Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:11](=O)[CH2:12]Cl)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[NH2:15][C:16]([NH2:18])=[S:17].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O.CO>[CH2:1]([O:3][N:4]=[C:5]([C:11]1[N:15]=[C:16]([NH2:18])[S:17][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: NC(N)=S
Reactant: CCON=C(C(=O)CCl)C(=O)OCC
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCON=C(C(=O)OCC)c1csc(N)n1
Temperature: 48 °C
Reaction time: 0.67 h
Yield: 34.8 %

Procedure:
A mixture of ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer) (38.7 g.), thiourea (13.2 g.), sodium acetate (14.3 g.), methanol (95 ml.) and water (95 ml.) was stirred at 48° C. for 40 minutes. After the resultant solution was adjusted to pH 6.5 with an aqueous solution of sodium bicarbonate, the appeared precipitates were collected by filtration and washed with diisopropyl ether to give ethyl 2-ethoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (14.7 g.), mp. 130° to 131° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:36])([F:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:36])([F:19])[F:35])[CH:22]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(C(F)(F)F)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(C(F)(F)F)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=1.02 min; [M+H]+=445.14.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[CH3:22][C:23]1[N:24]=[C:25]([N:33]2[CH2:38][CH2:37][CH2:36][NH:35][C:34]2=[O:39])[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:35]2[CH2:36][CH2:37][CH2:38][N:33]([C:25]3[S:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([CH3:22])[N:24]=3)[C:34]2=[O:39])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1sc(N2CCCNC2=O)nc1C
Reactant: Fc1ccc(CBr)cc1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCCN(Cc3ccc(F)cc3)C2=O)nc1C

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 1-(bromomethyl)-4-fluorobenzene to react with ethyl 4-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in quantitative yield: MS (ES+) m/z 378.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:12][CH2:11]2)=[CH:6][C:3]=1[C:4]#[N:5].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].O.[OH-].[Li+].C(OCC)(=O)C>CS(C)=O>[CH:10]1([C:7]2[CH:8]=[CH:9][C:2]([NH:1][C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[N+:21]([O-:23])=[O:22])=[C:3]([CH:6]=2)[C:4]#[N:5])[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: N#Cc1cc(C2CC2)ccc1N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C2CC2)ccc1Nc1cc(F)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
Heat a solution of 2-amino-5-cyclopropyl-benzonitrile (0.980 g, 6.16 mmol) with 2,4-difluoro-1-nitro-benzene (0.676 g, 6.16 mmol) and lithium hydroxide monohydrate (0.517 g, 12.33 mmol) in DMSO (12 ml) to 55° C. for 18 hours. Cool the reaction to ambient temperature and then add approximately 150 ml of ice water and stir the mixture for one hour. Precipitate the title compound and collect by filtration. Purify the solid via flash chromatography eluting with a linear gradient starting with 100% hexanes and going to 70% hexanes: 30% ethyl acetate to obtain 0.452 g (1.52 mmol, 25% yield) of the title compound as a yellow amorphous solid: Mass Spectrum (m/e): 298 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:15][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: O=CCCc1ccc(F)cc1
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCNCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the crude 3-(4-fluorophenyl)propanal and propylamine (3.0 g, 51 mmol) in CH2Cl2 and was treated with NaBH(OAc)3 and stirred at room temperature overnight. The reaction was quenched with 1 N NaOH, and washed successively with water and brine. The solvent was evaporated under vacuum to give 4.3 g of 3-(4-fluorophenyl)-N-propylpropan-1-amine.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH2:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:16]#[C:17][CH3:18]>O1CCCC1>[CH2:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:1][C:2]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:16]#[C:17][CH3:18]
Reactant: COC(=O)c1cccc(C)c1O
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)Oc2c(C)cccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 0.50 g (3.012 mmol) of methyl 2-hydroxy-3-methyl-benzoate in 20 mL of tetrahydrofuran (THF) is added 0.133 g (3.313 mmol) of a 60% oil dispersion of sodium hydride. The reaction mixture is stirred for 1 h at room temperature and then 0.739 g (3.012 mmol) of 4-but-2-ynyloxy benzenesulfonyl chloride is added. The resulting mixture is stirred at room temperature for 15 h and then quenched with saturated ammonium chloride solution. The resulting mixture is extracted with ether and the combined organics are then washed with water and brine. The organic layer is then dried over MgSO4, filtered and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide 0.93 g (83%) of methyl 2-({[4-(2-butynyloxy)phenyl]sulfonyl}oxy)-3-methylbenzoate as a white solid. Electrospray Mass Spec: 374.8 (M+H)+
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[C:24]3=[CH:28][CH:29]=[N:30][N:23]3[CH2:22][CH2:21][C:20]=2[C:19]=1[C:31]([O:33]C)=[O:32])(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+]>O1CCOCC1.O>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[C:24]3=[CH:28][CH:29]=[N:30][N:23]3[CH2:22][CH2:21][C:20]=2[C:19]=1[C:31]([OH:33])=[O:32])(=[O:15])=[O:16])[CH3:36]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCn1nccc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCn1nccc1-2
Temperature: 80 °C
Yield: 36.1 %

Procedure:
A mixture of methyl 8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 20, 0.057 g) and lithium hydroxide monohydrate (0.090 g) in dioxane (4 mL) and water (1 mL) was heated to 80° C. for 32 hours. The resultant mixture was concentrated in vacuo and the residue was acidified with aqueous citric acid solution (10%) and extracted into DCM, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-15% to give 8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylic acid (0.020 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]([C:14]2[CH:15]=[CH:16][C:17](=[O:23])[N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)=[N:6][C:7]=1[C:8]#[C:9][Si](C)(C)C.C([O-])([O-])=O.[K+].[K+].O.CCOC(C)=O>CO>[NH2:1][C:2]1[N:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]([C:14]2[CH:15]=[CH:16][C:17](=[O:23])[N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)=[N:6][C:7]=1[C:8]#[CH:9]
Reactant: CC(C)n1cc(-c2nc(C#C[Si](C)(C)C)c(N)nc2-c2ccccc2)ccc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.6 %

Procedure:
A mixture of 5-{5-amino-3-phenyl-6-[(trimethylsilyl)ethynyl]-2-pyrazinyl}-1-isopropyl-2(1H)-pyridone (300 mg) and sat. K2CO3 in MeOH (4.5 ml) was stirred at 25° C. for 3 hours. Water and EtOAc were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by short column (silica-gel; CH2Cl2) and recrystallized from EtOH to give 5-(5-amino-6-ethynyl-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C@H:6]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([O:9]C)=[O:8])[CH:2]=[CH2:3].BrCC=C>C(Cl)Cl>[CH2:1]([O:4][CH2:5][C@H:6]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([OH:9])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Solvent: ClCCl
Solvent: C=CCBr
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 3 h

Procedure:
(S)-methyl 3-(allyloxy)-2-(tert-butoxycarbonylamino)propanoate (200 mg, 0.91 mmol) and 3-bromoprop-1-ene (552 mg, 4.56 mmol) were dissolved in DCM (10 mL). Then Ag2O (654 mg, 2.74 mmol) was added at the room temperature. After stirring for 3 hours, the mixture was filtered, concentrated and purified by flash column chromatography to give the title compound A6-1 (149 mg, 63.1%) as light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:8]([O:11][Si](C)(C)C)[C:9]#[N:10])[CH:7]=1.[C:18](Cl)(Cl)=[O:19].[O:22]1CCCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:8]2[O:11][C:18](=[O:19])[NH:10][C:9]2=[O:22])[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(Br)cc1C(C#N)O[Si](C)(C)C
Reactant: C1CCOC1
Product: COc1ccc(Br)cc1C1OC(=O)NC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
By the procedure of Example 3, 2-(5-bromo-2-methoxyphenyl)-2-trimethylsiloxyethanenitrile (16 g., (0.049 mole) in 320 ml. of tetrahydrofuran was reacted with phosgene. After stirring 16 hours at room temperature, the reaction was quenched into 1 liter of crushed ice and extracted with two 500 ml. portions of ethyl acetate. The combined ethyl acetate extracts were back washed with two 200 ml. portions of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to solids. The solids were recrystallized from toluene to yield purified 5-(5-bromo-2-methoxyphenyl)oxazolidine-2,4-dione (10.7 g., m.p. 166°-167° C.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([O:18]C)=[O:17])[N:15]=1.[OH-].[Li+]>CO.O>[F:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([F:1])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COC(=O)c1csc(-c2c(F)cc(OC)cc2F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of methyl 2-(2,6-difluoro-4-methoxy-phenyl)thiazole-4-carboxylate (2.403 mmol, 685.5 mg) in methanol (15 mL) and water (5 mL) was added lithium hydroxide (1.9 equiv., 4.54 mmol, 111 mg). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 1N HCl (aq.), then partitioned between EtOAc and brine. The organic layer was concentrated. The residue was dried on highvac to afford 2-(2,6-difluoro-4-methoxy-phenyl)thiazole-4-carboxylic acid (650 mg, quant.) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][CH2:20][C:21]#[N:22].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:20]([CH2:21][NH:22][C:15]([C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:17])#[N:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1C(=O)O
Reactant: N#CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1C(=O)NCC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To 5.05 g (20.75 mmol) of the acid of step 2 dissolved in 40 mL DMF was added 1.92 g (20.75 mmol) aminoacetonitrile hydrochloride, 3.98 g (20.75 mmol) of EDCI, 2.80 g (20.75 mmol) of HOBT and 7.98 mL (72.63 mmol) of N-methylmorpholine. The reaction mixture was stirred at room temperature overnight, partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated to obtain 5.83 g of the crude tert-butyl (1S,2R)-2-{[(cyanomethyl)amino]carbonyl}cyclohexylcarbamate.
Reaction SMILES: [N-:1]([C:4]#[N:5])[C:2]#[N:3].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[NH2:11]>Cl.O>[C:2]([NH:1][C:4]([NH:11][C:10]1[CH:9]=[C:8]([Cl:7])[CH:14]=[C:13]([Cl:15])[CH:12]=1)=[NH:5])#[N:3]
Reactant: N#C[N-]C#N
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CNC(=N)Nc1cc(Cl)cc(Cl)c1
Yield: 76.4 %

