Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]([CH2:4][C:5]([O:7]CC)=O)[NH2:3].[N:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17])=[C:11]=[S:12].C(N(C(C)C)CC)(C)C>ClCCl>[NH2:3][N:2]1[CH2:4][C:5](=[O:7])[N:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=[O:17])[CH:14]=2)[C:11]1=[S:12]
Reactant: CCOC(=O)CNN
Reactant: O=C(O)c1cccc(N=C=S)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NN1CC(=O)N(c2cccc(C(=O)O)c2)C1=S
Reaction time: 96 h
Yield: 19.9 %

Procedure:
Ethyl hydrazinoacetate hydrochloride (155 mg, 1.00 mmol) was added to a stirred solution of 3-isothiocyanatobenzoic acid (179 mg, 1.00 mmol) and di-isopropylethylamine (523 uL, 3.00 mmol) in dichloromethane (4 mL). The mixture was stirred for 96 h, evaporated under reduced pressure and partitioned between aqueous acetic acid and ethyl acetate. The organic extracts were washed with water, saturated aqueous sodium chloride, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was chromatographed (silica gel, 5-15% methanol/ethyl acetate, then 20% methanol/ethyl acetate ±0.5% acetic acid) to give 1-amino-3-(3-carboxyphenyl)-2-thioxoimidazolidin-4-one (50 mg, 51%) contaminated with 6% uncyclised by-product, suitable for the next step. A solution of 1-amino-3-(3-carboxyphenyl)-2-thioxoimidazolidin-4-one (50 mg, 0.199 mmol) and 1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazole-4-carbaldehyde (55 mg, 0.239 mmol) in ethanol/methanol (2:1, 15 mL) was allowed to stand a room temperature for 96 h. The solid was filtered off, washed with ether and dried to give the title compound (42 mg, 46%) as a powder. LCMS, m/e 464 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]=[O:12]>C(=O)([O-])[O-].[K+].[K+]>[OH:12][CH2:11][NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)Cc1ccccc1
Reactant: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(Cc1ccccc1)NCO
Yield: 44.4 %

Procedure:
A mixture of phenylacetamide 12 (2 g, 15 mmol) in a solution of potassium carbonate (4%, 2 ml, 0.6 mmol) and an aqueous solution of formaldehyde (37%, 2 ml, 20 mmol) was refluxed for 15 min (until completely dissolved). The mixture was cooled and extracted with CH2Cl2 (2×30 ml). The combined organic phases were dried over MgSO4 and were concentrated under reduced pressure to give a crude product (1.35 g), recrystallization in toluene (20 ml) gave N-hydroxymethylphenylacetamide 11 (1.1 g, 44%) in the form of a white powder. M.p. 78° C. 1H NMR (CDCl3, 300 MHz) δ 7.50-7.20 (m, 5H), 6.48 (br s, NH), 4.69 (t, J=7.0 Hz, 2H), 3.67 (t, J=7 Hz, OH), 3.60 (s, 2H). 13C NMR (CDCl3, 75 MHz) δ 172.9, 134.4, 129.5, 129.0, 127.5, 64.2, 43.6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21]COC)=[C:6]([CH:20]=1)[C:7]([C:9]1[C:14]([CH:15]2OCC[O:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].Cl.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[C:7]([C:9]1[C:14]([CH:15]=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8]
Reactant: COCOc1ccc(Br)cc1C(=O)c1ncccc1C1OCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=Cc1cccnc1C(=O)c1cc(Br)ccc1O
Yield: 97.1 %

