Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:38]=[CH:37][C:31]4[O:32][C:33]([F:36])([F:35])[O:34][C:30]=4[CH:29]=3)=[C:20]([C:39]([F:42])([F:41])[F:40])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:44]>C(O)C>[ClH:44].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:38]=[CH:37][C:31]3[O:32][C:33]([F:35])([F:36])[O:34][C:30]=3[CH:29]=2)=[C:20]([C:39]([F:42])([F:41])[F:40])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc4c(c3)OC(F)(F)O4)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccc3c(c2)OC(F)(F)O3)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 87-4 (870 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (510 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([O:13][CH3:14])=[N:7][C:8](Cl)=[N:9][C:10]=1[CH3:11])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[C:24]=1B(O)O)[CH3:22]>COCCOC.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([O:13][CH3:14])=[N:7][C:8]([C:24]2[C:25]([CH2:29][CH3:30])=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:21][CH3:22])=[N:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)c1c(C)nc(Cl)nc1OC
Reactant: CCc1cccc(CC)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCc1cccc(CC)c1-c1nc(C)c(C(=O)OC)c(OC)n1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-4-methoxy-6-methyl-pyrimidine-5-carboxylic acid methyl ester (4.1 g, 19.0 mmol) in DME (100 mL) is added potassium carbonate (10.5 g, 76 mmol, 4 eq) in water (40 mL) followed by 2,6-diethylphenylboronic acid (6.77 g, 38 mmol, 2 eq). The resulting mixture is degassed by bubbling with argon for 20 min. Pd(PPh3)4 (5 mol %) is added and the resulting yellow biphasic solution is heated at 95° C. in a sealed tube with magnetic stirring for 18 h. The reaction mixture is cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (75 mL×3). The combined organic layers are washed with brine (75 mL), dried over magnesium sulfate, filtered and evaporated at reduced pressure. The resulting orange oil is purified by chromatography on silica gel (1:2 ether/hexanes) to afford the title compound as a colorless oil. 1H NMR (CDCl3) δ=7.29 (dd, 1H), 7.14 (d, 2H), 4.00 (s, 3H), 3.98 (s, 3H), 2.55 (s, 3H), 2.39 (q, 4H), 1.10 (t, 6H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH2:12]O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[N:16][C:15]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C>S(Cl)(Cl)=O>[C:1]1([C:7]2[NH:11][C:10]([CH2:12][N:27]3[CH2:28][CH2:29][N:24]([C:15]4[N:16]=[CH:17][C:18]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:14]=4)[CH2:25][CH2:26]3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1c[nH]c(-c2ccccc2)n1
Reactant: c1ccc2nc(N3CCNCC3)ncc2c1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: c1ccc(-c2ncc(CN3CCN(c4ncc5ccccc5n4)CC3)[nH]2)cc1
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
A sample of 2-phenyl-4-hydroxymethylimidazole (348 mg, 2 mmol) is heated for 5 min in thionyl chloride (5 mL) and subsequently concentrated. Chloroform (10 mL) is added and the solution reconcentrated. The resulting dark oil is then taken up in chloroform (10 mL) and treated with 1-quinazolin-2-ylpiperazine (428 mg, 2 mmol) and triethyl amine (2 mL). After 10 minutes, the reaction is washed with 2N NaOH solution, dried (Na2SO4) and concentrated to provide the title compound (Compound 4) as an oil (640 mg), the hydrochloride salt is prepared in a conventional manner, m.p. 101-105° C. (Compound 4a). 1H NMR (CDCl3) 9.0 (s, 1H), 7.9 (d, J=7 Hz, 2H), 7.65 (m, 2H), 7.55 (d, J=6 Hz, 1H), 7.2-7.4 (m, 4H), 7.0 (s, 1H, imidazole CH), 3.95 (m, 4H), 3.6 (s, 2H), 2.6 (t, J=5 Hz, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:23][C@H:24]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=1)[CH3:22].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C:32](=[O:33])[CH2:31][O:30][C:29]2[CH:28]=[CH:27][C:26]([CH2:25][C@H:24]([O:23][CH2:21][CH3:22])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:36][CH:35]=2)=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCNCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCc2ccccc2)cc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To a solution of N-[4-(benzyloxy)benzyl]-N-butylamine (3.59 g, 12.0 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (2.96 g, 10.0 mmol) in methylene chloride (100 mL) were added N,N-diisopropylethylamine (4.00 mL, 23.0 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (3.85 g, 12.0 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (100 mL) and the organic phase was washed with 5% HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-1% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 1.80 g (33%) of a whitish oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([OH:24])[CH3:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C@H:22]([OH:24])[CH3:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc([C@@H](C)O)nc3N21

Procedure:
A solution of 3.09 g (9.27 mmol) (4R,9aR)-6-(1-(RS)-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 33 mL dichloromethane was cooled to 0 deg C. and treated with 8.8 mL (12.7 g, 0.11 mol) trifluoroacetic acid. The cooling bath was removed and the volatile components were removed at a rotary evaporator. The remaining residue was purified by column chromatography on silica gel (0.032–0.063 mm) with dichloromethane:methanol:ammonia (19:1:0.1). The remaining oil was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution and extracted with dichloromethane until all product was removed from the aqueous phase. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The remaining light brown oil was purified by column chromatography on a Chiralpak-AD column with 7% ethanol/n-heptane yielding the desired compound as a light brown solid (36.5%).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:8]=[C:9]([NH2:21])[C:10]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:12]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[C:22](Cl)(=O)[C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:26]1[N:13]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10]2[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:5])=[O:6])=[CH:8][C:9]=2[N:21]=1)([CH3:25])([CH3:24])[CH3:22]
Reactant: CC(C)S(=O)(=O)c1ccc(NCC2CCOCC2)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)S(=O)(=O)c1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step C of Example 17 from 4-(isopropylsulfonyl)-N′-(tetrahydro-2H-pyran-4-ylmethyl)benzene-1,2-diamine (Step B) and pivaloyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:17][C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.Cl>COCCO.C(O)C>[Cl:24][C:23]1[CH:22]=[N:21][C:20]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH:3]=3)[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]=1[N:19]=2)[CH:14]=[CH:15][CH:16]=3
Reactant: Nc1cccc(CCCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Solvent: COCCO
Solvent: CCO
Product: Clc1cnc2nc1Nc1cccc(c1)CCCc1cccc(c1)N2
Temperature: 150 °C
Yield: 38.6 %

Procedure:
N-{3-[3-(3-Aminophenyl)propyl]phenyl}-2,5-dichloropyrimidin-4-amine (20 mg, 0.05 mmol) was stirred in 2-methoxyethanol (1.0 mL) and a solution of hydrogen chloride in ethanol (0.75 mL, 3.5 M). The mixture was heated to 150° C. for 30 minutes in a microwave. Purification by preparative LCMS gave the desired product (6.5 mg, 37%). LCMS for C19H18ClN4 (M+H)+: m/z=337.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:35])([F:34])[S:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([S:25][C:24]([F:35])([F:23])[F:34])=[CH:27][CH:28]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2n1Cc1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (434 mg) in DMF (5 mL) was added potassium carbonate powder (669 mg) and 4-(trifluoromethylthio) benzyl bromide (596 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a brown solid.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:11]1[N:12]=[C:13]([OH:16])[S:14][CH:15]=1)[C:6]([O:8]CC)=[O:7])[CH3:2].C(O)C.[OH-].[K+].Cl>O>[CH2:1]([O:3][N:4]=[C:5]([C:11]1[N:12]=[C:13]([OH:16])[S:14][CH:15]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)OCC)c1csc(O)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCON=C(C(=O)O)c1csc(O)n1

Procedure:
To a solution of 10 g. of ethyl α-ethoxyimino-(2-hydroxythiazol-4-yl)acetate in 30 ml. of ethanol is added a solution of 11.47 g. of KOH in 50 ml. of water at room temperature and the mixture is stirred for 25 minutes. The reaction mixture is condensed under reduced pressure and is made acidic with 10% aq. HCl. Ethyl acetate extract of the reaction mixture is extracted with 10% aq.NaHCO3. The aqueous layer is then made acidic with 10% aq.HCl and extracted again with ethyl acetate. From the ethyl acetate extract, after being washed, dried and condensed is obtained a crystalline substance. Recrystallization from benzene-ethanol gives α-ethoxyimino-(2-hydroxythiazol-4-yl)acetic acid. 7.5 g. Melting point: 131.5° C. (dec.).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.Br[CH:14]([OH:17])[CH2:15][CH3:16]>CCO>[OH:17][CH2:14][CH2:15][CH2:16][O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCC(O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCCCO)cc1

Procedure:
An aqueous solution of NaOH (1 mol) and KI (0.05 mmol) was added to a solution of 4-hydroxybenzoic acid (0.5 mmol) and 400 mL EtOH solution under a nitrogen atmosphere and stirred. After stirring for 30 minutes, an EtOH solution including bromopropanol (0.55 mmol) was dropped thereinto, and then, reacted for 24 hours after elevating to 80° C. A solvent was removed from a reaction product and hydrochloric acid-treatment was carried out. A solid phase was isolated through filteration, and 4-(3-hydroxypropoxy)benzoic acid as a compound of Formula 4 was synthesized.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([CH3:39])[CH3:38])=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=1>CC(N(C)C)=O>[CH:37]([O:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]4=[CH:5][C:4]=3[CH:3]=2)=[CH:31][C:32]=1[C:40]([F:41])([F:42])[F:43])([CH3:39])[CH3:38]
Reactant: CC(C)Oc1ccc(CCl)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (1.86 mmol) and cesium carbonate (2.8 mmol) in DMA (7.45 mL) was added 4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene (1.96 mmol). The reaction was stirred at 80° C. for 16 h. The mixture was filtered through Celite®. The solvent was removed under vacuum. The residue was purified by silica gel column chromatography to give the title compound as a solid. LCMS m/z=504.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (d, J=5.94 Hz, 6H), 1.44 (s, 9H), 2.14-2.25 (m, 1H), 2.51-2.58 (m, 1H), 2.59-2.67 (m, 1H), 2.71-2.81 (m, 1H), 3.57 (m, 1H), 3.91-3.99 (m, 1H), 4.06-4.13 (m, 1H), 4.72-4.83 (m, 1H), 5.05 (s, 2H), 5.99 (s, 1H), 6.75 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.18 (d, J=8.72 Hz, 1H), 7.28 (d, J=9.22 Hz, 1H), 7.62-7.68 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]2O.P(Cl)(Cl)([Cl:21])=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]2[Cl:21]
Reactant: CC(C)CC(=O)c1cnc2ccc(Br)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)CC(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 85 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
1-(6-Bromo-4-hydroxyquinolin-3-yl)-3-methylbutan-1-one (300 mg, 0.970 mmol) was added to phosphoryl chloride (9.7 mL) and the reaction was stirred at 85° C. for 1 h. After this time the reaction mixture was cooled to room temperature and slowly poured into a 2:1 solution of satd. aq. sodium bicarbonate/ethyl acetate that was cooled to 0° C. The organic layer was separated and was washed with satd. aq. sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the desired product (309 mg, 98%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 8.86 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.01 (d, J=8.9 Hz, 1H), 7.91 (dd, J=8.9, 2.0 Hz, 1H), 2.96 (d, J=6.9 Hz, 2H), 2.39-2.23 (m, 1H), 1.03 (d, J=6.7 Hz, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([O:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: Oc1ccccc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(Oc3ccccc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and phenol to give (6-methoxy-1-phenoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 333(MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:6]=[CH:7][CH:8]=1.[CH2:18]([C:20]1[C:21]([OH:30])=[C:22]([C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][C:25]=1O)[CH3:19]>>[C:27]([C:22]1[CH:23]=[CH:24][C:25]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=3)[C:15]#[N:16])[CH:6]=[CH:7][CH:8]=2)=[C:20]([CH2:18][CH3:19])[C:21]=1[OH:30])(=[O:29])[CH3:28]
Reactant: N#Cc1cncc(Sc2cccc(CO)c2)c1
Reactant: CCc1c(O)ccc(C(C)=O)c1O
Product: CCc1c(OCc2cccc(Sc3cncc(C#N)c3)c2)ccc(C(C)=O)c1O
Yield: 33.8 %

Procedure:
Using the method of Preparation 160 using 5-(3-(hydroxymethyl)phenylthio) nicotinonitrile (3.90 g, 16.1 mmol) and 1-(3-ethyl-2,4-dihydroxyphenyl)ethanone (2.90 g, 16.1 mmol) affords the title compound (2.20 g, 34%): 1H NMR (CDCl3) δ 1.10 (t, J=7.4 Hz, 3H), 2.57 (s, 3H), 2.71 (q, J=7.4 Hz, 2H), 5.18 (s, 2H), 6.43 (d, J=9.0 Hz, 1H), 7.44-7.49 (m, 3H), 7.51 (s, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.63 (dd, J=2.0, 2.3 Hz, 1H), 8.64 (t, J=2.0 Hz, 2H), 12.75 (s, 1H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])=O)(C)(C)C.[Cl:21][C:22]1[CH:23]=[C:24]([NH:38][C:39](OC2C=CC=CC=2)=[O:40])[C:25](=[CH:36][CH:37]=1)[C:26](OCC1C=CC=CC=1)=[O:27]>>[NH2:8][C:9]1[CH:10]=[C:11]([S:17]([N:20]2[C:26](=[O:27])[C:25]3[C:24](=[CH:23][C:22]([Cl:21])=[CH:37][CH:36]=3)[NH:38][C:39]2=[O:40])(=[O:18])=[O:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: COc1ccc(S(N)(=O)=O)cc1NC(=O)OC(C)(C)C
Product: COc1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1N
Yield: 16 %

Procedure:
400 mg (1.40 mmol) of 3-t-butoxycarbonylamino-4-methoxybenzenesulfonamide and 533 mg (1.40 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 17 to obtain 86 mg (yield 16%: 4 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 3.81 (3H, s), 7.26-7.37 (5H, m), 7.77 (1H, s), 7.90 (1H, d), 7.94 (1H, d), 11.73 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([C:25]([F:28])([F:27])[F:26])[NH:20][CH2:19][CH2:18]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:15]([F:14])[CH:16]=4)[CH:21]3[C:25]([F:26])([F:27])[F:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Fc1ccc2c(c1)CCNC2C(F)(F)F
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2cc(F)ccc2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][OH:20]>>[OH:20][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[NH:16][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH:10]1[CH3:15]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: Nc1ccccc1CO
Product: CC1CN(C(=O)OC(C)(C)C)CCC1Nc1ccccc1CO

Procedure:
The product was prepared from N-tert-butoxycarbonyl-3-methyl-4-piperidone (4.3 g) and 2-amino-benzyl alcohol (2.59 g) using the method of example 7 step (i). Yield 6.3 g as a mixture of diastereoisomers.
Reaction SMILES: [F-].[K+].[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[CH:17][Si](CC)(CC)CC)[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)[CH:4]([CH3:6])[CH3:5].O>C(#N)C>[CH2:3]([C:7]1[CH:8]=[CH:9][C:10]([C:13](=[CH2:17])[C:14]([OH:16])=[O:15])=[CH:11][CH:12]=1)[CH:4]([CH3:6])[CH3:5]
Reactant: CC[Si](C=C(C(=O)O)c1ccc(CC(C)C)cc1)(CC)CC
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C=C(C(=O)O)c1ccc(CC(C)C)cc1
Temperature: 25 °C

Procedure:
This desilylation (elimination) reaction may be performed, for example, by following the procedure of T. H. Chan et al. referred to above. A catalyst such as, for example, potassium fluoride is used for desilylation. α-(4'-isobutylphenyl)-β-triethylsilyl acrylic acid from Example 4 (0.02 mol) is dissolved in a suitable solvent such as, for example, acetonitrile (15-20 ml). Potassium fluoride (0.025 mol) is added to the solution, and the mixture stirred at a suitable temperature such as, for example, ambient temperature, for a suitable time, for example, about 2-10 hours. The contents are poured into water (about 20 ml), and transferred to a separatory funnel. The separated organic layers are washed with water, then dried (with MgSO4), and evaporated in vacuo to isolate the desilylated acrylic acid, which may be purified by conventional methods, if so desired.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[Na+].[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([N+:28]#[N:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>C(O)C.O>[CH3:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([NH:28]/[N:29]=[C:8](\[C:2](=[O:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])/[C:9]([O:11][CH3:12])=[O:10])=[CH:26][CH:27]=1)(=[O:21])=[O:20]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: CS(=O)(=O)c1ccc([N+]#N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)CC(=O)/C(=N\Nc1ccc(S(C)(=O)=O)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a mixture of dimethyl 3-oxopentanedioate (3.48 g, 20 mmol) in ethanol (12 mL) and water (40 mL) at room temperature was added sodium acetate (12.0 g, 146 mmol), and was followed by addition of 4-(methylsulfonyl)benzenediazonium solution (20 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. The product was collected by filtration, then washed with water (˜50 mL) and dried overnight under reduce pressure to yield 7.0 g (83%) of (E)-dimethyl 2-(2-(4-(methylsulfonyl)phenyl)hydrazono)-3-oxopentanedioate as a yellow solid. MS (ESI) 357 (M+H).
Reaction SMILES: [C:1]([N:4](C(C)(C)C)[S:5]([C:8]1[CH:9]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:19]=2)[C:11]([O:16]C)=[C:12]([CH:14]=[O:15])[CH:13]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2]>ClCCl>[C:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:19]=2)[C:11]([OH:16])=[C:12]([CH:14]=[O:15])[CH:13]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2]
Reactant: COc1c(C=O)cc(S(=O)(=O)N(C(C)=O)C(C)(C)C)cc1-c1cccc(S(N)(=O)=O)c1
Solvent: ClCCl
Product: CC(=O)NS(=O)(=O)c1cc(C=O)c(O)c(-c2cccc(S(N)(=O)=O)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
N-acetyl-N-tert-butyl-5-formyl-6-methoxy-biphenyl-3,3′-disulfonamide (100 mg, 0.21 mmol), prepared as in Reference 19, was dissolved in dichloromethane (10 mL). The solution was flushed with nitrogen for 5 minutes and then boron tribromide (1.0 mL, 1M solution in dichloromethane) was added. The mixture was stirred at room temperature for 1 hour and then concentrated under by evaporation under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue was passed through a short silica plug with pure ethyl acetate to give N-acetyl 5-formyl-6-hydroxy-biphenyl-3,3′-disulfonamide (74 mg) as a colorless oil.