Procedure:
To a solution of 4.45 g (0.05 mol) of sodium dicyanamide in 50 ml of 1N HCl is added 8.1 g (0.05 mol) of 3,5-dichloroaniline in 50 ml of H2O. The mixture is heated to about 80° C. to 100° C. for two hours. The mixture is then cooled, and the precipitated solids are recovered by filtration, washed and dried to give 8.75 g of the desired product having a melting point of 196° C.-198° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[O:18])[N:14]=[N:13]2)=[C:8]([OH:23])[CH:7]=1)=[O:5])[CH3:2].Br[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[O:18])[N:14]=[N:13]2)=[C:8]([O:23][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(O)c1
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OC(C)c2ccccc2)c1
Reaction time: 16 h
Yield: 33.4 %

Procedure:
A solution (500 μl; 70 μmol) of 1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-N-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (0.14M) in DMF, and a solution (500 μl; 105 μmol) of (1-bromoethyl)benzene (0.21M) in DMF, and a powder of potassium carbonate (30 mg) were mixed at room temperature, and the mixture was stirred for 16 hr. Water (2 ml) was added to the reaction mixture, and the mixture was extracted with dichloromethane (3 ml). The solvent was evaporated under reduced pressure, and the residue was dissolved in DMSO (1 ml) and purified by preparative HPLC (Gilson, Inc., high-throughput purification system, column: YMC CombiPrep ODS-A S-5 μm, 50×20 mm, solvent: solution A; 0.1% formic acid aqueous solution, solution B; 0.1% formic acid acetonitrile solution, gradient cycle: 0 min (solution A/solution B=95/5), 1.00 min (solution A/solution B=95/5), 5.20 min (solution A/solution B=5/95), 6.40 min (solution A/solution B=5/95), 6.50 min (solution A/solution B=95/5), 6.60 min (solution A/solution B=95/5), flow rate: 25 ml/min, detection method: UV 220 nm) to give the title compound (9.8 mg) (LC/MS purity 100%, ESI+:420 [M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:25][C:26]([Cl:31])([Cl:30])[C:27](Cl)=[O:28]>ClCCl>[CH3:16][NH:15][C:13](=[O:14])[C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:27](=[O:28])[C:26]([Cl:31])([Cl:30])[Cl:25])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)C(Cl)(Cl)Cl)cc2)ccn1
Reaction time: 0.25 h
Yield: 45.1 %

Procedure:
The clear solution of 4-(4-aminophenoxy)-N-methylpicolinamide (100 g, 0.411 mol) in dichloromethane (100 ml) was cooled to 0° C. to −5° C. and pyridine (83 ml, 1.02 mol) was added in one lot to the reaction mass. It was then agitated at same temperature for 15 minutes and a solution of trichloroacetyl chloride (60 ml, 0.535 mol) in dichloromethane (500 ml) was added dropwise maintaining temperature of the reaction mass below 0° C. The reaction mass was then stirred for 2-3 hours below 0° C. and quenched with water (500 ml) below 5° C. The organic phase was then separated and aqueous layer was reextracted with dichloromethane. The combined dichloromethane layer was washed with water, dried over sodium sulfate and evaporated under vacuum to obtain (72 g) of the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:9]1)=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)OCC2CCCNC2)cc1

