Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:8]=2[O:9][CH2:10][CH2:11][CH2:12][CH:13]([NH:15]C(=O)OC(C)(C)C)[CH3:14])[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:8]=2[O:9][CH2:10][CH2:11][CH2:12][CH:13]([NH2:15])[CH3:14])[N:3]=1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCC(C)NC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCC(C)N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To an ice-cold solution of tert-butyl (5-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)pentan-2-yl)carbamate (1.5 g, 3.70 mmol) in DCM (50 mL) was added TFA (5 mL). The reaction mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure and treated with saturated sodium bicarbonate solution (150 mL), and extracted with ethyl acetate (2×150 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get 5-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)pentan-2-amine (920 mg, 81%). LC-MS (M+H)+=306.2. 1H NMR: (400 MHz, CDCl3) δ ppm 8.97 (1H, s), 8.08 (1H, d, J=8.8 Hz), 8.00-7.91 (2H, m), 4.29-4.23 (2H, m), 3.27-3.25 (1H, m), 2.46 (3H, s), 2.16-2.03 (4H, m), 1.32-1.27 (3H, m).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:15][CH:14]=1.C(O)(=[O:28])C>O>[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:28])=[CH:15][CH:14]=1
Reactant: CC(=O)O
Reactant: Clc1ccc(Cc2ccccn2)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccccn1

Procedure:
164 G. (0.55 mol) of sodium dichromate was added to a stirred solution of 101 g. (0.5 mol) of 2-(p-chlorobenzyl)-pyridine in 450 ml. of acetic acid and the resulting mixture was stirred and refluxed for 3 hrs. The resulting dark green solution was cooled and poured into 1500 ml. of cold water. The precipitate which resulted was collected, washed with water and air dried to yield 2-(4-chlorobenzoyl)pyridine as white microprisms, mp. 62°-64° C. (ligroin).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH:31]([CH3:33])[CH3:32]>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:5]([O:22][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(C)C)c1OC(F)F
Temperature: 70 °C
Yield: 21.5 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and isobutylbromide (67 mg, 0.492 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-30% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 21.4%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH:8]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[NH:6][C:5]=2[N:4]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:3]=1>ClCCl.FC(F)(F)C(O)=O>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH:8]=[C:7]([C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)[NH:6][C:5]=2[N:4]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:3]=1
Reactant: Cc1nn(-c2ccccc2)c2[nH]c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc(=O)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nn(-c2ccccc2)c2[nH]c(-c3ccc(N4CCNCC4)cc3)cc(=O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of tert-butyl 4-(4-(3-methyl-4-oxo-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)piperazine-1-carboxylate (300 mg, 0.62 mmol, 1.00 equiv) in dichloromethane (6 mL), trifluoroacetic acid (3 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was then concentrated under vacuum. The pH value of the solution was adjusted to about 9-10 with sodium bicarbonate. The resulting solution was extracted with of ethyl acetate (2×10 mL), the organic layers combined and dried over anhydrous magnesium sulfate. The residue was applied onto a silica gel column with MeOH:DCM (1:40) to yield 3-methyl-1-phenyl-6-(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4(7H)-one as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:32][CH2:31][N:30]([S:35]([N:34]([CH3:39])[CH3:33])(=[O:37])=[O:36])[CH2:29][CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 102 %

