Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:27][CH2:26][C:21]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)(=O)=O)=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:68]([O:76][CH2:77][CH3:78])(=[O:75])[CH2:69][C:70]([O:72][CH2:73][CH3:74])=[O:71]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:22]1[C:21]2([CH2:20][CH2:19][CH:18]([C:15]3[CH:14]=[CH:13][C:12]([CH:69]([C:70]([O:72][CH2:73][CH3:74])=[O:71])[C:68]([O:76][CH2:77][CH3:78])=[O:75])=[CH:17][CH:16]=3)[CH2:27][CH2:26]2)[O:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C3CCC4(CC3)OCCO4)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C2CCC3(CC2)OCCO3)cc1
Yield: 14.8 %

Procedure:
4-(1,4-Dioxaspiro[4.5]dec-8-yl)phenyl 4-methylbenzenesulphonate (2.05 g, 5.27 mmol) was stirred with 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (502 mg, 1.05 mmol) and caesium carbonate (5.15 g, 15.81 mmol) in toluene (40 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was degassed several times then palladium(II) acetate (95 mg, 0.42 mmol) was added, followed by diethyl malonate (0.96 mL, 6.324 mmol). The mixture was heated under reflux for 40 h then was filtered through diatomaceous earth and concentrated by evaporation. The residue was adsorbed onto silica and purified by chromatography eluting with 0-40% EtOAc/isohexane to give the title compound (294 mg, 15%) as an oil; 1H NMR δ 1.18 (6H, t), 1.58-1.71 (4H, m), 1.75 (4H, t), 2.56 (1H, t), 3.89 (4H, q), 4.08-4.20 (4H, m), 4.88 (1H, s), 7.15-7.29 (4H, m); MS m/e MH+ 377.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:7]=1.O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]2[C:7]=1[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2
Reactant: COc1ccc(F)cc1CCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(F)c2c1CCCC2=O
Temperature: 90 °C

Procedure:
4-(5-Fluoro-2-methoxy phenyl)butanoic acid (15 g) was mixed with polyphosphoric acid (60 g) and stirred with an overhead stirrer. The reaction mixture was heated to 90° C. and stirred at this temperature for 45 minutes. The reaction mixture was allowed to cool, water (100 ml) and ethyl acetate (100 ml) were added. The mixture was neutralised with sodium hydrogen carbonate solution, the organic phase was collected. The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the crude product. This material was recrystallised from hexane-15% ethyl acetate to give the clean product.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:13]=1)=O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[BH4-].[Na+]>C(O)C>[C:28]([Si:25]([CH3:27])([CH3:26])[O:24][C@H:18]([C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C@@H:6]([CH2:4][OH:3])[CH2:10][CH2:9][C:8]2=[O:11])=[CH:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(N2C(=O)CC[C@@H]2C(=O)OCC)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Product: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(N2C(=O)CC[C@@H]2CO)cc1

Procedure:
To a flask containing ethanol and (R)-1-{4-[(S)-1-(tert-butyl-dimethyl-silanyloxy)-hexyl]-phenyl}-5-oxo-pyrrolidine-2-carboxylic acid ethyl ester was added aqueous potassium phosphate bibasic followed by an aqueous solution of sodium borohydride, while maintaining the reaction at ambient temperature (˜23° C.). The mixture was stirred at ambient temperature until all of the ethyl ester was consumed before quenching with water, and then extracted with MTBE. The combined organic extracts were washed with brine and concentrated under reduced pressure to give crude product as an off-white solid. The crude product was re-crystallized with heptanes to give a pure product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)[N:5]2[CH:21]=[CH:22][N:23]=[C:4]2[CH:3]=1.[CH3:24][C:25]1[S:26][C:27]([Sn](C)(C)C)=[CH:28][N:29]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][C:25]1[S:26][C:27]([C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=3)[N:5]3[CH:21]=[CH:22][N:23]=[C:4]3[CH:3]=2)=[CH:28][N:29]=1
Reactant: Cc1ncc([Sn](C)(C)C)s1
Reactant: C[Si](C)(C)CCOCn1cc(-c2nc(Cl)cc3nccn23)cn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ncc(-c2cc3nccn3c(-c3cnn(COCC[Si](C)(C)C)c3)n2)s1
Temperature: 100 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A flask charged with 7-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation G; 0.200 g, 0.572 mmol) and 2-methyl-5-(trimethylstannyl)thiazole (0.165 g, 0.629 mmol) was evacuated and backfilled with argon before 4 mL of dioxane were added and argon was bubbled through for 5 minutes. Tris(dibenzylideneacetone)dipalladium (0.0523 g, 0.0572 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.0545 g, 0.114 mmol) were added, argon was bubbled through the reaction for 10 minutes. The reaction flask was sealed and heated to 100° C. with stirring for 2 hours. The reaction mixture was loaded directly onto a silica gel column pre-wetted and eluted with a gradient of 25-100% ethyl acetate with 1% ammonium hydroxide to afford 2-methyl-5-(5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)thiazole (0.196 g, 0.475 mmol, 83.1% yield). MS (apci) m/z=413.1 (M+H).
Reaction SMILES: [CH:1]([C:4]([CH:6]([CH3:8])[CH3:7])=[O:5])([CH3:3])[CH3:2].[C:9]1([CH3:32])[CH:14]=[CH:13][C:12]([S:15](OCC2C([N+]([O-])=O)=CC=CC=2[N+]([O-])=O)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C1(S(C(S(C2CCCCC2)(=O)=O)=[N+]=[N-])(=O)=O)CCCCC1>>[CH3:2][C:1]([S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:32])=[CH:10][CH:11]=1)(=[O:17])=[O:16])([C:4](=[O:5])[CH:6]([CH3:8])[CH3:7])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCc2c([N+](=O)[O-])cccc2[N+](=O)[O-])cc1
Reactant: CC(C)C(=O)C(C)C
Agent: [N-]=[N+]=C(S(=O)(=O)C1CCCCC1)S(=O)(=O)C1CCCCC1
Product: Cc1ccc(S(=O)(=O)C(C)(C)C(=O)C(C)C)cc1

Procedure:
Using diisopropylketone, the reaction was carried out in the same manner as described in Synthesis Example 9, (2) and (3). The crude solid was recrystallized from n-hexane/benzene to afford 2,4-dimethyl-2-(p-toluenesulfonyl)pentan-3-one as white leaflets.
Reaction SMILES: [Na+].[Na+].[CH3:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([O-:9])=[O:8])[C:5]=1[C:13]([O-:15])=[O:14].[Mn]([O-])(=O)(=O)=O.[K+]>O>[CH3:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14]
Reactant: Cc1cccc(C(=O)[O-])c1C(=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C(=O)O)c1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Methylphthalic acid disodium salt (4.4 mmol) was dissolved in water (50 ml). Potassium permanganate (14.7 mmol) was added and the resulting solution was stirred for 18 h at room temperature. A precipitate was formed. The precipitate was filtered off and washed three times with hot water. The combined aqueous phase was evaporated under reduced pressure to approximately one third of the initial volume and cooled in an ice-bath. Concentrated HCl was added carefully for neutralization. Expected precipitation of hemimellitic acid did not occur. After evaporation of water in vacuo, the dark residue represented a complex mixture of compounds.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1>C(O)C.[Ni]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH2:22])[CH2:13][CH2:14]2)=[O:7])=[CH:25][CH:26]=1
Reactant: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3[N+](=O)[O-])CC2)cc1
Agent: [Ni]
Solvent: CCO
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3N)CC2)cc1
Reaction time: 2 h
Yield: 86.3 %

Procedure:
0.32 g (0.0009 mol) of 1-(2-nitro-benzyl)-piperidin-4-yl 4-methyl-benzoate was dissolved in 18 ml of ethanol and treated with 0.192 g of Raney-nickel. The mixture was hydrogenated at room temperature and under normal pressure for 2 hrs. The catalyst was filtered off and, after concentration, the residue was chromatographed on silica gel with ethyl acetate/hexane (1:4) as the eluent. 0.252 g (86%) of 1-(2-amino-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as yellowish crystals; m.p. 123°-1250°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30](C)C)[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][C@@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][OH:44])[CH2:36]1.C[C@H]1N(C)[C@@H](C)CN(CCO)C1>>[CH3:34][C@@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][O:44][C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([NH:13][C:14]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:15]=4[C:16]([CH3:33])=[N:17][N:18]5[CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=4)=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH2:36]1
Reactant: C[C@H]1CN(CCO)CCN1C
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(Cl)ccn34)c12
Agent: C[C@@H]1CN(CCO)C[C@H](C)N1C
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)[C@@H](C)C6)ccn45)cccc32)n1
Yield: 11 %

Procedure:
Prepared according to Example 7, Step F, substituting 7-chloro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide for 7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol to give the title compound (11%). MS (APCI), positive scan, m/z=553.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][N:13]([CH:16]3[CH2:18][CH2:17]3)[CH:14]=O)[CH:11]=1)[O:8][C:7]([CH3:20])([CH3:19])[CH2:6][C:5]2([CH3:22])[CH3:21].B>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][N:13]([CH:16]3[CH2:18][CH2:17]3)[CH3:14])[CH:11]=1)[O:8][C:7]([CH3:20])([CH3:19])[CH2:6][C:5]2([CH3:22])[CH3:21]
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(CN(C=O)C3CC3)c2O1
Agent: B
Solvent: C1CCOC1
Product: CN(Cc1cc(Br)cc2c1OC(C)(C)CC2(C)C)C1CC1
Yield: 110 %

Procedure:
A solution of 6-bromo-8-[(cyclopropyl-formyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman (Intermediate 8, 1.46 g, 4.0 mmol) in anhydrous tetrahydrofuran (30 mL) was treated with a 2M solution of borane:methylsulfide complex in tetrahydrofuran (5 mL, 10 mmol) and the resulting reaction mixture was refluxed for 2 h. It was then cooled in an ice bath, quenched cautiously with saturated aqueous sodium carbonate solution and extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a white solid (1.55 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:15][C:13]=3[N:14]=2)[CH:7]=1.[CH3:24][C:25]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])([CH3:28])[C:26]#[CH:27].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([NH:8][C:6]3[C:5]([Cl:22])=[CH:4][C:3]([F:23])=[C:2]([NH:1][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([C:25]([CH3:24])([CH3:28])[C:26]#[CH:27])[CH:30]=4)[CH:7]=3)[N:10]=[CH:11][C:12]=2[N:17]=1)(=[O:21])[CH3:20]
Reactant: C#CC(C)(C)c1cccc(C(=O)O)c1
Reactant: CC(=O)Nc1nc2cnc(Nc3cc(N)c(F)cc3Cl)nc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: C#CC(C)(C)c1cccc(C(=O)Nc2cc(Nc3ncc4nc(NC(C)=O)sc4n3)c(Cl)cc2F)c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
A solution of N-{5-[(5-amino-2-chloro-4-fluorophenyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (78 mg, 221 μmol) produced in Example D46(iii), 3-(1,1-dimethylprop-2-yn-1-yl)benzoic acid (79 mg, 442 μmol) produced in Example D20(iii) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (168 mg, 442 μmol) in pyridine (3 mL) was stirred at 90° C. for 5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=20/80→0/100), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (89 mg, 77%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:17][C:16](=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[Cl:21][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:17]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1nc(Cl)c2ccccc2n1

Procedure:
A mixture of 7.6 g of 2-(2-methylphenyl)quinazolin-4(3H)-one and 55 ml of thionyl chloride was treated with 2.35 g of dimethylformamide as described in Example I. The isolated solid was recrystallized from cyclohexane to give 5.1 g of 4-chloro-2-(2-methylphenyl)quinazoline, m.p. 103°-104°; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:22][OH:23])[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCSCC(CO)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCSCC(COS(C)(=O)=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of 3.0 grams (0.009 mole) (±)-1-S-hexadecyl-2-O-methylthioglycerol in 200 milliliters of DCM and 1.0 milliliter (0.010 mole) of triethylamine was added 1.2 grams (0.012 mole) of methanesulfonyl chloride and the reaction stirred at room temperature for 24 hours. The reaction mixture was then extracted twice with 200 milliliter portions of water, twice with 200 milliliter portions of 5% HCl, once with 200 milliliters of saturated NaHCO3, and once with 200 milliliters of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield 3.4 grams (89%) of a colorless oily residue. 1H-NMR (CDCl3): delta, 0.87(t, 3H, terminal methyl), 1.2-1.6[m, 28H, (CH2)14 ], 2.58(m, 2H, S--CH2), 2.62(m, 2H, CH--CH2 --S), 3.08(s, 3H, SO2 --CH3), 3.40-3.50(m, 4H, CH, CH3 --O), 4.35 (m, 2H, CH2 --OSO2).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(N)=[S:18].N.Cl>C(O)(C)C.O>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][SH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: N
Solvent: CC(C)O
Solvent: O
Product: SCc1cccc(Oc2ccccc2)c1

Procedure:
A solution of 30.8 g of m-phenoxybenzyl bromide in 70 ml of isopropanol is reacted with 9.5 g of thiourea in 30 ml of water and the reaction mixture is refluxed briefly. After cooling, 25 ml of a 25% ammonia solution are added and the mixture is heated briefly to reflux and then allowed to cool, whereupon it is acidified with 18% hydrochloric acid and extracted with methylene chloride. The extract is dried over magnesium sulfate and concentrated, affording the compound of the formula ##STR7## with a boiling point of 114°-116° C.'0.05 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO.ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([OH:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(O)c1cccc([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
26.4 g (160 mmol) of 1-(3-nitrophenyl)ethanone are suspended in 270 ml of methanol, and 6.1 g (160 mmol) of sodium borohydride are added in portions with ice cooling. The reaction mixture is subsequently stirred for a further 3 h without cooling, diluted with 300 ml of dichloromethane and washed with 3×200 ml of water. The organic phase is dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:22][O:23][C:24]1[C:32]2[C:31]([CH2:33][CH2:34][NH2:35])=[CH:30][S:29][C:28]=2[CH:27]=[CH:26][CH:25]=1.CCN(CC)CC.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[CH3:22][O:23][C:24]1[C:32]2[C:31]([CH2:33][CH2:34][NH:35][CH:2]3[C:10]4[C:5](=[CH:6][C:7]([O:11][C:12]5[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=5)=[CH:8][CH:9]=4)[CH2:4][CH2:3]3)=[CH:30][S:29][C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc2scc(CCN)c12
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Product: COc1cccc2scc(CCNC3CCc4cc(Oc5ccc(C(N)=O)cn5)ccc43)c12
Yield: 49.9 %

Procedure:
Using a method similar to Example 1, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 97 mg, 0.362 mmol), 2-(4-methoxy-benzo[b]thiophen-3-yl)-ethylamine HCl salt (J. Heterocycl. Chem. (1973), 10(3), 297-305, 93 mg, 0.435 mmol), Et3N (44 mg, 0.435 mmol), Ti(iPrO)4 (206 mg, 0.725 mmol), TiCl4 (1.0M/DCM, 0.725 ml, 0.725 mmol), and NaBH3CN (45 mg, 0.725 mmol) gives the title compound (83 mg) as a light yellow solid. Mass spectrum (ion spray): m/z=460 (M+1); 1HNMR (CDCl3): 8.58 (s, 1H), 8.15 (d, 1H), 7.42 (d, 1H), 7.33 (d, 1H), 7.25 (t, 1H), 7.02 (s, 1H), 6.98 (s, 1H), 6.94-6.91 (m, 2H), 6.75 (d, 1H), 5.82 (br. s, 2H), 4.30 (t, 1H), 3.91 (s, 3H), 3.29 (t, 2H), 3.09 (m, 2H), 3.01 (m, 1H), 2.83 (m, 1H), 2.45 (m, 1H), 1.90 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2OS(C(F)(F)F)(=O)=O)(=[O:3])[CH3:2].[CH2:22]([O:26][C:27]1[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([CH:36]([CH3:38])[CH3:37])=[CH:29][C:28]=1B(O)O)[CH2:23][CH2:24][CH3:25].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O.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>[CH2:22]([O:26][C:27]1[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([CH:36]([CH3:37])[CH3:38])=[CH:29][C:28]=1[C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=2)[N:10]=[CH:9][CH:8]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)c1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2c1
Reactant: CCCCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOc1c(-c2ccnc3ccc(C(C)=O)cc23)cc(C(C)C)cc1C(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 6-acetyl-quinolin-4-yl ester (321.7 mg, 1.008 mmol) and (2-butoxy-3,5-diisopropyl-phenyl)-boronic acid (315.3 mg, 1.133 mmol) (see Example 17, step B) in toluene (10 mL) was added 2N Na2CO3 (1.1 mL) and Pd(PPh3)4 (117.1 mg, 0.101 mmol). The solution was stirred at 80° C. for 2 h under N2 atm. The mixture was poured into brine (30 mL) and extracted with ethyl acetate (30 mL). The organic phase was dried, filtered, and concentrated. The crude material was purified by flash chromatography (2:8) ethyl acetate:hexanes to give 1-[4-(2-butoxy-3,5-diisopropyl-phenyl)quinolin-6-yl]-ethanone (378 mg, 93% yield) as a light yellow crystalline solid. Mp 132.8° C. 1H NMR (400 MHz, DMSO-d6): δ 9.01 (d, 1H, J=4.4), 8.40 (d, 1H, J=2.0), 8.25 (2d, 1H, J=2.0, 8.8), 8.16 (d, 1H, J=8.8), 7.50 (d, 1H, J=4.4), 7.24 (m, 1H), 7.00 (d, 1H, J=2.4),3.36 (m, 1H), 3.26 (m, 1H), 3.16 (m, 1H), 2.94 (m, 1H), 2.58 (s, 3H), 1.29 (m, 12H), 1.10 (m, 2H), 0.79 (m, 2H), 0.47 (t, 3H, J=7.3). 13C NMR (75 MHz, DMSO-d6): δ 197.1, 152.3, 151.6, 149.6, 147.2, 144.2, 141.6, 134.0, 129.7, 128.5, 127.2, 126.5, 125.4, 123.0, 73.0, 33.0, 31.1, 26.4, 24.0, 23.9, 23.8, 23.0, 17.9, 12.9. IR (CHCl3, cm−1): 2963, 2934, 2872, 1681. MS [EI+] 404 (M+H)+. Analytical (C27H33NO2): Calculated C, 80.36; H, 8.24; N, 3.47. Found: C, 79.98; H, 8.57; N, 3.46.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][C:13]([NH:15][CH:16]1[C:33](=[O:34])[N:18]2[CH:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:20]([N:23]=[C:24]=[O:25])=[CH:21][S:22][C@H:17]12)=[O:14]>>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][C:13]([NH:15][CH:16]1[C:33](=[O:34])[N:18]2[C:19]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[C:20]([NH:23][C:24]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:25])[CH2:21][S:22][C@H:17]12)=[O:14]
Reactant: CC(C)(C)OC(=O)C1C(N=C=O)=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)C1=C(NC(=O)N2CCOCC2)CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12

Procedure:
Benzhydryl 7-phenylacetamido-3-isocyanato-2-cephem-4-carboxylate reacts with 2 equivalents of isopropylamine in tetrahydrofuran at 0° for approximately 1 hour to provide benzhydryl 7-phenylacetamido-3-isopropylureido-3-cephem-4-carboxylate. Likewise morpholine reacts under similar conditions with tert-butyl 7-(2-thienylacetamido)-3-isocyanato-2-cephem-4-carboxylate to provide tert-butyl 7 -(2-thienylacetamido)-3-morpholinocarbonylamino-3-cephem-4-carboxylate. When 4'-methoxybenzyl 7-(tert-butoxycarbonylamino)-3-isocyanato-2-cephem-4carboxylate is reacted with 2.5 equivalents of N-methylaniline in methylene chloride at 0° for about 1 hour, the product isolated, after chromatography, is 4'-methoxybenzyl 7-(tert-butoxycarbonylamino)-3-(N-methyl-N-phenylureido)-3-cephem-4-carboxylate.
Reaction SMILES: C(N[C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:15](=O)[C:16](Cl)=[O:17])=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)(=O)C.Cl.C([O:24][C:25](=[NH:40])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][C:32]([N+:36]([O-:38])=[O:37])=[CH:33][CH:34]=2)[N:29]([CH3:39])[CH:28]=1)(C)C>>[CH3:14][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][CH:13]=2)[C:9]([NH:40][C:25](=[O:24])[CH3:26])([C:15]2[C:16](=[O:17])[NH:24][C:25](=[O:40])[C:26]=2[C:27]2[C:35]3[C:30](=[CH:31][C:32]([N+:36]([O-:38])=[O:37])=[CH:33][CH:34]=3)[N:29]([CH3:39])[CH:28]=2)[CH2:10]1
Reactant: CC(C)OC(=N)Cc1cn(C)c2cc([N+](=O)[O-])ccc12
Reactant: CC(=O)Nc1ccc2c(C(=O)C(=O)Cl)cn(C)c2c1
Agent: Cl
Product: CC(=O)NC1(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)CN(C)c2ccccc21

Procedure:
ss) N-{1-Methyl-3-[4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1H-indol-3-yl}-acetamide was prepared from (6-acetylamino-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride and 2-(1-methyl-6-nitro-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride.