Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:18].[Sn].Cl>C(O)C>[C:12]1([C:8]2[CH:7]=[C:6]3[C:11]([CH2:3][C:4](=[O:18])[NH:5]3)=[CH:10][CH:9]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CSC1C(=O)Nc2cc(-c3ccccc3)ccc21
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: O=C1Cc2ccc(-c3ccccc3)cc2N1

Procedure:
A mixture of 3.5 g. (0.014 mole) of 3-methylthio-6-phenylindolin-2-one, 7 g. of tin, 10 ml. of concentrated hydrochloric acid and 50 ml. of ethanol was refluxed 4 hours under nitrogen. The hot mixture was filtered and the filtrate concentrated to give a tan solid. The solid was further purified by vacuum sublimation at 0.01 mm. and 200° C. and then crystallized from benzene to give 0.5 g. (17%) of product as a white solid which melted at 173°-175° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:19])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9].[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:26](=[O:28])[CH3:27])=[C:14]([CH3:19])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: Cc1cc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Chloro-1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid (1.1 g) was dissolved in 10 ml of pyridine, then 2 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 2 hours and evaporated to dryness under reduced pressure. The residue was purified by column chromatography using 20 g of silica gel. The desired fractions were combined and evaporated to dryness under reduced pressure and the residue was recrystallized from aqueous ethanol to give 0.7 g of 4-chloro-1-(4-acetoxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid as colorless needles, m.p. 200°-203° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl.[Cl:10][CH2:11][C:12](=N)OC>C(Cl)Cl>[Cl:10][CH2:11][C:12]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: COC(=N)CCl
Reactant: Nc1ccccc1S
Agent: Cl
Solvent: ClCCl
Product: ClCc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of aminothiophenol (8.3 g) in methylene chloride at 0° C. is added methyl chloroacetimidate hydrochloride [prepared according to procedures described by R. Rogers and D. G. Nielson, Chem. Rev., 61, 179 (1961)] (8.6 g). The reaction is allowed to warm to room temperature while stirring overnight. The mixture is washed with water three times; dried over magnesium sulfate and concentrated to an oil. The oil is distilled (120°-135° C. at 0.5 mm Hg) to give 7.8 g (71% yield) of product.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH:13]=[C:12]([C:15]2[NH:34][C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29]([CH3:33])[N:28]=[CH:27]5)[C:17]=3[CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[CH3:33][N:29]1[C:30]2[C:26](=[CH:25][C:24]([NH:23][C:22]3[C:17]4[CH:16]=[C:15]([C:12]5[CH2:13][CH2:14][NH:9][CH2:10][CH:11]=5)[NH:34][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:32][CH:31]=2)[CH:27]=[N:28]1
Reactant: Cn1ncc2cc(Nc3ncnc4[nH]c(C5=CCN(C(=O)OC(C)(C)C)CC5)cc34)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ncc2cc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 4.0 M solution of HCl in 1,4-dioxane (4.7 mL; 20 eq) was added to a suspension of 4-[4-(1-methyl-1H-indazol-5-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (415.4 mg, 0.9324 mmol, 1 eq) in 1,4-dioxane (8 mL) and stirred at rt for 2 h. The solid was filtered off, washed several times with dioxane, and dried under vacuum, yielding the title compound, as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.65 (s, br, 2H), 3.32 (s, br, 2H), 3.80 (s, br, 2H), 4.11 (s, 3H), 6.50 (s, 1H), 7.04 (s, br, 1H), 7.51 (dd, J=8.8, 1.6 Hz, 1H), 7.83 (d, J=9.2 Hz, 1H), 7.98 (s, 1H), 8.15 (s, 1H), 8.26 (s, 1H), 9.43 (s, br, —NH+—NH), 11.56 (s, br, —NH), 13.09 (s, H+). MS (ES+): m/z 346.16 (31) [MH+]. HPLC: tR=1.57 min (ZQ2000, polar—5 min).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[C:28]([CH3:33])=[N:29][O:30][C:31]=1[CH3:32])=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[C:28]([CH3:33])=[N:29][O:30][C:31]=3[CH3:32])[C:25]2=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: Cc1noc(C)c1N=C=O
Product: COc1cccc2c1ncc1c(=O)n(-c3c(C)noc3C)c(=O)n(C3CCCC3)c12
Yield: 83.7 %

Procedure:
1-Cyclopentyl-3-(3,5-dimethyl-isoxazol-4-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (17 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 4-isocyanato-3,5-dimethyl-isoxazole (0.05 mmol) following general procedure C. LCMS: m/z 407 [M+1]+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1>C(Cl)Cl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])=[CH:22][CH:23]=1
Reactant: O=C=Nc1ccccc1
Reactant: Fc1ccc(CNC2CCCC2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N(Cc1ccc(F)cc1)C1CCCC1
Yield: 90.3 %