Procedure:
A mixture solution of 2-(5-bromo-2-methoxymethoxybenzoyl)-3-(1,3-dioxolan-2-yl)pyridine (4.27 g), hydrochloric acid (9 ml) and THF (81 ml) was stirred for 14 hours at room temperature. The reaction mixture was neutralized with an aqueous sodium hydroxide, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give a mixture (3.22 g) of 2-(5-bromo-2-hydroxybenzoyl)-3-formylpyridine and 2-(5-bromo-2-hydroxybenzoyl)-3-(1,3-dioxolan-2-yl)pyridine (about 7:2). A mixture of the said mixture (3.22 g), ethylene glycol (560 mg), p-toluenesulfonic acid monohydrate (170 mg) and toluene (40 ml) was subjected to heating under reflux azeotropically. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 2-(5-bromo-2-hydroxybenzoyl)-3-(1,3-dioxolan-2-yl)pyridine (2.92 g) (Compound E-2). The physical properties and spectrum data are shown in Table 16 and Table 18.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][NH2:37])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][NH:37][C:15]2[N:14]=[C:13]([C:11]3[S:10][C:9]4[CH:21]=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[CH:6]=[CH:7][C:8]=4[CH:12]=3)[C:18]([CH3:19])=[CH:17][N:16]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CNC(=O)c1ccc2cc(-c3nc(Cl)ncc3C)sc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2cc(-c3nc(NCCC4CCN(C(=O)OC(C)(C)C)CC4)ncc3C)sc2c1
Temperature: 95 °C
Yield: 43.2 %

Procedure:
A stirred mixture of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-6-carboxylic acid methylamide (400 mg, 1.20 mmol), 4-(2-aminoethyl)-piperidine-1-carboxylic acid tert-butyl ester (688 mg, 3.01 mmol) and diisopropylethylamine (467 mg, 3.61 mmol) in 1,4-dioxane (4 mL) is heated at 95° C. under nitrogen for 3 days. At room temperature the mixture is concentrated and the crude product is chromatographed on silica gel, eluting with EtOAc in dichloromethane 0-35%, to give 4-{2-[5-methyl-4-(6-methylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester as a solid (264 mg, 43% yield). The intermediate is subjected to deprotection by dissolving this material (264 mg, 0.518 mmol) in MeOH (12 mL) and bubbling anhydrous HCl gas for 5 minutes. The hot, yellow solution is allowed to sit at room temperature for 2 hours, then concentrated to give the title compound as a yellow solid (246 mg, 98% yield). ES+(m/z) 410 [M(free base)+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13](=O)[CH2:14][CH3:15])[CH2:8][CH2:7][CH2:6]2.[CH3:17][NH2:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH:13]([NH:18][CH3:17])[CH2:14][CH3:15])[CH2:8][CH2:7][CH2:6]2
Reactant: CCC(=O)C1CCCc2cc(OC)ccc21
Reactant: CN
Product: CCC(NC)C1CCCc2cc(OC)ccc21

Procedure:
Using the product of Example 105 with the procedure described in Example 98 but replacing the ethylamine with methylamine gave the desired product.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH3:7]/[C:8](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:9]\[CH:10]=[O:11].Cl>>[OH:11][C@@H:10]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])/[CH:9]=[C:8](\[CH3:7])/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COP([O-])OC
Reactant: C/C(=C\C=O)c1ccccc1
Agent: Cl
Product: COP(=O)(OC)[C@H](O)/C=C(\C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes, then (E)-β-methylcinnamaldehyde (0.40 mmol) was added thereto. After reacting for 81 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S,E)-1-hydroxy-3-methyl-3-phenyl-2-propenylphosphonate as a final product in a yield of 93%. The chemical reaction in this Example is shown in chemical formula 35.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2=[CH:13][S:14][CH:15]=[C:4]2[C:3]1=[O:16].[C:17](Cl)(=[O:19])[CH3:18]>C1C=CC=CC=1>[C:17]([N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:16])[C:4]2=[CH:15][S:14][CH:13]=[C:5]12)(=[O:19])[CH3:18]
Reactant: CN1C(=O)c2cscc2Nc2ccccc21
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Product: CC(=O)N1c2cscc2C(=O)N(C)c2ccccc21
Reaction time: 3 h

