Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH:25]([O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1)([CH3:27])[CH3:26].O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:32]3[CH:31]=[N:30][C:29]([O:28][CH:25]([CH3:27])[CH3:26])=[CH:34][CH:33]=3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CC(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc(OC(C)C)nc3)n2n1
Temperature: 110 °C
Yield: 37.2 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 100 mg, 0.290 mmol), 2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (78 mg, 0.296 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21 mg, 29 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.966 mL of 1,4-dioxane and 0.483 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (50-85% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (48.1 mg, 37.2%). 1H NMR (DMSO-d6) δ: 11.13 (s, 1H), 8.85 (dd, J=2.5, 0.5 Hz, 1H), 8.30-8.35 (m, 1H), 7.95 (d, J=8.8 Hz, 2H), 7.92 (s, 1H), 7.55 (d, J=8.6 Hz, 2H), 6.92 (dd, J=8.7, 0.6 Hz, 1H), 6.32 (d, J=0.5 Hz, 1H), 5.32 (spt, J=6.2 Hz, 1H), 5.13 (br. s., 1H), 3.50 (s, 1H), 2.34 (s, 3H), 1.39 (s, 6H), 1.29 (d, J=6.1 Hz, 6H); ESI-MS: m/z 446.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[C:8](=[O:21])[N:7]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[C:6]=2[CH:30]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([S:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)(=[O:12])=[O:11])[C:8](=[O:21])[N:7]([CH2:22][C:23]([OH:25])=[O:24])[C:6]=2[CH:30]=1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(CC(=O)OC(C)(C)C)c3cc(Cl)ccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)n2c(=O)n(CC(=O)O)c3cc(Cl)ccc32)cc1
Temperature: 25 °C

Procedure:
1.10 g (2.43 mmol) of tert-butyl [6-chloro-3-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]acetate (XIIg) were dissolved in dichloromethane (40 ml) and, while stirring at room temperature, trifluoroacetic acid (20 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 0.82 g (95%) of white solid
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([Li])(C)(C)C.CCCCC.[CH3:24][C:25]([CH3:27])=[O:26]>C(OCC)C>[Cl:8][C:6]1[CH:7]=[C:2]([C:25]([OH:26])([CH3:27])[CH3:24])[CH:3]=[C:4]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=1
Reactant: Clc1cc(Br)cc(C2OCCO2)c1
Reactant: CC(C)=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)(O)c1cc(Cl)cc(C2OCCO2)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-(3-bromo-5-chlorophenyl)-1,3-dioxolane (3.34 g, 12.68 mmol) in anhydrous diethyl ether (40 mL) in a dried flask was slowly added a 1.70 M solution of tert-butyl lithium in pentane (15.0 mL, 25.50 mmol) at −78° C. under nitrogen to give a pinkish-yellow suspension. The reaction mixture was stirred at −78° C. for 45 min under nitrogen atmosphere. After 45 min, the reaction mixture was warmed to −30° C. and stirred at that temperature for 2 h. Acetone (2.0 mL, 25.35 mmol) was added drop wise to the above solution and the reaction mixture stirred at −30° C. for another 3 h. The reaction mixture was quenched with a saturated NH4Cl solution (20 mL) at −30° C. and the reaction mixture was warmed slowly to room temperature (30 min) and then diluted with diethyl ether (25.0 mL). The ether layer was separated and then washed with water (1×25 mL), dried over anhydrous Na2SO4, filtered and evaporated on the rot-yap to give a pale yellow viscous liquid (5.45 g from two runs). GC-MS analysis (EI mode) of the product shows the desired product's mass: m/z 241 (35ClM+) and m/z 243 (37ClM+), Calcd for C12H15BrClO3: 242.67. LC-MS analysis of the crude product shows the desired product's mass: m/z 243 (35ClM+H), m/z 245 (37ClM+H), m/z 225 (35ClM+H−H2O), m/z 227 (37ClM+H−H2O). 1H NMR (400 MHz, CDCl3): δ 1.54 (s, 6H, (CH3)2C—OH), 3.90-4.25 (M, 4H, 2×—CH2—O—), 5.75 (s, 1H, O—CH-0), 7.34 (s, 1H), 7.43 (d, 2H). 1H NMR spectrum of the sample was consistent with the suggested structure of the product.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:16][C@H:17]2[CH2:25][CH2:24][C@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[C@@H:18]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:14][OH:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:16][C@H:17]2[CH2:25][CH2:24][C@H:23]3[C@@H:19]([CH2:20][N:21]([C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH2:22]3)[C@@H:18]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:14][OH:15])[CH:4]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:8]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccccc1[C@H]1[C@@H]2CNC[C@H]2CC[C@@H]1O[C@H](CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1[C@H]1[C@@H]2CN(C(=O)C(C)C)C[C@H]2CC[C@@H]1O[C@H](CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound from EXAMPLE 2 in CH2Cl2 was added isobutyric chloride, triethylamine and a catalytic amount of DMAP. The mixture was stirred at room temperature for 2 hr. The solvent was removed and the residue was heated with 10 mL 2 N NaOH in 40 mL methanol at 50° C. for 1 hr. Methanol was removed under vacuum. The residue was diluted with water and the aqueous was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and the solvent was removed. The residue was purified by preparative TLC (80:20 EtOAc:hexane), 0.07 mg. M++1: 558.16.
Reaction SMILES: [C:1]([C:3]([C:18]#[N:19])=[C:4](SC)[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[CH3:15])#[N:2].[CH2:20]([NH2:23])[C:21]#[CH:22]>C(#N)C>[C:1]([C:3]([C:18]#[N:19])=[C:4]([NH:23][CH2:20][C:21]#[CH:22])[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[CH3:15])#[N:2]
Reactant: C#CCN
Reactant: CSC(NCCSCc1[nH]cnc1C)=C(C#N)C#N
Solvent: CC#N
Product: C#CCNC(NCCSCc1[nH]cnc1C)=C(C#N)C#N
Reaction time: 48 h

Procedure:
A mixture of the product of Step A (4.3 g, 14.7 mmole) and propargylamine (8.6 ml) in acetonitrile (43 ml) was stirred at reflux temperature under a positive pressure of nitrogen for 15 hours then at room temperature for an additional 48 hours. The reaction mixture was filtered to remove by-product and the filtrate was evaporated under reduced pressure. The residual gum was placed on silica gel and chromatographed by gradient elution using methylene chloride-methanol. The appropriate fractions were combined and the product recrystallized from acetonitrile to give the title compound; mp 112.5°-115°.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][S:15]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:8]=1.Br[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1>CN(C=O)C>[CH3:3][O:4][C:5](=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]([CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[S:15]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:8]=1
Reactant: Clc1cccc(OCCBr)c1
Reactant: COC(=O)Cc1cccc(CNS(=O)(=O)c2cccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(CN(CCOc2cccc(Cl)c2)S(=O)(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
To a solution of sodium hydride (60% in mineral oil, 0.016 g, 0.3996 mmol) in 2 mL DMF was added (3-((pyridine-3-sulfonylamino)-methyl)-phenyl)-acetic acid methyl ester (from Preparation 14, 0.096 g, 0.333 mmol) at 0° C. and the reaction was stirred at room temperature for 30 minutes. After cooling to 0° C., 1-(2-bromo-ethoxy)-3-chloro-benzene (from Preparation 29, 0.094 g, 0.399 mmol) was added and the reaction was stirred at room temperature overnight. The DMF was removed in vacuo. The residue was diluted with EtOAc and the organic solution was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (0.5% MeOH/CH2Cl2 to 2% MeOH/CH2Cl2) to afford the title compound of Step A (0.025 g). MS 475 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C@@H:6]([OH:8])[CH3:7])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl.FC(F)(F)S(O)(=O)=O>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C@@H:6]([O:8][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:7])[CH3:2]
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CCOC(=O)C[C@H](C)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C[C@H](C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 200.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of (S)-(+)-3-hydroxybutyric acid ethyl ester (100 g, 0.76 mol) in methylene chloride (1.0 L), benzyl 2,2,2-trichloroacetoimidate (381 g, 1.5 mol) and trifluoromethanesulfonic acid (6.7 mL, 76 mmol) were gradually added, and the mixture was stirred at room temperature overnight. The precipitated solid was filtered, and after the mother liquid was successively washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, it was dried with sodium sulfate and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and after the solid was filtered again, the solvent of the mother liquid was distilled off under reduced pressure to give (3S)-3-(benzyloxy)butanoic acid ethyl ester (339 g) as a mixture. The present compound was used for the subsequent reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19]>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:18]=[O:19])[CH:25]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2cccc(C=O)c2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 3-formylbenzene-boronic acid gives “A75”; method 1: HPLC/MS: 1.29 min, [M+H]=319;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][C:5]2([CH3:12])[CH3:11].N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19](=[O:21])[CH3:20])[CH2:6][C:5]2([CH3:12])[CH3:11]
Reactant: CC1(C)CNc2ccc(Br)cc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CC(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-1H-indole (1.6 g, 7.1 mmol) in DCM (40 mL) and pyridine (1.1 mL, 14.2 mmol) was added acetic anhydride (1 mL, 11 mmol). The reaction was stirred at room temperature overnight, then solvent was removed in vacuo and the residue partitioned between water and saturated aqueous NH4Cl. The organic phase was separated, dried (MgSO4), filtered and concentrated to give the title compound (1.8 g), used without further purification. Analytical data were consistent with those reported in Preparation 61.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].O>C(O)C>[N:7]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[CH:15][CH:16]=2)[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1
Reactant: CC(=O)NCc1ccc(CN2CCN(C(C)=O)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)NCc1ccc(CN2CCNCC2)cc1
Yield: 92.6 %

Procedure:
A solution of N-(4-((4-acetylpiperazin-1-yl)methyl)-phenylmethyl)acetamide (11.5 g) and sodium hydroxide (4.0 g) in ethanol (20 ml)-water (20 ml) was refluxedunder heating for 18 hr. The reaction mixture was extracted with chloroform and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-brown oil (9.1 g). The obtained pale-brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol:aqueous ammonia=9:1:0.3) to give the title compound (7.4 g) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.[Cl:15][C:16]1[C:17]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:26]2[CH2:27][CH2:28][N:23]([C:17]3[C:16]([Cl:15])=[CH:21][C:20]([Cl:22])=[CH:19][N:18]=3)[CH2:24][CH2:25]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Product: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCN(c2ncc(Cl)cc2Cl)CC1
Yield: 101.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-methanesulfonylbenzoic acid (279 mg) and 1-(3,5-dichloropyridin-2-yl)piperazine (232 mg), the title compound (0.5 g) was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8]([C:17]([F:20])([F:19])[F:18])[C:7]=1[C:21]([O:23]CC)=[O:22])[CH2:2][CH2:3][CH3:4].[OH-].[K+].CO>O>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8]([C:17]([F:20])([F:19])[F:18])[C:7]=1[C:21]([OH:23])=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(OCCCC)c(C(=O)OCC)c(C(F)(F)F)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCOc1cc(OCCCC)c(C(=O)O)c(C(F)(F)F)n1
Yield: 89.7 %

Procedure:
A mixture of 25.6 g (0.0705 mol) of product of Example 5, 20 g of KOH and 250 ml of methanol was held at reflux for 16 hours. The reaction mixture was concentrated under reduced pressure to give a solid. This solid was dissolved in water (250 ml) and extracted with ether. Three layers were separated. The top layer (ether) was discarded. The bottom two layers were acidified with 100 ml of concentrated HCl. The organic layer was separated and extracted into ether. The ether extracts were dried and concentrated to give 21.2 g (89%) of solid which was crystallized from hexane at low temperature to give 5.1 g of pure product: mp 90°-93.5° C. and 5.1 g of second crop, mp 89°-92.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:6]=2[CH:5]=[C:4]([C:14]([OH:16])=[O:15])[CH:3]=1.Cl.[CH3:18]O>>[CH3:18][O:15][C:14]([C:4]1[CH:3]=[C:2]([CH3:1])[C:7]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:6]=2[CH:5]=1)=[O:16]
Reactant: CO
Reactant: CCCc1nc2c(C)cc(C(=O)O)cc2[nH]1
Agent: Cl
Product: CCCc1nc2c(C)cc(C(=O)OC)cc2[nH]1

Procedure:
7-Methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid (30.0 g, 137 mmol) was dissolved in MeOH (550 mL) and added to a round bottom flask, followed by the addition of 20 mL of a hydrogen chloride solution (30:70, conc. HCl:water). The mixture was refluxed for 12 hours then concentrated under reduced pressure to afford the title compound as a yellow solid (31.8 g, 137 mmol). MS m/z: [M+H+] calcd for C13H16N2O2, 233.12. found 233.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:15]=1)=[O:5])C.[OH-].[K+].O>C(O)C>[C:4]([C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:15]=1)([OH:5])=[O:3]
Reactant: CCCCCCCCCCOc1ccc(Oc2cccc(C(=O)OCC)c2)cc1CCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCOc1ccc(Oc2cccc(C(=O)O)c2)cc1CCC(=O)O
Reaction time: 18 h
Yield: 41.7 %

Procedure:
A solution of 510 mg of 5-(3-ethoxycarbonylphenoxy)-2-(decyloxy)benzenepropanoic acid in 20 ml of ethanol was treated with an excess of potassium hydroxide in a small amount of water. After stirring for 18 hours, the solution was concentrated in vacuo. Diethyl ether and water added, the layers were separated, and the aqueous layer was acidified with 1N hydrochloric acid. The aqueous layer was extracted with diethyl ether, and this extract was dried over sodium sulfate and concentrated in vacuo. Two crystallizations from ethyl acetate/hexane provided 200 mg of the desired title product, m.p. 102°-104° C.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:6]=1[I:20].[OH-].[Li+]>O.C1COCC1>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:9]2[CH:8]=[CH:7][C:6]([I:20])=[C:5]([CH2:4][C:3]([OH:21])=[O:2])[CH:10]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1cc(OCc2ccc(F)cc2)ccc1I
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(OCc2ccc(F)cc2)ccc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the [5-(4-fluoro-benzyloxy)-2-iodo-phenyl]-acetic acid methyl ester (example 20c, 3 g, 7.49 mmol) and lithium hydroxide (215 mg, 8.99 mmol) in water and THF (1:1 v:v, 40 mL) was stirred at room temperature for 2 h. The THF was evaporated and the mixture acidified to pH 3-4 with 0.1N HCl. After extraction with ethyl acetate, drying of the organic layer with magnesium sulfate, filtration and evaporation a white solid was obtained (2.9 g, 100%). MS: m/e=384.9 (M−H+).
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].[CH2:22]([O:29][C:30]1[CH:39]=[C:38]2[C:33]([C:34](Cl)=[N:35][CH:36]=[N:37]2)=[CH:32][C:31]=1[O:41][CH3:42])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]1[CH:39]=[C:38]2[C:33]([C:34]([N:18]3[CH2:19][CH2:20][CH:15]([N:5]4[C:6](=[O:14])[C:7]5[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=5)[N:3]([CH3:2])[C:4]4=[O:21])[CH2:16][CH2:17]3)=[N:35][CH:36]=[N:37]2)=[CH:32][C:31]=1[O:41][CH3:42])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Product: COc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)ncnc2cc1OCc1ccccc1
Yield: 42 %

Procedure:
The procedure similar to that described in Example 57 was repeated, except that 369.0 mg (1.05 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 7-benzyloxy-4-chloro-6-methoxyquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 233.8 mg (yield: 42%) of Compound 87 was obtained as white crystals.
Reaction SMILES: [OH:1]O.[OH-].[Na+].[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]3[O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])=[CH:13][C:8]=2[O:7][CH2:6]1>CO>[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH:15]3[O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35](=[O:1])[NH2:36])=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: OO
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCO3)C(OCc2ccccc2C#N)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCO3)C(OCc2ccccc2C(N)=O)C1
Yield: 57 %

Procedure:
0.5 ml of hydrogen peroxide (33%) and 0.2 ml of 2N sodium hydroxide solution were added to a solution of 236 mg (0.54 mmol) of tert-butyl (3RS,4RS)-4-benzo[1,3]dioxol-5-yl-3-(2-cyano-benzyloxy)-piperidine-1-carboxylate in 5 ml of methanol. The reaction solution was heated under reflux for 2 hours. Subsequently, the same amounts of hydrogen peroxide and sodium hydroxide solution were again added and the solution was heated for a further 2 hours. Thereafter, the solution was cooled and evaporated under reduced pressure. For purification, the residue was chromatographed on silica gel using a 9:1 mixture of methylene chloride and ether as the eluent. There were obtained 140 mg (57% of theory) of tert-butyl (3RS,4RS)-4-benzo[1,3]dioxol-5-yl-3-(2-carbamoyl-benzyloxy)-piperidine-1-carboxylate as a colourless solid; MS: 455 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([S:23][CH:24]5[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:33])=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:35].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([S:23]([CH:24]5[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]5)=[O:35])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:33])=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(SC4CCN(C(C)C)CC4)cc2OCC3)n(C(C)C)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(S(=O)C4CCN(C(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(1-isopropylpiperidin-4-ylsulfanyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 49 (102 mg, 0.219 mmol) in DCM (10 mL) was added TFA (84 μL, 1.09 mmol) followed by a solution of m-CPBA (42 mg, 0.241 mmol) in DCM (2 mL). The resulting mixture was stirred for 15 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 20-45% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH affording 242 as a colorless solid (92 mg, 87%). LCMS: RT 2.54 min [M+H]+ 483.1. 1H NMR (DMSO, 400 MHz): δ 8.58 (1H, d, J=8.39 Hz), 7.96 (1H, s), 7.36 (1H, dd, J=8.39, 1.75 Hz), 7.26 (1H, d, J=1.72 Hz), 5.86-5.73 (1H, m), 4.57 (4H, s), 2.90-2.59 (4H, m), 2.26 (3H, s), 2.17-2.02 (2H, m), 1.84 (1H, bd, J=12.25 Hz), 1.58-1.38 (9H, m), 0.92 (6H, dd, J=6.52, 1.72 Hz)