Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C[Al](C)C.[NH2:14][C:15]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][S:17][C:16]=1[C:26](OC)=[O:27]>C1(C)C=CC=CC=1>[NH2:14][C:15]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][S:17][C:16]=1[C:26]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:27]
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: COc1ccc(N)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)c2scc(-c3ccccc3)c2N)cc1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
p-Anisidine (29 mg, 0.24 mmol) was dissolved in toluene (2 ml) in a reaction vessel, and trimethylaluminum (2 M in TIIF, 0.12 ml) was added thereto at 0° C. After stirring for 10 min, to the mixture was added methyl 3-amino-4-phenylthiophene-2-carboxylate (50 mg, 0.21 mmol). The resulting mixture was heated to reflux at 120° C. for 16 hr. The completion of the reaction was confirmed by TLC. The reaction mixture was allowed to cool to room temperature, extracted with EtOAc, dried over anhydrous MgSO4, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane:EtOAc=5:1) to give (57 mg, 0.18 mmol, 84% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[S:21][C:20]2[C:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1>>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:19]3[C:20]4[S:21][C:13]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[CH:14][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:24][CH:25]=2)=[CH:31][CH:32]=1
Reactant: COc1ccc(Nc2ccc(Nc3ncnc4cc(Br)sc34)cc2)cc1
Reactant: COc1ccccc1B(O)O
Product: COc1ccc(Nc2ccc(Nc3ncnc4cc(-c5ccc(OC)cc5)sc34)cc2)cc1

Procedure:
The title compound was prepared from 2-methoxybenzeneboronic acid and N-(6-bromo-thieno[3,2-d]pyrimidin-4-yl)-N′-(4-methoxy-phenyl)-benzene-1,4-diamine by a procedure analogous to example 2. M.P. 159-169° C.; LC-MS: 454.31 (MH+); HPLC RT: 7.003 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][NH:17][C:16]2=[O:23].[H-].[Na+].[CH3:26]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]([CH3:26])[C:16]2=[O:23]
Reactant: CI
Reactant: COc1ccc(OC)c(CCc2ccc3nc[nH]c(=O)c3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(CCc2ccc3ncn(C)c(=O)c3c2)c1
Reaction time: 0.5 h

Procedure:
34 mg of 6-[2-(2,5-dimethoxyphenyl)ethyl]-4-quinazolinone are dissolved in 4 ml of dimethylformamide and treated with 4 mg of sodium hydride (80% in mineral oil). After stirring for 30 minutes, 0.1 ml of methyl iodide are added, and stirring is continued for 1 hour. The mixture is poured onto water and extracted with ethyl acetate. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography (cyclohexane/ethyl acetate=1/2) of the residue gives the title compound as colourless crystals. mp: 83-85°.
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]=3[CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:20]1[CH:32]=[CH:31][C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[C:22]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>[Cu]I>[N:1]1([C:6]2[CH:18]=[CH:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([C:20]4[CH:32]=[CH:31][C:30]5[C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=6)[C:22]=5[CH:21]=4)[C:8]=3[CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1ccc2c(c1)[nH]c1cc(-n3cccn3)ccc12
Reactant: Brc1ccc2c3ccccc3n(-c3ccccn3)c2c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Product: c1ccc(-n2c3ccccc3c3ccc(-n4c5ccccc5c5ccc(-n6cccn6)cc54)cc32)nc1
Temperature: 90 °C
Yield: 60 %

Procedure:
Under a nitrogen atmosphere, 10 mmol of 2-(1H-pyrazol-1-yl)-9H-carbazole, 10 mmol of 2-bromo-9-(pyridin-2-yl)-9H-carbazole, 1 mmol of copper(I)iodide, 25 mmol of potassium carbonate, and 2 mmol of L-proline were combined in stirring degassed dimethyl sulfoxide. The mixture was heated to 90° C. for 3 days before being cooled and separated between dichloromethane and water. The water layer was washed twice with dichloromethane and the organics were combined and washed once with brine. The organic fraction was dried with magnesium sulfate and concentrated under reduced pressure and subjected to column chromatography of silica with dichloromethane/ethyl acetate as the eluent. After concentrating under reduced pressure, 2′-(1H-pyrazol-1-yl)-9-(pyridin-2-yl)-9H-2,9′-bicarbazole was isolated in a 60% yield.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2C(O)=O)=[O:14])[N:4]=1.Cl>N1C2C(=CC=CC=2)C=CC=1.O.[Cu]>[S:20]1[C:16]([NH:15][C:13](=[O:14])[CH2:12][N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:29])([F:1])[F:28])=[N:4]2)=[CH:17][C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][C:19]1=2
Reactant: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)Nc1sc2c(c1C(=O)O)CCCC2
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)Nc1cc2c(s1)CCCC2
Temperature: 200 °C
Yield: 93.6 %

Procedure:
2-[2-(3-Trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (200 mg, 0.47 mmol) and copper powder (45 mg, 0.70 mmol) were suspended in quinoline (4 mL) and the resulting mixture heated in a Biotage SmithCreator microwave at 200° C. for 10 min. The mixture was diluted with water (5 mL), acidified to pH 1 with 5 M HCl, and extracted with diethyl ether (3×50 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue obtained was purified by silica gel chromatography using DCM as eluent, to afford the title compound as an off-white solid (170 mg, 0.44 mmol, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([N+:16]([O-])=O)=[CH:11][CH:10]=1.[C:19](O)(=O)C>CN(C=O)C.CCOC(C)=O.C(O)C.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[CH:15]=[CH:19][NH:16][C:12]2=[CH:11][CH:10]=1
Reactant: Cc1nc(-c2c(F)cccc2F)ccc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Fe]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1-c1ccc2[nH]ccc2n1
Temperature: 125 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A solution of 6-(2,6-difluorophenyl)-2-methyl-3-nitropyridine (1.929 g, 7.71 mmol) in DMF (25 mL) was treated with n,n-dimethylformamide dimethyl acetal (1.331 mL, 10.02 mmol). The reaction was heated to 125° C. under N2. After 3 h, the reaction was cooled to 23° C., diluted with EtOAc (200 ml) and washed with brine (150 ml), dried over MgSO4, concentrated in vacuo, affording a purple solid that was carried forward to the next step without further manipulation. A suspension of that solid in ethanol (40.0 mL) and acetic acid (40 mL) was treated with iron powder—325 mesh (4.31 g, 77 mmol, Aldrich). The reaction was heated to 90° C. under N2. After 2 h, the reaction was cooled to 23° C., filtered through Celite, concentrated in vacuo and purified by silica gel chromatography (eluent: 0.5-3% MeOH/DCM), affording 5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridine (1.271 g, 72%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:39]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.Cl[CH2:42][C:43]1[N:47]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH:46]=[N:45][N:44]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([O:38][CH2:42][C:43]5[N:47]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH:46]=[N:45][N:44]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:39]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)Cn1cnnc1CCl
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(O)cc2)CCN3CC(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(OCc4nncn4CC(C)C)cc2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-(4-hydroxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g), 3-chloromethyl-4-isobutyl-4H-1,2,4-triazole hydrochloride (0.15 g) and potassium carbonate (0.4 g), N,N-dimethylformamide (5 ml) was added, and the mixture was stirred overnight under nitrogen atmosphere at room temperature. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methoxy]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 27) (0.31 g) as yellow amorphous.
