Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]([F:22])([F:23])[O:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(Cc2cccc(OC(F)(F)F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cc2cccc(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.1 %

Procedure:
To a solution of ethyl 4-[3-(trifluoromethoxy)benzyl]benzoate (Preparation 149, 950 mg, 2.93 mmol) in THF/MeOH/water (4:3:2, 27 mL) was added lithium hydroxide (246 mg, 5.86 mmol) and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and acidified with 1M hydrochloric acid solution. The resulting precipitate was filtered off and dried to give the title compound as a white solid (600 mg, 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].Cl[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Clc1ncccn1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(Nc2ncccn2)c1
Temperature: 170 °C
Yield: 21 %

Procedure:
A mixture of 3-nitroaniline (6.14 g), 2-chloropyrimidine (4.85 g) and potassium carbonate (6.15 g) in dimethylsulfoxide (50 ml) was heated at 170° C. for 5 hours. The mixture was cooled and poured into a mixture of ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resulting solid was collected and washed with isopropyl ether to give 2-(3-nitrophenylamino)pyrimidine (1.92 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[OH:12])=O.[NH2:13][C:14]([NH2:16])=[S:15].C(=O)([O-])O.[Na+]>C(O)C>[NH2:16][C:14]1[S:15][CH:2]=[C:3]([C:5]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=2[OH:12])[N:13]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1cc(Cl)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(-c2cc(Cl)ccc2O)cs1
Temperature: 25 °C
Yield: 69 %

Procedure:
A mixture of 2-bromo-1-(5-chloro-2-hydroxyphenyl)ethanone (156.9 mg, 0.63 mmol), thiourea (47.9 mg, 0.63 mmol) and ethanol (3 mL) was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (98.6 mg, 64.5%) as a light yellowish white powder.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@@H:7]1[O:9][CH2:8]1)(=[O:4])=[O:3].C1O[C@H]1CO>>[CH3:1][S:2]([O:5][CH2:6][C@H:7]1[O:9][CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OC[C@H]1CO1
Agent: OC[C@H]1CO1
Product: CS(=O)(=O)OC[C@@H]1CO1

Procedure:
(S)-Glycidyl Methanesulfonate was synthesized in an analogous manner to Intermediate F, Step 1, substituting (R)-(+)-glycidol for (S)-(−)-glycidol. This was used in further transformations as a solution of (S)-glycidyl methanesulfonate in DMF, without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)=[CH:4][C:3]=1[O:18][C:19]([F:22])([F:21])[F:20]>C1COCC1.[Pd]>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)=[CH:4][C:3]=1[O:18][C:19]([F:21])([F:20])[F:22]
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1OC(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(N)cn2)cc1OC(F)(F)F
Reaction time: 18 h
Yield: 88.4 %

Procedure:
A suspension of 2-[4-methyl-3-(trifluoromethoxy)phenoxy]-5-nitropyridine (Intermediate 30, 594 mg, 1.89 mmol) and Pd/C 5% w/w (40 mg) in THF (3 mL) was hydrogenated under 5 bar of H2, at 35° C. for 18 hrs. The mixture was filtered to remove the catalyst, diluted with ethyl acetate (10 mL) and washed with an aqueous 13% solution of NaCl (10 mL). The organic layer, dried over Na2SO4, was evaporated to give the title compound (475 mg) as brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[N:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>C(O)(=O)C.ClCCl.CO>[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[N:20]=[CH:21][C:22]([C:25](=[NH:45])[NH2:26])=[N:23][CH:24]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1cnc(C#N)cn1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1cnc(C(=N)N)cn1)n2C)c1ccccn1
Yield: 19 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(2-cyanopyrazin-5-yl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 19% of theory, C25H27N9O3 (501.6); Rf value: 0.28 (silica gel; dichloromethane/methanol=4:1+1% glacial acetic acid); EKA mass spectrum: (M+H)+=502; (M+H+Na)+=262.5.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][OH:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C.N1C=CC=CC=1>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH2:19][O:20][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:21][CH:22]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A solution of 3.51 g of methanesulfonyl chloride in 5 ml of diethyl ether was added dropwise over a period of 0.5 hour to a stirred solution of 7.0 g of 4-benzyloxyphenethyl alcohol in 20 ml of pyridine at 0° C. Stirring was continued for 2 hours while the mixture was allowed to warm to room temperature. The mixture was then partitioned between 150 ml of 2N hydrochloric acid and dichloromethane. The organic phase was separated, washed with water, dried over sodium sulfate, filtered, and evaporated. Trituration of the residue with n-hexane brought about crystallization. The crystals were removed by filtration and dried, whereby 8.9 g (95%) of 1-benzyloxy-4-(2-methanesulfonyloxyethyl)benzene having a melting point of 60°-64° C. were obtained.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:14])[NH:12][C:11](=[O:13])[CH2:10]1.[CH3:15][O:16][CH:17](Cl)[CH3:18].[OH-].[Na+]>CCCCCC>[CH3:15][O:16][CH:17]([N:12]1[C:9]([CH3:14])([CH3:8])[CH2:10][C:11]1=[O:13])[CH3:18]
Reactant: CC1(C)CC(=O)N1
Reactant: COC(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(C)N1C(=O)CC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7.3 g of triethylamine and then a mixture of 19.8 g (0.2 mole) of 4,4-dimethyl-azetidin-2-one and 43.2 g of triethylamine are added dropwise, at 0° C., to a solution of 38 g (0.4 mole) of α-chloroethyl methyl ether in 60 ml of hexane. The mixture is stirred for a further 2 hours at 0° C. and 10 ml of 50% strength sodium hydroxide solution and 20 g of powdered sodium hydroxide are added. After a further 30 minutes, the hexane solution is decanted, the deposit is rinsed with hexane and the hexane extracts are concentrated on a rotary evaporator. This yields 25.5 g (81% of theory) of 1-α-methoxyethyl-4,4-dimethyl-azetidin-2-one. 1H-NMR (CDCl3): 1.4 ppm (d); 1.5 ppm (s); 2.75 ppm (s); 3.3 ppm (s); 4.8-5.1 ppm (q).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17](I)=[C:16]([CH2:19][CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cu][C:22]#[N:23]>O.ClCCl>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([C:22]#[N:23])=[C:16]([CH2:19][CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1I
Solvent: O
Solvent: ClCCl
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1C#N

Procedure:
1.8 g (5 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-6-ethyl-5-iodopyrimidine (Example 1) and 1.0 g of copper(I) cyanide were stirred at 200° C. for 30 minutes without solvent. After cooling, the mixture was taken up in water/dichloromethane, the organic phase was again extracted by stirring with aqueous ammonia solution, and the extract was dried and concentrated. The crude product was purified by chromatography on silica gel using petroleum ether/ethyl acetate (7:3), to give 750 mg (52.4% of theory) of a colorless oil which crystallized on standing.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12](C1C=CC(O)=C(C=1)C(OCC)=O)=O>CO>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: CCOC(=O)c1cc(C=O)ccc1O
Solvent: CO
Product: COC(=O)c1cc(O)ccc1O
Yield: 94 %

Procedure:
2,5-Dihydroxybenzoic acid was converted to its methyl ester using catalytic sulfuric acid in methanol following the same protocol as for esterification 2c in 94% yield. mp 86.4°-88.5° C. IR(KBr): cm-1 3346, 1684.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6]3[C:20](=[O:21])[NH:19][CH:18]([O:22][C:23](=O)C)[C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[CH3:28][S:29]([OH:32])(=[O:31])=[O:30]>CO>[CH3:28][S:29]([OH:32])(=[O:31])=[O:30].[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6]3[C:20](=[O:21])[NH:19][CH:18]([O:22][CH3:23])[C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: CC(=O)OC1NC(=O)C2=C1CN=C(c1ccccc1Cl)c1cc(Cl)ccc12
Agent: CS(=O)(=O)O
Solvent: CO
Product: COC1NC(=O)C2=C1CN=C(c1ccccc1Cl)c1cc(Cl)ccc12

