Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([O:12][CH2:13][CH3:14])=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[CH:8][N:7]=1)=O)C.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1COCC1>[CH2:13]([O:12][C:11]1[C:6]([CH2:4][OH:3])=[N:7][CH:8]=[C:9]([O:15][CH2:16][CH3:17])[CH:10]=1)[CH3:14]
Reactant: CCOC(=O)c1ncc(OCC)cc1OCC
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOc1cnc(CO)c(OCC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.9 %

Procedure:
To the 3,5-diethoxy-pyridine-2-carboxylic acid ethyl ester solution (250 mg, 1.04 mmol) in CH2Cl2 (10 ml), a solution of DIBAL in THF (1N, 3 mL) is added, and stirred at room temperature for 20 minutes. Excess reagent is quenched with Glauber's salt (Na2H2SO4·10H2O), filtered and concentrated to afford (3,5-diethoxy-pyridin-2-yl)-methanol (166 mg, 80% yield); 1H NMR (300 MHz, CDCl3): 7.77 (s, 1H), 6.69 (s, 1H), 4.65 (s, 2H), 4.15 (q, J=6.9 Hz, 2H), 3.65 (q, J=6.9 Hz, 2H), 1.45 (t, J=6.9 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[C:4]([CH2:12][CH2:13][CH3:14])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:16]([O:18][C:19](=[O:45])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36]OS(C)(=O)=O)[C:23]=1[CH2:42][CH2:43][CH3:44])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:16]([O:18][C:19](=[O:45])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:15][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]([OH:11])[C:4]=2[CH2:12][CH2:13][CH3:14])[C:23]=1[CH2:42][CH2:43][CH3:44])[CH3:17]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOS(C)(=O)=O
Reactant: CCCc1c(O)c(Cl)cc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCOCCOc1c(C(C)=O)ccc(OCC(=O)OCC)c1CCC
Yield: 30.8 %

Procedure:
A mixture of 0.512 g (0.00224 mol) of 1-(5-chloro-2,4-dihydroxy-3-propylphenyl)ethanone, 1.000 g (0.00224 mol) of [4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester and 0.620 g (0.00448 mol) of anhydrous potassium carbonate in 20 ml of anhydrous acetone and 10 ml of anhydrous dimethylformamide was stirred at reflux for 24 hours. The reaction mixture was filtered and concentrated in vacuo to an oil which was treated with ethyl acetate and sodium chloride solution. The crude oil obtained on concentration of the ethyl acetate was purified by column chromatography, eluting with 20-30% ethyl acetate-hexane to yield 0.400 g (31% yield) of [4-acetyl-3-[2-[2-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]2-propylphenoxy]acetic acid ethyl ester as a pale yellow oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH:8]([C:10]1[N:11]=[N:12][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:14]([CH3:16])[N:15]=1)[NH2:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][C:14]1[N:15]=[C:10]([NH:8][NH:9][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][CH3:1])[N:11]=[N:12][C:13]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCC(=O)Cl
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)NNc1nnc(-c2ccccc2)c(C)n1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A solution of n-valeryl chloride (1.93 g) in methylene chloride (3 ml) was added dropwise to a stirred solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.224 g) and triethylamine (1.784 g) in methylene chloride (40 ml) under ice cooling, and the stirring was continued for 30 minutes. The reaction mixture was evaporated and the resultant residue was extracted with ethyl acetate after addition of water. The extract was washed successively with 5% hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate, and then concentrated to a small volume under reduced pressure. The resultant residue was crystallized from diethyl ether, collected by filtration, washed with diethyl ether and dried to give 5-methyl-6-phenyl-3-(2-valerylhydrazino)-1,2,4-triazine (3.406 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:38])[NH:20][C:21]3[N:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=4[F:37])=[CH:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:39]([OH:41])=[O:40].C[O-].[Na+:44].CO>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:38])[NH:20][C:21]3[N:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][C:28]=4[F:37])=[CH:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:39]([O-:41])=[O:40].[Na+:44]
Reactant: O=C(Nc1ccc(-c2ccc(C(F)(F)F)cc2F)nn1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(-c2ccc(C(F)(F)F)cc2F)nn1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 6-chloro-7-(4-(6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.071 g, 0.12 mmol) in 1:1 THF/methanol (2 ml) was added a 0.5M solution of sodium methoxide in methanol (0.24 ml, 0.12 mmol), and the reaction was stirred at ambient temperature for 2 hours. The reaction was concentrated to yield the desired compound (0.071 g, 0.12 mmol, 96% yield). MS (apci) m/z=588.0 (M-Na+2H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:2]2[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1
Reactant: CN1CCCNCC1
Reactant: CCOC(=O)c1ccc(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(N2CCCN(C)CC2)s1
Temperature: 80 °C
Yield: 12.7 %

Procedure:
Palladium(II)acetate (0.135 g, 0.60 mmol) was added to ethyl 5-bromothiophene-2-carboxylate (1.411 g, 6 mmol), 1-methyl-1,4-diazepane (0.822 g, 7.20 mmol), BINAP (0.374 g, 0.60 mmol) and cesium carbonate (2.74 g, 8.40 mmol) in dioxane (40 mL) warmed to 80° C. for 18 h under nitrogen. The crude reaction mixture was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH. Fractions were evaporated to dryness to afford the crude product. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 3M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 5-(4-methyl-1,4-diazepan-1-yl)thiophene-2-carboxylate (0.204 g, 12.67%) as a yellow gum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][CH:12]=[C:13]([CH:16]=[O:17])[C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][CH:24]=1.C(=O)(O)[O-]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][CH:12]=[C:13]([CH:16]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[OH:17])[C:14]=1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: COC(=O)c1ncc(C=O)c(C)c1OCc1ccccc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COC(=O)c1ncc(C(O)c2ccc(F)cc2)c(C)c1OCc1ccccc1

Procedure:
1.0 g of methyl 3-(benzyloxy)-5-formyl-4-methylpicolinate (3.50 mmol, 1 eq) was dissolved in 20.0 mL of tetrahydrofuran and 4.2 mL of a 4-fluorophenyl magnesium bromide solution (1M in tetrahydrofuran, 4.20 mmol, 1.2 eq) was added at −78° C. over a period of 1 hr. The reaction mixture was then stirred for 20 min. −78° C. A saturated bicarbonate solution was added and reaction mixture was extracted with ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)C.Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:25][CH:26]1[CH2:27][CH2:28]1)[C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1coc(-c2ccnc(N(CC3CC3)C(=O)OC(C)(C)C)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC1CC1)c1cc(-c2nc(C(=O)O)co2)ccn1
Yield: 95.7 %

Procedure:
A solution of ethyl 2-(2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxylate (13.88 g) and 2M aqueous sodium hydroxide solution (140 mL) in a mixed solvent of ethanol (140 mL)/THF (140 mL) was stirred at room temperature for 4 hr, and neutralized with 2M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (12.32 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:14][C:15]1[C:22]([F:23])=[C:21]([C:24]([F:27])([F:26])[F:25])[C:20]([F:28])=[C:19]([F:29])[C:16]=1[CH2:17]Br>>[N+:11]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:17][C:16]2[C:19]([F:29])=[C:20]([F:28])[C:21]([C:24]([F:25])([F:27])[F:26])=[C:22]([F:23])[C:15]=2[F:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([O-:13])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Product: O=C(O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1[N+](=O)[O-]
Yield: 64.4 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-nitrobenzoic-acid (1.03 g, 5.65 mmole) and 2,3,5,6-tetrafluoro-4-trifloromethylbenzyl bromide (1.01 g, 6.04 mmole)(ACROS, 33074-0010), 1.50 g (76.3% yield) of 2-nitro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1
Reactant: Cc1cc2ccccc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc2ccccc2o1
Temperature: 25 °C
Yield: 102.6 %

Procedure:
A suspension of 2-methylbenzofuran (0.708 g) and N-bromosuccinimide (0.963 g) in carbon tetrachloride (10 ml) was heated at reflux temperature for 2.5 hours. To the mixture was added 2,2'-azobis(isobutyronitrile) (0.1 g) and heated at the same temperature for additional 1 hour. The reaction mixture was allowed to cool to room temperature. The resultant precipitates were filtered off by suction. The filtrate was concentrated in vacuo to give 2-bromomethylbenzofuran (1.16 g), which was used in a following reaction step without further purification.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].[S:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[S:26][CH:30]=[CH:29][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: c1cscn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Product: O=C(c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1)c1nccs1