Procedure:
A mixture of 7 g. of 4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2.7 g. of acetyl chloride in 75 ml. of benzene is heated under reflux with stirring for 3 hours. The reaction mixture is cooled in an ice bath and two crops of brown crystals are collected, washed with benzene, dried and combined. Concentration of the benzene provides a third crop which is combined with the first two crops, heated to boiling in 250 ml. of ethyl acetate and filtered while hot. An equal amount of hexane is added, the mixture is cooled and the solid is collected, washed with hexane and dried, giving the desired product, mp. 197°-199° C.
Reaction SMILES: [Na+].[Cl:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:6][C:7]1[NH:8][C:9](=[O:20])[C:10]2[C:15]([CH3:16])=[C:14]([C:17]([O-:19])=[O:18])[S:13][C:11]=2[N:12]=1.[OH-].[Na+].Cl>O>[Cl:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:6][C:7]1[NH:8][C:9](=[O:20])[C:10]2[C:15]([CH3:16])=[C:14]([C:17]([OH:19])=[O:18])[S:13][C:11]=2[N:12]=1
Reactant: Cc1c(C(=O)[O-])sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid mono sodium salt (2.503 g), 1 mol/L aqueous sodium hydroxide solution (6.4 mL) and water (22.5 mL) was dissolved by stirring with heating. The reaction mixture was allowed to cool under room temperature, neutralized with 1 mol/L hydrochloric acid (12.8 mL), and water (8.3 mL) was added. The mixture was stirred with heating under reflux for 8 hr, and further at about 70° C. for 8 hr. Water (50 mL) was added (solvent amount was set to 100 mL), and the mixture was cooled to about 21° C. The suspension was poured into a G2 glass filter (diameter 3 cm), and the pressure reduction was started at 50 hpa. The time necessary to the increase of pressure by the completion of filtration was 4 minutes 5 seconds. The height of the solid at that time was 2.1 cm (bulk 14.8 cm3). Then, an operation of washing the obtained solid with water (25 mL), followed by reduced pressure filtration at 50 hpa was repeated 3 times to confirm that the filtrate had pH 7. At this point, the total filtration time necessary for increasing the pressure was 6 minutes 33 seconds and the height of the final solid was 1.6 cm (bulk 11.3 cm3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH3:39])(=[O:38])=[O:37])[CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[C:23]([C:25](=[NH:28])[NH:26][OH:27])[CH:22]=[CH:21][C:20]=1[OH:29])(=[O:18])=[O:17])[CH3:2].[CH2:41](O)[CH2:42]CC.[ClH:46]>>[ClH:46].[CH2:1]([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH3:39])(=[O:37])=[O:38])[CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[C:23]([C:25](=[NH:28])[NH:26][OH:27])[CH:22]=[CH:21][C:20]=1[OH:29])(=[O:18])=[O:17])[CH2:2][CH2:41][CH3:42]
Reactant: CCCCO
Reactant: CCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C(=N)NO)ccc1O
Agent: Cl
Product: CCCCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C(=N)NO)ccc1O

Procedure:
Method 1) A solution of 1.499 g of ethyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]-ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate in 20 mL of 34% hydrogen chloride n-butanol solution was stirred at 60° C. for 3 hours. After being concentrated under reduced pressure, the reaction mixture was recrystallized from n-butanol-diisopropyl ether to give 1.472 g of n-butyl[4-[2-[2-hydroxy-5-(N-hydroxycarbamimidoyl)benzenesulfonylamino]ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate hydrochloride as a white crystal.
Reaction SMILES: [CH:1]1([CH:6]([C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:19])O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:22][CH:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][C:9]=1[CH3:19]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)cc1C(O)C1CCCC1
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)cc1C(Cl)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of cyclopentyl(2-methyl-5-phenylfuran-3-yl)methanol (0.9 g) in toluene (20 mL) was added thionyl chloride (0.5 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (1.0 g, 100%) as an oil.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([CH2:4][S:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)CC2CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(CC1CC1)C1CCNCC1
Temperature: 25 °C

