Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[K+].CO>[O:1]([CH:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Oc1ccccc1)c1ccc(Oc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Oc1ccccc1)c1ccc(Oc2ccccc2)cc1

Procedure:
A mixture of 3.75 g of methyl α-(phenoxy)-α-[p-(phenoxy)phenyl]acetate in 20 ml of 20% KOH and 5 ml of methanol is refluxed overnight to afford, after acidification, a white solid, mp 144°-146° C. (from chloroform-petroleum ether).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ccc(O)cn1
Reactant: ClCc1ccccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2Cl)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.4 %

Procedure:
5-Hydroxy-2-methylpyridine (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 5.00 g, 45.8 mmol) was dissolved in DMF (90 mL) and K2CO3 (6.9 g, 50 mmol) and tetrabutylammonium iodide (2 g, 5.4 mmol) were added. 2-Chlorobenzyl chloride (6.4 mL, 50.6 mmol) was added and the mixture was stirred at room temperature for 20 h. The reaction mixture was partitioned between EtOAc (300 mL) and H2O (300 mL). The organic layer was dried (Na2SO4), filtered, evaporated, and purified by chromatography (30% EtOAc/hexane) to give 5-(2-chloro-benzyloxy)-2-methyl-pyridine (7.00 g, 66%) as a yellow oil.
Reaction SMILES: C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22]>N1C=CC=CC=1.C(N(CC)CC)C>[S:18]1[C:19]2=[N:27][CH:26]=[CH:25][CH:24]=[C:20]2[C:21](=[O:22])[NH:15]1
Reactant: O=C(O)c1cccnc1S
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=c1[nH]sc2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a solution of diphenylphosphoryl azide (39.41 g, 0.139 mol) in pyridine (160 ml) and triethylamine (19 ml) was added 2-mercaptonicotinic acid (21.57 g, 0.139 mol) portionwise at 0° C. The reaction mixture was stirred overnight at room temperature and afterwards concentrated in vacuo. Ethanol (15 ml) was added at 30° C. to the crude product. Filtration at room temperature afforded a yellow solid which was washed with ethanol (15 ml) and dried in vacuo (10 mbar). 17.04 g (89%) of the title compound were obtained as light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:20]([N:23]([CH3:25])[CH3:24])OC>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][C:9]=1[N:10]=[CH:20][N:23]([CH3:25])[CH3:24])=[O:4]
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Reaction time: 36 h

Procedure:
A solution of 3-amino-5-(4-chlorophenyl)thiophene-2-carboxylic acid methyl ester (5.0 g) in DMF (30 μL) was mixed with dimethoxymethyldimethylamine (5 mL) and stirred for 36 hours. The reaction solution was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The product with the molecular weight of 322.82 (C15H15ClN2O2S) was obtained in this way; MS (ESI): 323 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH:15]([C:16]([O:18]CC)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:21]([O:23]CC)=[O:22])[NH:3]1.[OH-].[Na+].Cl>C(O)C>[O:1]=[C:2]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:21]([OH:23])=[O:22])[NH:3]1
Reactant: CCOC(=O)C1CCCCCCCCCCC(C(=O)OCC)C(=O)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCCCCCCCCCC(C(=O)O)C(=O)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diethyl 2-oxo-1-azacyclotetradecane-3,14-dicarboxylate (1.14 g, 3.2 mmol; mixture of both diastereomers) is dissolved in ethanol (32.0 mL). Sodium hydroxide (9.6 mL of a 1N aqueous solution, 9.6 mmol) is added dropwise, and the solution is stirred at room temperature for 3 hours. The reaction is then acidified to pH 3 with 1N hydrochloric acid, and partitioned between ethyl acetate and water. The aqueous phase is extracted several times with ethyl acetate, the combined organic layers are dried (Na2SO4), and the solvent is evaporated to give both diastereomers of 2-oxo-1-azacyclotetradecane-3,14-dicarboxylic acid.
Reaction SMILES: [Li+].[OH-].[CH3:3][N:4]([CH3:26])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([CH:17]=1)[C:13]([O:15]C)=[O:14])(=[O:7])=[O:6].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH3:3][N:4]([CH3:26])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([CH:17]=1)[C:13]([OH:15])=[O:14])(=[O:6])=[O:7]
Reactant: COC(=O)c1cc(S(=O)(=O)N(C)C)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Temperature: 50 °C

Procedure:
LiOH (20.56 mg, 0.86 mmol) was added to a stirred solution of methyl 5-[(dimethylamino) sulfonyl]-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 62; 300 mg, 0.86 mmol) in a mixture of tetrahydrofuran and water (3:1, 40 ml). The mixture was heated at 50° C. for 6 h, and then diluted with ethyl acetate (50 ml). 10% Aqueous HCl was added to the mixture to adjust pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to yield the title compound as a white solid. 230 mg.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:15][C:16]1[S:20][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:18][N:17]=1.Cl>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[S:20][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:18][N:17]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nnc(N)s1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)s1
Yield: 73 %

Procedure:
To a solution of p-acetamidobenzenesulfonyl chloride (1.98 g, 8.47 mmol) in pyridine (20 mL) was added ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (1.2 g, 7.06 mmol). The reaction mixture was stirred at room temperature for 4.5 h, than 2 M HCl (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×60 mL). The organic extracts were washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 19:1 to give the product as a solid, mp 201-202° C., in 73% yield (1.91 g, 5.15 mmol); 1H NMR (300 MHz, DMSO-d6) δ 1.29 (t, 3H, J=6.9 Hz), 2.08 (s, 3H), 4.37 (q, 2H, J=7.8 Hz), 7.74 (m, 4H), 10.32 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 13.9, 14.0, 24.1, 62.9, 118.6, 127.1, 134.9, 143.2, 147.2, 157.5, 167.6, 169.0; MS (LCQ, ESI+) Calcd for C13H15N4O5S2 371.0, found 371.0 (M+H)+; HRMS (ESI+, m/z) Calcd for C13H15N4O5S2 371.0484, found 371.0472 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>C1COCC1>[F:17][C:18]1[CH:19]=[C:20]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CCCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCc1ccc(-c2cccc(F)c2)cc1
Temperature: 60 °C
Yield: 82.4 %

Procedure:
In a nitrogen atmosphere, a solution prepared by mixing 50.00 g of 4-propylbromobenzene, 0.87 g of tetrakis-triphenylphosphine palladium, 60 mL of an aqueous potassium carbonate solution (2 mol/L), and 150 mL of THF was heated to 60° C., and 35.14 g of 3-fluorophenylboronic acid was added to the solution over 20 minutes. After the resultant mixture was stirred at 60° C. for 3 hours, the mixture was allowed to cool, and an organic layer was separated by adding hexane. The organic layer was washed with saturated brine and dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure. As a result of purification by silica gel column chromatography, 44.32 g of 3-fluoro-1-(4-propylphenyl)benzene was produced.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>O.C(Cl)Cl>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(O)C1CCN(C(=O)c2ccc(F)cc2)CC1
Reaction time: 2 h

Procedure:
Piperidine-4-carboxylic acid (25.8 g, 200 mmol) and potassium carbonate (82.9 g, 600 mmol) are combined in water (500 mL) and methylene chloride (1 L) at 0° C. 4-Fluorobenzoyl chloride (31.7 g, 200 mmol) is dissolved in methylene chloride (200 mL) and added to the first mixture dropwise over 45 min. The mixture is stirred for 2 hr, after which the aqueous layer is separated and acidified to pH 1.5 with concentrated HCl. The aqueous mixture is extracted three times with methylene chloride, and the organic extracts are dried over magnesium sulfate and evaporated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1.C1N=[CH:17][N:16]([C:19](N2C=NC=C2)=[O:20])[CH:15]=1.C1CCN2C(=NCCC2)CC1.CNC>C(#N)C>[CH3:12][C:8]1([CH3:13])[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:19](=[O:20])[N:16]([CH3:17])[CH3:15])[S:3][C:4]=2[C:10](=[O:11])[CH2:9]1
Reactant: CC1(C)CC(=O)c2sc(N)nc2C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)C(=O)Nc1nc2c(s1)C(=O)CC(C)(C)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 2-amino-5,5-dimethyl-5,6-dihydro-4H-benzothiazol-7-one (151 g, 0.768 mol) in acetonitrile (5 L) are added CDI (249 g, 1.53 mol) and DBU (233 g, 1.53 mol). The reaction mixture is stirred overnight at 100° C. Dimethylamine (310 g, 3.83 mol) is added at RT and the stirring is continued overnight at 100° C. After cooling to RT, the reaction mixture is concentrated in vacuo and the residue is poured into ice water. The pH of the mixture is adjusted to pH 5 with HCl (6 M). The aqueous mixture is extracted with ethyl acetate (4×500 mL). The combined organic layers are washed with brine (500 mL) and dried over anhydrous Na2SO4. The solvent is evaporated in vacuo to give crude product. The crude product is washed with water to give 3-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-1,1-dimethyl-urea (169 g, 82% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:13](SCC)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.Br.[OH2:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:13]([OH:27])[N:12]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O
Reactant: CCSc1nc(Nc2ccc(OC)c(Cl)c2)cc(-c2ccccc2)n1
Agent: Br
Product: Oc1nc(Nc2ccc(O)c(Cl)c2)cc(-c2ccccc2)n1
Temperature: 30 °C

Procedure:
A mixture of compound (3-chloro-4-methoxyphenyl)-(2-ethylsulfanyl-6-phenylpyrimidin-4-yl)amine and 47% hydrobromic acid solution in water (10 mL) was stirred at refluxing temperature for 12 hours. The reaction mixture was cooled to temperature in the range of 20-40° C. and excess of acid was removed under vacuum. The mixture was then neutralized with ammonia solution. The solid thus obtained was filtered off and dried under vacuum to afford the title compound as a pale brown color solid.
Reaction SMILES: [C:1]([C:5]1([OH:20])[C:9]([CH3:11])([CH3:10])[CH2:8][O:7][CH:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.C1C(=O)N([Br:33])C(=O)C1.[Cl-].[Na+]>O>[Br:33][C:15]1[CH:16]=[CH:17][C:12]([CH:6]2[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([OH:20])[C:9]([CH3:11])([CH3:10])[CH2:8][O:7]2)=[CH:13][C:14]=1[O:18][CH3:19]
Reactant: COc1cccc(C2OCC(C)(C)C2(O)C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C2OCC(C)(C)C2(O)C(C)(C)C)ccc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
2.16 g (7.77 mmol) of 3-t-butyl-3-hydroxy-2-(3-methoxyphenyl)-4,4-dimethyl-2,3,4,5-tetrahydrofuran (compound (5)) was added to a mixed solvent of 20 ml of THF and 2 ml of H2O, followed by stirring at 0° C. To this solution, 1.54 g (8.65 mmol) of NBS was added, and while gradually raising the temperature to room temperature, stirring was continued overnight. Then, 140 mg (0.787 mmol) of NBS was further added, followed by stirring for 6 hours. The reaction mixture was put into a saturated sodium chloride aqueous solution and extracted with ethyl acetate. The extract layer was washed sequentially with an aqueous sodium thiosulfate solution and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated. The concentrated product was crystallized from a mixed solvent of ethyl acetate and hexane to obtain 1.323 g of 2-(4-bromo-3-methoxyphenyl)-3-t-butyl-3-hydroxy-4,4-dimethyl-2,3,4,5-tetrahydrofuran (compound (6)) in a yield of 47.7%.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1>>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C=NC1CCCCC1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)NC1CCCCC1
Yield: 66.7 %

