Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([OH:10])[CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].I[CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[O:18][C:19]=1[CH3:20].CCOCC>CN(C)C=O>[CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)[O:18][C:19]=2[CH3:20])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1CCC[C@H](O)C1
Reactant: Cc1cccc(-c2nc(CI)c(C)o2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CC[C@@H]1CCC[C@H](OCc2nc(-c3cccc(C)c3)oc2C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 g of cis-3-allylcyclohexanol are dissolved in 30 ml of dimethylformamide, and 750 mg of sodium hydride (60% strength suspension in paraffin oil) are added. After 30 minutes, 6.7 g of 4-iodomethyl-5-methyl-2-(3-methylphenyl)oxazole, dissolved in 20 ml of dimethylformamide, are added dropwise. The mixture is stirred at room temperature for 1 hour. 200 ml of methy tert-buthyl ether are then added to the reaction mixture, and the mixture is washed three times with water. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 1.56 g of 4-(cis-3-allylcyclohexyloxymethyl)-2-(3-methylphenyl)-5-methyloxazole as an oil. C21H27NO2 (325.45), MS (ESI): 326 (M+H+), Rf(n-heptane:ethylacetate=2:1)=0.28.
Reaction SMILES: Cl.[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:29])[CH2:27][F:28])([C@@:6]1([CH3:30])[CH2:5][C@@H:4]2[OH:31])[CH2:24][NH:23][CH2:22]3.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:29])[CH2:27][F:28])([C@@:6]1([CH3:30])[CH2:5][C@@H:4]2[OH:31])[CH2:24][N:23]([CH2:37][C:36]1[CH:39]=[CH:40][C:33]([F:32])=[CH:34][CH:35]=1)[CH2:22]3
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3C[C@H]4CNC[C@@]4(C(=O)CF)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3C[C@H]4CN(Cc5ccc(F)cc5)C[C@@]4(C(=O)CF)[C@@]3(C)C[C@H](O)[C@@]12F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
A mixture of compound 166 (145 mg, 0.315 mmol), 4-fluorobenzylbromide (0.059 ml, 0.473 mmol) and TEA (0.132 ml, 0.946 mmol) in DCM (10 ml) is stirred at RT overnight. The mixture is diluted with DCM and treated with 5% NaHCO3. The organic phase is then washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated and the crude is purified by silica gel flash chromatography (eluent DCM(AcOEt 7/3 to 1/1) to yield a solid that is triturated in Et2O. Title compound (54 mg, 32.2% yield) is recovered by filtration.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][N:22]([CH3:34])[C:23]([NH:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)=[O:24])([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:33][C:28]1[CH:27]=[C:26]([NH:25][C:23](=[O:24])[N:22]([CH2:21][C:11]2([C:14]3[CH:15]=[CH:16][C:17]([I:20])=[CH:18][CH:19]=3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH3:34])[CH:31]=[C:30]([Cl:32])[CH:29]=1
Reactant: CN(CC1(c2ccc(I)cc2)CCN(C(=O)OC(C)(C)C)CC1)C(=O)Nc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CC1(c2ccc(I)cc2)CCNCC1)C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.8 %

Procedure:
To a solution of 4-[3-(3,5-dichloro-phenyl)-1-methyl-ureidomethyl]-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.218 g, 0.35 mmol) in CH2Cl2 (4.5 mL) at 0° C. was added TFA (1.5 mL, to give a 25% v/v solution). The reaction mixture was warmed to room temperature and stirred for 4 h. The solvent was removed by rotary evaporation and the residue was dissolved in EtOAc (25 mL) and washed with 10% aqueous NaHCO3 (2×25 mL). The organic extracts were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give 3-(3,5-dichloro-phenyl)-1-[4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-1-methyl-urea (˜0.19 g, 100%).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:14]=[C:13]([SH:15])[CH:12]=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1)([OH:3])=[O:2].[C:16](C1OC2C(CCC)=C(S)C=CC=2C(=O)C=1)(O)=O>>[C:1]([C:4]1[O:5][C:6]2[CH:14]=[C:13]([SH:15])[CH:12]=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1)([O:3][CH3:16])=[O:2]
Reactant: O=C(O)c1cc(=O)c2ccc(S)cc2o1
Reactant: CCCc1c(S)ccc2c(=O)cc(C(=O)O)oc12
Product: COC(=O)c1cc(=O)c2ccc(S)cc2o1

Procedure:
Following the procedure of Step 4 of Example 1 but substituting an equivalent amount of the acid from Step 3 above for 2-carboxy-7-mercapto-8n-propyl-4-oxo-4H-1-benzopyran, there was obtained the title compound, m.p. 147°-150°.
Reaction SMILES: [C:1]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17]S(C)(=O)=O)=[CH:9][CH:8]=1)([O:3][CH2:4][CH3:5])=[O:2].[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1O>>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:17][CH2:16][CH:15]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:8][CH:9]=1)=[O:33]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(I)cc2)cc1
Reactant: Oc1ccccc1Cl
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccccc2Cl)NS(=O)(=O)c2ccc(I)cc2)cc1
Yield: 63.1 %

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(carbethoxymethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (430 mg) was reacted with 2-chlorophenol (163 mg) to obtain (RS)-3-(2-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)propanamide (285.8 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.O.[CH3:11]C1C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)C1CCOCC1
Yield: 15 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-carboxylic acid (50 g, 385 mmol) in anhydrous methanol (500 mL) was added 4-methylbenzenesulfonic acid hydrate (72.5 g, 385 mmol). The mixture was refluxed for 2 hr. The solvent was removed in vacuo. Ethyl ether and water was added. The organic phase was washed with water and brine, then dried over Na2SO4, filtered and concentrated to give methyl tetrahydro-2H-pyran-4-carboxylate (8.3 g, 75%) which was used in next step without purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[N:12]1([CH:17]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=3)=[O:23])[CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C=O)C.C1COCC1>[N:1]1([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:22]([N:19]3[CH2:20][CH2:21][C@H:17]([N:12]4[CH2:13][CH2:14][CH2:15][CH2:16]4)[CH2:18]3)=[O:23])=[CH:29][CH:28]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(c1ccc(CCl)cc1)N1CCC(N2CCCC2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cn2ccc3ccccc32)cc1)N1CC[C@H](N2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
A solution of indole (0.15 mmol, 19 mg) in a mixture of DMF/THF (1:4, 2 mL) is treated with sodium hydride (50 mg) followed by [1,3′]bipyrrolidinyl-1′-yl-(4-chloromethyl-phenyl)-methanone (0.15 mmol, 43 mg), stirred at room temperature overnight and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, MeOH and water (1.5 mL) and purified by reverse-phase semi-preparative HPLC1 to give the title product as a white powder (8 mg), identified by HPLC and mass spectral analyses. Retention time 1.86 min., MS [374.2 m/e (M+H)].
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Br:22])[CH:18]=2)[CH:13]=1>C1C=CC=CC=1>[Br:22][C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([NH:11][S:2](=[O:4])(=[O:3])[NH2:5])[CH:13]=2)[CH:18]=1
Reactant: Nc1ccc2cc(Br)ccc2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: O=CO
Product: NS(=O)(=O)Nc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 19.5 h

Procedure:
A solution of chlorosulfonyl isocyanate (870 μl, WAKO) in benzene (10 ml) was added dropwise with formic acid (377 μl, WAKO) under ice cooling, warmed to room temperature, stirred for 19.5 hours, then heated to 40° C. and further stirred for 4 hours. The reaction mixture was added dropwise with a solution (5 ml) of 2-amino-6-bromonaphthalene (443 mg) in benzene under ice cooling, warmed to room temperature and stirred for 21.5 hours. The reaction mixture was filtered, and the obtained solid was added with ethyl acetate and mixed. The mixture was filtered again, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=2:1) to obtain the title compound (Intermediate 28, 158 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][N:27]2[CH:31]=[C:30]([C:32]([O:34]CC)=[O:33])[N:29]=[CH:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2)[CH2:26][N:27]1[CH:31]=[C:30]([C:32]([OH:34])=[O:33])[N:29]=[CH:28]1
Reactant: CCOC(=O)c1cn(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)cn1
Temperature: 100 °C

Procedure:
To a solution of ethyl 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methyl)-1H-imidazole-4-carboxylate (0.034 g, 0.068 mmol) in THF was added a solution of lithium hydroxide (0.0082 g, 0.34 mmol) in 1.0 mL of water. The reaction mixture was heated to 100° C. for 18 h. The crude reaction mixture was concentrated in vacuo. The residue was diluted with water and the pH was adjusted to 1 with aq. HCl. The solid was collected by filtration, rinsed with water and Et2O, and dried in vacuo at 50° C. for 2 h to afford 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)-1H-imidazole-4-carboxylic acid. MS (ESI) m/z: calculated: 470.1; Observed: 471.0 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][NH:26][CH2:27][CH3:28])[CH:7]=1)[CH3:2].[C:30](Cl)(=[O:32])[CH3:31]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][C:16]=2[CH2:25][N:26]([C:30](=[O:32])[CH3:31])[CH2:27][CH3:28])[CH:7]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cc(CC(=O)OCC)ccc1OC
Reactant: CC(=O)Cl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and acetyl chloride.
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.I[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[BrH:35].C(O)(=O)C>C(OCC)C>[BrH:35].[CH2:25]([C:22]1[CH:23]=[N:24][C:19]([N:18]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:5])=[O:27])[S:12][CH:13]=2)=[N:20][CH:21]=1)[CH3:26]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: CCCCCCI
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(CC)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 1-iodohexane as starting materials and by an operation similar to that of Example 326 was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]2[CH:10]([C:11](=[O:23])[N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:13]=1)[CH2:9]2)(=O)=O.[C:26]1([C:32]2[O:33][C:34]3[CH2:35][NH:36][CH2:37][CH2:38][C:39]=3[N:40]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)Cl>CS(C)=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:12]2[N:13]=[C:7]([N:36]3[CH2:37][CH2:38][C:39]4[N:40]=[C:32]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[O:33][C:34]=4[CH2:35]3)[CH:8]3[CH:10]([CH2:9]3)[C:11]2=[O:23])=[CH:16][CH:17]=1
Reactant: c1ccc(-c2nc3c(o2)CNCC3)cc1
Reactant: COc1ccc(CN2N=C(OS(=O)(=O)C(F)(F)F)C3CC3C2=O)cc1
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(CN2N=C(N3CCc4nc(-c5ccccc5)oc4C3)C3CC3C2=O)cc1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
322 mg (0.85 mmol) 4-(4-methoxy-benzyl)-5-oxo-3,4-diaza-bicyclo[4.1.0]hept-2-en-2-yl trifluoro-methanesulphonate dissolved in 4 ml DMSO and some molecular sieve are added to 400 mg (1.69 mmol) 2-phenyl-4,5,6,7-tetrahydro-oxazolo[5,4-C]pyridine. The mixture is stirred for 5 h at 40° C. and then combined with DCM. It is extracted 1× each with sat. sodium carbonate solution and sat. saline solution, the org. phase is dried on magnesium sulphate and the solv. is eliminated by rotary evaporation i.V., the residue is purified through silica gel (eluant: DCM/methanol).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]([CH:7]1[CH2:11][C:10](=[O:12])[CH:9]=[C:8]1[C:13]([O:15][CH3:16])=[O:14])=[O:6]>CO>[CH3:16][O:15][C:13]([CH:8]1[CH2:9][CH:10]([OH:12])[CH:11]=[C:7]1[C:5]([O:4][CH3:3])=[O:6])=[O:14]
Reactant: COC(=O)C1=CC(=O)CC1C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=CC(O)CC1C(=O)OC
Yield: 93.1 %

Procedure:
NaBH4 (0.66 g, 17.5 mmol) dissolved in MeOH (23 mL) was added to a cold solution (−30° C.) of the ketone 23a (3.18 g, 16.1 mmol). After nine minutes the excess of NaBH4 was destroyed by adding brine (80 mL). The mixture was concentrated and extracted with ethyl acetate (4×80 ml). The organic phases were dried, filtrated and concentrated which gave the title compound (3.0 g, 92%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:24]([CH2:25][CH2:26][C:27](O)=[O:28])=[CH:23][O:22][N:21]=2)=[CH:16][CH:15]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:27](=[O:28])[CH2:26][CH2:25][C:24]1[C:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[N:21][O:22][CH:23]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)CCc1conc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1conc1-c1ccc(Cl)cc1)NCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of 3-trifluoromethylbenzylamine (0.75 ml), 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.90 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.82 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.03 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(3-trifluoromethylbenzyl)-3-[3-(4-chlorophenyl)-4-isoxazolyl]propionamide (1.27 g, yield 87%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from isopropyl ether-hexane. melting point: 80–81° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:13])=[O:14]
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CN
Temperature: 80 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of intermediate 47, 2-azidomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide, (660 mg, 2.6 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was added triphenylphosphine (740 mg, 2.8 mmol), and the mixture stirred under nitrogen for 1 hr. The tetrahydrofuran was evaporated in vacuo and a mixture of the residue and 6N HCl (3 mL) in MeOH (5 mL) was heated at 80° C. for 20 hrs. This was washed with CH2Cl2, and the aqueous phase basified with dilute NH4OH and extracted with CH2Cl2. The organic extract was dried (Na2SO4), filtered and concentrated to provide 210 mg (0.91 mmol, Yield 35%) of the title compound; 1H NMR (500 MHz, CDCl3) δ ppm: 2.84 (6H, s) 4.10 (2H, s) 7.23-7.29 (1H, m) 7.53-7.60 (2H, m); LC/MS m/z 233 (M+H).
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:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37](=[O:41])[N:38]([CH3:40])C)[CH:27]=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].[CH2:42](OC(CCC1C(OCCCC(OCC)=O)=CC=CC=1CCCCCCOC1C=C(C=C(C2C=CSC=2)C=1)C(O)=O)=O)C.C(N)C>>[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:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37](=[O:41])[NH:38][CH2:40][CH3:42])[CH:27]=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: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccsc2)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Agent: CCN
Product: CCNC(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccsc2)c1

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(3-dimethylcarbamoyl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid starting from 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-thiophen-3-yl-benzoic acid and ethylamine.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.[C:18]1([C:24]2[O:40][C:27]3[N:28]=[CH:29][N:30]=[C:31]([O:32][C:33]4[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=4)[C:26]=3[CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:39][C:36]2[CH:35]=[CH:34][C:33]([O:32][C:31]3[C:26]4[CH:25]=[C:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[O:40][C:27]=4[N:28]=[CH:29][N:30]=3)=[CH:38][CH:37]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ncnc3oc(-c4ccccc4)cc23)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ncnc3oc(-c4ccccc4)cc23)cc1

Procedure:
After adding toluene (1 ml), acetonitrile (0.5 ml) and 4-fluorophenyl isocyanate (0.03 ml) to 4-(6-phenyl-furo[2,3-d]pyrimidin-4-yloxy)phenylamine (40 mg), the mixture was heated to reflux for 30 minutes. After cooling, the precipitated crystals were filtered out and washed with toluene to obtain the title compound (42 mg) as light yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[N:35]=[CH:36][O:37][C:38]=1[C:39]1([NH2:42])[CH2:41][CH2:40]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:42][C:39]5([C:38]6[O:37][CH:36]=[N:35][C:34]=6[CH3:33])[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1ncoc1C1(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ocnc5C)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(4-methyloxazol-5-yl)cyclopropanamine (0.06 g, 0.46 mmol, 1.0 eq), HOBT (0.062 g, 0.46 mmol, 1.0 eq), EDC.HCl (0.08, 0.46 mmol, 1.0 eq), in DCM at ambient temperature and under a nitrogen atmosphere was added diisopropylehtylamine (0.19 ml, 1.3 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by Preparative TLC (Eluent Hexane:Ethyl acetate 1:1, 300 ml).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:15][NH:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1.C(N(CC)CC)C>ClCCCl>[CH3:15][N:16]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNc1nccs1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(=O)(=O)N(C)c2nccs2)cc1
Temperature: 100 °C
Yield: 79.2 %

Procedure:
To methyl 4-chlorosulfonylbenzoate (4 g, 17.05 mmol), N-methylthiazol-2-amine (1.95 g, 17.05 mmol), 1,2-dichloroethane (20 mL), and triethylamine (2.38 mL, 17.05 mmol) were added and the reaction was heated at 100° C. in a pressure vessel for 20.5 hours on a heat block. The solvent was evaporated under reduced pressure. The crude compound was dissolved in dichloromethane and filtered. The filtrate was purified by silica gel chromatography utilizing a gradient of 0-30% ethyl acetate in dichloromethane to yield methyl 4-[methyl(thiazol-2-yl)sulfamoyl]benzoate (4.22 g, 79.2%). 1H NMR (400 MHz, DMSO) δ 8.16 (d, J=8.5 Hz, 2H), 7.95 (d, J=8.5 Hz, 2H), 7.46 (d, J=3.6 Hz, 1H), 7.44 (d, J=3.6 Hz, 1H), 3.89 (s, 3H), 3.39 (s, 3H). ESI-MS m/z calc. 312.0, found 313.3 (M+1)+; Retention time: 1.52 minutes (3 min run).