Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:31][CH3:32])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:21]>C(#N)C>[CH2:31]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7](=[O:15])[C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:26]1)[CH3:32]
Reactant: CCN(CC)CCC1CCCNC1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Solvent: CC#N
Product: CCN(CC)CCC1CCCN(C(=O)N2c3ccccc3NC(=O)c3cccnc32)C1
Yield: 54 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 3-[2-(diethylamino)ethyl]piperidine in a yield of 54% of theory. Colourless crystals, m.p. 110°-113° C. (acetonitrile).
Reaction SMILES: [F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[N:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:40]=[C:34]6[CH2:35][N:36]([CH3:39])[CH2:37][CH2:38][N:33]6[N:32]=5)[C:27](=[O:41])[N:26]([CH3:42])[CH:25]=4)[C:17]=3[CH:18]=[O:19])[C:14](=[O:15])[C:3]=12.[BH4-].[Na+].O>CO>[F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[C:17]([CH2:18][OH:19])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:40]=[C:34]6[CH2:35][N:36]([CH3:39])[CH2:37][CH2:38][N:33]6[N:32]=5)[C:27](=[O:41])[N:26]([CH3:42])[CH:25]=4)[CH:21]=[CH:22][N:23]=3)[C:14](=[O:15])[C:3]=12
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c7c(c(F)c6C5=O)CCCC7)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c7c(c(F)c6C5=O)CCCC7)c4CO)cn(C)c3=O)cc2C1
Reaction time: 3 h
Yield: 66.6 %

Procedure:
To a solution of 135b (280 g, 0.49 mmol) in MeOH (50 mL) was added NaBH4 (56 g, 1.47 mmol) at room temperature. After the reaction was stirred for 3 h, LCMS indicated the reaction was completed. Then the mixture was poured into H2O (50 mL) and extracted with DCM (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase prep-HPLC to afford 135 (187 mg, 67%) as a white solid. MS: [M+H]+ 572. 1H NMR (500 MHz, CDCl3) δ 8.47 (d, J=5.5, 1H), 7.95 (d, J=2.0, 1H), 7.70 (d, J=2.0, 1H), 7.42 (s, 1H), 7.35 (d, J=5.5, 1H), 5.70 (s, 1H), 4.96 (t, J=7.0, 1H), 4.62 (s, 1H), 4.45 (s, 1H), 4.33 (s, 1H), 4.07-4.12 (m, 4H), 3.84 (s, 1H), 3.70 (s, 3H), 3.60 (s, 2H), 2.88 (t, J=5.5, 2H), 2.61 (s, 2H), 2.57 (s, 2H), 2.48 (s, 3H), 1.86-1.90 (m, 2H), 1.77 (s, 2H)
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C(OC([N:35]1[C@H:39]([CH:40]=O)[CH2:38][O:37]C1(C)C)=O)(C)(C)C.Cl.O1CCOCC1>>[NH2:35][C@H:39]([CH2:40][NH:26][CH:23]1[CH2:24][CH2:25][N:20]([C:17]2[S:18][CH:19]=[C:15]([C:7]3[CH:6]=[CH:5][C:4]4[C:3]([CH3:27])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=4[CH:8]=3)[N:16]=2)[CH2:21][CH2:22]1)[CH2:38][OH:37]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: Br
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NC[C@@H](N)CO)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The preparation is carried out starting from 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrobromide and (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester. The protecting group is cleaved off by means of a 4N HCl/dioxane solution: The reaction mixture was stirred at room temperature for 2 h and evaporated to dryness. The product is converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13].Cl.[OH-].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:21][CH:20]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCCCOc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 2,4-dichloro-5-fluoropyrimidine (0.5 g, 3.0 mmol) and 4-n-butoxyaniline (0.49 g, 3 mmol) in acetone/H2O (1:9 mL) at room temperature was added concentrated HCl (0.1 mL). The mixture was heated at reflux for 1 h, cooled to room temperature, and made basic with 2 N NaOH (2 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude black solid was purified by chromatography (4:1 hexanes/EtOAc) to afford 2-chloro-N4-(4-n-butyloxyphenyl)-5-fluoro-4-pyrimidineamine (0.71 g, 80%) as a brown oil: 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=2.7 Hz, 1H), 7.51-7.46 (m, 2H), 6.95-6.89 (m, 2H), 6.83 (bs, 1H), 3.99-3.95 (t, J=6.5 Hz, 2H), 1.82-1.57 (m, 2H), 1.53-1.43 (m, 2H), 0.98 (t, J=7.2 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[O:37][C:36]([CH2:38][CH3:39])=[N:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([C:36]1[O:37][C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])=[CH:34][N:35]=1)[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: CCc1ncc(CCl)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ncc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)o1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (170 mg; compound B50) is reacted with 5-(chloromethyl)-2-ethyl-1,3-oxazole (60 mg; compound D9) in the presence of potassium carbonate (111 mg) in DMF (5 ml). Using WU2 the title compound is obtained after flash column chromatography [silica gel, eluent: cyclohexane/EtOAc=1/2 (v/v)] as a solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:13]2[C:14]([S:23][CH3:24])=[N:15][N:16]3[C:21]([I:22])=[CH:20][CH:19]=[CH:18][C:17]=23)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH:1]1([CH2:4][NH:5][C:13]2[C:14]([S:23][CH3:24])=[N:15][N:16]3[C:21]([I:22])=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:2][CH2:3]1
Reactant: CSc1nn2c(I)cccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CSc1nn2c(I)cccc2c1NCC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the crude tert-butyl N-cyclopropylmethyl-N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate dissolved in ethyl acetate (1 mL) was added 4N hydrochloric acid/ethyl acetate (10 mL), and the reaction mixture was stirred for 2 hours at room temperature. After completion of the reaction, saturated aqueous sodium bicarbonate was added to the reaction mixture while cooling with ice for neutralization. The reaction mixture was extracted with ethyl acetate, and after washing the organic extract with water and brine, it was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (20 g) and the title compound (506 mg) was obtained as a yellow oil from the ethyl acetate:n-hexane (1:3) fraction.
Reaction SMILES: O.[F:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[CH:12][C:13](=[O:32])[N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:18]=3)[N:15]=2)[CH:6]=[C:7]([F:9])[CH:8]=1.Br[C:34]1[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.C(=O)([O-])O.[Na+]>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(#N)C>[NH2:40][C:37]1[N:38]=[CH:39][C:34]([C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[CH2:16][N:14]2[C:13](=[O:32])[CH:12]=[CH:11][C:10]([C:5]3[CH:4]=[C:3]([F:2])[CH:8]=[C:7]([F:9])[CH:6]=3)=[N:15]2)=[N:35][CH:36]=1
Reactant: CC1(C)OB(c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)OC1(C)C
Reactant: Nc1cnc(Br)cn1
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: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1cnc(-c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)cn1
Temperature: 80 °C

Procedure:
5 ml of water and 5 ml of acetonitrile are added to 150 mg (0.35 mmol) of 6-(3,5-difluorophenyl)-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-2H-pyridazin-3-one, 63 mg (0.35 mmol) of 5-bromopyrazin-2-ylamine and 167 mg (1.99 mmol) of sodium hydrogencarbonate, and the mixture is degassed a number of times. Under an argon atmosphere, 20 mg (0.017 mmol) of tetrakis(triphenylphosphine)palladium(0) are added, and the mixture is subsequently heated at 80° C. for 15 h with stirring. A further 20 mg (0.017 mmol) of tetrakis(triphenylphosphine)palladium(0) are subsequently added, and the mixture is stirred at 80° C. for a further 24 h. The hot suspension is filtered. The filtrate is concentrated to half. After cooling to room temperature, the resultant precipitate is filtered off with suction and washed with a little water. The residue is purified by means of preparative HPLC; yield: 21 mg of “A280”; HPLC: Rt=2.68 min (method C); LC-MS: 392 (M+H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11].[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>O1CCCC1.O>[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][C:10]([CH3:12])([CH3:11])[C:9]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C)C
Reactant: BrCc1ccccc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1ccccc1Br
Reaction time: 0.5 h
Yield: 169 %

Procedure:
Lithium diisopropylamide (2M in hexane, 1.5 mL, 3.0 mmol) was added to a solution of ethyl isobutyrate (233 mg, 2.01 mmol) in tetrahydrofuran (1 mL) at −78° C. and the reaction mixture was stirred at this temperature for 30 min. Then, a solution of 2-bromobenzyl bromide (250 mg, 1.00 mmol) in tetrahydrofuran (1 mL) was added dropwise. The reaction mixture was stirred at −78° C. for another 1 hr and then at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over sodium sulfate, and concentrated to give 482 mg of ethyl 3-(2-bromophenyl)-2,2-dimethylpropanoate as a yellow oil. The crude intermediate was used directly in the next step.
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4]CC1.C(OC(C)C)(OC(C)C)O[CH:11]([CH3:13])[CH3:12].C(O)(C)C.O.S([O-])(O)(=O)=O.[Na+]>>[CH:11]([O:8][C:1]1[CH2:7][CH2:6][CH2:5][CH:4]=1)([CH3:13])[CH3:12]
Reactant: O=C1CCCCCC1
Reactant: CC(C)OC(OC(C)C)OC(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)OC1=CCCC1
Temperature: 50 °C
Yield: 60.1 %

Procedure:
To a mixture of 56.0 grams (0.50 mol) of cycloheptanone, 107.0 grams (0.56 mol) of triisopropyl orthoformate and 44 grams of isopropanol (0.73 mol) in a 500 ml three-neck round bottom flask was added 2.8 grams (0.020 mol) of sodium hydrogensulfate monohydrate. Upon catalyst addition, the reaction temperature rose to 45° C., and was heated and maintained at 50° C. for about 5 hours. The progress of the reaction was monitored by GC until the ketone concentration was below 2%. The isopropanol and isopropyl formate by-products were removed by distillation under reduced pressure while the temperature of the reaction mixture was increased to a maximum of 60° C. The reaction mixture was cooled to room temperature and the pH value adjusted to about 7˜8 by adding 0.4 of gram potassium iso-propoxide. The mixture was then heated under reduced pressure to remove unreacted cycloheptanone and 1-isopropoxy-1-cyclopentene was isolated as a clear liquid at a yield of 60.1%. The purity of the product exceeded 98%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]3=[O:24])[CH:17]=2)[C:11]([O:13]C)=[O:12])=[N:6][CH:7]=1.[OH-].[Li+]>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]3=[O:24])[CH:17]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(N2CCOCC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc(N3CCOCC3=O)c2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with methyl 3-(5-methylpyridin-2-yl)-5-(3-oxomorpholino)benzoate (50 mg, 0.15 mmol), methanol (1.2 mL) and lithium hydroxide (11 mg, 0.46 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was acidified to pH=5 and concentrated under reduced pressure to get the title compound-LiCI mixture as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.CN(C)C1C=CN=CC=1>[Si:14]([O:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(CO)N1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC1CCC(=O)N1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice cold solution of 5-hydroxymethylpyrrolidin-2-one (5 grams, 43.4 mmol) in dichloromethane (174 mL) was added imidazole (6.5 grams, 95.5 mmol), 4-dimethylaminopyridine (530 mg, 4.3 mmol) followed by tert-butyldiphenylsilyl chloride (12.53 grams, 45.57 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane, washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain title compound of 15.37 grams, as gummy liquid, which was taken up for the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[N:25][C@H:24]([C:23]([O:22][CH3:21])=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CS(=O)(=O)c1ccc(C(=O)c2ccc(Br)cc2)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CC(C)C)N=C(c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)cc1

Procedure:
A solution of (4-bromophenyl)[4-(methylsulfonyl)phenyl]methanone (202 mg, 0.59 mmol), L-leucine methyl ester hydrochloride (328 mg, 2.0 mmol) and camphor sulfonic acid (52 mg, 0.22 mmol) in toluene was refluxed for 18 hours using a Dean-Stark trap. The solvent was removed in vacuo and the resulting residue was purified by chromatography using EtOAc and hexane as eluant to give a 1:1 mixture of the title compound and the starting (4-bromophenyl)[4-(methylsulfonyl)phenyl]methanone.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:35]1[N:36]=[C:37]([NH:40]C(=O)C(F)(F)F)[S:38][CH:39]=1)[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:30]([OH:32])=[O:31])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][C:23]([C:27]([OH:29])=[O:28])=[N:24][O:25][CH3:26])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6].O.O.O.C([O-])(=O)C.[Na+].Cl>O>[CH3:1][O:2][N:3]=[C:4]([C:35]1[N:36]=[C:37]([NH2:40])[S:38][CH:39]=1)[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:30]([OH:32])=[O:31])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][C:23]([C:27]([OH:29])=[O:28])=[N:24][O:25][CH3:26])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CON=C(Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1)C(=O)O

Procedure:
A mixture of 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-[1-(2-carboxy-2-methoxyiminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer: in the 7-position) (1.70 g) and sodium acetate. trihydrate (3.26 g) in water (14 ml) was stirred overnight at room temperature. The solution was adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling and the resultant precipitates were filtered and washed with water to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(2-carboxy-2-methoxyiminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer: in the 7-position).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][NH:34][CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44](O)(=[O:47])[CH2:45][OH:46].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[O:32][CH2:31][CH:30]4[CH2:33][N:34]([C:45](=[O:46])[CH2:44][OH:47])[CH2:35][CH2:36][N:29]4[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: O=C(O)CO
Reactant: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(C3CN4CCN(C(=O)CO)CC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To a stirred solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, 0.10 mmol), triethylamine (43 μL, 0.31 mmol), and glycolic acid (8 mg, 0.10 mmol) in DMF (1 mL), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (51 mg, 0.11 mmol) was added at 0° C. The reaction was allowed to stir for 30 minutes while warming to rt. The mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous K2CO3 solution (10 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was triturated with Et2O to obtain 20 mg (36%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.35 to 7.27 (m, 5H), 7.11 (dd, 1H), 6.71 (s, 1H), 5.64 (s, 2H), 5.16-5.12 (m, 1H), 4.35-3.96 (m, 3H), 3.88-3.85 (m, 1H), 3.67-3.55 (m, 1H), 3.36-3.27 (m, 1H), 3.12-3.01 (m, 1H), 2.79-2.64 (m, 2H), 2.55-2.41 (m, 3H), 2.19-2.10 (m, 2H); LC-MS [M+H]+=539, RT=2.19 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=3)[C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][C:6]=2[C:5]1=[O:28]>C(Cl)(Cl)Cl.C(#N)C.[O-2].[O-2].[Mn+4]>[OH:1][CH2:2][CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][CH:15]=3)[C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][C:6]=2[C:5]1=[O:28]
Reactant: O=c1c2cc(-c3ccccc3)c(-c3ccc(CO)cc3)nc2ccn1CCO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=Cc1ccc(-c2nc3ccn(CCO)c(=O)c3cc2-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
A solution of 6-(2-hydroxyethyl)-2-[4-(hydroxymethyl)phenyl]-3-phenyl-1,6-naphthyridin-5(6H)-one (35 mg, 0.094 mmol) in a mixture of chloroform (3 mL) and acetonitrile (3 mL) containing a suspension of activated manganese dioxide (230 mg, 2.6 mmol) was warmed at 70° C. for 1.5 hours. This suspension was filtered, rinsed with chloroform and the solvents evaporated. This residue was triturated with diethyl ether and some pure title compound was isolated by filtration. The mother liquors were subjected to column chromatography on silica gel and upon elution with 50-100% ethyl acetate/hexane and then 0.25-0.75% methanol/ethyl acetate additional product was obtained. 1H-NMR (500 MHz, CDCl3): δ 10.02 (1H, s), 8.74 (1H, s), 7.80 (2H, d, J=8 Hz), 7.62 (2H, d, J=8 Hz), 7.44 (1H, d, J=7.6 Hz), 7.27-7.31 (4H, m), 7.20-7.22 (2H, m), 6.89 (1H, d, J=7.5 Hz), 4.25 (2H, t, J=4.8 Hz), 4.04 (2H, br s), 2.56 (1H, br s).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH:18]([N:31]1[C:39]2[C:34](=[CH:35][C:36](/[C:40](/[CH3:45])=[CH:41]/[C:42](O)=[O:43])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:18]([N:31]1[C:39]2[C:34](=[CH:35][C:36](/[C:40](/[CH3:45])=[CH:41]/[C:42]([NH:1][C:2]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:43])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2)c1
Reactant: CCOC(=O)CCCOc1ccc(C)cc1N
Product: C/C(=C\C(=O)Nc1cc(C)ccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2)c1

Procedure:
305 mg of compound 49 was obtained in a similar manner to those described in the Examples 1 and 2 using 558 mg of ethyl 4-(2-amino-4-methylphenoxy)butyrate and 455 mg of 3-(1-benzhydrylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[N:10]=[C:11]([CH3:14])[S:12][CH:13]=1.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[N:18][CH:17]=1.Cl>CN(C=O)C.O>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:8][C:9]3[N:10]=[C:11]([CH3:14])[S:12][CH:13]=3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[N:18][CH:17]=1
Reactant: COc1cc2c(Cl)cnnc2cc1O
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Cl)cnnc2cc1OCc1csc(C)n1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 47.9 %

Procedure:
The starting material 4-chloro-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline was obtained by adding potassium carbonate (786 mg, 5.7 mmol) followed by 4-chloromethyl-2-methylthiazole (308 mg, 2 mmol) to a suspension of 4-chloro-7-hydroxy-6-methoxycinnoline (0.4 g, 1.9 mmol), (prepared as described for the starting material in Example 10), in DMF (10 ml). After stirring for 4.5 hours at 60° C. the reaction mixture was diluted with water and acidified to pH4 with 2M hydrochloric acid. After extraction with ethyl acetate, the organic layer was washed with water and then brine, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography using methylene chloride/ethyl acetate (2/8) as eluent to give 4-chloro-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline as a solid (293 mg, 48%).