Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:49]=[CH:50][C:51]=1[F:52])[O:31][C:32]1[CH:46]=[CH:45][C:35]2[N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[S:38][C:34]=2[C:33]=1[C:47]#[N:48]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:28]1[CH:29]=[C:30]([O:31][C:32]2[CH:46]=[CH:45][C:35]3[N:36]=[C:37]([NH:39][C:40]([CH:42]4[CH2:44][CH2:43]4)=[O:41])[S:38][C:34]=3[C:33]=2[C:47]#[N:48])[CH:49]=[CH:50][C:51]=1[F:52])=[O:6]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Reactant: N#Cc1c(Oc2ccc(F)c(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (108 mg, 0.482 mmol) in tetrahydrofuran (1.5 mL) were added oxalyl chloride (52 μL, 0.601 mmol) and N,N-dimethylformamide (10 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (1.5 mL). N-[6-(3-Amino-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (150 mg, 0.407 mmol) produced in Example 30(vi) was added to the solution, and the mixture was stirred at room temperature for 10 min. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (116 mg, 50%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:23][CH:22]([CH2:24][S:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:21][C:20]3=[O:33])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH2:34].[OH-].[Li+]>O.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH:19]([CH2:23][CH:22]([OH:34])[CH2:24][S:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]([OH:21])=[O:33])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)NC3CC(CSCc4ccccc4)OC3=O)cc2)cc1
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSCc3ccccc3)C(=O)O)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of 3-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-2-oxo-5-[(benzylthio)methyl]-tetrahydrofuran 17a (40 mg, 0.083 mmol) in water (3 mL) and THF (3 mL) is added slowly lithium hydroxide monohydrate (35 mg, 0.82 mmol). The reaction mixture is stirred overnight, then concentrated to dryness. The resulting mixture is diluted with water, and then the mixture is extracted twice with Et2O. The Et2O layer is discarded and the aqueous layer is neutralized carefully with 1N HCl to pH 6, then extracted three times with EtOAc. The combined EtOAc layer is washed with brine, dried over MgSO4 and concentrated to a solid which is recrystallized from EtOAc/hexane (1:4) to give the desired product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:13]([OH:14])=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[C:15]([O:17][CH3:18])=[O:16])([O-])=O.C(O)C.C(OCC)(=O)C>[Pt].C(Cl)Cl>[NH2:1][C:4]1[C:13]([OH:14])=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1C(=O)OC
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)c1ccc(O)c(N)c1C(=O)OC
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
A mixture of dimethyl 3-nitro-4-hydroxyphthalate (28.9 g, 0.113 mol), ethanol and 5% platinum on carbon (2.80 g, 50% aqueous) is shaken on a Parr hydrogenator under hydrogen for 1.75 hours at room temperature. The reaction mixture is filtered through diatomaceous earth and the filtrate is concentrated in vacuo to give a pale green solid residue. Chromatography (silica gel, ethyl acetate:methylene chloride eluent) affords the title product as a pale yellow solid, 3.69 g, mp 112°-113° C., identified by NMR and IR spectral analyses.
Reaction SMILES: [C:1](CC(C)C(Cl)=O)(OC)=[O:2].[CH3:11][CH:12]1[CH2:18][CH2:17][C:16](=O)[O:15][C:13]1=[O:14].C(CCC(C)C(Cl)=O)(OC)=O.CC1CC(=O)OC(=O)C1.[CH3:40][OH:41]>>[C:40]([CH:17]([CH3:16])[CH2:18][CH:12]([CH3:11])[C:13]([OH:15])=[O:14])([O:2][CH3:1])=[O:41]
Reactant: COC(=O)CC(C)C(=O)Cl
Reactant: CC1CCC(=O)OC1=O
Reactant: CO
Agent: CC1CC(=O)OC(=O)C1
Agent: COC(=O)CCC(C)C(=O)Cl
Product: COC(=O)C(C)CC(C)C(=O)O

Procedure:
The starting materials for said compounds 1, 2, 4, 6, 11 and 12 are the 3-carbomethoxy-2-methylpropanoyl chloride, 2-methylglutaric anhydride, 4-carbomethoxy-2-methylbutanoyl chloride, 3-methylglutaric anhydride and the erythro or threo 4-carbomethoxy-4-(2-phenethyl)-2-methylbutanoyl chloride respectively. That of compound 8 and 9 may be prepared as follows: The solution of 6.0 of meso-2,4-dimethylglutaric acid anhydride [J. Am. Chem. Soc. 77, 1862 (1955)] in 4 ml of methanol is refluxed for one hour and evaporated, to yield the erythro 4-carbomethoxy-2,4-dimethylbutanoic acid. It is converted into the acid chloride by refluxing it with 10.9 g of oxalyl chloride in 50 ml of methylene chloride for 2 hours, and evaporating said mixture.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([N:11]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(NCc2cccnc2)c1
Reactant: CCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
Into a 0° C. solution of N-(3-methoxycarbonylphenyl) pyrid-3-ylmethylamine (204 g, 0.842 mole, 1 eq) in dichloroethane (3610 mL) and pyridine (1775 mL) was added ethanesulfonyl chloride (114 mL, 1.2 mole, 1.43 eq). The reaction was allowed to warm to room temperature overnight. The dark red reaction was stirred with potassium carbonate (204 g) for 30 minutes and then filtered and concentrated to dryness. The residue was purified by Biotage, eluting with 3:1 to 2:1 DCM/EtOAc mixture to give the title compound as a white solid (137.0 g, 49% yield).
Reaction SMILES: [CH2:1]([N:3]([CH3:17])[C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:1]([N:3]([CH3:17])[C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH3:18])[C:12]([CH3:13])([CH3:15])[CH3:14])[CH3:2]
Reactant: CCN(C)C(=O)c1ccccc1NC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCN(C)C(=O)c1ccccc1N(C)C(C)(C)C
Temperature: 40 °C
Yield: 95.6 %

Procedure:
A mixture of N-ethyl-N-methyl 2-(N-tert-butylamino)benzamide (1.89 g, 8.1 mmol), potassium carbonate (2.2 g, 15.9 mmol), and methyl iodide (2.3 g, 16.2 mmol) in DMF (40 mL) was heated overnight at 40° C., then was partitioned between EtOAc and water. The EtOAc was dried (MgSO4), concentrated, and purified by HPLC with 1:4 ethyl acetate/cyclohexane to afford 1.923 g of N-ethyl-N-methyl 2-(N-methyl-N-tert-butylamino)benzamide as a yellow oil, a 96% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([OH:27])[C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:28]=1.C[O-].[Na+].C([NH2:34])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH:20]([OH:27])[C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([NH2:34])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:28]=1
Reactant: NC=O
Reactant: COC(=O)c1nc2n(c1C(O)c1ccnn1C)C1CC(C1)c1ccc(Br)cc1-2
Agent: C[O-]
Agent: [Na+]
Product: Cn1nccc1C(O)c1c(C(N)=O)nc2n1C1CC(C1)c1ccc(Br)cc1-2
Yield: 94 %

Procedure:
10-Bromo-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L. Methyl 10-bromo-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford 181 mg (94% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=O)=[CH:4][C:3]=1[CH3:16].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[S:26])=[CH:4][C:3]=1[CH3:16]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(C(=O)NC[Si](C)(C)C)ccc1Br
Solvent: Cc1ccccc1
Product: Cc1cc(C(=S)NC[Si](C)(C)C)ccc1Br
Temperature: 25 °C
Yield: 123.7 %

Procedure:
To a suspension of 4-bromo-3-methyl-N-trimethylsilanylmethyl-benzamide (32.75 g, 109.1 mmol) in toluene (250 mL) was added Lawesson's reagent (31.32 g, 77.44 mmol) at room temperature. The mixture was heated at reflux for 1 h and cooled to ambient temperature. After adsorption of the reaction mixture on silica gel, the solvents were distilled off in vacuum. The residue was purified by flash chromatography on silica gel to give the title compound (30.3 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]=1.[CH3:8][C:9]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:10]=1[NH2:11]>>[ClH:1].[ClH:1].[CH3:8][C:9]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:10]=1[NH:11][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: ClC1=NCCCC1
Product: Cc1cc(N)ccc1NC1=NCCCC1
Product: Cl
Yield: 59.4 %

Procedure:
The title compound (8.2 g) was prepared by the methods of Examples 8 and 9 using 2-chloroazacyclohex-1-ene (0.10 mole), prepared as in Example 2, and 7.6 g (0.05 mole) of 2-methyl-4-nitroaniline. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:37][C:38]1[S:42][C:41]([O:43][C:44]2[CH:45]=[C:46]([CH3:60])[C:47]3[CH:51]([CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[O:50][B:49]([OH:58])[C:48]=3[CH:59]=2)=[N:40][N:39]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:37][C:38]1[S:42][C:41]([O:43][C:44]2[CH:45]=[C:46]([CH3:60])[C:47]3[CH:51]([CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[O:50][B:49]([OH:58])[C:48]=3[CH:59]=2)=[N:40][N:39]=1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(N)s3)cc(C)c21
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(NC(=O)CNC(=O)OC(C)(C)C)s3)cc(C)c21
Reaction time: 8 h

Procedure:
To a solution of N-tert-butoxy carbonyl-glycine (1.05 g, 6 mmol) in DMF (15 mL) was added HATU (2.85 g, 7.5 mmol), ethyl 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.74 g, 5 mmol) and DIEA (1.73 mL). The mixture was stirred at room overnight. The mixture was concentrated to afford the target molecule.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O.[CH:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].[F-].[Cs+]>C(COC)OC.C(O)C>[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([C:12]2[CH:11]=[CH:10][C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][C:7]=2[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:32][CH:31]=1)=[O:29]
Reactant: CCOC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(OCCCOC)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)CCc1ccc(-c2ccc(C=O)cc2)c(OCCCOC)c1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
Ethyl 3-[3-(3-methoxypropoxy)-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl]propanoate (5 g, 12 mmol) was dissolved in dimethoxyethane (70 mL) and ethanol (7 mL). 4-Formylbenzeneboronic acid (2.0 g, 13 mmol) was added and argon was bubbled in the mixture, for 15 minutes. Cesium fluoride (4 g, 26 mmol) and tetrakistriphenylphosphine palladium (0.69 g, 0.6 mmol) were added and the mixture was brought to reflux under an argon atmosphere for 4 hours. After cooling to room temperature, solvents were evaporated under reduced pressure and the residue was dissolved in ethyl acetate/water (100 mL/100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 9/1) to yield 3.42 g (76%) of the desired product as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][C:6]([OH:24])([CH3:23])[CH:7]=[CH:8][CH:9]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.O>[C:25]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:10]1[CH:9]([CH:8]=[CH:7][C:6]([OH:24])([CH3:23])[CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH2:13][CH2:12][C:11]1=[O:14])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCOCCC(C)(O)C=CC1CCC(=O)C1CCCCCCCO
Solvent: c1ccncc1
Solvent: O
Product: CCOCCC(C)(O)C=CC1CCC(=O)C1CCCCCCCOC(C)=O
Reaction time: 72 h

Procedure:
A solution of 7-[2-(5-ethoxy-3-hydroxy-3-methylpent-1-enyl)-5-oxocyclopentyl]heptanol [0.4 g; prepared as hereinbefore described in Example 7(iv)] in dry pyridine (4 ml.) was treated with acetic anhydride (4 ml.) and the resulting solution was allowed to stand at ambient temperature for 3 days and then diluted with water (100 ml.) with external cooling by means of an ice-bath. The resulting aqueous solution was extracted three times with chloroform, and the combined extracts were dried over sodium sulphate. Evaporation in vacuo gave a crude product which was purified by preparative thin layer chromatography on silica gel using a mixture of toluene, dioxan and acetic acid (65:15:1 by volume) as eluant, to give 2-(7-acetoxyheptyl)-3-(5-ethoxy-3-hydroxy-3-methylpent-1-enyl)cyclopentanone (0.17 g.). Elemental analysis: Found: C, 68.7; H, 10.3%; C22H38O5 requires C, 69.1; H, 10.0%. N.M.R. (approximately 10% w/v solution in deuterochloroform): multiplets at 1.0-1.9δ, 1.9-2.9δ, singlet at 2.05δ, multiplet at 3.35δ, triplet at 4.05δ, (J = 6.5 cycles/second), multiplet at 5.6δ.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=1>C1COCC1.C(O)C>[O:9]([CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)Nc1nc(CCl)cs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)Nc1nc(COc2ccccc2)cs1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
To a solution of sodium hydride (55 mg, 60% dispersion in mineral oil, 1.38 mmol) in THF (1 ml) at 0° C. was added phenol (100 mg, 1.06 mmol). After stirred at 0° C. for 10 minutes, the reaction solution was warmed to room temperature and stirred for 10 minutes. The reaction solution was cooled to 0° C. again, and was added a solution of N-(4-(chloromethyl)thiazol-2-yl)acetamide in ethanol (1 ml). The reaction was stirred at room temperature overnight and then was heated at 70° C. for 5 hours. The reaction solution was concentrated and the residue was purified via preparative HPLC to afford N-(4-phenoxymethyl-thiazol-2-yl)-acetamide as a tan amorphous solid (50 mg, 20%). LC/MS m/z 249.15 (M-1)+; HPLC Rt: 2.875 min.
Reaction SMILES: C[C:2](C)=[O:3].[S:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])[O:24][CH3:25])=[C:18]([CH3:27])[CH:17]=1.C=O>C(=O)([O-])[O-].[K+].[K+].O>[S:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:2][OH:3])[C:23](=[O:26])[O:24][CH3:25])=[C:18]([CH3:27])[CH:17]=1
Reactant: CC(C)=O
Reactant: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1C
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)N(CO)c1ccc(OCc2nc3ccccc3s2)cc1C
Temperature: 30 °C
Reaction time: 12 h
Yield: 73.4 %

Procedure:
A mixture of 130 ml of acetone and 0.5 ml of water was added to a mixture of 10.01 g of methyl N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]carbamate (prepared as described in Example 21(c) below) and 5.0 g of paraformaldehyde at room temperature. 0.30 g of potassium carbonate were added to the resulting mixture and the mixture was then stirred for 12 hours at 30° C. while subjected to ultrasonic irradiation. At the end of this time the reaction mixture was filtered and the solvent was removed from the filtrate by evaporation under reduced pressure to give a residue which was purified by column chromatography through silica gel, using a gradient of dichloromethane and acetone as the eluent, gradually changing from a 9:1 by volume mixture of dichloromethane and acetone to a final 4:1 by volume mixture, to give 8.02 g (yield 73.4%) of the title compound as a solid having a melting point of 121°-123° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30]1>>[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[C:31]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)=[CH:30]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC1(C)OB(c2coc3ccccc23)OC1(C)C
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3coc4ccccc34)nc21

Procedure:
Following the procedures for 140, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-(benzofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was converted to 138. LCMS: M+H+=491.2. 1H-NMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.58 (m, 1H), 7.66 (m, 1H), 7.40 (m, 2H), 4.66 (s, 2H), 4.31 (m, 4H), 3.90 (s, 3H), 3.80 (m, 4H), 3.68 (s, br, 1H), 3.12 (m, 2H), 2.90 (m, 2H), 1.90 (m, 2H), 1.56 (m, 3H), 1.06 (s, 6H)
Reaction SMILES: C([NH:8]C1C=C(C=C(S(Cl)(=O)=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.Cl[S:29]([C:32]1[C:33]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[C:34]([O:41][CH2:42][C:43]2[CH:47]=[CH:46][S:45][CH:44]=2)[CH:35]=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38])(=[O:31])=[O:30]>>[C:48]1([C:33]2[C:32]([S:29](=[O:31])(=[O:30])[NH2:8])=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][C:34]=2[O:41][CH2:42][C:43]2[CH:47]=[CH:46][S:45][CH:44]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=C(O)c1cc(OCc2ccsc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Product: NS(=O)(=O)c1cc(C(=O)O)cc(OCc2ccsc2)c1-c1ccccc1

Procedure:
By replacing in Example 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid with 5-chlorosulfonyl-4-phenyl-3-(3-thenyloxy)benzoic acid, and following the procedure described, 4-phenyl-5-sulfamyl-3-(3-thenyloxy)-benzoic acid is obtained with a melting point of 222°-223° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][C:16]([O:19][CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:17][CH:18]=2)=[C:9]([F:30])[CH:8]=1)(=[O:5])=[O:4].C(OI(C1C=CC=CC=1)OC(=O)C)(=[O:35])C>C(O)(=O)C.C(OC(=O)C)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:32][C:2]([F:1])([F:31])[S:3]([O:6][C:7]1[CH:12]=[C:11]([OH:35])[C:10]([C:13]2[N:14]=[N:15][C:16]([O:19][CH:20]3[CH2:25][C:24]([CH3:26])([CH3:27])[NH:23][C:22]([CH3:28])([CH3:29])[CH2:21]3)=[CH:17][CH:18]=2)=[C:9]([F:30])[CH:8]=1)(=[O:4])=[O:5]
Reactant: CC1(C)CC(Oc2ccc(-c3ccc(OS(=O)(=O)C(F)(F)F)cc3F)nn2)CC(C)(C)N1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC1(C)CC(Oc2ccc(-c3c(O)cc(OS(=O)(=O)C(F)(F)F)cc3F)nn2)CC(C)(C)N1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
3-Fluoro-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl trifluoromethanesulfonate (0.48 g, 1.01 mmol), PhI(OAc)2 (0.46 g, 1.41 mmol), and Pd(OAc)2(68 mg, 0.10 mmol) were dissolved in a mixture of acetic acid (4 mL) and acetic anhydride (4 mL). The mixture was stirred at 80° C. for 3 h. The crude reaction was purified by catch and release using SiliaBond Propylsulfonic Acid® (5 eq, CH3CN as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was concentrated in vacuo and 3-fluoro-5-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl trifluoromethanesulfonate was afforded as a green solid (0.50 g, 100%). [M+H]: 494.3; 1H NMR (400 MHz, MeOD) δ 8.09 (t, J=8.5 Hz, 1H), 7.99 (dd, J=9.5, 2.5 Hz, 1H), 7.50 (dd, J=10.5, 2.5 Hz, 1H), 7.45 (dd, J=8.5, 2.5 Hz, 1H), 7.24 (d, J=9.5 Hz, 1H), 5.82 (tt, J=11.0, 4.0 Hz, 1H), 2.24 (dd, J=12.5, 4.0 Hz, 2H), 1.43 (t, J=12.0 Hz, 2H), 1.36 (s, 6H), 1.25 (s, 6H).
Reaction SMILES: [CH2:1]([NH:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:21])[CH:19]=O.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1COCC1.CO>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:18]([CH3:21])[CH3:19]
Reactant: c1ccc(CNOCc2ccccc2)cc1
Reactant: CC(C)C=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CN(Cc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of II (1 eq.), 2-methylpropanal (1 eq.) and BH3(pyridine) (1 eq.) in THF:MeOH (1:3) was added PPTS (1 eq.). The reaction mixture was stirred at rt for 12 h and afforded, after aqueous workup and purification by column chromatography, III as a colorless oil.