Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[CH2:20]([O:19][C:17]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 4-hydroxymethylpiperidine (2.0 g, 17.4 mmol) in dry dichloromethane (DCM, 100 mL) was cooled to 0° C., treated with triethylamine (4.8 mL, 34.8 mmol) followed by benzyl chloroformate (3.7 mL, 34.8 mmol), allowed to warm to room temperature and stirred for two hours. The mixture was partitioned between DCM (50 mL) and water (30 mL). The layers were separated and the aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were washed with brine (1×30 mL), dried over Na2SO4 and evaporated to a residue, that was purified by column chromatography using a gradient of 70 to 100% EtOAc in hexanes as eluant to give 3.85 g (89%) of E-12 as clear oil: 1H NMR (CDCl3) δ 1.17 (m, 2H), 1.72 (m, 3H), 2.15 (br s, 1H), 2.78 (t, 2H, J=12.24), 3.47 (d, 2H, J=6.04), 4.20 (d, 2H, J=11.68), 5.12 (s, 2H), 7.33 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.CS[C:32]1[N:33](C(OCC)=O)[CH2:34][CH2:35][N:36]=1.CC(O)=O.C([O-])(O)=O.[Na+]>CCO>[NH:36]1[CH2:35][CH2:34][N:33]=[C:32]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCN=C1SC
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(CCc2ccc(NC3=NCCN3)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 10.3 %

Procedure:
A mixture of N-{4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (150 mg), ethyl 2-(methylthio)-4,5-dihydro-1H-imidazole-1-carboxylate (78.9 mg), AcOH (0.3 ml) and EtOH (3 ml) was refluxed for 7 hours under N2 atmosphere. After cooled to r.t., the reaction mixture was made basic with saturated NaHCO3. The mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by preparative silica gel chromatography with CHCl3/MeOH (10:1) as an eluent. The amorphous substance was solidified with ethyl ether to give N-{4-{2-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (17.9 mg) as an off-white amorphous solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]34[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]5)[CH2:16]3)[CH2:22]4)=[O:14])[S:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].[CH3:29][O:30][CH2:31][CH2:32]Br>>[CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]([CH2:32][CH2:31][O:30][CH3:29])[C:10](=[N:12][C:13]([C:15]34[CH2:22][CH:21]5[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]5)[CH2:16]3)[CH2:24]4)=[O:14])[S:11][C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: COCCBr
Reactant: CS(=O)(=O)c1ccc2nc(NC(=O)C34CC5CC(CC(C5)C3)C4)sc2c1
Agent: [H-]
Agent: [Na+]
Product: COCCn1c(=NC(=O)C23CC4CC(CC(C4)C2)C3)sc2cc(S(C)(=O)=O)ccc21

Procedure:
The product from Example 62A, sodium hydride (60% solution in mineral oil) and 2-bromoethyl methyl ether were processed as described for Example 17B to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61-1.80 (m, 6 H), 1.87-1.94 (m, 6 H), 1.99-2.07 (m, 3 H), 3.24 (s, 3 H), 3.26 (s, 3 H), 3.78 (t, J=5.4 Hz, 2 H), 4.63 (t, J=5.3 Hz, 2 H), 7.82-7.91 (m, 1 H), 7.93-8.03 (m, 1 H), 8.46 (d, J=1.7 Hz, 1 H); MS (ESI+) m/z 449 (M+H)+; Anal. Calculated for C22H28N2O4S2: C, 58.90; H, 6.29; N, 6.24. Found: C, 58.86; H, 6.30; N, 6.25.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.CC(C)([O-])C.[K+]>C(O)CCC>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH2:8][CH2:7][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: BrCCc1ccc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCO
Product: c1ccc2cc(CCn3ccnc3)ccc2c1

Procedure:
A mixture of imidazole (1.02 g, 0.015 mol), 2-(2-bromoethyl)naphthalene (3.53 g, 0.015 mol) and potassium tert-butoxide (1.68 g, 0.015 mol) in dry butan-1-ol (100 ml) was stirred and heated under reflux for 29 h.
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])C(=O)C=1)C1C=CC=CC=1.[CH3:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][O:37][C:38]2[CH:43]=[CH:42][NH:41][C:40](=[O:44])[CH:39]=2)=[N:34][CH:35]=1>>[OH:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][N:41]2[CH:42]=[CH:43][C:38]([O:37][CH2:36][C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][N:34]=3)=[CH:39][C:40]2=[O:44])=[C:19]([CH3:26])[CH:20]=1
Reactant: COc1ccc(COc2cc[nH]c(=O)c2)nc1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: COc1ccc(COc2ccn(CC(=O)c3ccc(CO)cc3C)c(=O)c2)nc1
Yield: 59 %

Procedure:
1-[2-(4-Hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-methoxy-pyridin-2-ylmethoxy)-1H-pyridin-2-one is prepared following preparation 1c employing 4-(5-methoxy-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 11b) instead of 4-benzyloxy-1H-pyridin-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].C(O[C:13](S)=[S:14])C.[OH-].[K+].Cl>C(O)C.O>[SH:14][C:13]1[O:9][C:3]2[CH:4]=[C:5]([OH:6])[CH:7]=[CH:8][C:2]=2[N:1]=1
Reactant: Nc1ccc(O)cc1O
Reactant: CCOC(=S)S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Oc1ccc2nc(S)oc2c1
Yield: 90 %

Procedure:
To a solution of 4-aminoresorcinol (1 eq) and ethylxanthic acid (3 eq) in ethanol was added potassium hydroxide (2.1 eq). The mixture was refluxed for two hours then diluted with water and acidified using 1N HCl to a pH of 4. The product was extracted into ethyl acetate then concentrated. The resulting solid was triturated with dichloromethane to give pure product with a 90% yield. MH+=168.1.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([SH:33])[CH:29]=[CH:30][C:31]=1[Cl:32]>CCCCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([S:33][C:28]4[CH:29]=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[CH:27]=4)[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Sc4ccc(Cl)c(Cl)c4)cc23)CC1
Temperature: 110 °C
Yield: 36.1 %

Procedure:
A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 3,4-dichloro-thiophenol (165 uL, 1.3 mmol), NatBuO (0.44 g, 4.5 mmol), Pd(PPh3)4 (74 mg, 0.065 mmol) in n-BuOH (10 mL) was heated at 110° C., 3 h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL×3), separated and dried (MgSO4), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO2, n-pentane:ethyl acetate 9.5:0.5→8:2) to give 230 mg of the title compound as colorless oil (yield 36%). 1H NMR (CDCl3) δ 8.10-8.20 (m, 2H), 7.90 (bs, 1H), 7.65-7.75 (m, 2H), 7.10-7.55 (m, 3H), 3.50-3.65 (m, 4H), 3.20-3.30 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[NH2:16][C:17]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[C:20]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[NH:19][N:18]=1>C(N(CC)CC)C>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:20]2[NH:19][N:18]=[C:17]([NH:16][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:21]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:33][CH:32]=1
Reactant: Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 15 %