Procedure:
This compound is prepared by method C using compound 12j and thiazole
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH2:19]([C:26]1[O:27][C:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:29]([C:31](O)=[O:32])[N:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:29]3[N:30]=[C:26]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:27][C:28]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)c1nc(Cc2ccccc2)oc1-c1ccccc1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(Cc4ccccc4)oc3-c3ccccc3)cn2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-benzyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.06 min; [M+H]+=467.69.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.[CH2:25](O)[CH2:26][CH2:27][CH3:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH2:25][CH2:26][CH2:27][CH3:28])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: CCCCO
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Product: CCCCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Yield: 77 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and 1-butanol (7.4 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107. The title compound was obtained in 77% yield (18.5 mg). 1H NMR (500 MHz, CDCl3) δ ppm 0.95 (t, J=7.39 Hz, 3 H) 1.37-1.46 (m, 2 H) 1.65-1.72 (m, 2 H) 2.44 (s, 3 H) 4.27 (t, J=6.65 Hz, 2H) 6.88 (s, 1 H) 7.36 (dd, J=8.06, 7.67 Hz, 1 H) 7.42 (ddd, J=8.06, 2.32, 1.22 Hz, 1 H) 7.45 (dd, J=8.67, 1.95 Hz, 1 H) 7.71 (dd, J=8.67, 0.52 Hz, 1 H) 7.70-7.71 (m, 1 H) 7.71 (dd, J=1.95, 0.52 Hz, 1 H) 7.84 (ddd, J=7.67, 1.50, 1.21 Hz, 1 H). MS (ESI+) m/z 438 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]([O:19]C)=[O:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO>[Br:1][C:2]1[C:3]([F:21])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]([OH:19])=[O:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nn(-c2cccc(Br)c2F)cc(OC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cn(-c2cccc(Br)c2F)nc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a suspension of methyl 1-(3-bromo-2-fluorophenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (4.16 g, 11.7 mmol) in MeOH (46 mL) was added 1 M NaOH aqueous solution (23 mL) at 0° C. The mixture was stirred at room temperature for 1 h. To the solution was added 1 M HCl aqueous solution (23 mL) at 0° C. The mixture was concentrated in vacuo. The precipitates were collected by filtration, washed with water and dried in vacuo at 50° C. to yield the title compound (3.76 g, 94% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.87 (3H, s), 7.43 (1H, td, J=8.1, 1.5 Hz), 7.76-7.85 (1H, m), 7.98 (1H, ddd, J=8.0, 6.5, 1.3 Hz), 8.86 (1H, s), 14.84 (1H, brs).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=2)[O:2]1.O.[NH2:26][NH2:27]>C(O)CC>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[C:5]3[CH:4]=[C:3]4[O:2][CH2:1][O:9][C:8]4=[CH:7][C:6]=3[CH2:10][C:11](=[O:12])[NH:27][N:26]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccc(OC)cc1)OCO2
Reactant: NN
Solvent: CCCO
Solvent: O
Product: COc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1

Procedure:
The title compound was prepared from methyl 4,5-methylenedioxy-2-(4-methoxybenzoyl)phenylacetate (102 mg, 0.31 mmol) and hydrazine hydrate (30 μL, 0.53 mmol) in 1-propanol (8 mL), mp: 194°-196° C. 1H NMR (CDCl3) 8.48 (s, 1H), 7.55 (d, 2H, J=8.8), 6.94 (d, 2H, J=8.8), 6.83 (s, 1H), 6.66 (s, 1H), 6.03 (s, 2H), 3.86 (s, 3H), 3.44 (s, 2H). Anal. calcd. for C17H14N2O4 : C, 65.80; H, 4.55; N, 9.03. Found: C, 65.56; H, 4.57; N, 8.72.
Reaction SMILES: [CH3:1][O:2][P:3](=[O:14])([O:12][CH3:13])[O:4][CH:5]1[CH2:9][O:8]C(C)(C)[O:6]1.Cl>ClCCl.CO.COC>[CH3:1][O:2][P:3](=[O:14])([O:12][CH3:13])[O:4][CH:5]([OH:6])[CH2:9][OH:8]
Reactant: COP(=O)(OC)OC1COC(C)(C)O1
Agent: COC
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COP(=O)(OC)OC(O)CO
Temperature: 25 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
To a solution of phosphoric acid 2,2-dimethyl-[1,3]-dioxolan-4-yl ester dimethyl ester (600 mg, 2.5 mmol) in 3.0 mL of dichloromethane and 0.5 mL of methanol was added 3.5 mL of 1 M solution of hydrogen chloride in dimethylether dropwise. The reaction mixture was stirred for 5 h at room temperature and concentrated. The residue was purified by silica gel chromatography eluting with CH2Cl2-Methanol (9:1) to yield 321 mg (69%) of phosphoric acid 1,2-dihydroxy-ethyl ester dimethyl ester as an oil. 1H NMR (400 MHz, DMSO-d6) δ 4.99 (d, J=5.2 Hz, 1H, OH), 4.66 (t, J=5.6 Hz, 1H, OH), 3.93-3.98 (m, 1H), 3.78-3.83 (m, 1H), 3.65 (d, J=11.2 Hz, 6H), and 3.27-3.37 (m, 3H). 31P NMR (162 MHz, d6-DMSO) δ 2.51.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Br-].C([N+](C)(C)C)C1C=CC=CC=1.CC(O)=O.CC(O)=O.[Pd]>[C:6]1([N:5]2[CH2:4][C:3]3[C:18](=[CH:19][CH:20]=[CH:21][CH:2]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Brc1ccccc1CN(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: c1ccc(N2Cc3ccccc3-c3ccccc32)cc1
Temperature: 120 °C
Reaction time: 9 h

Procedure:
10 g (0.295 mol) of (2-bromobenzyl)diphenylamine are dissolved in 500 ml of dimethylformamide under protective atmosphere. 3.4 g (0.075 mol) of benzyltrimethylammonium bromide and 6.1 g (0.443 mol) of potassium carbonate are added to this solution. 0.99 g (0.004 mol) of Pd(OAC)2 is subsequently added under protective gas, and the mixture is stirred at 120° C. for 9 h. After this time, the reaction mixture is cooled to room temperature and extracted with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is recrystallised from n-heptane. The yield is 6 g (80%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:27][CH:28]([CH3:30])[CH3:29]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:18]1
Reactant: CC(C)CI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(CC(C)C)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and 1-iodo-2-methylpropane.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]=[C:5]([C:22](OCC)([O:25]CC)[CH2:23][Br:24])[C:6]([NH:8][CH:9]1[C:20](=[O:21])[N:11]2[CH:12]([C:17]([OH:19])=[O:18])[CH:13]([OH:16])[CH2:14][S:15][C@H:10]12)=[O:7]>C(Cl)Cl>[CH3:2][O:3][N:4]=[C:5]([C:22](=[O:25])[CH2:23][Br:24])[C:6]([NH:8][CH:9]1[C:20](=[O:21])[N:11]2[CH:12]([C:17]([OH:19])=[O:18])[CH:13]([OH:16])[CH2:14][S:15][C@H:10]12)=[O:7]
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: Cl
Solvent: ClCCl
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 121.5 %

Procedure:
6 N Hydrochloric acid (2 ml) was added to a solution of 7-(2-methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 500 mg) in methylene chloride (5 ml) under ice-cooling and stirred at room temperature for 70 minutes. The precipitates were collected by filtration, washed with a saturated aqueous solution of sodium chloride (5 ml) and methylene chloride (1 ml) successively, and dried over phosphorus pentachloride to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 517 mg), purity: 57.8%.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([S:26][CH3:27])=[C:21](B(O)O)[CH:22]=1>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:18]=[C:17]([CH3:16])[CH:22]=[CH:21][C:20]=2[S:26][CH3:27])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CSc1ccc(C)cc1B(O)O
Product: CSc1ccc(C)cc1-c1nc2cc(F)cc(F)c2c(Cl)c1C

Procedure:
Essentially prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (130 mg, 0.51 mmol) and 5-methyl-2-(methylthio)phenylboronic acid to give 4-chloro-5,7-difluoro-3-methyl-2-(5-methyl-2-(methylthio)phenyl)-quinoline. Mass Spectrum (ESI) m/e=350.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3Br)[N:18]=2)=[CH:8][C:7]=1[CH3:26].[CH:28]1(B(O)O)[CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.COCCOC>[CH:28]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:17]2[N:18]=[C:14]([CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([O:2][CH3:1])=[O:27])=[C:7]([CH3:26])[CH:8]=3)[S:15][CH:16]=2)[CH2:30][CH2:29]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)COc1ccc(OCc2nc(-c3ccccc3Br)cs2)cc1C
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: COCCOC
Solvent: CCO
Product: COC(=O)COc1ccc(OCc2nc(-c3ccccc3C3CC3)cs2)cc1C

Procedure:
{4-[4-(2-Bromo-phenyl)-thiazol-2-ylmethoxy]-2-methyl-phenoxy}-acetic acid methyl ester (30 mg, 0.067 mmol), cyclopropylboronic acid (6.9 mg, 0.080 mmol) and sodium carbonate (21 mg, 0.20 mmol) are dissolved in water (120 μL), ethanol (90 μL) and 1,2-dimethoxyethane (360 μL). Pd(PPh3)4 (10 mol %) is added, and the mixture is subjected to microwave (180° C.) for 5 min in a sealed tube to give crude methyl 2-(4-((4-(2-cyclopropylphenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetate, which is used without further purification in Step B.