Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1N=CC=CN=1.[CH3:26][O-:27].[Na+]>CO>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:27][CH3:26])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: C[O-]
Agent: Clc1ncccn1
Agent: [Na+]
Solvent: CO
Product: COc1ncnc2c1CN(Cc1ccccc1)CC2

Procedure:
A 1 L flask was charged with 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (39.6 g, 0.152 mol) and methanol (300 mL), and the mixture was heated to dissolve the chloropyrimidine. 4.37 M of sodium methoxide in methanol (105 mL) was added slowly to the warm mixture and the stirred mixture rapidly turned cloudy. The resultant suspension was heated under reflux for 2 h. After cooling, the mixture was concentrated in vacuo to ca 100 mL. The residue was poured into water (600 mL), and extracted with CH2Cl2 (200 mL×2). The combined organic layers were washed with brine (400 mL), dried (Na2SO4), filtered and concentrated in vacuo to a light brown oil (38.9 g, 100%). MS: 256.1 [M+1]+.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C@H](CCCCCCCCCCC)CC(O)=O)C1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:23]
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OCc1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dicyclohexylcarbodiimide (963 mg, 4.67 mmol), 4-dimethylaminopyridine (574 mg, 4.70 mmol) and (R)-3-benzyloxytetradecanoic acid (1.50 g, 4.48 mmol) were added to a solution of the compound of Reference Example 5 (1.96 g, 3.71 mmol) in methylene chloride (30 ml) and the mixture was stirred at room temperature for 18 hours. Dicyclohexylurea produced during the reaction was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate. The ethyl acetate layer was successively washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using cyclohexane:ethyl acetate 4:1 as the eluant to give the desired product (2.79 g, yield 89%).
Reaction SMILES: [B:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([S:21][CH3:22])[N:13]=[C:12]2[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:6][CH:5]=1)([OH:3])[OH:2].[C:27]1(C)C=CC=C[CH:28]=1.C(O)CCO>O>[CH2:23]([C:12]1[N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([B:1]3[O:2][CH2:28][CH2:27][O:3]3)=[CH:5][CH:6]=2)[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([S:21][CH3:22])[N:13]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1nc(SC)c(C(=O)OCC)n1Cc1ccc(B(O)O)cc1
Reactant: Cc1ccccc1
Solvent: OCCCO
Solvent: O
Product: CCCCc1nc(SC)c(C(=O)OCC)n1Cc1ccc(B2OCCO2)cc1

Procedure:
A mixture of 1.292 g of ethyl 1-[(4-boronophenyl)-methyl]-2-butyl-4-(methylthio)-1H-imidazole-5-carboxylate of Preparation 3, 25 ml of toluene and 0.710 ml of 1,3 propanediol was stirred at reflux for 4 hours while eliminating the water formed. After evaporating to dryness under reduced pressure, the residue was crystallized hot and cold from heptane, filtered and washed to obtain 1.12 g of the desired product.
Reaction SMILES: CC1NN(C2C=CC=CC=2)C(=O)C=1.[CH3:14][S:15][C:16]1[S:17][C:18]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:19]=2[N+:20]=1CCCS(O)(=O)=O.C(N(CC)CC)C>CO>[Cl:32][C:29]1[CH:30]=[CH:31][C:18]2[S:17][C:16]([S:15][CH3:14])=[N:20][C:19]=2[CH:28]=1
Reactant: CSc1sc2ccc(Cl)cc2[n+]1CCCS(=O)(=O)O
Agent: Cc1cc(=O)n(-c2ccccc2)[nH]1
Solvent: CCN(CC)CC
Solvent: CO
Product: CSc1nc2cc(Cl)ccc2s1
Reaction time: 1 h