Procedure:
To a suspension of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.17 mmol) in toluene (1 mL) was added N,N-dimethylsulfamoyl chloride (27 mg, 0.19 mmol) and triethylamine (73 μL, 0.52 mmol). The reaction was stirred at rt for 17 h. Additional N,N-dimethylsulfamoyl chloride (27 mg, 0.19 mmol) and triethylamine (73 μL, 0.52 mmol) were added and the reaction continued to stir at rt for 6 h. The mixture was partitioned between EtOAc (20 mL) and H2O (20 mL). The layers were separated and the organic phase was washed with saturated, aqueous NaHCO3 (20 mL), brine, dried (Na2SO4) and concentrated. The resulting solid was triturated with Et2O and was collected by vacuum filtration to afford 92 mg (99%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (s, 1 H), 7.90 (s, 1 H), 7.80 (d, 1 H), 7.59 (s, 1 H), 7.28-7.37 (m, 5 H), 7.14 (d, 1 H), 6.63 (s, 1 H), 5.65 (s, 2 H), 3.67 (d, 2 H), 3.22-3.33 (m, 1 H), 3.01 (t, 2 H), 2.77 (s, 6 H), 2.07 (d, 2 H), 1.62-1.77 (m, 2 H); ES-MS m/z 531.26 [M+H]+, HPLC RT (min) 2.75.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[N:3]=1.FC(F)(F)C(O)=O.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>ClCCl>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([NH:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:23][CH:24]=2)[N:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1nc(NCCc2ccc(O)cc2)nc2nc(-c3ccco3)nn12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)Oc1ccc(CCNc2nc(N)n3nc(-c4ccco4)nc3n2)cc1

Procedure:
7-Amino-2-(2-furyl)-5-[2-(4-hydroxyphenyl)ethyl]amino[1,2,4-triazolo[1,5-a][1,3,5]triazine (1 g, prepared as described in Example 81) was suspended in dichloromethane (20 ml) and trifluoroacetic acid (20 ml) was added with stirring. Pivaloyl chloride (0.4 ml) was added dropwise at ambient temperature. The mixture was stirred for 2 hours and then the dichloromethane and trifluoroacetic acid was removed in vacuo. The residue was purified by chromatography on silica (100 g) eluting with dichloromethane containing methanol (5.0% v/v). The solid obtained (1.2 g) was crystallised from toluene and finally from isopropanol (25 ml) to give 7-amino-2-(2-furyl)-5-[2-(4-pivaloyloxyphenyl)ethyl]amino[1,2,4]-triazolo[1,5-a][1,3,5]triazine as a solid; m.p. 208°-210° C.; microanalysis, found: C, 59.6; H, 6.1; N, 21.7%; C21H24N7O3 0.5 C3H7OH requires C, 59.9; H, 6.0; N, 21.7%; NMR 1.06(d, ca 3H, (CH3)2CHOH), 1.3(s, 9H, CH3C), 2.9(t, 2H, CH2Ar), 3.55 (t, 2H, CH2N), 3.80(heptet, ca 0.5 H, (CH 3)2 CHOH), 6.68(dd, 1H, furyl-4H), 7.01 and 7.30 (A2B2 pattern, 4H, phenyl-H), 7.08 (d, 1H, furyl-3H) and 7.82(d, 1H, furyl-5H); m/e 422 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[CH2:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][NH:36]1>CN(C=O)C>[Br:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([C:7]([N:36]2[CH2:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:35]2)=[O:9])[CH:10]=1
Reactant: O=C(O)c1cc(Br)c(O)cc1O
Reactant: c1ccc2c(c1)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1cc(Br)c(O)cc1O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 42.1 %