Procedure:
A solution of 0.6 g of 8-chloro-6-(2-chlorophenyl)-3-acetoxy-3,4-dihydropyrrolo[3,4-d][2]benzazepin-1(2H)-one and 3 ml of a 1 M methanolic solution of methanesulfonic acid in 10 ml of methanol was stirred at room temperature for 30 minutes. The solution was concentrated at reduced pressure to half the volume, diluted with ether, and the resulting precipitate was collected by filtration to give orange crystals. Recrystallization from a mixture of methanol and ether gave 8-chloro-6-(2-chlorophenyl)-3,4-dihydro-3-methoxypyrrolo[3,4-d][2]benzazepin-1(2H)-one methanesulfonate as off-white prisms, mp 157°-160° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)=O.[NH2:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[S:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:11][C:7]1[CH:6]=[C:5]([C:3]2[N:12]=[C:13]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[S:14][CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(F)c3)cs2)CC1
Yield: 97.5 %

Procedure:
A solution of 2-bromo-1-(3-fluorophenyl)ethanone (1.95 g, 8.98 mmol), tert-butyl 4-(aminocarbonothioyl)piperidine-1-carboxylate (2.00 g, 8.18 mmol) and potassium carbonate (2.26 g, 16.4 mmol) in dimethylformamide (60 ml) was stirred at 110° C. for 1.5 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (2.89 g, 97.0%) as an oil.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([OH:17])[C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[CH3:18]O>>[Cl:6][C:7]1[CH:8]=[C:9]([OH:17])[C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([O:14][CH3:18])=[O:13]
Reactant: O=C(O)c1cc(Cl)cc(O)c1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)cc(O)c1O
Temperature: 25 °C

Procedure:
A mixture of methanol (60 ml) and sulfuric acid (5.2 ml) was stirred at room temperature. 5-Chloro-2,3-dihydroxybenzoic acid (0.11 mol) was added. The reaction mixture was stirred and refluxed for 20 hours, and then poured out onto ice. The precipitate was filtered off, washed with water, and dried, yielding 18.48 g of methyl 5-chloro-2,3-dihydroxybenzoate (intermediate 9; mp: 102° C.).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][N:3]=1.CC([O-])=O.[K+].[N:15](OCCC(C)C)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.CC(O)=O>[I:1][C:2]1[CH:7]=[C:6]2[CH:8]=[N:15][NH:9][C:5]2=[CH:4][N:3]=1
Reactant: CC(C)CCON=O
Reactant: Cc1cc(I)ncc1N
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Ic1cc2cn[nH]c2cn1
Yield: 83.3 %

Procedure:
To a suspension of 2-iodo-4-methyl-5-pyridinamine (5 g, 21.4 mmol) in toluene (340 mL) was added HOAc (19 mL), and the mixture was stirred vigorously until it became clear. Then KOAc (15.78 g, 160.23 mmol) was added. To this white suspension, isoamyl nitrite (3.16 mL, 23.5 mmol) was added dropwise at rt, and the resulting mixture was stirred for 2 days. The reaction mixture was diluted with EtOAc and treated with NaHCO3 (sat.) to pH 10. The reaction mixture was extracted with EtOAc, washed with brine, dried, and concentrated in vacuo to afford the crude product. Purification by flash chromatography afforded 5-iodo-1H-pyrazolo[3,4-c]pyridine (4.37 g, 83.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:22][CH2:23][CH2:24][CH2:25]Br)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.[ClH:32].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(CCN3C=CN=C3)N=2)C=CC=1OC>>[ClH:32].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:22][CH2:23][CH2:24][CH2:25][N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NN(CCCCBr)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Reactant: c1c[nH]cn1
Agent: COc1ccc(C2=NN(CCn3ccnc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(CCCCn3ccnc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound 114 and imidazole as described for compound 113. The reaction mixture was evaporated and the residue dissolved in 2N HCl. After extraction with dichloromethane and drying over magnesium sulfate, the solvent was evaporated. The residue crystallized on treating with ethyl acetate. M.p. 192°-194° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1.Cl[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][N:26]=1>>[Cl:31][C:30]1[C:25]([N:21]2[CH2:20][CH2:19][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:5]4[C@H:4]([CH2:3][O:2][CH3:1])[CH2:8][O:7][C:6]4=[O:9])=[CH:11][CH:12]=3)=[O:17])[CH2:23][CH2:22]2)=[N:26][CH:27]=[C:28]([Cl:32])[CH:29]=1
Reactant: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)cc1
Reactant: Clc1cnc(Cl)c(Cl)c1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(Cl)cc3Cl)CC2)cc1
Yield: 66 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-4-methoxymethyl-3-[4-(piperazine-1-carbonyl)phenyl]oxazolidin-2-one (473 mg) described in Preparation Example 165 and 2,3,5-trichloropyridine (405 mg), the title compound (455 mg) was obtained.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[CH:2]([C:3]1[CH:11]=[CH:10][C:8]([O:9][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: OCCCCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: COc1cc(C=O)ccc1OCCCCCCO
Yield: 90.1 %

Procedure:
A flame-dried, 100 mL round bottom flask equipped with a claisen arm and reflux condenser was charged, under argon, with vanillin (1, 1.0 g, 6.6 mmol), tetrabutylammonium iodide (369 mg, 1 mmol), and potassium carbonate (1.38 g, 10 mmol). These were suspended in 10 mL of anhydrous acetonitrile and then 6-chlorohexanol (1.05 ml, 7.9 mmol) was added dropwise. The reaction was protected from light and refluxed for 15 hours at which time TLC analysis showed complete consumption of the starting material. The solvent was evaporated in vacuo and the residue was then dissolved in 50 mL of ethyl acetate and extracted with water (2×100 mL), brine (1×100 mL), and water (1×100 mL). The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo to give 1.5 g (90%) of 2 as a white solid. Rf=0.29 (33% ethyl acetate/hexane). Mp 55.0-56.0° C. 1H NMR (400 MHz, DMSO-d6): δ9.83 (s, 1), 7.53 (dd, J=2.0 Hz, 8.0 Hz, 1), 7.39 (d, J=2.0 Hz, 1), 7.17 (d, J=8.4 Hz, 1), 4.36 (t, J=5.2 Hz, 1), 4.07 (pt, J=2.4 Hz, 2.8 Hz, 2), 3.83 (s, 3), 3.39 (dd, J=5.6 Hz, 11.6 Hz, 2), 1.75 (m, 2), 1.45-1.34 (m, 6) ppm.
Reaction SMILES: C(OC([N:6]1[CH2:12][CH:11]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:15])[C:10]2=[N:22][C:23]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)=[CH:24][C:25](=[O:26])[N:9]2[CH2:8][CH2:7]1)=O)C.Br>>[O:26]=[C:25]1[N:9]2[C:10]([CH:11]([NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[O:15])[CH2:12][NH:6][CH2:7][CH2:8]2)=[N:22][C:23]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)=[CH:24]1
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NC(=O)c2ccccn2)C1
Agent: Br
Product: O=C(NC1CNCCn2c1nc(-c1ccncn1)cc2=O)c1ccccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 0.075 g (0.17 mmol) of (+/−)-4-oxo-9-[(pyridine-2-carbonyl)-amino]-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester (example 1) dissolved in 0.6 mL (3.44 mmol) of hydrobromic acid (33 wt % solution in glacial acetic acid). The resulting mixture was stirred at 100° C. for 8 hours, cooled and evaporated to dryness. Toluene was added to the residue and evaporated. MeOH added to the residue and evaporated. After an acido-basic work-up, the crude was triturated with diethyl ether and filtered to afford 0.035 g (45%) of the product as a white powder and free base.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=1[CH3:31])[O:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:22]C(=O)OCC)=S)=[N:17][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].O[NH3+].C([N:38](CC)C(C)C)(C)C.C(O)C>CO>[NH2:38][C:20]1[N:19]=[C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:28]=[CH:29][C:30]([CH3:31])=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]=3)=[CH:18][N:17]2[N:22]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(C)c(NC(=O)OC(C)(C)C)c2)cn1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CO
Solvent: CCO
Product: Cc1ccc(Oc2ccc3nc(N)nn3c2)cc1NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 12 h
Yield: 167.7 %

Procedure:
A mixture of ethyl {[(5-{3-[(tert-butoxycarbonyl)amino]-4-methylphenoxy}pyridin-2-yl)amino]carbonothioyl}carbamate (11.5 g, 15.4 mmol), hydroxylammonium chloride (15.4 g, 0.223 mol), N,N-diisopropylethylamine (23.0 mL, 0.132 mol), ethanol (200 mL) and methanol (200 mL) was stirred at 80° C. for 12 hr. The reaction solution was concentrated under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give the title compound (9.18 g, 100%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH:15]=O)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25]>>[CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH:15]=[C:23]3[S:19][C:20](=[O:25])[NH:21][C:22]3=[O:24])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17]
Reactant: O=C1CSC(=O)N1
Reactant: COC(=O)CN1C(=O)COc2ccc(C=O)cc21
Product: COC(=O)CN1C(=O)COc2ccc(C=C3SC(=O)NC3=O)cc21

Procedure:
Following the general method as outlined in Example 1, starting from (6-Formyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-acetic acid methyl ester (intermediate 64) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]([NH:28][C:29](=[O:33])[CH2:30][C:31]#[N:32])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:34][CH:35]([CH3:38])[CH:36]=O.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]([NH:28][C:29](=[O:33])[C:30]([C:31]#[N:32])=[CH:34][CH:35]([CH3:38])[CH3:36])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)C=O
Reactant: C[C@@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)CC#N
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)C=C(C#N)C(=O)N[C@@H](C)Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
A suspension of N-[(2S)-1-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]propan-2-yl]-2-cyanoacetamide (250 mg, 0.56 mmol, 1.00 equiv), 2-methylpropanal (81 mg, 1.12 mmol, 2.00 equiv) and piperidine (47 mg, 0.55 mmol, 1.00 equiv) in methanol (15 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1). The purified product was re-purified on Prep-HPLC eluting with TFA (0.05%)/H2O and CH3CN. The organic phase was removed off under reduced pressure. The aqueous phase was adjusted to 10 with potassium carbonate, which was extracted with DCM. The organic layers were combined, washed with brine, dried over sodium sulfated, filtrated and concentrated. This resulted in 46.4 mg (17%) of the title compound as a white solid. LC-MS m/z: 500 (M+1). H-NMR (400MHz, CDCl3, ppm): 8.49 (s, 1H), 8.12 (d, J=7.2Hz, 1H), 7.60 (t, J=8.8 Hz, 1H), 7.44 (m, 3H), 7.25-7.21 (m, 1H), 7.13 (d, J=8.4Hz, 2H), 6.94 (dd, J=8.4, 2.4Hz, 1H), 6.88 (dd, J=11.2, 2.4Hz, 1H), 5.51 (brs, 2H), 4.74-4.55 (m, 3H), 3.00-2.95 (m, 1H), 1.21 (d, J=6.8, 3H), 1.15 (d, J=6.8Hz, 6H).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[S:10](=O)(=[O:13])([OH:12])[OH:11]>>[S:10]([C:7]1[CH:8]=[C:2]([CH:1]=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=1)([OH:13])(=[O:12])=[O:11]
Reactant: O=Cc1ccccc1O
Reactant: O=S(=O)(O)O
Product: O=Cc1cc(S(=O)(=O)O)ccc1O

Procedure:
reacting salicylaldehyde with fuming sulfuric acid to yield 5-sulfosalicylaldehyde;