Procedure:
3-Methyl-1-phenylpyrazolin-5-one (1.045 g) was mixed with 2.03 g (0.006 mol) 2-methylthio-5-chloro-3-(3'-sulfopropyl)benzothiazolium, inner salt in 50 ml methanol. Triethylamine (0.62 g) was added. The mixture was stirred for one hour, the solvent evaporated, and the residue dissolved in isopropanol. The resulting solution was treated with 0.6 g KOAc in methanol to precipitate the dye. Filtering yielded 2.17 g (72%), mp 271°-276° C., λmax=383 (ε=19,000).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:10]=1.C(N(CC)CC)C.[CH:32]1([NH2:35])[CH2:34][CH2:33]1.Cl>C(Cl)Cl.O>[CH:32]1([NH:35][S:11]([C:9]2[CH:10]=[C:5]([O:4][C:3]3[C:2]([Cl:1])=[CH:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][C:17]=3[Cl:24])[CH:6]=[CH:7][C:8]=2[O:15][CH3:16])(=[O:13])=[O:12])[CH2:34][CH2:33]1
Reactant: NC1CC1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)NC1CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 68.4 %

Procedure:
To a cooled solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-benzenesulfonyl chloride (920 mg, 2.2 mmol) in CH2Cl2 (25 mL) at 0° C. was added triethylamine (470 μL, 3.4 mmol) and cyclopropylamine (170 μL, 2.5 mol). The resulting mixture was stirred at 0° C. for 5 min, then at RT for 6 h. Water (30 mL) and 1N HCl (1 mL) was added and the solution was extracted with EtOAc (3×50 mL). The combined EtOAc extracts were dried and concentrated. The product was purified by chromatography to give the title compound of Step B (652 mg). MS (APCl) Calc.: 432.0, Found: 430.9 (M−1).
Reaction SMILES: C1C=CC([I+][C:8]2[C:13]([C:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=CC=1.O.[NH2:18][C:19]1[C:20]([Cl:28])=[C:21]([CH:25]([CH3:27])[OH:26])[CH:22]=[CH:23][CH:24]=1>C(O)(C)C>[Cl:28][C:20]1[C:21]([CH:25]([OH:26])[CH3:27])=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: CC(O)c1cccc(N)c1Cl
Reactant: O=C([O-])c1ccccc1[I+]c1ccccc1
Solvent: CC(C)O
Solvent: O
Product: CC(O)c1cccc(Nc2ccccc2C(=O)O)c1Cl
Yield: 65.6 %

Procedure:
A mixture of diphenyliodonium-2-carboxylate monohydrate (11.4 g, 33.3 mmol), 3-amino-2-chloro-α-methylbenzenemethanol (5.2 g, 30.3 mmol), and cupric acetate (0.5 g) in isopropanol (100 mL) is heated at reflux for 12 hours under an argon atmosphere. The solvent is evaporated under vacuum and the remaining dark oil is taken up in 10% aqueous KOH. The insoluble material is removed by filtration through Celite-545, and the filtrate is extracted with ether to remove nonacidic impurities. The aqueous solution is acidified to pH=3 with concentrated HCl. The resulting precipitate is collected by filtration and purified by column chromatography (silica, ethyl acetate) to give pure 2-[[2-chloro-3-(1-hydroxyethyl)phenylamino]benzoic acid (5.8 g, 60%), mp=169-171° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([C:17](=[O:22])N(OC)C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[CH3:37])([CH3:27])([CH3:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:17](=[O:22])[CH2:37][C:31]1[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:30]=1[C:29](=[O:38])[NH:28][C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(C)c(C(=O)NC(C)(C)C)c1
Product: Cc1ccc(CC(=O)[C@@H](Cc2ccccc2F)NC(=O)OC(C)(C)C)c(C(=O)NC(C)(C)C)c1

Procedure:
Using general procedure 2 with [(R)-2-(2-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (2.15 g, 6.6 mmol) and N-tert-butyl-2,5-dimethyl-benzamide (4.0 g, 20 mmol), followed by purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>ClCCl>[CH:19]1([NH:18][C:16]([C:11]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:25])[CH2:23][CH3:24])=[CH:3][CH:4]=3)[C:12]=2[CH2:13][CH2:14][CH3:15])=[O:17])[CH2:20][CH2:21]1
Reactant: CCC(=O)Cl
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Solvent: ClCCl
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)CC)cc1
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.29 g) obtained in Example 1d) in dichloromethane (10 ml) was added propionyl chloride (0.09 ml) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was diluted with dichloromethane, and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/4 to 1/1) to give the title compound as a white powder (0.11 g, 31%).
Reaction SMILES: [Cl:1][CH2:2][CH:3]([CH2:28][Cl:29])[O:4][C:5]1[C:6]([N+:25]([O-])=O)=[C:7]([CH2:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.C1COCC1>[Pd].CO>[Cl:29][CH2:28][CH:3]([CH2:2][Cl:1])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:13])=[O:14])[C:6]=1[NH2:25]
Reactant: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OC(CCl)CCl
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OC(CCl)CCl
Reaction time: 20 h

Procedure:
A mixture of 1-[3-(2-chloro-1-chloromethyl-ethoxy)-2-nitro-phenylmethanesulfonyl]-naphthalene (3) (2.4 g, 5.3 mmoles) and 10% Pd/C in a 1:1 mixture of THF and methanol was hydrogenated on a Parr hydrogenator at 40 lb/in2 for 20 hours. The mixture was filtered through Celite. The filtrate was diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (2.02 g, 4.77 mmoles), identified by HNMR analysis.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH2:12]([C@@H:14]1[NH:18][C:17](=[O:19])[C:16]([F:21])([F:20])[C@@H:15]1[OH:22])[CH3:13].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH2:12]([C@@H:14]1[N:18]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=2)[C:17](=[O:19])[C:16]([F:20])([F:21])[C@@H:15]1[OH:22])[CH3:13]
Reactant: CC[C@@H]1NC(=O)C(F)(F)[C@@H]1O
Reactant: COc1cc(Br)ccc1C#N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@H]1[C@@H](O)C(F)(F)C(=O)N1c1ccc(C#N)c(OC)c1

Procedure:
Using 4-bromo-2-methoxybenzonitrile (2.14 g), (4R,5S)-5-ethyl-3,3-difluoro-4-hydroxypyrrolidin-2-one (2.00 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (954 mg), tris(dibenzylideneacetone)dipalladium(0) (554 mg) and cesium carbonate (4.84 g), and in the same manner as in Example 62, the title compound was obtained as a white powder (yield: 895 mg, 30%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([CH:11]=[O:12])=[C:8]([CH3:13])[CH:7]=[C:6]([CH3:14])[C:5]=2[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>COCCOC.C(Cl)Cl.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:13][C:8]1[CH:7]=[C:6]([CH3:14])[C:5]2[N:4]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:16])=[O:17])[CH:3]=[C:2]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]=2[C:9]=1[CH:11]=[O:12]
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(C=O)c(C)cc(C)c32)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3c(C=O)c(C)cc(C)c32)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a suspension of 3-bromo-5,7-dimethyl-1-tosyl-1H-indole-4-carbaldehyde (100 mg, 0.246 mmol), phenylboronic acid (60.0 mg, 0.492 mmol), and K3PO4 (157 mg, 0.738 mmol) in DME (1 mL)/H2O (0.5 mL), Pd(OAc)2 (5.53 mg, 0.025 mmol) and S-phos (CAS#657408-07-6) (20.21 mg, 0.049 mmol) were added the mixture was stirred at 80° C. for 15 h. The reaction mixture was cooled to room temperature and diluted with CH2Cl2 and water. The layers were partitioned. The organic layer was separated, dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel flash column chromatography [heptane/(30% EtOAc in CH2Cl2)=1/0 to 4/6] to give the title compound. MS (ESI+) m/z 404.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34](O)=[O:35])=[CH:30][CH:29]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:34](=[O:35])[CH2:33][O:32][C:31]3[CH:37]=[CH:38][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:25][CH:24]=3)[S:9][C:10]=2[N:11]=1
Reactant: COc1ccc(OCC(=O)O)cc1
Reactant: Cc1ccc(CCc2nc3c(N4CCNCC4)nc(N)nc3s2)cc1
Product: COc1ccc(OCC(=O)N2CCN(c3nc(N)nc4sc(CCc5ccc(C)cc5)nc34)CC2)cc1
Yield: 68 %

