropwise over 45 min to a solution of [(S)-6-hydroxy-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester (4.71 g), (S)-4-bromo-5-trifluoromethyl-indan-1-ol (6.00 g), and tri-n-butyl-phosphine (6.9 mL) in tetrahydrofuran (50 mL) at −10° C. The resulting solution is stirred in the cooling bath for 2.5 h and then diluted with water. The resulting mixture is extracted with ethyl acetate. The combined extracts are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30) to give the title compound. LC (method 2): tR=0.85 min; Mass spectrum (ESI+): m/z=471/473 (Br) [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]=[C:8]([C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[CH2:9][C:10]#[N:11].[OH-].[Na+]>C1COCC1>[NH2:11][CH2:10][CH2:9][CH:8]([C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[OH:7]
Reactant: N#CCC(=O)c1ccsc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCC(O)c1ccsc1
Temperature: 25 °C

Procedure:
To a stirred suspension of LAH (1.45 g, 38.1 mmol) in dry THF (120 mL) was added a solution of 3-oxo-3-(thiophen-3-yl)propanenitrile (4.8 g, 31.8 mmol) in dry THF (40 mL) dropwise at 0° C. under nitrogen atmosphere. The mixture was warmed to 25° C. and then heated at 65° C. for 6 hours. After cooling to 0° C., a saturated solution of sodium hydroxide (2 mL) was added dropwise and the mixture was filtered. The filtrate was concentrated to dryness to give crude 3-amino-1-thiophen-3-yl-propan-1-ol which was used in next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].[C:10]1([CH3:19])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>>[Cl:8][C:6]1[N:5]=[N:4][C:3]([NH2:9])=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:19])[CH:7]=1
Reactant: Nc1nnc(Cl)cc1Br
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1cc(Cl)nnc1N

Procedure:
The title compound was prepared in analogy to example 1, intermediate b, from 4-bromo-6-chloropyridazin-3-amine (CAS RN 446273-59-2) and o-tolylboronic acid (CAS RN 16419-60-6). Light brown solid (41%). MS (ESI+): m/z=220.064 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[NH:26][N:27]=1.N1NC(=O)C=CC=1>>[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[N:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:10][C@H:11]([N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:12]4)[S:8][C:4]=3[CH:3]=2)[N:27]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cc1ccc(=O)[nH]n1
Agent: O=c1cccn[nH]1
Product: Cc1ccc(=O)n(-c2ccc3nc([C@H]4C[C@H](N5CCCC5)C4)sc3c2)n1

Procedure:
The title compound was prepared according to the procedure described in Example 22, substituting the product of Example 62A for the product of Example 1E and substituting 6-methyl-3(2H)-pyridazinone for 3(2H)-pyridazinone. 1H NMR (300 MHz, CDCl3) δ ppm 8.12 (t, J=2.03 Hz, 1H) 8.03 (t, J=8.48 Hz, 1H) 7.66 (dd, J=8.48, 2.37 Hz, 1H) 7.17 (d, J=9.49, 1H) 7.00 (d, J=9.49 Hz, 1H) 3.56-3.72 (m, 1H) 3.07 (m, 1H) 2.48-2.78 (m, 6H) 2.41 (s, 3H) 1.87-1.96 (m, 2H) 1.77-1.87 (m, 2H) 1.49-1.73 (m, 2H). MS: (M+H)+=367.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:10])(O)[C:5]1=[CH2:11])([CH3:3])=[CH2:2].[CH:12]([O:14]CC)=[CH2:13]>P(=O)(O)(O)O>[CH:12]([CH2:13][CH2:11][C:5]1[CH:4]([C:1]([CH3:3])=[CH2:2])[CH2:8][CH2:7][C:6]=1[CH3:10])=[O:14]
Reactant: C=COCC
Reactant: C=C(C)C1CCC(C)(O)C1=C
Agent: O=P(O)(O)O
Product: C=C(C)C1CCC(C)=C1CCC=O
Yield: 68.5 %