Procedure:
6.1 g (0.05 mol) of phenyl isocyanate were added dropwise to a solution of 9.65 g (0.05 mol) of N-4-fluorobenzyl-N-cyclopentylamine in 80 ml of anhydrous methylene chloride, while cooling with ice and stirring. The mixture was stirred for 30 minutes at room temperature and for 30 minutes at 40° C., the solvent was stripped off in vacuo, and the residue was recrystallized from acetonitrile. 14.1 g of N-4-fluorobenzyl-N-cyclopentyl-N'-phenylurea of melting point 120° to 121° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]([CH3:22])=O>CCCCCC.C(OCC)(=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[C:20]#[C:22][C:12]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCC#CC#CCOc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
In a flask were placed 3.78 g (0.024 mole) of 1-chloro-2,4-nonadiyne thus obtained, 3.32 g (0.02 mole) of ethyl 4-hydroxybenzoate, 5.5 g (0.04 mole) of potassium carbonate, and 50 ml of acetone and the mixture was refluxed by heating for 11 hours. After allowing to cool the reaction mixture to room temperature, the reaction mixture was poured in 250 ml of ice-water and the product was extracted with methylene chloride. After distilling off the solvent of the organic layer, the residue formed was purified by a silica gel column chromatography(developing solvent: hexane/ethyl acetate=3/1) to provide 4.0 g (yield 70%) of ethyl 4-(2,4-nonadiynyloxy)-benzoate.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1.[Cl:12]N1C(=O)CCC1=O.Cl.O>CN(C=O)C.O1CCOCC1>[CH:11]1[C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=[C:6](/[C:7](/[Cl:12])=[N:8]\[OH:9])[CH:10]=1
Reactant: ON=Cc1ccc(CCl)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: O/N=C(/Cl)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
4-Chloromethylbenzaldehyde oxime (12.69 g, 74.82 mmol) was dissolved in DMF (250 ml), N-chlorosuccinimide (12.00 g, 89.87 mmol), and then 4N hydrogen chloride in 1,4-dioxane (120 ml) were added, and the mixture was stirred at room temperature for 30 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (15.27 g, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:6]=1[O:7][CH2:8][C:9](OC)=[O:10])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([C:5]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:6]=1[O:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)COc1cc(C)ccc1C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)C)c(OCCO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
To a solution of (methyl 2-(2-tert-butyl-5-methylphenoxy)acetate (7.16 g, 30.3 mmol) was added a 2.0M solution of LAH in THF (15.2 mL, 30.3 mL) under an ice-water bath. The resulting mixture was allowed to stir at room temperature for 10 minutes before it was quenched with ice chips. The solvent was removed, and 20 mL of 2.0N aqueous HCl solution was added. The resulting mixture was extracted with DCM (30 mL×3). The extract was washed with water, saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by CombiFlash to give 6.22 g of 46.3, which was eluted with 0-40% EtOAc in hexane.). MS ESI (pos.) m/e: 209 (+H). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J=8.0Hz, 1H), 6.76 (d, J=8.0Hz, 1H), 6.73 (s, 2H), 4.15 (dd, 2H), 4.04 (dd, 2H), 2.34 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]COCC)=[O:9])=[C:6]([O:15][CH2:16][C:17]2[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=2)[CH:5]=[CH:4][CH:3]=1.CO.Cl>O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:15][CH2:16][C:17]2[N:18]=[C:19]([O:25][CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[N:22]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOCOC(=O)c1c(Cl)cccc1OCc1nc(OC)cc(OC)n1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cc(OC)nc(COc2cccc(Cl)c2C(=O)O)n1
Yield: 96.2 %

Procedure:
3.8 g of ethoxymethyl 6-chloro-2-[(4,6-dimethoxy-2-pyrimidyl)methyloxy]benzoate was stirred in a mixed solvent of 30 ml of methanol and 10 ml of water, 0.5 ml of concentrated hydrochloric acid was added, and the mixture was subjected to reaction at room temperature for about 2 hours. The reaction solution was diluted with water and extracted with chloroform, the extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 3.1 g of 6-chloro-2-[(4,6-dimethoxy-2-pyrimidyl)methyloxy]benzoic acid (yield 95%).
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([OH:31])[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])C.[CH2:33]([OH:37])[CH:34]([CH3:36])[CH3:35].Cl.O1CCOCC1>>[CH2:33]([O:37][C:4](=[O:3])[C@H:5]([OH:31])[CH2:6][N:7]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:22][CH:23]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])[CH:34]([CH3:36])[CH3:35]
Reactant: CCOC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1
Reactant: CC(C)CO
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)COC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.9 %

Procedure:
(R)-3-[N-(3′-Chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxy-isoxazole-5-carbonyl)-hydrazino]-2-hydroxy-propionic acid ethyl ester (1.5 g, 3.3 mmol) was dissolved in isobutyl alcohol (20 mL, 200 mmol) and 4 M HCl in dioxane (10 mL, 40 mmol) was added. The mixture was stirred at room temperature for 6 hours. The mixture was concentrated, dissolved in water/MeCN/MeOH, and purified (Interchim C18 reverse phase chromatography column, 25-75% MeCN in water for 22 minutes). The clean fractions were combined and lyophilized to yield the title compound (948 mg; purity 99%). MS m/z [M+H]+ calc'd for C24H26ClN3O6, 488.15. found 488.4.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[C:5]([CH3:10])[C:4]=1[CH3:11].[CH2:12]([OH:15])[CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][O:15][C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[C:5]([CH3:10])[C:4]=1[CH3:11]
Reactant: OCCO
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [Na]
Product: Cc1c(OCCO)cc[n+]([O-])c1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
4.60 g (0.2 mol) of metallic sodium was dissolved in 80 ml of ethylene glycol under cooling with ice to obtain a solution. This solution was stirred in a nitrogen atmosphere at 100° C. for one hour, followed by the addition of 15.76 g (0.1 mol) of 4-chloro-2,3-dimethylpyridine N-oxide at a room temperature. The obtained mixture was stirred at 120° C. for 2 hours. After the completion of the reaction, the reaction mixture was distilled to dryness to remove the ethylene glycol. The obtained residue was purified by silica gel column chromatography (solvent: chloroform/methanol=19:1) to obtain 13.28 g of 4-(2-hydroxyethoxy)-2,3-dimethylpyridine N-oxide as a white crystal.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:18]([Cl:29])[CH:17]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].[CH3:38][NH:39][CH2:40][CH2:41][OH:42].O>CN(C)C=O>[Cl:29][C:18]1[CH:17]=[C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:39]([CH2:40][CH2:41][OH:42])[CH3:38])=[C:6]([O:30][CH3:31])[CH:7]=3)[N:12]=[CH:11][CH:10]=2)[CH:21]=[CH:20][C:19]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: CNCCO
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCBr)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCN(C)CCO)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 106 %

Procedure:
A starting compound (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-propylurea, 50 mg), potassium carbonate (138 mg), and 2-(methylamino)ethanol (0.040 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 53 mg (yield 106%) of the title compound.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]1[CH:32]=[CH:31][C:13]([O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[C:23]([C:28](O)=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)=[O:7])(C)(C)C.[NH4+].O[N:35]1C2C=CC=CC=2N=N1>>[NH2:35][C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][O:14][C:13]2[CH:31]=[CH:32][C:10]([CH2:9][CH2:8][C:6]([OH:5])=[O:7])=[CH:11][CH:12]=2)[CH:17]=1)=[O:29]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(-c3ccccc3C(=O)O)c2)cc1
Agent: [NH4+]
Product: NC(=O)c1ccccc1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1

Procedure:
The title compound was synthesized in the same manner as in Example 285 from 3′-[4-(2-tert-butoxycarbonylethyl)phenoxymethyl]biphenyl-2-carboxylic acid and 1-hydroxybenzotriazole ammonium salt. colorless crystals (yield 66%). MS (APCI−): 374 (M−H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].C1([Mg]Br)C=CC=CC=1.[Li]CCCC.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Br:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH:23]([OH:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]=1[OH:8]
Reactant: O=Cc1ccccc1
Reactant: Oc1c(Br)cncc1Br
Agent: Br[Mg]c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Oc1c(Br)cncc1C(O)c1ccccc1
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a heterogeneous mixture of 3,5-dibromo-4-hydroxypyridine (2.53 g, 10 mmol, prepared following the procedure in Synthesis, 2001, 14, 2175-2179) in anhydrous THF (20 mL) at −78° C. under Ar-atm was added phenylmagnesium bromide solution (11 mL of 1 M solution in THF, 11 mmol). After stirring for 15 min. was added n-BuLi solution (5.5 mL of 2 M solution in cyclohexane), and the reaction mixture was stirred for 15 min at −78° C. under Ar-atm. To this mixture benzaldehyde (2.15 mL) was added and the reaction mixture was stirred for 2 h −78° C. under Ar-atm. The reaction mixture was quenched by adding HOAc (3 mL) and TFA (3 mL), concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc/MeOH/750:250:50 followed by hexane/EtOAc/MeOH/Et3N/460:460:50:10 to afford the desired product (2.85 g, 91%) as a white solid. 1H NMR (CD3OD) δ 8.13 (s, 1H), 8.04 (s, 1H), 7.41-7.20 (m, 5H), 5.94 (s, 1H); MS (ESI+) m/z 280, 282 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2=[N:10][C:11]([Br:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:27][C@H:26]([CH3:28])OS1(=O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[N:15]([C@H:26]([CH3:28])[CH2:27][NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:9]2=[N:10][C:11]([Br:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(Br)nc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2ccc(Br)nc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
This compound was prepared in analogy to example 3, intermediate j) from 6-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo- [1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][O:26]C3CCCCO3)=[CH:19][C:18]=2[F:33])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]>CCO.Cl.O>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][OH:26])=[CH:19][C:18]=2[F:33])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(C#CCOC2CCCCO2)cc1F
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(C#CCO)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
3,4-Difluoro-2-{2-fluoro-4-[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]anilino}-N-(2-hydroxyethoxy)benzamide (115 mg, 0.25 mmol) was dissolved in EtOH (4 mL) to which was added 1 M HCl (5 drops). This reaction mixture was stirred overnight at RT, then the mixture was diluted with water (50 mL) and extracted with EtOAc (4×30 mL). The combined EtOAc fractions were washed with water (2×20 mL), brine (50 mL) and dried (Na2SO4) then the solvent removed under reduced pressure to afford a white solid which was purified by filtration through a plug of silica gel (EtOAc as eluant) to afford 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]-N-(2-hydroxyethoxy)benzamide as a cream solid (94 mg, 100%); m.p. (Et2O/hexane) 169–172° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.84 (br s, 1 H), 8.91 (br s, 1 H), 7.46–7.40 (m, 1 H), 7.29–7.19 (m, 2 H), 7.10 (dd, J=8.3, 1.6 Hz, 1 H), 6.78 (ddd, J=8.9, 8.9, 4.8 Hz, 1 H), 5.29 (t, J=5.9 Hz, 1 H), 4.76 (br s, 1 H), 4.27 (d, J=5.9 Hz, 2 H), 3.84 (t, J=4.8 Hz, 2 H), 3.56 (t, J=4.8 Hz, 2 H). Anal. calcd. for C18H15F3N2O4: C, 56.9; H, 4.0; N, 7.4. Found C, 56.8; H, 4.0; N, 7.4.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][O:20][C:12]3=[CH:11][C:10]=2[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br.Br[CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][O:20][C:12]3=[CH:11][C:10]=2[N:9]([CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2c[nH]c3cc4c(cc3c2=O)OCO4)cc1C
Reactant: BrCc1ccncc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ccncc3)c3cc4c(cc3c2=O)OCO4)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 71 mg (0.22 mmol) of 7-(3,4-dimethyl-benzoyl)-5H-[1,3]dioxolo[4,5-g]quinolin-8-one, 23 mg of 60% sodium hydride, 72 mg of 4-bromomethylpyridine hydrobromide and 1.3 mL of N,N-dimethylformamide. Yield: 61 mg of a white solid: LC-MSD, m/z for C25H20N2O4 [M+H]+=413.5; HPLC retention time: 1.2 min.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[ClH:38]>CCOC(C)=O>[ClH:38].[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1C1CCNCC1)OCC1c2ccccc2-c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in Example 16 (Step b) from tert-butyl 4-(2-[(fluoren-9-ylmethoxy)carbonylamino]phenyl)piperidine-carboxylate (Step a) (7.49 g, 15 mmol) and satd anhydrous HCl in EtOAc (50 mL). The title compound was obtained as a white solid (6.51 g). MS (ESI, pos. ion) m/z: 399 (M+1); MS (ESI, neg. ion) m/z: 397 (M−1). Calc'd for C26H27ClN2O2: 398.20.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][N:8]([CH3:30])[CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(NCC)C.[Li].[CH2:37]([O:39][C:40]([C:42]1[NH:43][C:44]2[C:49]([C:50]=1[CH:51]=O)=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH3:38]>C1COCC1>[CH2:37]([O:39][C:40]([C:42]1[NH:43][C:44]2[C:49]([C:50]=1[CH:51]=[CH:10][CH2:9][N:8]([CH3:30])[CH3:7])=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH3:38]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C=O
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2ccccc2c1C=CCN(C)C
Reaction time: 0.5 h

Procedure:
Butyllithium (1.1 equiv.) was added to a suspension of (2-dimethylaminoethyl)triphenylphosphonium bromide in THF (0.2 M) at 0° C. After stirring for 30 minutes, lithium diethylamine (1.1 equiv.) was added dropwise followed by the cold suspension of 3-formyl-1H-indole-2-carboxylic acid ethyl ester (3.96 g, 18.2 mmol) in THF. The resulting orange suspension was stirred for 18 hours. The reaction was then quenched with saturated ammonium chloride and extracted with 10% MeOH in DCM. The organic layer was washed with saturated sodium bicarbonate, dried and concentrated to give 3-(3-dimethylaminopropenyl)-1H-indole-2-carboxylic acid ethyl ester as a brownish-red waxy solid.