Reaction SMILES: [F:1][C:2]1[C:7]2=[N:8][O:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Cl:11][S:12]([O-])(=[O:14])=[O:13]>C(Cl)(Cl)Cl>[Cl:11][S:12]([C:5]1[C:6]2[C:7](=[N:8][O:9][N:10]=2)[C:2]([F:1])=[CH:3][CH:4]=1)(=[O:14])=[O:13]
Reactant: Fc1cccc2nonc12
Reactant: O=S(=O)([O-])Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(F)c2nonc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.0 g of 7-fluoro-2,1,3-benzoxadiazole were dissolved in 10 ml of chloroform and then 11.0 ml of chlorosulfonate at 0° C. were dripped into the solution. After reacting at room temperature for one hour, the solution was stirred and reacted for an additional two hours. Next, the reaction solution was transferred to 200 g of ice water, and extracted with chloroform very quickly. The extract was then water washed and dried with magnesium sulfate before filtering. The filtrate was then reduced pressure concentrated. The remaining extract was subjected to silica gel column chromatography (chloroform as mobile phase; 2 cm×60 cm) in 5 ml fractions. The respective fractions were analyzed using thin layer chromatography (silica gel, chloroform). The fraction having an Rf value of about 0.5 was then collected and reduced pressure concentrated. 4.0 g of a pale brown needle-shaped crystalline substance with a melting point of between 64° and 66° C. were obtained.
Reaction SMILES: [CH3:1][C:2]([CH:11]=[CH:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][CH2:4][P:5]1(=[O:10])[O:9][CH2:8][CH2:7][O:6]1.CC(C=CC=C(C)CCC=C(C)C)=CCP(=O)(O)O.CC(C)=CCC/C(/C)=C/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)/C=C/C=C(\C)/CCC=C(C)C.O1CCOP1=O>P(=O)([O-])[O-]>[CH3:1][C:2]([CH:11]=[CH:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[C:3]=[CH:4][P:5]1(=[O:10])[O:9][CH2:8][CH2:7][O:6]1
Reactant: CC(C)=CCCC(C)=CC=CC(C)=CCP1(=O)OCCO1
Agent: CC(C)=CCC/C(C)=C/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C=C(\C)CCC=C(C)C
Agent: CC(C)=CCCC(C)=CC=CC(C)=CCP(=O)(O)O
Agent: O=[PH]([O-])[O-]
Product: CC(=C=CP1(=O)OCCO1)C=CC=C(C)CCC=C(C)C

Procedure:
The reaction was conducted in the manner described in the procedure of Example V using the following reagents: 196 mg (0.636 mmole) of the above-named allenic phosphonate (produced in accordance with Example VI), 4.0 mL of absolute ethyl alcohol, and 47 mg (1.24 mmoles) of sodium borohydride. Isolation of the product as described in the procedure of Example V afforded 207 mg of a phosphonate that was shown by IR and proton NMR analysis (300 MHz) to have a structure different from the anticipated 2-[3,7,11-trimethyldodeca-2,4,6,10-tetraenyl]-1,3,2-dioxaphospholan-2-one. The product was identified as 3,7,11-trimethyl-2,4,6,10-dodecatetraenyl-phosphonic acid, ethyl beta-hydroxyethyl diester--an allylic phosphonate that can still be used in the synthesis of lycopene. The formation of this product can be explained by the facile ethanolysis of the strained heterocyclic ring (i.e., a 1,3,2-dioxaphospholan-2-one) present in the starting material. The proton NMR spectrum of this product exhibited a multiplet at δ 4.124 (4H's, 2×POCH2), a multiplet at δ 3.777 (CH2 bonded to an OH), a doublet of doublets (J=23.1, 8.4 Hz) at δ 2.78 (CH2P), and a triplet (J=6.9 Hz) at δ 1.31 (CH3 in the phosphonate moiety).
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl.O.O.C(Cl)Cl.C(O)(=O)C>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:38])[CH2:32][CH2:31]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(C(C)=O)c1
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
To a solution of 1-{5-[3-butyl-6-(piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenyl}-ethanone dihydrochloride (50 mg, 0.095 mmol) in dichloromethane (2.0 mL) was added formaldehyde solution in water (37%, 0.2 mL), and 0.1 mL of acetic acid. Then sodium triacetoxyborohydride (200 mg) was added. And the mixture was stirred at room temperature for 10 min then condensed. It was then diluted with water/DCM, neutralized with sat NaHCO3 powder, organic layer was separated washed with water, brine and dried (Na2SO4). The solvent was removed in vacuo and the residue was purified by column chromatography using 5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to provide 1-{5-[3-Butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenyl}-ethanone (30 mg). This compound was dissolved in DCM (2.0 mL) and 1.0 mL of 4.0 M HCl in dioxane was added. Solvents were evaporated resulting solid was washed with ether and dried to provide the title compound (33 mg). LCMS: m/z 467 [M+1]. 1H NMR (400 MHz, CD3OD) 7.94 (1H, s), 7.83-7.87 (1H, m), 7.68-7.74 (1H, m), 7.39 (1H, t), 5.35-5.43 (1H, m), 4.65-4.71 (1H, m), 3.65 (1H, d), 3.38-3.50 (2H, m), 3.28-3.30 (2H, m), 3.09-3.14 (2H, m), 2.84 (3H, s), 2.67 (3H, s), 2.5 (1H, d), 2.41 (1H, d), 2.24-2.31 (1H, m), 2.05-2.13 (2H, m), 1.80-1.84 (2H, m) 1.64-1.72 (3H, m), 1.51-1.56 (4H, m), 1.28-1.34 (3H, m), 0.83 (3H, t).
Reaction SMILES: C(C1C=CC([CH:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=CC=1)C1C=CC=CC=1.CC(C1C=CC(O)=CC=1O)=O>>[C:19]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCOC(=O)CCCCC(Br)c1ccc(Cc2ccccc2)cc1
Agent: CC(=O)c1ccc(O)cc1O
Product: CCCCCC(=O)OCC

Procedure:
Following the procedure of Example 15, 3.75 g. of ethyl 6-(4-benzylphenyl)-6-bromo-hexanoate and 1.94 g. of 2,4-dihydroxyacetophenone were reacted to provide the intermediate ethyl hexanoate derivative which was then hydrolyzed to provide 0.95 g. of the title product as an oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].O>CN1C(=O)CCC1>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:12]2[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]2)=[N:3][CH:4]=1
Reactant: O=S1(=O)CCNCC1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(N2CCS(=O)(=O)CC2)nc1
Yield: 41.1 %

Procedure:
A solution of methyl 6-chloronicotinate (3.43 g, 20 mmol), thiomorpholine 1,1-dioxide (2.70 g, 20 mmol) and sodium carbonate (2.54 g, 24 mmol) in NMP (40 mL) was heated to 90° C. for 3 days. The reaction mixture was poured into water and the white solid formed was filtered off to give 2.22 g 6-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-nicotinic acid methyl ester. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over Na2SO4, filtered and the solvents were evaporated. The residue was triturated with diethyl ether and the solid filtered off to yield another 1.18 g 6-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-nicotinic acid methyl ester.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][CH:31]1[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[CH:31]1([CH2:30][N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:33][CH2:32]1
Reactant: BrCC1CC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC2CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), (bromomethyl)cyclopropane (0.16 mL), potassium carbonate (0.38 g) and N,N-dimethylacetamide (10 mL) was stirred at 70° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.54 g, 93%).
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([OH:28])[C:25]([C:29]3[N:30]=[CH:31][O:32][CH:33]=3)=[CH:24][C:23]=2[CH2:34][CH3:35])[C:12]=1[CH2:36][CH2:37][CH3:38].[OH-].[Li+]>CO>[CH2:34]([C:23]1[CH:24]=[C:25]([C:29]2[N:30]=[CH:31][O:32][CH:33]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:36][CH2:37][CH3:38])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:39])=[O:2])[CH3:35]
Reactant: CCCc1c(OCCCOc2cc(O)c(-c3cocn3)cc2CC)cccc1Oc1ccccc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOc2cc(O)c(-c3cocn3)cc2CC)cccc1Oc1ccccc1C(=O)O
Temperature: 60 °C
Yield: 37.3 %

Procedure:
To a solution of 2-{3-[3-(2-ethyl-5-hydroxy-4-oxazol-4-yl-phenoxy)propoxy]-2-propylphenoxy}benzoic acid methyl ester (89 mg, 0.14 mmol) in methanol (2 mL) was added 1 M lithium hydroxide solution (0.28 mL) and the resulting mixture warmed at 60° C. for 3.5 h. The mixture was cooled to room temperature and concentrated in vacuo. The aqueous residue was diluted with water and the pH adjusted to ˜4. The mixture was extracted three times with methylene chloride. The combined organic extracts were dried (sodium sulfate), filtered, and concentrated in vacuo to provide 27 mg (92%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) δ 12.83 (bs, 1H), 10.12 (bs, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 7.78 (dd, J=8, 1 Hz, 1H), 7.64 (s, 1H), 7.47 (t, J=8 Hz, 1H), 7.16 (m, 2H), 6.80 (t, J=8 Hz, 2H), 6.56 (s, 1H), 6.35 (d, J=8 Hz, 1H), 4.20 (t, J=6 Hz, 2H), 4.12 (t, J=6 Hz, 2H); 2.54 (m, 4H), 2.24 (quintet, J=6 Hz, 2H), 1.43 (hextet, J=8 Hz, 2H), 1.10 (t, J=8 Hz, 3H), 5 0.80 (t, J=8 Hz, 3H); TOF MS ES+ exact mass calculated for C30H32NO7 (p+1): m/z=518.2179. Found: 518.2206; IR (KBr, cm−1) 2961, 1696, 1460, 1222. Anal. Calcd for C30H31NO7: C, 69.62; H, 6.04; N, 2.71. Found: C, 68.71; H. 5.82; N, 2.65.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Br:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1F>CN(C=O)C>[Br:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[C:2]([CH3:1])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
To a solution of diethyl 2-methylpropanedioate (21.8 g, 125.0 mmol) in anhydrous DMF (125 mL) was slowly added NaH (5.2 g, 130 mmol) at 0° C. under an atmosphere of nitrogen. The resulting reaction mixture was allowed to stir for 10 minutes at 0° C., and then at room temperature for 10 minutes. 2-bromo-1-fluoro-4-nitro-benzene (25.0 g, 113.6 mmol) was quickly added and the reaction mixture turned bright red. After stirring for 10 minutes at room temperature, the crude mixture was evaporated to dryness and then partitioned between dichloromethane and brine. The layers were separated and the combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by silica gel column chromatography (petroleum ether/EtOAc 10:1) to give diethyl 2-(2-bromo-4-nitrophenyl)-2-methylmalonate (33.0 g, 78%)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][CH2:8][C:9]1([CH3:27])[O:13][N:12]=[C:11]([S:14][CH2:15][C:16]2[C:17]([C:23]([F:26])([F:25])[F:24])=[N:18][N:19]([CH3:22])[C:20]=2[OH:21])[CH2:10]1.[CH:28](I)([CH3:30])[CH3:29].O>CN(C)C=O.C(OCC)(=O)C>[Cl:7][CH2:8][C:9]1([CH3:27])[O:13][N:12]=[C:11]([S:14][CH2:15][C:16]2[C:17]([C:23]([F:26])([F:25])[F:24])=[N:18][N:19]([CH3:22])[C:20]=2[O:21][CH:28]([CH3:30])[CH3:29])[CH2:10]1
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1c(CSC2=NOC(C)(CCl)C2)c(C(F)(F)F)nn1C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
0.5 g (3.5 mmoles) of anhydrous potassium carbonate was added, at room temperature, into a solution of 1.0 g (2.9 mmoles) of 5-chloromethyl-3-(5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. Thereto was added, at room temperature, 0.6 g (3.5 mmoles) of isopropyl iodide. The mixture was stirred for 30 minutes to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 0.5 g (yield: 45.0%) of 5-chloromethyl-3-(1-methyl-5-isopropoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline.