Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([C:24](O)=[O:25])=[N:12][CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH3:58][O:59][C:60](=[O:63])[CH2:61][NH2:62]>CN(C=O)C>[CH3:58][O:59][C:60](=[O:63])[CH2:61][NH:62][C:24]([C:11]1[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:15][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][N:12]=1)=[O:25]
Reactant: COC(=O)CN
Reactant: O=C(O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid HCl, 2, (8.06 g, 21.7 mmol) in DMF (100 mL) at 0° C. under N2 is added diisopropylethylamine (11.35 mL, 65.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (6.23 g, 32.6 mmol) and 1-hydroxybenzotriazole (HOBt) (0.294 g, 2.2 mmol). The solution is stirred for 5 minutes and glycine methyl ester hydrochloride (4.09 g, 32.6 mmol) is added. The reaction is allowed to warm slowly to room temperature and stirred 3 days. The reaction volume is partially concentrated under reduced pressure then diluted with EtOAc and washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer is dried (MgSO4), filtered and concentrated under reduced pressure to afford a yellow oil that is purified over silica (EtOAc:heptane gradient 1:1 to 1:0) to afford 3.5 g (40% yield) of the desired product as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (1H, t, J=4.9 Hz), 7.95 (1H, d, J=1.8 Hz), 7.38-7.44 (2H, m), 7.22-7.35 (8H, m), 6.85 (1H, d, J=2.6 Hz), 5.14 (2H, s), 5.03 (2H, s), 4.18 (2H, d, J=5.5 Hz), 3.69 (3H, s). HPLC-MS: m/z 407 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:25][CH2:26][N:27]([C:30]([CH:32]2[CH2:37][CH2:36][N:35]([C:18]([C:12]3[S:13][C:14]4[CH2:15][CH2:16][O:17][C:8]5[CH:7]=[C:6]([C:4]6[CH:5]=[N:1][NH:2][CH:3]=6)[CH:22]=[CH:21][C:9]=5[C:10]=4[N:11]=3)=[O:19])[CH2:34][CH2:33]2)=[O:31])[CH2:28][CH2:29]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CN1CCN(C(=O)C2CCNCC2)CC1
Product: CN1CCN(C(=O)C2CCN(C(=O)c3nc4c(s3)CCOc3cc(-c5cn[nH]c5)ccc3-4)CC2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (4-methylpiperazin-1-yl)(piperidin-4-yl)methanone (1.2 equiv) to give 205 (M+1 507.0)
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O[CH2:6][C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C:19](=[O:25])[CH2:18][CH2:17]4)[CH2:14][CH2:13][C:12]1=[CH:11][C:10](=[O:26])[CH2:9][CH2:8]2.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCCC1>[C:1]([O:4][CH2:6][C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C@@H:19]([OH:25])[CH2:18][CH2:17]4)[CH2:14][CH2:13][C:12]1=[CH:11][C@@H:10]([OH:26])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=O)OC[C@]12CC[C@H](O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
A tetrahydrofuran solution of 19-hydroxyandrost-4-ene-3,17-dione acetate is added to lithium tri-t-butoxyaluminum hydride in tetrahydrofuran and the resultant solution stirred overnight at room temperature. An aqueous solution of sodium potassium tartrate is added with stirring until a readily filterable precipitate forms. The filtrate is concentrated under reduced pressure and diluted with ether. The resulting solution is washed with water, dried over magnesium sulfate, and the ether removed under vacuum. The residual androst-4-ene-3β,17β,19-triol 19-acetate so obtained is recrystallized from acetone.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](O)[C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[C:5]1=[O:22])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>C1(C)C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13]([Cl:24])[C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[C:5]1=[O:22])(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)N1C(=O)C(=C(O)c2ccc(Br)cc2)c2ccccc21
Solvent: Cc1ccccc1
Product: CC(=O)N1C(=O)C(=C(Cl)c2ccc(Br)cc2)c2ccccc21

Procedure:
1-acetyl-3-[1-hydroxy-1-(4-bromo-phenyl)methylidene}-2-indolinone and 2 equivalents of PCl5 are heated in toluene for 1 hour at 100° C. The mixture is filtered, evaporated down in vacuo and petroleum ether is added to the oily evaporation residue.
Reaction SMILES: [F:1][C@@H:2]1[C:29]2[C@:24]([CH3:31])([CH:25]=[CH:26][C:27](=[O:30])[CH:28]=2)[C@:23]2(Br)[C@H:4]([C@H:5]3[C@:20]([CH3:34])([CH2:21][C@@H:22]2[OH:33])[C@@H:8]([C:9](=[O:19])[CH2:10][O:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C@H:7]([CH3:35])[CH2:6]3)[CH2:3]1.N1C(C)=CC(C)=CC=1C>>[F:1][C@@H:2]1[C:29]2[C@:24]([CH3:31])([CH:25]=[CH:26][C:27](=[O:30])[CH:28]=2)[C:23]2[C@@H:22]([OH:33])[CH2:21][C@@:20]3([CH3:34])[C@@H:5]([CH2:6][C@@H:7]([CH3:35])[C@@H:8]3[C:9](=[O:19])[CH2:10][O:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:4]=2[CH2:3]1
Reactant: CCCCCC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(Br)[C@@H](O)C[C@@]21C
Solvent: Cc1cc(C)nc(C)c1
Product: CCCCCC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2C3=C([C@@H](O)C[C@@]21C)[C@@]1(C)C=CC(=O)C=C1[C@@H](F)C3

Procedure:
15.0 g. of 6α-fluoro-9α-bromo-11β-hydroxy-21-hexanoyloxy-16α-methyl-1,4-pregnadiene-3,20-dione is dissolved in 25 ml. of collidine and agitated for 15 minutes at 170° C. After cooling, the collidine hydrobromide is filtered off and the filtrate combined with ether until no precipitate is formed any longer. The precipitate is filtered off, and the filtrate is extracted with hydrochloric acid and sodium bicarbonate; then, it is washed neutral, dried, and concentrated. The viscous crude product amounting to 17.7 g. is purified by chromatography over a silica gel column, and recrystallization from acetone-hexane yields 6α-fluoro-11β-hydroxy-21-hexanoyloxy-16α-methyl-1,4,8-pregnatriene-3,20-dione, m.p. 155° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][N:14]([C@@H:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH3:17])[C:13](=[O:26])[CH2:12]2)[CH3:10])[C:5]2[N:27]([CH3:30])[CH:28]=[N:29][C:4]=2[CH:3]=1.[O:31]1[CH2:34][CH:33]([N:35]2[CH2:40][CH2:39][N:38]([C:41]3[CH:42]=[N:43][C:44]([Sn](CCCC)(CCCC)CCCC)=[CH:45][CH:46]=3)[CH2:37][CH2:36]2)[CH2:32]1.[F-].[K+]>O1CCOCC1.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>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C@H:16]([N:14]2[CH2:15][C@H:11]([C@H:9]([O:8][C:6]3[C:5]4[N:27]([CH3:30])[CH:28]=[N:29][C:4]=4[CH:3]=[C:2]([C:44]4[CH:45]=[CH:46][C:41]([N:38]5[CH2:37][CH2:36][N:35]([CH:33]6[CH2:32][O:31][CH2:34]6)[CH2:40][CH2:39]5)=[CH:42][N:43]=4)[N:7]=3)[CH3:10])[CH2:12][C:13]2=[O:26])[CH3:17])=[CH:19][CH:20]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(N2CCN(C3COC3)CC2)cn1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cc4ncn(C)c34)CC2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(N5CCN(C6COC6)CC5)cn4)cc4ncn(C)c34)CC2=O)cc1
Temperature: 140 °C
Yield: 100.4 %

Procedure:
Into the mixture of (R)-4-((R)-1-((6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.05 (60 mg, 0.14 mmol) and 1-(oxetan-3-yl)-4-(6-(tributylstannyl)pyridin-3-yl)piperazine 7.16 (78 mg, 0.154 mmol) in dioxane (3 mL) was added tetrakis(triphenylphosphine)palladium (16 mg) and KF (24 mg). Then the mixture was flushed with Argon, and heated by microwave at 140° C. for 20 min. The reaction was diluted with 50 mL of ethyl acetate and filtered to remove the solid. After removal of solvent, the residue was purified by silica gel column chromatography to provide 86 mg of (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-((R)-1-((3-methyl-6-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one. LCMS [M+H]+: 612.27.
Reaction SMILES: O=P(Cl)(Cl)Cl.C[N+](C)=[CH:8][Cl:9].[Cl-].[F:12][CH2:13][C:14]1([CH2:21][F:22])[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.C([O-])(O)=O.[Na+]>ClCCl.CN(C)C=O>[Cl:9][C:8]1[CH2:18][CH2:19][C:14]([CH2:21][F:22])([CH2:13][F:12])[CH2:15][C:16]=1[CH:17]=[O:20]
Reactant: O=C1CCC(CF)(CF)CC1
Reactant: C[N+](C)=CCl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=CC1=C(Cl)CCC(CF)(CF)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a 100 mL pear flask was added N,N-dimethylformamide (498 μl) and dichloromethane (8.9 mL) to give a colorless solution. The solution was cooled to 0° C. and POCl3 (550 μl) was added dropwise and then the mixture was warmed to room temperature for 30 minutes. In the meantime, to a 100 mL pear shaped flask was added EXAMPLE 353C (870 mg, 5.36 mmol) in dichloromethane (8941 μl) to give a colorless solution. The Vilsmeier reagent was then taken up in a syringe and added dropwise to the 4,4-bis(fluoromethyl)cyclohexanone (870 mg) solution at room temperature. The resulting solution was stirred overnight. The reaction was poured into saturated aqueous NaHCO3 and ice, warmed to room temperature and extracted with dichloromethane (3×30 mL). The organics were combined, dried over MgSO4, filtered and concentrated by rotary evaporation. The residue was purified by regular phase flash column chromatography (Analogix (0-60% hexanes/ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[C:14]([C:35]([O:37][CH3:38])=[O:36])[C:15]2[N:16]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:17]3[CH:18]=[C:19]([Cl:25])[CH:20]=[CH:21][C:22]=3[C:23]=2[N:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:25][C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[N:24]=[C:12]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)[CH:13]=[C:14]([C:35]([O:37][CH3:38])=[O:36])[C:15]=3[N:16]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:17]=2[CH:18]=1
Reactant: COC(=O)c1cc(Br)nc2c3ccc(Cl)cc3n(Cc3ccc(OC)cc3)c12
Reactant: Cc1ccc(B(O)O)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: COC(=O)c1cc(-c2ccc(C)nc2)nc2c3ccc(Cl)cc3n(Cc3ccc(OC)cc3)c12
Temperature: 70 °C
Yield: 28.3 %

Procedure:
A flask containing a mixture of 6-methylpyridin-3-ylboronic acid (0.592 g, 4.32 mmol), methyl 2-bromo-7-chloro-5-(4-methoxybenzyl)-5H-pyrido[3,2-b]indole-4-carboxylate (1.24 g, 2.70 mmol), powdered potassium phosphate tribasic (1.38 g, 6.48 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.222 g, 0.540 mmol), and Pd(OAc)2 (0.061 g, 0.270 mmol) was flushed with nitrogen. THF (10 mL) was added and the reaction was heated at 70° C. for 15 hr. This was partitioned between EtOAc and water. The organic phase was washed with water and brine, dried with sodium sulfate, and the solvent was removed. Silica gel chromatography (step gradient elution with DCM containing 0 to 3% EtOAc) afforded methyl 7-chloro-5-(4-methoxybenzyl)-2-(6-methylpyridin-3-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (360 mg, 0.763 mmol, 28% yield) as a solid. MS (ESI) m/z 472.12 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 9.18 (1H, s), 8.33-8.42 (2H, m), 7.98 (1H, s), 7.47 (1H, s), 7.34 (1H, d, J=8.24 Hz), 7.28 (1H, d, J=7.93 Hz), 6.86 (2H, d, J=8.24 Hz), 6.75 (2H, d, J=8.55 Hz), 5.66 (2H, s), 3.78-3.84 (3H, m), 3.69-3.74 (3H, m), 2.63 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Br[CH2:24][CH2:25][CH2:26][Cl:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:24][CH2:25][CH2:26][Cl:27])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCCBr
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCCCl
Temperature: 45 °C
Yield: 33.8 %

Procedure:
A mixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.2 g, 3.3 mmol), (prepared as described for the starting material in Example 48), 1-bromo-3-chloropropane (1.6 ml, 16 mmol) and potassium carbonate (2.1 g, 15 mmol) in DMF (25 ml) was heated at 45° C. for 3 hours. The mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (3×70 ml). The organic extracts were combined, washed with water and brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with hexane/ethyl acetate, collected by filtration and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-7-(3chloropropoxy)-6-methoxyquinazoline (492 mg; 34%).
Reaction SMILES: Cl[C:2](=[N:7][OH:8])[C:3](Cl)=[N:4][OH:5].[CH2:9]([NH2:12])[CH2:10][NH2:11]>CO>[N:4](=[C:3]1[C:2](=[N:7][OH:8])[NH:12][CH2:9][CH2:10][NH:11]1)[OH:5]
Reactant: NCCN
Reactant: ON=C(Cl)C(Cl)=NO
Solvent: CO
Product: ON=C1NCCNC1=NO
Temperature: 5 °C