Procedure:
12 drops of 85% phosphoric acid were added to a mixture, cooled to -15° C in a laboratory autoclave, of 76 g of 3-isopropenyl-1-methyl-2-methylene-cyclopentan-1-ol and 72 g of ethyl vinyl ether. After gassing with argon, the autoclave was brought, in an oil bath of 180° C, to an internal temperature of 150° C (this took about 15 minutes) and held at this temperature until a distinct drop in pressure occurred (about 100 minutes). The reaction mixture was then quenched, taken up in ether, washed with aqueous bicarbonate solution and water, the solution dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The crude product (110 g), obtained as a yellow oil, was fractionated and yielded 61 g (68%) of pure 2-(2-formylethyl)-3-isopropenyl-1-methyl-cyclopent-1-ene having a woody, earthy fragrance; boiling point 0.2 = 64°-65° C; nD20 = 1.4888; IRfilm : νmax = 3080, 2725, 1725, 1642, 1440, 1370, 1060 and 895 cm-1.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)C.[ClH:27].[OH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[OH:38])[CH2:32][CH2:33][NH2:34].C(O)CCC>O>[ClH:27].[CH2:17]([O:16][C:14]([N:6]([CH2:5][CH:4]1[C:35]2[C:31](=[CH:30][C:29]([OH:28])=[C:37]([OH:38])[CH:36]=2)[CH2:32][CH2:33][NH:34]1)[C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)c1ccc(C)cc1)OCC
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: Cc1ccc(N(CC2NCCc3cc(O)c(O)cc32)C(=O)OCc2ccccc2)cc1
Yield: 63.4 %

Procedure:
N-benzyloxycarbonyl-p-toluidinoacetaldehyde diethyl acetal (6 g) and 3,4-dihydroxyphenethylamine hydrochloride (2.5 g) were added to a mixture of n-butyl alcohol (60 ml) and water (8.5 ml) and then the mixture was refluxed for 9.5 hours in a stream of nitrogen. In the course of the reaction, the above-mentioned acetal (0.6 g) was twice added to the mixture, after 5 hours and after 7.5 hours from the beginning of the reaction. The reaction mixture was concentrated and the residue was washed with ether and dissolved in hot water (300 ml). After the insoluble material was filtered off, the filtrate was washed with ethyl acetate and treated with activated charcoal. The aqueous layer was concentrated to dryness to give amorphous 1-(N-benzyloxycarbonyl-p-toluidinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.8 g), mp 125° C. (dec).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:17]1[C:22]([OH:23])=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[CH:19][C:18]=1[CH3:28])=[O:16])(=O)C.[OH-].[Na+].Cl>CO>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:17]1[C:22]([OH:23])=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[CH:19][C:18]=1[CH3:28])=[O:16]
Reactant: COc1cc(C)c(C(=O)CCCCCCCCCCOC(C)=O)c(O)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)c(C(=O)CCCCCCCCCCO)c(O)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution (300 ml) of 6-(11-acetoxy-1-oxoundecyl)-2,3-dimethoxy-5-methylphenol (34 g) in methanol is added sodium hydroxide (7 g), and the mixture is stirred at room temperature for 2 hours. After 5 N hydrochloric acid is added to the reaction mixture to neutralize, the solvent is distilled off to give crude crystals. The product is washed with water and recrystallized from ether-hexane (1:1) to give colorless needles of 6-(11-hydroxy-1-oxoundecyl)-2,3-dimethoxy-5-methyl-phenol (30 g). m.p. 81° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCBr
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(F)cc2)CC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
The o-alkylation procedure described for 10 (example 5, step 2) was used. To a stirred suspension of 4-[(4-fluorophenyl)(3,3,5,5 tetramethylcyclohexylidene) methyl]phenol 9 (0.590 g, 1.74 mmol), K2CO3 (0.482 g, 3.5 mmol), and acetone (50 mL) was added ethyl 4-bromobutyrate (0.62 mL, 4.4 mmol) under a nitrogen atmosphere at RT. The reaction mixture was refluxed for 6 h, cooled to RT and filtered. Standard work-up followed by purification afforded 0.712 g (90%) of compound 12 as a white foam. 1H NMR (300 MHz, CDCl3): δ 7.14 (d, J=5.7 Hz, 1H), 7.11 (d, J=5.7 Hz, 1H), 7.07 (d, J=8.7 Hz, 2H), 6.98 and 6.95 (dd, J=8.7 Hz, J2=8.7 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 3.99 (t, J=6.00 Hz, 2H), 3.49 (t, J=6.3 Hz, 2H), m, 2H), 2.11 (quint., J=6.30 Hz, 2H), 2.00 (s, 2H), 1.96 (s, 2H), 1.31 (br s, 2H), 1.27 (t, J=7.2 Hz, 3H), 0.95 (s, 6H), 0.94 (s, 6H). LCMS (ESI): m/z 475 (M+Na)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([CH3:12])[CH:6]=1)[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:6][C:7]=2[CH3:12])=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(Br)c(C)c1
Reactant: OB(O)c1ccc(F)cc1
Product: CCOC(=O)c1ccc(-c2ccc(F)cc2)c(C)c1