Procedure:
This compound was prepared from 2-(4-methylphenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 68%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[C:29]([F:30])=[CH:28][C:20]([C:21]([O:23]C(C)(C)C)=[O:22])=[C:19]([F:31])[CH:18]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:13][C:12]([F:15])([F:14])[CH2:11]1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[C:29]([F:30])=[CH:28][C:20]([C:21]([OH:23])=[O:22])=[C:19]([F:31])[CH:18]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][C:12]([F:14])([F:15])[CH2:13]1
Reactant: CC(C)(C)OC(=O)c1cc(F)c(Oc2cnc(OCC3CC(F)(F)C3)c(Cl)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)c(Oc2cnc(OCC3CC(F)(F)C3)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
tert-Butyl 4-({5-chloro-6-[(3,3-difluorocyclobutyl)methoxy]pyridin-3-yl}oxy)-2,5-difluorobenzoate (Preparation 7, 0.400 g, 0.87 mmol) was dissolved in THF (5.0 mL) and methanol (5.0 mL). Then an aqueous solution of sodium hydroxide was added (3.0 M, 5.0 mL) and the mixture was stirred at room temperature under nitrogen for 3 hours. Aqueous solution of HCl (1.0 M, 75.0 mL) was added and the mixture was extracted with EtOAc (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (trilution method) to afford the title compound (0.31 g, 88%):
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:36])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20](B(O)O)[C:21]4[S:25][C:24]([NH:26][C:27](=[O:31])[NH:28][CH2:29][CH3:30])=[N:23][C:22]=4[CH:32]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.OO.S(=O)(=O)(O)[OH:40]>[OH-].[Na+].O>[CH2:29]([NH:28][C:27]([NH:26][C:24]1[S:25][C:21]2[C:20]([OH:40])=[CH:19][C:18]([C:15]3[CH:16]=[N:17][C:12]([N:9]4[CH2:8][CH2:7][C:6]([CH3:36])([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]4)=[N:13][CH:14]=3)=[CH:32][C:22]=2[N:23]=1)=[O:31])[CH3:30]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(B(O)O)c2s1
Reactant: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(O)c2s1
Reaction time: 72 h
Yield: 78 %

Procedure:
A stirred suspension of [5-[2-(4-ethoxycarbonyl-4-methyl-1-piperidyl)pyrimidin-5-yl]-2-(ethylcarbamoylamino)-1,3-benzothiazol-7-yl]boronic acid (166 mg, 0.286 mmol) in aqueous NaOH solution (2 M, 1.3 mL) was treated with excess hydrogen peroxide (27.5% aqueous solution, 0.45 mL) and kept at rt for 3 days by which time LCMS showed complete reaction. The resultant mixture was diluted with water (30 mL) and acidified by the addition of a small amount of conc. sulfuric acid. The precipitated solid was collected by filtration, washed with water (10 mL) and dried in vacuo to give Compound 26 as a white solid (102 mg, 78% yield). 1H NMR (DMSO-d6): δ 10.37 (1H, s), 8.67 (2H, s), 7.37 (1H, s), 6.85 (1H, s), 6.77 (1H, t, J=5.86 Hz), 4.30 (2H, dt, J=13.75, 4.56 Hz), 3.36 (2H, ddd, J=13.34, 9.92, 3.07 Hz), 3.22 (2H, p, J=6.69 Hz), 2.04 (2H, dt, J=13.63, 3.69 Hz), 1.42 (2H, ddd, J=13.55, 10.29, 3.91 Hz), 1.22 (3H, s), 1.13 (3H, t, J=7.19 Hz). m/z: 457 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.N1C=CC=CC=1.Cl>O>[CH3:1][NH:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: C1CNCCN1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Yield: 74.3 %

Procedure:
A mixture of 1.95 g of 1-methylamino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 3.05 g of anhydrous piperazine and 20 ml of dry pyridine is refluxed for 6 hours. The solvent is stripped off in vacuo, the residue is taken up in 20 ml of water, the pH is brought to 7-8 with half-concentrated hydrochloric acid, with cooling, and the precipitate is filtered off with suction, washed with ice-water and dried at 100° C. in vacuo. 1.8 g of 1-methylamino-6,8-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of decomposition point 276°-278° C. are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:35])[CH2:32][O:33][CH3:34])[CH:25]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([N+:43]([O-])=O)=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.CC(O)=O.[Pt]>[NH2:43][C:40]1[CH:39]=[CH:38][C:37]([N:7]2[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:35])[CH2:32][O:33][CH3:34])[CH:25]=4)=[CH:15][CH:14]=3)=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]2)=[CH:42][CH:41]=1
Reactant: [H][H]
Reactant: COCC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc([N+](=O)[O-])cc3)c3ccccc23)ccn1
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Product: COCC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(N)cc3)c3ccccc23)ccn1

Procedure:
A solution of N-(4-(4-(3-(3-tert-butyl-1-(4-nitrophenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide (270 mg, 0.443 mmol) in a mixture of MeOH (20 mL) and AcOH (1.0 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 40° C., 55 mm, 10% Pt—C Cat-Cart, full hydrogen mode). The reaction mixture was evaporated in vacuo and the residue was partitioned between EtOAc (15 mL) and saturated aq. NaHCO3 (15 mL). The organic layer was separated and was washed with brine (15 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 20-100%, gradient elution) to afford the title compound, Example 1, as a pale brown solid (115 mg, 43%); Rt 4.87 min (Method 1 basic); m/z 580 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.25 (9H, s), 3.30 (3H, s), 3.98 (2H, s), 5.41 (2H, s), 6.34 (1H, s), 6.68-6.71 (3H, overlapping m), 7.14 (2H, d), 7.33 (1H, d), 7.57 (1H, m), 7.63-7.67 (2H, overlapping m), 7.83 (1H, d), 7.98 (1H, dd), 8.09 (1H, d), 8.18 (1H, d), 8.65 (1H, s), 9.18 (1H, s), 10.04 (1H, s).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[N:12][C:11]=1[C:22]#[N:23]>O1CCCC1>[NH2:9][C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([Br:1])=[N:12][C:11]=1[C:22]#[N:23]
Reactant: N#Cc1ncn(Cc2ccccc2)c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: N#Cc1nc(Br)n(Cc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
N-bromosuccinimide (3.55 g, 19.9 mmol) was added portionwise to a suspension of 5-amino-1-benzyl-1H-imidazole-4-carbonitrile (3.59 g, 18.1 mmol) in tetrahydrofuran (50 ml) and the reaction mixture stirred at room temperature for 10 minutes. The solvent was evaporated in vacuo and the residue extracted from a saturated aqueous solution of sodium hydrogen carbonate (50 ml) into ethyl acetate (300 ml), dried over magnesium sulphate, filtered and evaporated in vacuo. The crude material was purified by column chromatography over silica gel eluting with 2-3% dichloromethane:methanol. The material was recrystalised from ethyl acetate, then triturated with diethyl ether to yield the title compound as a pink solid (2.7 g, 9.7 mmol, 53%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1>>[N:22]1([CH2:21][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: ClCn1nnc2ccccc21
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cn2nnc3ccccc32)c(=O)[nH]c1=O
Yield: 28.6 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 1-chloromethyl-1H-benzotriazole were reacted by the same way with the example 1 to obtain the titled compound (112 mg, yield: 28.6%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][NH:28][CH3:29].O>CN(C=O)C>[CH3:24][O:25][CH2:26][CH2:27][N:28]([CH3:29])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:3]=1
Reactant: CNCCOC
Reactant: O=[N+]([O-])c1ccc(F)cc1OCCc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CN(C)C=O
Product: COCCN(C)c1ccc([N+](=O)[O-])c(OCCc2cccc(C(F)(F)F)c2)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Dissolved 4-fluoro-1-nitro-2-[2-(3-trifluoromethylphenyl)ethoxy]benzene (200 mg, 0.61 mmol) in DMF (1 mL) and added N-(2-methoxyethyl)methylamine (270 mg, 3.04 mmol). Reaction Mixture was warmed to 60° C. and stirred for 18 h. The reaction mixture was poured into H2O and extracted with EtOAc (2×). The combined organics were washed with brine and dried over Na2SO4. The title compound was carried on crude to the next step.