Procedure:
A solution of 5-bromo-2,4-dihydroxy-benzoic acid (520 mg, 2.33 mmol) in DMF (5 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (471 mg, 2.45 mmol) then HOBt (362 mg, 2.68 mmol). After 25 min. 2,3-dihydro-1H-isoindole (0.5 mL, 2.63 mmol) was added then the mixture was stirred at r.t. for 18 h. The solvent was removed in vacuo then the residue was taken up in ethyl acetate and washed with 1N hydrochloric acid, saturated sodium bicarbonate solution and brine then dried (MgSO4) and concentrated. The residue was triturated with methanol to afford the title compound as a grey solid (328 mg, 44%). 1H NMR (DMSO-d6) 10.45 (1H, s), 10.32 (1H, s), 7.36 (1H, br.s), 7.35 (1H, s), 7.28 (3H, br.s), 6.59 (1H, s), 4.77 (2H, br.s), 4.71 (2H, br.s). MS: [M+H]+ 332/334.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:33][C:34]2[CH:45]=[CH:44][C:37]([C:38]([NH:40][CH:41]3[CH2:43][CH2:42]3)=[O:39])=[CH:36][CH:35]=2)[CH:12]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH2:15][N:14](CC3C=CC(OC)=CC=3OC)[C:13]2=[O:32])(=[O:10])=[O:9])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:38]([NH:40][CH:41]3[CH2:43][CH2:42]3)=[O:39])=[CH:44][CH:45]=2)[CH:12]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:32])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2CCCC(C)(C)C(N(Cc3ccc(C(=O)NC4CC4)cc3)S(=O)(=O)c3ccc(Cl)cc3)C2=O)c(OC)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCCNC(=O)C1N(Cc1ccc(C(=O)NC2CC2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
4-({(4-Chloro-benzenesulfonyl)-[1-(2,4-dimethoxy-benzyl)-4,4-dimethyl-2-oxo-azepan-3-yl]-amino}-methyl)-N-cyclopropyl-benzamide (95 mg) was dissolved in a mixture of trifluoroacetic acid/trifluoromethanesulfonic acid/dichloromethane=40:1:59 (2 ml) and stirred at room temperature for 15 minutes. After evaporation flash chromatography (heptane/ethyl acetate gradient) yielded 65 mg (90%) of 4-{[(4-chloro-benzenesulfonyl)-(4,4-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-N-cyclopropyl-benzamide as a foam; MS: m/e=504.2 (MH+), 521.3 (M+NH4+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH3:19])[CH:5]=1.FC(F)(F)S(O[C:27]1[C:32]([CH3:34])([CH3:33])[CH2:31][CH2:30][CH2:29][CH:28]=1)(=O)=O>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:31]2[C:32]([CH3:34])([CH3:33])[CH2:27][CH2:28][CH2:29][CH:30]=2)=[C:6]([CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CC1(C)CCCC=C1OS(=O)(=O)C(F)(F)F
Product: COC(=O)c1ccc(C2=CCCCC2(C)C)c(C)c1
Yield: 55.8 %

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester of Example 28, Step A (0.300 g, 1.09 mmol) and 6,6-dimethyl-cyclohex-1-en-1-yl trifluoromethanesulfonate (0.338 g, 1.31 mmol) were reacted in the manner of Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with 5% ethyl acetate in hexane, afforded the title compound (0.157 g) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1
Reactant: CN1CCNCC1
Reactant: Fc1ccccc1C(Cl)=NNc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CN1CCN(C(=NNc2ccc(Cl)cc2Cl)c2ccccc2F)CC1
Reaction time: 16 h
Yield: 118.8 %

Procedure:
To a stirred mixture of α-chloro-2-fluorobenzaldehyde 2,4-dichlorophenylhydrazone (51.0 g, 0.16 mol) and tetrahydrofuran (500 ml) under N2 was added dropwise, 1-methylpiperazine (35.4 g, 0.35 mol). The reaction was allowed to stir for 16 hours and then was cooled in an ice bath for 30 minutes. The mixture was filtered and washed with cold tetrahydrofuran leaving behind the insoluble 1-methylpiperazine hydrochloride. The filtrate was concentrated to afford 72.5 g of 1-{[(2,4-dichlorophenyl) hydrazono](2-fluorophenyl)methyl}-4-methylpiperazine as an oil. To a stirred mixture of the oil (72.5 g, 0.19 mol) and tetrahydrofuran (200 ml), under N2, was added dropwise, potassium tert-butoxide (23.5 g, 0.21 mol) dissolved in tetrahydrofuran (400 ml). The reaction was allowed to stir at ambient temperature for 58 hours. The reaction mixture was concentrated to an oily residue, which was partitioned between ether and H2O. The ether extract was washed with H2O, dried with MgSO4 and concentrated to 58.0 g of an oil. A 9.0 g sample of the oil was flash chromatographed over 500 g silica gel eluting with 20% methanol-CH2Cl2. Concentration of appropriate fractions afforded 5.7 g (55%) of an oil. The oil was dissolved in anhydrous ether and fumaric acid (2.0 g, 1.1 eq) was added. The mixture was stirred overnight and the solid was collected by filtration to afford 4.6 g of product. A 3.8 g sample was recrystallized twice from ethyl acetate to afford 2.2 g of 1-(2,4-dichlorophenyl)-3-(4-methyl-1-piperazinyl)-1H-indazole, m.p. 150°-152° C.
Reaction SMILES: [Se](O)(O)=[O:2].[CH2:5]([O:7][C:8](=[O:22])[CH2:9][C:10]1[C:11]([Cl:21])=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([CH3:20])[CH:16]=[CH:15]2)[CH3:6]>O1CCOCC1.O>[CH2:5]([O:7][C:8](=[O:22])[CH2:9][C:10]1[C:11]([Cl:21])=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([CH:20]=[O:2])[CH:16]=[CH:15]2)[CH3:6]
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(C)nc12
Reactant: O=[Se](O)O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1c(Cl)ccc2ccc(C=O)nc12
Temperature: 100 °C
Yield: 77 %

Procedure:
Selenious acid (193 mg, 1.50 mmol, 1.1 equiv) was added to a solution of (7-chloro-2-methyl-quinolin-8-yl)-acetic acid ethyl ester in dioxane (12 ml). The reaction mixture was heated to 100° C. After 20 and 40 minutes, additional portions of selenious acid (88 mg each) were added, and heating was continued for a total of 90 minutes. After cooling, the reaction mixture was diluted with water, filtered, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography (gradient of hexane/EtOAc 100:0 to 80:20) to afford the title compound (292 mg, 77%). 1H NMR (400 MHz, CDCl3): δ=10.18 (s, 1H), 8.31 (d, J=8.1 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H), 4.61 (s, 2H), 4.22 (q, J=7.3 Hz, 2H), 1.28 (t, J=7.3 Hz, 3H). MS (ES+): 278.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(O)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(O)cc1C(=O)O
Reaction time: 2 h

Procedure:
Combine methyl 2-methoxy-5-hydroxybenzoate (0.37 g, 2.0 mmol) and a 1 M aqueous sodium hydroxide solution (20 mL, 20 mmol) in methanol (20 mL). After 2 hours, adjust the pH to about 2 using a 1 M aqueous hydrochloric acid solution and extract with dichloromethane. Dry the organic layer over MgSO4, filter, and evaporate in uacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C)=[O:10])=[CH:4][C:3]=1[NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:15].[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:15]
Reactant: COC(=O)Cc1ccc(Cl)c(NC(=O)Nc2ccccn2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(Cl)c(NC(=O)Nc2ccccn2)c1

Procedure:
For ester cleavage, 2.47 mmol (790 mg) of methyl 4-chloro-3-[[(2-pyridinylamino)carbonyl]amino]benzeneacetate is saponified with 1N NaOH analogously to the instructions above. Product 7 is obtained without recrystallization. Yield: 693 mg of yellowish solid.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].[CH3:10][C:11]([CH3:13])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCCCC>[OH:2][CH2:1][C:3]1([CH2:4][CH3:5])[CH2:8][O:9][C:11]([CH3:13])([CH3:10])[O:7][CH2:6]1
Reactant: CC(C)=O
Reactant: CCC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCCC
Product: CCC1(CO)COC(C)(C)OC1

Procedure:
In a 3-liter reaction vessel, 292.1 g (2.18 mol) of trimethylolpropane, 474.0 g (8.17 mol) of acetone, 6.0 g (0.0315 mol) of p-toluene sulfonic acid monohydrate, and 900 ml of hexane were placed and refluxed for 24 hours with removing the formed water off the reaction system. The reaction product was neutralized with aqueous solution of sodium hydroxide, and distilled under a reduced pressure to give 5-hydroxymethyl-5-ethyl-2,2-dimethyl-1,3-dioxane.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[C:5]([Cl:16])=[C:4]([NH:17][C:18]2[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=2)[N:3]=1.Cl.[F:25][C:26]1[CH:27]=[N:28][C:29]([C@@H:32]([NH2:34])[CH3:33])=[N:30][CH:31]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:16][C:5]1[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[N:7][C:2]([NH:34][C@H:32]([C:29]2[N:30]=[CH:31][C:26]([F:25])=[CH:27][N:28]=2)[CH3:33])=[N:3][C:4]=1[NH:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: Cc1cc(Nc2nc(Cl)nc(N(C)S(=O)(=O)N(C)C)c2Cl)n[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(N(C)S(=O)(=O)N(C)C)c2Cl)n[nH]1
Temperature: 160 °C
Yield: 89.4 %