Procedure:
A mixture of 8.5 g (23 mmol) 3-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester and 28.7 mL (115 mmol) 4N HCl in dioxane in 30 mL dioxane was evaporated to dryness. This yielded 7.57 g (97%) of the title compound as viscous yellow oil which was used without further purification. MS(m/e): 270 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:19])[CH:3]=1.[C:20]1([CH2:26][C:27](Cl)=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C1COCC1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:5][C:4](=[O:19])[C:3]=1[CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)CCC1(c2ccccc2)CC(O)=CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)CCC1(c2ccccc2)CC(O)=C(CCc2ccccc2)C(=O)O1

Procedure:
The title compound was prepared as described in General Method 5 using 2.0 mmol of 5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one, 2.1 mmol of phenylacetyl chloride, 2.1 mmol of triethylamine, and 10 mL of THF, followed by 10 mL of toluene and catalytic DMAP. Chromatography of the residue afforded 1.0 mmol of the intermediate acyl compound. Reduction of this intermediate was effected with 2 mmol of sodium cyanoborohydride. The product was obtained as a solid (m.p. 125°-126° C.). 1H NMR (DMSO-d6) δ0.76 (m, 7H), 1.12 (m, 1H), 1.38 (m, 1H), 1.87 (m, 2H), 2.27-2.46 (m, 4H), 2.97 (q, 2H), 6.98-7.38 (m, 10H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][CH2:18][O:19][CH3:20])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C>C1COCC1>[CH3:20][O:19][CH2:18][CH2:17][NH:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([B:25]([OH:26])[OH:24])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCCNS(=O)(=O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCNS(=O)(=O)c1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
n-Butyllithium (2.5M in hexanes, 8.36 mL, 20.89 mmol) was added dropwise to a solution of 4-bromo-N-[2-(methoxy)ethyl]benzenesulfonamide (0.5 g, 1.72 mmol) and triisopropylborate (4.8 mL, 20.89 mmol) in THF (15 mL) at −78° C. The mixture was stirred at −78° C. for 3 h and allowed to warm up to ambient temperature, stirred at ambient temperature overnight. The mixture was quenched with water (5 mL) and concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 30% 2M NH3 in MeOH/CH2Cl2 to give 400 mg (89%) of [4-({[2-(methoxy)ethyl]amino}sulfonyl)phenyl]boronic acid as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.06-7.28 (m, 4H), 3.25-3.19 (m, 2H), 3.16-3.06 (m, 3H), 2.88-2.74 (m, 2H); LRMS (ESI), m/z 258 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][CH:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36].C[O-].[Na+:40].CO>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:34])[NH:20][CH:21]3[CH2:22][CH2:23][CH:24]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O-:37])=[O:36].[Na+:40]
Reactant: O=C(NC1CCC(c2ccc(Cl)cc2)CC1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC1CCC(c2ccc(Cl)cc2)CC1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Yield: 100 %

Procedure:
To a suspension of 6-chloro-7-(4-(4-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.045 g, 0.0833 mmol) in 1:1 THF/methanol (5 ml) was added 0.5M sodium methanolate in methanol (0.170 ml, 0.0849 mmol), and the reaction was stirred for 3 weeks, then concentrated to yield 47 mg of the title compound (100% yield). MS (apci) m/z=562.1 (M-Na+2H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:18]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[N:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)(=O)C.C[O-].[Na+].O>CO>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([C:18]2[CH:19]=[C:20]([C:21]([F:22])([F:23])[F:24])[N:15]3[N:14]=[CH:13][C:12]([C:10]4[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[CH:11]=4)=[C:16]3[N:17]=2)=[CH:26][CH:27]=1
Reactant: CC(=O)OCc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)ccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)ccn1
Reaction time: 17 h
Yield: 77.4 %

Procedure:
To a stirred solution of 4-[5-(4-trifluoromethyl-phenyl)-7-trifluoromethyl -pyrazolo[1,5-a]pyrimidin-3-yl]-pyridin-2-ylmethyl acetate (0.16 g, 0.33 mmol) in MeOH (1 ml) was added at room temperature NaOMe (5.4M in MeOH, 0.2 ml). The reaction mixture was stirred for 17 h, poured into water (40 ml) and extracted with dichloromethane (3 times 40 ml). The combined organic layers were washed with brine (100 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate) to yield the title compound (112 mg, 78%) as an orange solid. MS (ISP) 439.3 [(M+H)+]; mp 2102° C.