Procedure:
The desired product was prepared by substituting 4-bromo-3-methylbenzoic acid ethyl ester and 4-fluorophenylboronic acid for Example 186B and Example 186A, respectively, in Example 186C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[NH:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30]1>CN1CCCC1=O>[CH2:1]([NH:8][C:9]1[NH:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:34][CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCC1
Reactant: O=S(=O)(Oc1ccc2nc(NCc3ccccc3)[nH]c2c1)c1ccc(F)cc1
Solvent: CN1CCCC1=O
Product: O=S(=O)(Oc1ccc2nc(NCc3ccccc3)[nH]c2c1)c1ccc(NC2CCCC2)cc1

Procedure:
A solution of 4-fluoro-benzenesulfonic acid 2-benzylamino-3H-benzoimidazol-5-yl ester (20 mg) and cyclopentylamine (21 μl) in N-methylpyrrolidinone (0.5 ml) was heated at 110° C. in a sealed tube for 2 hours. The reaction mixture was then purified by triggered LC/MS to give 4-cyclopentylamino-benzenesulfonic acid 2-benzylamino-3H-benzoimidazol-5-yl ester as an off-white solid (4 mg). Mass spectrum: 463 [M+H]+; retention time=8.35 minutes.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][OH:7].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([O:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH3:3])[N:14]=[CH:13][N:12]=1
Reactant: CC(C)(C)CCO
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)CCOc1cc(Cl)ncn1
Reaction time: 0.17 h

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.11 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.23 g of 3,3-dimethyl-1-butanol was added dropwise at 0° C., followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of tetrahydrofuran containing 0.3 g of 4,6-dichloropyrimidine dissolved therein, followed by stirring at the same temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.41 g of 4-chloro-6-(3,3-dimethylbutyloxy)pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N+:15]([O-])=[CH:14][C:13]1[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@H:23]([CH3:27])[N:22]3[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C([N:32]=C=O)=O.C(Cl)(Cl)Cl>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH2:32])[C:13]1[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@@H:23]([CH3:27])[N:22]3[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1COCc2nc3c[n+]([O-])c4ccc(OCc5ccccc5)cc4c3n21
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C[C@@H]1COCc2nc3c(N)nc4ccc(OCc5ccccc5)cc4c3n21
Reaction time: 1 h
Yield: 67 %

Procedure:
(11S)-2-(Benzyloxy)-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (2.02 g, 5.59 mmol) and trichloroacetyl isocyanate (0.87 mL, 7.27 mmol) were dissolved in dichloromethane (50 mL) under an atmosphere of N2. After one hour, the reaction was quenched with a small amount of methanol, and the solvent was removed under reduced pressure. The resulting residue was suspended in methanol (50 mL) and treated with NaOMe (25% in MeOH, 8 mL) for 20 hours. The volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane and water, adjusting to pH 11 with NH4OH. The aqueous layer was extracted with dichloromethane (3×). The combined organic layers were then washed with brine and dried over Na2SO4, filtered, and concentrated to give a light-brown foam. Chromatography (SiO2, 0-20% CMA/CHCl3) gave (11R)-2-(benzyloxy)-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (1.35 g) as an off white solid, mp 100-120° C.
Reaction SMILES: [C:1](Cl)(=[O:6])[O:2][CH:3]([Cl:5])[CH3:4].[CH:8]([OH:11])([CH3:10])[CH3:9].N1C=CC=CC=1>C(Cl)Cl>[C:1](=[O:6])([O:11][CH:8]([CH3:10])[CH3:9])[O:2][CH:3]([Cl:5])[CH3:4]
Reactant: CC(C)O
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)OC(C)Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a solution of 1-chloroethyl carbonochloridate (10 g, 69.9 mmol) in DCM (200 mL) was added a solution of isopropanol (5.9 mL, 76.9 mmol) and pyridine (6.75 mL, 83.9 mmol) in DCM (50 mL) at −20° C. The reaction was stirred at 0° C. for 2 h, then at rt for another 2 h. The mixture was washed with 1N HCl solution (250 mL×2), followed by brine (250 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as colorless oil (9.6 g, 82.4%). The product was used in the next step without further purification. The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: I[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:58])/[C:29](=[N:55]\[O:56][CH3:57])/[C:30]3[N:31]=[C:32]([NH:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:10].[CH3:60][NH:61][C:62]1[S:63][C:64]2[CH:69]=[CH:68][N:67]=[CH:66][C:65]=2[N:70]=1.Cl>C1COCC1.C(O)=O.O>[NH2:35][C:32]1[S:33][CH:34]=[C:30](/[C:29](=[N:55]/[O:56][CH3:57])/[C:28]([NH:27][CH:26]2[C:25](=[O:59])[N:7]3[C:8]([C:9]([O-:11])=[O:10])=[C:3]([CH2:2][N+:67]4[CH:68]=[CH:69][C:64]5[S:63][C:62]([NH:61][CH3:60])=[N:70][C:65]=5[CH:66]=4)[CH2:4][S:5][C@H:6]23)=[O:58])[N:31]=1
Reactant: CNc1nc2cnccc2s1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: O=CO
Solvent: C1CCOC1
Product: CNc1nc2c[n+](CC3=C(C(=O)[O-])N4C(=O)C(NC(=O)/C(=N\OC)c5csc(N)n5)[C@H]4SC3)ccc2s1
Yield: 27.5 %

Procedure:
A solution of AgClO4 (207 mg, 1.0 mmole) in THF (1 ml) was added in approximately four equal portions, during one hour, to a stirred solution at 25° C. of benzhydryl 3-iodomethyl-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate [VIIa] (913 mg, 1.0 mmole) and 2-methylaminothiazolo[4,5-c]pyridine (165 mg, 1.0 mmole) in THF (8 ml). Stirring was continued for an additional hour. The mixture was filtered through diatomaceous earth and the filtrate concentrated. A solution of the residue in CH2Cl2 was washed with dilute aqueous HCl and then with brine. The CH2Cl2 layer was dried over Na2SO4 and concentrated to leave the crude protected quaternized cephalosporin as a brown froth. Concentrated HCl (0.5 ml) was added to a stirred solution of the froth in 95-97% formic acid (15 ml) at 25° C. The solution was stirred for 50 minutes and then was diluted with H2O (20 ml). The resulting mixture was filtered and the filtrate concentrated on a rotary evaporator. The residue was suspended in H2O (20 ml), and the pH of the stirred mixture was adjusted to 5.1 with dilute NaOH. The mixture was filtered and the product isolated from the filtrate by high performance low pressure liquid chromatography (HPLPLC). The filtrate was applied to a glass column (300×22 mm) which was packed with Waters PrepPAK-500/C18. The column was eluted first with H2O and then with H2O-10% acetonitrile to elute the title compound. The appropriate fractions were combined and partially concentrated to remove the CH3CN. The aqueous solution was lyophilized to afford 154 mg of the title compound (Iy).
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Mg]Br)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:2]2[C:6]3[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=3[CH2:4][CH2:3]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)CC2
Product: CCOC(=O)c1cc2c([nH]1)C(c1ccc(Cl)cc1)CC2

Procedure:
The title compound was synthesized in two steps. First, ethyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.3 g, 1.55 mmol) was reacted with 4-chlorophenyl magnesium bromide (6.2 mL, 1 M in ether, 6.2 mmol, 4 equiv) according to General Procedure 3 to give the endocyclic olefin-containing compound ethyl 6-(4-chlorophenyl)-1,4-dihydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation according to General Procedure 6, and was purified by column chromatography (Isco CombiFlash) using a 0-30% gradient (EtOAc/Heptane) over 22 minutes. 90.7 mg. LCMS m/e 312 (M+Na). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.11 Hz, 3H), 2.27 (dddd, J=12.83, 8.60, 6.36, 6.21 Hz, 1H), 2.58-2.83 (m, 2H), 2.85-3.01 (m, J=12.81, 8.47, 8.47, 4.28 Hz, 1H), 4.27 (tt, J=7.12, 3.63 Hz, 3H), 6.73 (d, J=1.64 Hz, 1H), 7.06 (q, J=4.42 Hz, 2H), 7.28 (d, J=8.35 Hz, 2H), 8.63 (br. s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].C([Si](C)(C)[O:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][OH:16])=[CH:25][CH:24]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(O)cc1
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(Cl)ccc1Oc1ccc(OCCO)cc1
Yield: 75.5 %

Procedure:
In a manner similar to the method described in Example 50a, 5-chloro-2-fluorobenzaldehyde (1.2 g, 7.6 mmol) (Aldrich) was reacted with 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenol (2.1 g, 7.8 mmol) prepared in Example 60b and K2CO3 in N,N-dimethylacetamide at 170° C. for 0.5 h to give 5-chloro-2-[4-(2-hydroxy-ethoxy)-phenoxy]-benzaldehyde as a colorless oil (Yield 1.68 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:15])[C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-])=O)[CH:8]=[CH:7][CH:6]=2.[BH4-].[Na+]>O1CCOCC1.CO.O.[Ni](Cl)Cl>[NH2:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([Cl:1])[N:3]=[C:4]2[CH3:15]
Reactant: Cc1nc(Cl)cc2c([N+](=O)[O-])cccc12
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc(Cl)cc2c(N)cccc12
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-1-methyl-5-nitroisoquinoline (2.0 g, 9.0 mmol) in dioxane (48 mL) and MeOH (10 mL) was added nickel (11) chloride hydrate (66 mg, 0.4 mmol), followed by sodium borohydride (0.7 g, 18 mmol). After stirring for two hours, the mixture was quenched by the addition of water (30 mL). The mixture was extracted with EtOAc, then the combined organics were washed with 10% NH4OH (aq) then saturated NaCl (aq). The organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 20% EtOAc/hexanes to afford the title compound: 1H NMR (500 MHz, CDCl3): δ 7.55 (s, 1H), 7.53 (d, J=8.5 Hz, 1H); 7.39 (t, J=8.5 Hz, 1H); 6.96 (d, J=8.0 Hz, 1H); 2.98 (s, 3H).