Procedure:
Using the general method of Example 47, cyclohexyl isocyanate (61 μL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.14 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-cyclohexylurea as a white solid. Analysis: Calculated for C24H35N7O: % C, 65.88; % H, 8.06; % N, 22.41. 1H NMR (300 MHz, CDCl3) δ 8.60 (dd, J=4.4, 1.4 Hz, 1 H), 8.08 (d, J=8.5 Hz, 1 H), 7.44 (dd, J=8.5, 4.4 Hz, 1 H), 5.55 (br s, 2 H), 4.92 (t, J=5.8 Hz, 1 H), 4.82 (apparent t, J=7.8 Hz, 2 H), 4.13 (d, J=8.6 Hz, 1 H), 3.48 (m, 1 H), 3.35 (apparent q, J=6.4 Hz, 2 H), 2.93 (apparent t, J=7.8 Hz, 2 H), 1.80-2.05 (m, 4 H), 1.45-1.75 (m, 6 H), 1.2-1.4 (m 2 H), 1.0-1.2 (m, 2 H), 1.03 (t, 7.4 Hz, 3 H); HRMS (EI) calcd for C24H35N7O (M+) 437.2903, found 437.2903.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][N:5]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]1[CH3:18].[Br:24]Br>C(O)(=O)C>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][N:5]1[C:6]([CH3:18])=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:12])[C:9]([Br:24])=[C:10]1[CH3:11]
Reactant: CCOC(=O)c1c(C)n(Cc2c(F)cccc2F)c(C)cc1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)n(Cc2c(F)cccc2F)c(C)c(Br)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
1-(2,6-Difluorobenzyl)-2,6-dimethyl-3-ethoxycarbonyl-4-pyridone (2.43 g, 7.6 mmol) was dissolved in glacial acetic acid (25 mL) and treated with bromine (490 μL, 9.5 mmol). The resulting mixture was stirred at room temperature for 8 hours and poured into ice/water. The product was extracted with dichloromethane, and the extracts were washed with 10% aqueous NaHCO3, 5% aqueous Na2S2O3 and brine. The organics were dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was triturated with diethyl ether to give the product as a white solid (1.32 g, 3.3 mmol, 43%). 1H NMR (CDCl3, 300 MHz): 7.41-7.31 (m, 1H), 7.00-6.92 (m, 2H), 5.31 (s, 2H), 4.37 (q, J=6.9 Hz, 2H), 2.66 (s, 3H), 2.37 (s, 3H), 1.37 (t, J=6.9 Hz, 3H); LRMS m/z 400.1 (M+−1), 402.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[Br:9]Br.C(OCC)(=O)C>C(Cl)(Cl)Cl>[Br:9][C:5]1[S:4][C:3]([CH:7]=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: Cc1ccsc1C=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(Br)sc1C=O
Temperature: 0 °C

Procedure:
26 g of 3-methyl-2-thiophenecarboxaldehyde was dissolved in 100 ml of chloroform and the solution was stirred by cooling with ice 11 ml of bromine was added dropwise thereto. The temperature was elevated to room temperature and the mixture was stirred overnight. About 1 l of ethyl acetate was added thereto and the mixture was washed with water, then with a saturated aqueous sodium hydrogencarbonate solution and finally with a saturated aqueous common salt solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 46.8 g of 5-bromo-3-methyl-2-thiophenecarboxaldehyde in the form of a dark brown solid, which was subjected to the subsequent reaction without purification.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[OH:12])=[O:2].C(N(C(C)C)CC)(C)C.[CH3:22][O:23][CH2:24]Cl>ClCCl>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:12][CH2:22][O:23][CH3:24])=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cc(C(=O)O)ccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
4-Formyl-3-hydroxybenzoic acid (2.20 g, 13.2 mmol) was suspended in dichloromethane (40 mL), and the suspension was added with diisopropylethylamine (9.20 mL, 52.8 mmol) and chloromethyl methyl ether (2.01 mL, 26.5 mmol) under ice-cooling. Then, the reaction mixture was warmed to room temperature and stirred for 1 hour. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol (40 mL), and the solution was added with 2 mol/L aqueous potassium hydroxide solution (40 mL), and stirred at room temperature for 1 hour. Methanol was evaporated under reduced pressure and the residue was added with 4 mol/L hydrochloric acid and water. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-formyl-3-methoxymethoxybenzoic acid (2.21 g, yield 80%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[O:17][C:18]2[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=2[F:26])[C:5]2[CH:27]=[CH:28][NH:29][C:4]=2[C:3]1=[O:30].CN1C=C(C2C=C([N+]([O-])=O)C=CC=2OC2C=CC=CC=2)C2C=CNC=2C1=O>>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([O:17][C:18]2[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=2[F:26])=[C:8]([C:6]2[C:5]3[CH:27]=[CH:28][NH:29][C:4]=3[C:3](=[O:30])[N:2]([CH3:1])[CH:7]=2)[CH:13]=1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2c(F)cc(F)cc2F)c2cc[nH]c2c1=O
Agent: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Product: Cn1cc(-c2cc(N)ccc2Oc2c(F)cc(F)cc2F)c2cc[nH]c2c1=O

Procedure:
Example 49b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 49a for the product of Example 2b, to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:7]=1[CH3:14].C(N(CC)CC)C.S(Cl)([Cl:25])=O.O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Cl:25])=[CH:8][C:7]=1[CH3:14]
Reactant: COC(=O)CCc1ccc(CO)cc1C
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCc1ccc(CCl)cc1C
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a 0° C. solution of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methyl ester (1.02 g, 4.90 mmol) in anhydrous CH2Cl2 (15 mL) is added triethylamine (0.75 mL, 5.38 mmol) followed by thionyl chloride (0.40 mL, 5.48 mmol). The mixture is allowed to warm to RT overnight. Water is added, and the mixture is extracted with CH2Cl2. The organics are dried with MgSO4 and concentrated. The crude material is purified by flash chromatography to yield the title compound (1.01 g, 91%).
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[C:5]([Br:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]([CH2:27][OH:28])[CH:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:19][C:5]1[C:6]2[C:7](=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=2)[C:2]([NH:20][C:21]2[N:26]=[CH:25][N:24]=[C:23]([CH2:27][OH:28])[CH:22]=2)=[N:3][CH:4]=1
Reactant: Clc1cccc(Cl)c1-n1cc2c(Br)ncc(Br)c2n1
Reactant: Nc1cc(CO)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: OCc1cc(Nc2ncc(Br)c3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Yield: 65.5 %

Procedure:
A suspension of 4,7-dibromo-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (317 mg, 0.75 mmol), (6-amino-pyrimidin-4-yl)-methanol (104 mg, 0.83 mmol), Pd2(dba)3 (17 mg, 0.019 mmol), Xantphos (43 mg, 0.075 mmol) and cesium carbonate (489 mg, 1.5 mmol) in dioxane (11 mL) was sealed in a microwave vial, purged with nitrogen, and irradiated in a microwave reactor at 150° C. for 1 hour. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (50-100% ethyl acetate in cyclohexane), to afford the title compound as a white solid (229 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.84 (br s, 1H), 9.31 (s, 1H), 8.72 (d, J=1.2 Hz, 1H), 8.61-8.60 (m, 1H), 8.16 (s, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.83 (s, 1H), 7.74 (dd, J=7.2, 1.6 Hz, 1H), 5.60 (t, J=5.8 Hz, 1H), 4.53 (d, J=5.7 Hz, 2H). LCMS (Method D): RT=3.21 min, m/z: 467 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[C:5]([Cl:10])=[C:6]([OH:9])[C:7]=1[OH:8].Br[CH2:22]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[C:7]2[O:8][CH2:22][O:9][C:6]=2[C:5]([Cl:10])=[C:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:19][CH2:20]3)=[CH:14][CH:13]=2)[CH:3]=1
Reactant: BrCBr
Reactant: Oc1c(Br)cc(Cc2ccc(C3CC3)cc2)c(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1c(Cc2ccc(C3CC3)cc2)cc(Br)c2c1OCO2
Temperature: 90 °C
Reaction time: 12 h
Yield: 64.6 %

Procedure:
To a solution of phenol 192 (1.75 g, 4.95 mmol) in DMF (25 mL) were added dibromomethane (0.42 mL, 5.94 mmol) and Cs2CO3 (5.7 g, 17.3 mmol) at r.t. The mixture was stirred at 90° C. for 12 hours. The mixture was cooled to r.t. and filtered off to remove inorganic salts. The filtrate was extracted with EtOAc/aq. 50% NaCl solution (100 mL/500 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 193 (1.17 g, 65%).