Procedure:
To an ice-cold solution of tert-butyl 4-(cyclopropylmethylsulfonyl)piperidine-1-carboxylate (53, 0.9 g, 2.96 mmol) in CH2Cl2 (15 mL) was added TFA (3.0 mL). The mixture stirred at room temperature and stirred for 3 h and was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (25 mL) and the organic layer was washed with saturated NaHCO3 solution (10 mL), H2O (15 mL) brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (Isco CombiFlash Companion unit, 40 g Redisep column, 30% to 50% EtOAc in hexanes) to give 4-(cyclopropylmethylsulfonyl)piperidine as a white foam (54, 0.38 g, 63%); 1H NMR (300 MHz, MeOH-d4): δ 3.27-3.24 (m, 1H), 3.23-3.12 (m, 2H), 2.99 (d, J=7.2 Hz, 2H), 2.63 (dt, J=2.4, 12.0 Hz, 2H), 2.10-2.01 (m, 2H), 1.77-1.60 (m, 2H), 1.27-1.14 (m, 1H), 0.83-0.64 (m, 2H), 0.45-0.39 (m, 2H);
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)CCC.I[C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[N:24][CH:25]=1>C1(C)C=CC=CC=1.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>[S:7]1[CH:8]=[CH:9][N:10]=[C:6]1[C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[N:24][CH:25]=1
Reactant: Nc1cncc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Nc1cncc(-c2nccs2)c1
Temperature: 115 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
The mixture of 2-tributylstannylthiazole (2.24 g, 6.00 mmol), 5-iodopyridin-3-ylamine (1.10 g, 5.00 mmol) and Pd(Ph3P)4 (580 mg, 0.5 mmol) in 50 mL toluene was degassed using Ar. The mixture was then stirred under Ar at 115° C. for 3 h. The mixture was concentrated and subjected to flash column (0 to 7% MeOH in DCM) to isolate 5-(thiazol-2-yl)pyridin-3-amine (740 mg, 84% yield).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br.Br[CH2:16][CH2:17][CH2:18][NH2:19].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:19][CH2:18][CH2:17][CH2:16][N:5]1[CH2:4][CH2:3][C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6]1
Reactant: CC1(c2ccccc2)CCNCC1
Reactant: NCCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1(c2ccccc2)CCN(CCCN)CC1
Yield: 18.2 %