Procedure:
Under a stream of argon gas, 333 mg of benzenesulfonyl chloride was added dropwise to 4 ml of a tetrahydrofuran solution containing 150 mg of 3-amino-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole and 191 mg of triethylamine, followed by stirring at room temperature for 1.5 hours. After the reaction mixture was concentrated under reduced pressure, the resulting residue was purified by column chromatography using 20 g of silica gel [with an elution solvent comprising chloroform-methanol (100:1)]. Thus, 35 mg (15% yield) of the title compound was obtained as a pale-yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][N:12]([C:15]3[C:16]([O:23][CH3:24])=[N:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[C:34]([Cl:40])[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=1>CCOC(C)=O>[Cl:40][C:34]1[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=[C:32]([NH:31][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][N:12]([C:15]3[C:16]([O:23][CH3:24])=[N:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=3)[C:13]=2[CH3:14])[CH:33]=1
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C)c1C(O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-methyl-1H-pyrazole-3-carboxylate (Step 55.3) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). tR: 4.76 min (HPLC 1); tR: 1.09 min (LC-MS 2); ESI-MS: 573/575 [M+H]+ (LC-MS 2); Rf=0.18 (EtOAc).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([O:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]2[O:19][CH:18]=[C:17]([C:20]#[N:21])[C:16](=[O:22])[C:15]=2[CH:23]=1)[CH3:10])(=[O:7])[CH3:6].[N-:24]=[N+:25]=[N-:26].[Na+]>O1CCCC1>[C:5]([O:8][CH:9]([C:11]1[CH:23]=[C:15]2[C:14](=[CH:13][CH:12]=1)[O:19][CH:18]=[C:17]([C:20]1[NH:26][N:25]=[N:24][N:21]=1)[C:16]2=[O:22])[CH3:10])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)c1ccc2occ(C#N)c(=O)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC(C)c1ccc2occ(-c3nnn[nH]3)c(=O)c2c1
Reaction time: 1.5 h

Procedure:
To a mixture of 45 parts by volume of tetrahydrofuran and 4.005 parts of anyhydrous aluminum chloride there are added 3.86 parts of 6-(1-acetoxyethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile and 2.925 parts of sodium azide, and the resulting mixture is refluxed under stirring for 1.5 hours. After cooling, the solvent is distilled off. To the solid residue are added 2.1 parts of sodium nitrite and ice-water, and the mixture is well shaken. The insoluble material is recovered by filtration and recrystallized from ethyl acetate. The procedure yields 1.88 parts of 6-(1-acetoxyethyl)-3-(1H-tetrazol-5-yl)-chromone as colorless crystals. Melting point: 231°-232° C
Reaction SMILES: [C:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C:23]1[CH:22]=[CH:21][C:20]([C:27]([O:29]C)=[O:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O>CO>[C:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C:23]1[CH:22]=[CH:21][C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)c3ccccc3)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H]3c4ccc(C(=O)O)cc4CC[C@H]3[C@@H]1CC[C@@H]2C(=O)c1ccccc1

Procedure:
A mixture of methyl 17β-benzoyl-estra-1,3,5(10)-triene-3-carboxylate, K2CO3, water and methanol is heated at reflux for about 5 hours. Acidification followed by conventional workup yields title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:19][N:18]=4)[N:14]=[CH:15][C:10]=3[C:9]([CH3:29])=[C:8]([C:30]([O:32]CC)=[CH2:31])[C:7]2=[O:35])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>ClCCl.C(OCC)C.C([O-])(O)=O.[Na+]>[C:30]([C:8]1[C:7](=[O:35])[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:19][N:18]=3)[N:14]=[CH:15][C:10]=2[C:9]=1[CH3:29])(=[O:32])[CH3:31]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCOCC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCOCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
8-Cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-2-(5-morpholin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (0.490 g, 1.03 mmol) was dissolved in dichloromethane (5 mL). 2 N HCl in diethyl ether (3 mL) was added and the resulting mixture was stirred at room temperature for 4 hours. Then, additional 2 N HCl in diethyl ether (2 mL) was added and the mixture was stirred for an additional 12 hours. The reaction mixture was diluted with dichloromethane and aqueous NaHCO3. The layers were separated and the organic layer-was dried over MgSO4, filtered, and the solvent evaporated to give a yellow solid. The solid was recrystallized from a mixture of hexanes, ethyl acetate and dichloromethane to give 6-acetyl-8-cyclopentyl-5-methyl-2-(5-morpholin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (0.280 g, 60.7%). MS (APCI); M++1: Calc'd, 449.2. Found 449.2. 1H NMR δ (400 MHz, DMSO-d6) 8.79 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H), 7.31 (dd, J=2.9, 9.0 Hz, 1H), 5.86 (m, 1H), 3.88 (m, 4H), 3.15 (m, 4H), 2.54 (s, 3H), 2.36 (s, 3H), 2.32 (m, 2H), 2.05 (m, 2H), 1.87 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11](=[O:26])[N:12]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].Cl[CH2:30][O:31][CH3:32].Cl>CN(C)C=O.O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:30][O:31][CH3:32])[C:6]3[C:11](=[O:26])[N:12]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(=O)c2[nH]c3ccc(F)cc3c12
Reactant: COCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ccccc2)c(=O)c2c1c1cc(F)ccc1n2COC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.5 %

Procedure:
A suspension of 3.9 g (11 mmol) of ethyl 8-fluoro-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxylate in 200 ml of dimethylformamide is added to a suspension of 0.66 g (16 mmol) of sodium hydride in 100 ml of dimethylformamide. The mixture is stirred for 1.5 h at room temperature and a solution of 1.15 ml (14.3 mmol) of chloromethoxymethane in 10 ml of tetrahydrofuran is added. The mixture is stirred for 2 h, a solution of dilute hydrochloric acid is added and the precipitate is collected by filtration and dried under reduced pressure. 4.1 g (10.4 mmol) of solid are isolated, which solid is used as is in the following stage.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20].[Cl-].[Mg+2].[Cl-]>O1CCCC1.COCCO>[CH2:22]([O:21][C:19]([C:18]1[C:9]2=[C:8]3[C:13](=[CH:12][CH:11]=[CH:10]2)[CH2:14][CH2:15][CH:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[N:7]3[CH:17]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C(=O)CBr
Reactant: c1ccc2c(c1)CCC(C1CCCC1)N2
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: COCCO
Product: CCOC(=O)c1cn2c3c(cccc13)CCC2C1CCCC1
Reaction time: 15 h
Yield: 49.5 %

Procedure:
To a solution of 2-cyclopentyl-1,2,3,4-tetrahydroquinoline (4.0 g, 20 mmol) in tetrahydrofuran (15 ml) was added ethyl bromopyruvate (˜90% purity; 1.38 ml, 9.9 mmol) and the reaction stirred for 15 h. The resulting precipitate was filtered and washed with tetrahydrofuran (20 ml). The filtrate was evaporated in vacuo. The resulting residue was dissolved in tetrahydrofuran (10 ml) and 2-methoxyethanol (10 ml) and the solution added dropwise to a refluxing solution of magnesium (II) chloride (1.05 g, 11 mmol) in 2-methoxyethanol (10 ml). The reaction mixture was refluxed for 2 h and then a further portion of magnesium (II) chloride (1.05 g, 11 mmol) added and refluxing continued overnight. The reaction was cooled and the solvent removed in vacuo. The resulting brown oil was dissolved in dichloromethane (150 ml) and washed with 2 M HCl (50 ml), saturated potassium carbonate (50 ml) and brine (50 ml). The organics were dried (MgSO4), filtered and the solvent removed in vacuo. The resulting oil was purified by flash chromatography using 33-67% (v/v) dichloromethane in heptane to give 4-cyclopentyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid ethyl ester (1.45 g, 4.9 mmol).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:60]/[O:61][C:62]([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)/[C:27]([NH:29][C@@H:30]2[C:58](=[O:59])[N:32]3[C:33]([C:42]([O:44][CH:45]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])=[C:34](OS(C)(=O)=O)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:81][C:82]1[CH:87]=[CH:86][N:85]=[CH:84][CH:83]=1.C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:60]/[O:61][C:62]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:75]2[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=2)[C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)/[C:27]([NH:29][C@@H:30]2[C:58](=[O:59])[N:32]3[C:33]([C:42]([O:44][CH:45]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[O:43])=[C:34]([S:81][C:82]4[CH:87]=[CH:86][N:85]=[CH:84][CH:83]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Sc1ccncc1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(Sc2ccncc2)CS[C@@H]2[C@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Temperature: 5 °C
Reaction time: 1 h
Yield: 13.5 %

Procedure:
To a solution of diphenylmethyl 7β-[2-(2-tritylaminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-methanesulfonyloxy-3-cephem-4-carboxylate (10.01 g, 8.98 m mol) in DMF (200 ml) was added 4-mercaptopyridine (2.00 g, 18.0 m mol) at −15° C., followed by dropwise addition of N,N-diisopropylethylamine (1.16 g, 8.98 m mol). The mixture was stirred at −15° C. for 4.5 hours and at 5° C. for 1 hour. The mixture was poured into a mixture of ice water (1.2 l) and 6N HCl (3 ml) and the precipitates were collected by filtration and washed with water. The powder was dissolved in THF, and ethyl acetate and water were added. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give diphenylmethyl 7β-[2-(2-tritylaminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-(4-pyridylthio)-3-cephem-4-carboxylate (1.37 g).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22])=[O:15])[CH3:12].[Cl:23][C:24]1[CH:35]=[CH:34][C:27]([C:28](N(OC)C)=[O:29])=[CH:26][CH:25]=1>C1COCC1>[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:28](=[O:29])[C:27]2[CH:34]=[CH:35][C:24]([Cl:23])=[CH:25][CH:26]=2)[C:17]1=[O:22])=[O:15])[CH3:12]
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCCCC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCC(C(=O)c2ccc(Cl)cc2)C1=O
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of LHMDS (21 mL, 2.1 mmol) in 50 mL of anhydrous THF under a nitrogen atmosphere at −78° C. was added 2-oxo-cyclohexanecarboxylic acid ethyl ester Compound 1a (1.80 g, 10.0 mmol) in 10 mL of anhydrous THF. The resultant homogeneous mixture was left to stir at −78° C. for 40 min followed by the drop wise addition of 4-chloro-N-methoxy-N-methyl-benzamide Compound 1b (2.0 g, 10 mmol) in 10 mL of anhydrous THF. The reaction mixture was allowed to stir for 18 hours and allowed to warm to ambient temperature. The reaction mixture was quenched with water (50 mL) and the organic layer was extracted with EtOAc (200 mL) and washed with brine, separated and dried with anhydrous Na2SO4, then filtered and concentrated in vacuo to yield 3-(4-chloro-benzoyl)-2-oxo-cyclohexanecarboxylic acid ethyl ester Compound 1c (1.7 g) as an oil, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([O:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].OS([O-])(=O)=O.[Na+]>CCOCC>[C:5]([O:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:1][CH3:2])([OH:22])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc21
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCC1(O)CCN(C(=O)OC(C)(C)C)c2ccccc21
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a flame-dried 5-mL rb flask containing ethylmagnesium bromide (4.0 mL of a 3.0M solution in Et2O, 12.0 mmol, 3.0 equiv), at -10° C. was added dropwise a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolone (1.0 g, 4.0 mmol) in Et2O (4 mL). The reaction mixture was stirred at -10° C. for 15 min, then allowed to warm to rt over 10 min. A 1.0M solution of NaHSO4 (10 mL) was then rapidly added. The resulting biphasic mixture was extracted with EtOAc (3×10 mL), and the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc, 4:1), affording 800 mg (71%) of the desired product as a clear yellow oil (Rf0.14, hexanes/EtOAc, 4:1). Data for 1-tert-butoxycarbonyl-4-ethyl-1,2,3,4-tetrahydro-4-hydroxyquinoline: 1H NMR (400 MHz, CDCl3) 7.68 (d, 1H, J=8.4, 8-H), 7.47 (dd, 1H, J=7.9, 1.7, 5-H), 7.21 (ddd, 1H, J =7.4, 7.4, 1.6, 6-H), 7.09 (ddd, 1H, J=7.8, 7.8, 1.1, 7-H), 4.03 (ddd, 1H, J=12.9, 7.1, 4.7, 2 -H), 3.47 (ddd, 1H, J=13.1, 8.6, 4.3, 2-H), 2.11 (ddd, 1H, J=13.5, 8.6, 4.8, 3-H), 1.86 (m, 3H, 3-H, CH2CH3), 1.52 [s, 9H, C(CH3)3 ], 0.89 (t, 3H, J=7.5, CH3).