Procedure:
A microwave reaction vessel was charged with N-{2,5-dichloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N′,N′-trimethylsulfamide (Method 24, 83.9 mg, 0.221 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 78.4 mg, 0.443 mmol), and DIPEA (0.120 ml, 0.682 mmol). Anhydrous n-BuOH (1 ml) was added, and the tube was sealed and heated in a microwave reactor at 160° C. for 2 hours. The reaction mixture was purified by silica gel chromatography (by ISCO Combiflash with gradient EtOAc and hexane) to afford the title compound as a white solid (95.8 mg, 89.6%). LC-MS, 485 (M+1). 1H-NMR (DMSO-d6, 400 MHz, 80° C.) δ 11.48-12.40 (br, 1H), 8.77 (s, 1H), 7.85-8.66 (br, 1H), 6.98-7.61 (br, 1H), 6.23 (s, 1H), 5.14-5.11 (m, 1H), 2.93 (s, 3H), 2.83 (s, 6H), 2.21 (s, 3H), 1.53 (d, 3H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)[CH:29]=[C:30](I)[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[NH:40]1[C:48]2[C:43](=[CH:44][C:45](B(O)O)=[CH:46][CH:47]=2)[CH:42]=[CH:41]1>>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)[CH:29]=[C:30]([C:45]3[CH:44]=[C:43]4[C:48](=[CH:47][CH:46]=3)[NH:40][CH:41]=[CH:42]4)[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: O=C(O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3cccc(F)c3)c2)c1CCC(=O)O
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3cccc(F)c3)cc(-c3ccc4[nH]ccc4c3)c2)c1CCC(=O)O
Yield: 30.5 %

Procedure:
A similar procedure as described in Example 5, step 2 was used, starting from 4-{2-(2-carboxy-ethyl)-3-[6-(3′-fluoro-5-iodo-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid (116 mg, 0.18 mmol) and 1H-indol-5-ylboronic acid (66 mg, 0.54 mmol) to obtain 4-(2-(2-carboxy-ethyl)-3-{6-[3′fluoro-5-(1H-indol-5-yl)-biphenyl-3-yloxy]-hexyl}-phenoxy)-butyric acid (35 mg, 31%) as an amorphous light yellow solid: ES(+)-HRMS m/e calculated for C39H40FNO6 (M+Na)+ 660.2732, found 660.2735.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:33]([N:35]([CH2:36][CH3:37])[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32])[CH3:34]
Reactant: CCNCC
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (50 mg), diethylamine (24 mg), and potassium carbonate (76 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the cooled reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (7 mg, yield 13%).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC(OCC(C)C)=O.[NH3:23].C([O-])(O)=O.[Na+]>C1COCC1.CN1CCCC1=O>[C:4]([O:3][C:1]([N:8]1[CH2:11][CH:10]([C:12](=[O:14])[NH2:23])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: N
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC(C(N)=O)C1
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
To 1.0 g (4.97 mmol) boc-azetidine-3-carboxylic acid in 10 mL anhydrous THF was added 0.55 mL of 1-methyl-2-pyrrolidinone. The reaction mixture was cooled to −20° C., then 0.62 mL (4.72 mmol) isobutyl chloroformate was added and the reaction was stirred for 5 minutes. 1.51 mL (24.85 mmol) aqueous ammonia (28% w/w) was added and the mixture was stirred at −20° C. for 2 hours. 5 mL aqueous NaHCO3 (1 M) was added and the mixture was allowed to reach room temperature over 1 hour. The mixture was extracted with DCM (3×10 mL), the organic layers were combined, washed with aqueous NaHCO3 (1 M), aqueous citric acid (1 M) and dried over Na2SO4. After filtration and evaporation of the solvent the product was used in the next step without further purification.