Procedure:
4-Methyl-4-phenylpiperidine (1.00 g, 5.70 mmol, 1.00 equiv), 3-bromopropylamine hydrobromide (1.87 g, 8.55 mmol, 1.00 equiv) and potassium carbonate (1.97 g, 14.2 mmol, 2.5 equiv) were stirred in refluxing dioxane (20 mL) for 36 hours. After removal of the solvent, water (50 mL) was added and the pH was adjusted to 11-12 by addition of 1N aqueous NaOH. The mixture was extracted with CH2Cl2 (150 mL+3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, CHCl3-MeOH—NH3 (2M in MeOH) 100:20:10) to give 241 mg (18%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: [CH3:1][C:2]1[NH:8][CH:7]=[C:6]([C:9]([OH:11])=[O:10])[C:4](=[O:5])[CH:3]=1.N1C=CC=CC=1.[Br:18]Br>C(O)(=O)C>[Br:18][C:3]1[C:4](=[O:5])[C:6]([C:9]([OH:11])=[O:10])=[CH:7][NH:8][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc(=O)c(C(=O)O)c[nH]1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: Cc1[nH]cc(C(=O)O)c(=O)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To 6-methyl-4-(1H)-pyridone-3-carboxylic acid (prepared according to the procedure described in J. Org. Chem., 1972, 37, 1145-1148) (10.0 g, 65.4 mmol) and dry pyridine (5.2 ml) in acetic acid (200 ml) at 100° C. was added bromine (14.6 g, 91.5 mmol) in acetic acid (30 ml) dropwise over 1 hour. Heating was continued for 2 hours then cooled to room temperature. The precipitate which formed on cooling was collected by filtration, and washed with methanol to give the product as a cream coloured solid (10.62 g, 70%). 1H NMR (250 MHz, DMSO-d6) δ14.75 (1H, br s), 13.45 (1H. br s), 8.58 (1H, s), 2.53 (3H, s); MS (ES+) m/z 232/234 MH]+, 214/216 [(M-(H2O))H]+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:22]([NH2:30])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH:22]([NH:30][C:9]([CH2:8][NH:7][C:6](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=2)=[O:11])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: NC(c1cccc(F)c1)c1cccc(F)c1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and C,C-bis-(3-fluoro-phenyl)-methylamine (CA [261925-16-0]).
Reaction SMILES: [O:1]=[C:2]([C:9]([F:12])([F:11])[F:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13]I.[Cl-].[NH4+].O>C(COC)OC.[Cl-].[Na+].O>[O:1]=[C:2]([C:9]([F:10])([F:11])[F:12])[CH:3]([CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CI
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (7.05 g of a 50% oil dispersion, 0.15 mol) was washed 3 times with 25 ml of dimethoxyethane to remove the oil and then suspended in 220 ml of dimethoxyethane, under an argon atmosphere and cooled in an ice bath. A solution of ethyl 3-keto-4,4,4-trifluorobutanoate (25.77 g, 0.14 mol) in 25 ml of dimethoxyethane was added dropwise from an addition funnel to the stirred suspension. After the addition was completed, the cooling bath was removed and the reaction mixture stirred for 30 minutes past the cessation of hydrogen gas evolution. Methyl iodide (43.0 ml, 0.70 mole) was added by syringe and the reaction mixture refluxed overnight. The reaction was cooled to room temperature and poured into a separatory funnel containing a 1:1:1 mixture of saturated ammonium chloride:brine:water. The layers were separated and the aqueous phase extracted with 100 ml ether. The combined organic phase and ether extract was washed with brine, dried over magnesium sulfate and filtered. The solvents were removed by distillation at atmospheric pressure using a Vigreaux column leaving ethyl 3-keto-2-methyl-4,4,4-trifluorobutanoate as the pot residue. Rf: (EtAc/hexane - 20:80)
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16])[CH:12]=2)[C:7]([CH3:20])=[N:6]1.[OH-].[K+:27]>C(O)C>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([F:19])([F:18])[C:15]([O-:17])=[O:16])[CH:12]=2)[C:7]([CH3:20])=[N:6]1.[K+:27]
Reactant: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(C(F)(F)C(=O)O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(C(F)(F)C(=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound [183](89 mg) in ethanol (2 mL) was added an aqueous solution of 1N-potassium hydroxide (233 μL) at room temperature, and then the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give the titled compound (98 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]#[N:14])[CH:7]=1.[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(Cl)Cl>[C:16]([C:10]1[NH:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH3:15])=[C:12]([C:13]#[N:14])[CH:11]=1)(=[O:18])[CH3:17]
Reactant: Cc1ccc(Cl)cc1-c1[nH]ccc1C#N
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C#N)c(-c2cc(Cl)ccc2C)[nH]1
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a mixture of 2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carbonitrile (1.80 g, 8.28 mmol) in DCM (40 mL) was added acetyl chloride (0.936 mL, 13.14 mmol) at room temperature, under nitrogen. The resultant mixture was cooled to 0° C. and anhydrous aluminum trichloride (2.62 g, 19.8 mmol) was added in small portions during a period of 10 min, keeping the internal temperature below 5° C. Upon complete addition, the mixture was brought to room temperature and allowed to stir for 30 min. Then, the mixture was slowly poured in a solution of ice-cooled 1 M HCl (18 mL). The aqueous layer was separated and extracted twice with DCM (40 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was chromatographed on silica gel (10 to 20% EtOAc/hexane) to afford the title compound (2.0 g, 86%).