Procedure:
Dichloroglyoxime (15.7 g, 0.10 mole) and methanol (400 ml) were placed in a one-liter, round-bottom flask. This solution was cooled to 5° C. by means of a salt-ice bath. While the solution was vigorously stirred, a solution of 12.0 g (0.20 mole) of ethylene diamine in 30 ml of methanol was added in one portion. The mixture was stirred for 10 minutes; then the solvent was removed at reduced pressure. The remaining solid was slurried with 20 ml of water and the crude 2,3-dioximinopiperazine was collected and washed with methanol. The crude product weighed 10.2 g (70%). It can be recrystallized from water (70% recovery) to give the pure compound, 2,3-dioximinopiperazine, with a melting point of 195°-196° C. (dec).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>C(N(CC)CC)C.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>[CH3:14][C:7]1([CH3:15])[CH2:8][CH2:9][C:10](=[O:13])[C:11]2[CH:12]=[C:3]([C:1]#[C:2][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:4]=[CH:5][C:6]1=2
Reactant: C#Cc1ccc2c(c1)C(=O)CCC2(C)C
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4 g (21.7 mmol) of 7-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound E ) flushed for 15 minutes with a stream of argon, and 6 g (21.7 mmol) of ethyl 4-iodobenzoate in 100 ml of triethylamine was added 5 g (7.2 mmol) of bis(triphenylphosphine)palladium(II) chloride and 1.4 g (7.2 mmol) of cuprous iodide. The mixture was flushed with argon for 5 minutes and then stirred at ambient temperature for 18 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. Purification by flash chromatography (silica, 10 % EtOAc-hexane) yielded the title compound as a white solid. PMR (CDCl3) : δ1.41 (3H, t, J=7.2 Hz), 1.41 (6H, s), 2.04 (2H, t, J=6.5 Hz), 2.76 (2H, t, J=6.5 Hz), 4.40 (2H, q, J=7.2 Hz), 7.44 (1H, d, J=8.2 Hz), 7.59 (2H, d, J=8.4 Hz), 7.68 (1H, dd, J=1.8, 8.2 Hz), 8.04 (2H, d, J=8.4 Hz), 8.15 (1H, d, J=1.8 Hz).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1[OH:13].C(N(C(C)C)C(C)C)C.[CH3:23][O:24][CH2:25]Cl.C(N(CC)CC)C>ClCCl.O>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1[O:13][CH2:23][O:24][CH3:25]
Reactant: COCCl
Reactant: Oc1cc2c(c(F)c1F)OCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COCOc1cc2c(c(F)c1F)OCCC2
Reaction time: 0.08 h

Procedure:
15.0 g (80.6 mmol) of 7,8-difluorochroman-6-ol are dissolved in 135 ml of dichloromethane, and 16.5 ml (94.2 mmol) of N-ethyldiisopropylamine are added with ice-cooling. After 5 min, 7.34 ml (97.0 mmol) of chloromethyl methyl ether are metered in the temperature range from 15 to 30° C. After 18 h at 20° C., 50 ml of triethylamine are added, and the batch is stirred again for 18 h. Water is added to the reaction mixture, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, and the combined organic phases are washed successively with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:MTBE=2:1), giving 7,8-difluoro-6-methoxymethoxychroman as a yellowish solid.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:8][CH2:7][CH:6]([CH:9]=[CH:10][C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>[OH-].[Na+].C(O)C>[OH:3][CH:4]1[CH2:8][CH2:7][CH:6]([CH:9]=[CH:10][CH:11]([OH:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: CCCCCC(=O)C=CC1CCC(=O)C1CCCCCCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(O)C=CC1CCC(O)C1CCCCCCC(=O)O
Temperature: 10 °C
Reaction time: 24 h
Yield: 58.7 %

Procedure:
A solution of sodium borohydride (0.035 g., 0.0009 mole) in 0.2N aqueous sodium hydroxide (0.35 ml.) was added dropwise to a solution of 7-[2-oxo-5-(3-oxo-1-octenyl)cyclopentyl]heptanoic acid (0.14 g., 0.0004 mole) in ethanol (3 ml.) and N aqueous sodium hydroxide (0.42 ml., 0.0004 mole). The resulting solution was stirred for 1 day, and then the ethanol was removed in vacuo. A small quantity of water was added, and the solution was extracted twice with diethyl ether (to remove non-acidic material). The aqueous solution was covered with a layer of diethyl ether and acidified to pH 1 by the dropwise addition of concentrated hydrochloric acid, cooling the solution to about 10°C. The ether layer was separated and the aqueous layer extracted twice more with diethyl ether. The combined ether extracts were dried over magnesium sulphate and evaporated to give 7-[2-hydroxy-5-(3-hydroxy-1-octenyl)cyclopentyl]heptanoic acid (0.08 g., 57%), νmax 1700 cm-1 and 980 cm-1 (liquid film), which required no further purification. N.M.R. (approximately 10% solution in deuterochloroform) 0.9 δ (triplet J=5c/s, terminal CH3), 1.1-2.0 δ (broad band, cyclic and chain CH2), 2.3 δ (triplet J=6c/s, CH2C=O) ~ 4.0 δ (broad mutiplet ##EQU5## 5.25 δ (broad singlet, OH), 5.4δ (broad peak ##EQU6##
Reaction SMILES: [C:1]([O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2].[Br:17]Br.C(OCC)(=O)C>C(O)(=O)C.O>[C:1]([O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([Br:17])[C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: COc1cc(C=O)cc(OC)c1OC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(C=O)c(Br)c(OC)c1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
To a mixture of 4-acetoxy-3,5-dimethoxy benzaldehyde (5.4 g, 20 mmol) and 5.4 g (40 mmol) of NaOAc.3H2O in acetic acid (14 mL) and water (2 mL) was added dropwise bromine (1.2 mL, 24 mmol). The mixture was stirred at RT overnight and repartitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic layer was washed with saturated sodium bicarbonate solution, water and brine and dried over anhydrous sodium sulfate. Removal of the solvent gave 5.6 g of 4-acetoxy-2-bromo-3,5-dimethoxybenzaldehyde (80%).
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+].CC(C)=O.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][C:37](Cl)=[O:38]>O>[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][C:37]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[O:38]
Reactant: O=C(Cl)Cc1cccs1
Reactant: Cn1nnnc1C=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1nnnc1C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
In 40 ml of water were dissolved 416 mg of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylic acid and 660 mg of sodium hydrogencarbonate. To the solution was added 10 ml of acetone and further added dropwise with stirring at 0°-5° C., 20 ml of an acetone solution containing 323 mg of 2-thienylacetyl chloride. The mixture was stirred for 30 minutes under ice-cooling and for additional 3 hours at room temperature. The acetone was distilled off at room temperature under reduced pressure. The residual solution was washed with ether, adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The ethyl acetate was removed under reduced pressure, and, upon washing the residue with ether, there was obtained 590 mg of 7-(2-thienylacetamido)-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylic acid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)=[O:27])C1C=CC=CC=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:48]1([O:53][C:54](=[O:60])[C@H:55]([CH:57]([CH3:59])[CH3:58])[NH2:56])[CH2:52][CH2:51][CH2:50][CH2:49]1>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][NH:56][C@H:55]([C:54]([O:53][CH:48]2[CH2:49][CH2:50][CH2:51][CH2:52]2)=[O:60])[CH:57]([CH3:58])[CH3:59])[CH2:30][CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2CCC(CC=O)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)[C@H](N)C(=O)OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)c1cc(C(=O)N2CCC(CCN[C@H](C(=O)OC3CCCC3)C(C)C)CC2)c(O)cc1O

Procedure:
Prepared from Intermediate D and L-valine cyclopentyl ester tosylate. 1H NMR (300 MHz, d3-MeOD) 6.95 (1H, s), 6.34 (1H, s), 5.31-5.44 (1H, m), 4.08-4.35 (2H, m), 3.94 (1H, d, J=3.8 Hz), 3.05-3.25 (3H, m), 2.96 (2H, t, J=12.5 Hz), 2.26-2.42 (1H, m), 1.89-2.08 (3H, m), 1.61-1.88 (8H, m), 1.13-1.24 (12H, m) and 1.05 (6H, d, J=6.8 Hz) LC/MS: purity 85%, m/z 475 [M+H]+