Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28])[NH2:15]>CC(O)C>[ClH:1].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28])[NH:15][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1ccccc1COc1ccc(N)cc1Cl
Reactant: Clc1ncnc2ccsc12
Solvent: CC(C)O
Product: COc1ccccc1COc1ccc(Nc2ncnc3ccsc23)cc1Cl
Product: Cl
Yield: 78 %

Procedure:
4-Chlorothieno[3,2-d]pyrimidine (0.102 g, 0.60 mmol) and 3-chloro-4-(2-methoxybenzyloxy)aniline (prepared according to the published method: WO 96/09294) (0.161 g, 0.65 mmol) were reacted in 2-propanol (4 ml) for 1.25 hours, according to Procedure A. The product was obtained as pale cream prisms (0.203 g, 78%) with m.p. 210-212° C.; (Found: C, 55.28; H, 4.00; N, 9.44. C20H16ClN3O2S.HCl requires: C, 55.31; H, 3.92; N, 9.67%); δH [2H6]-DMSO 11.19 (1H, br s, NH), 8.88 (1H, s, 2-H), 8.48 (1H, d, J 7, 6 H or 7 H) 7.87 (1H, d, J 5, 2′-H), 7.55-7.62 (2H, m, 6′-H, 4″-H), 7.48 (1H, d, J 7, 6H or 7H), 7.28-7.40 (2H, m, 5′-H, 6″-H), 7.09 (1H, d, J 9, 3″-H), 7.00 (1H, t, J 9, 5″-H), 5.22 (2H, s, CH2), 3.85 (3H, s, OCH3).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[O:9]>O.O.C(O)(=O)C(O)=O>[CH:1]1[CH:2]=[C:3]([CH2:4][C:6]2[C:1]([OH:7])=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:8]([OH:9])=[CH:5][CH:6]=1
Reactant: C=O
Reactant: Oc1ccccc1
Agent: O=C(O)C(=O)O
Solvent: O
Product: Oc1ccccc1Cc1ccccc1O
Temperature: 70 °C
Yield: 30.4 %

Procedure:
There were mixed 2000 g of phenol and 172.5 g of 37% formalin (P/F=10) and then 5.6 g of oxalic acid dihydrate was added to the mixture, followed by reacting the mixture with heating at 70° C. for 4 hours. Then the reaction system thus obtained was heated to 160° C. under atmospheric pressure to remove the water and a small amount of phenol and further heated at a pressure of 20 mm Hg till the temperature reached 170° C. to remove unreacted phenol. Then the product was heated at 210° C. and a pressure of 6 mm Hg to further remove the remaining unreacted phenol to give 350 g of a crude bisphenol F.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1>O1CCOCC1.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(Br)cc1
Reactant: c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccco2)cc1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of 0.5 g (1.6 mmol) of material from Example 27 and 0.6 g (1.7 mmol) of 2-tributylstannyl)-furan in 5 mL of dioxane was added 0.1 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium (0). The mixture was heated to reflux for 16 hours, cooled to ambient temperature and diluted with 5 mL of ethyl ether. The mixture was washed once with 5 mL of saturated aqueous potassium fluoride, the organic layer was separated and the aqueous portion was extracted three times with 5 mL each of ethyl ether. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (25 g of silica gel, 25% ethyl acetate/hexane) of the residue afforded a yellow oil which was recrystallized from ethyl ether/hexane to afford 0.2 g (51%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][S:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].N1CCCCC1>C(O)C.CCOCC>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][S:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:27]2[S:23][C:24](=[O:29])[NH:25][C:26]2=[O:28])=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1CSc1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1oc(-c2ccccc2)nc1CSc1ccc(C=C2SC(=O)NC2=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-[(5-Methyl-2-phenyl-4-oxazolyl)methylthio]benzaldehyde (0.05 mol), thiazolidine-2,4-dione (11.7 g, 0.10 mol and piperidine (0.85 g, 0.01 mol)are combined in 300 mL absolute ethanol, and the mixture refluxed for 24 hours, cooled to 0° C., diluted slowly with 600 mL of ether and, after stirring for 1 hour at 0° C. present title recovered by filtration. If desired, the product is triturated with 150 mL of warm acetic acid (40°-50° C.). The resulting slurry is cooled to room temperature, diluted with 300 mL of ether, and purified title productrecovered by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=3)[NH2:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:28][S:29]([Cl:32])(=[O:31])=[O:30]>>[ClH:1].[ClH:32].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([NH:24][S:29]([CH3:28])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=3)[CH2:17][CH2:18]2)[CH:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cc(Cl)cc2n1
Reactant: CS(=O)(=O)Cl
Product: Cc1ccc2c(N3CCN(CCc4cccc(NS(C)(=O)=O)c4)CC3)cc(Cl)cc2n1
Product: Cl
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield using a similar procedure to example E43 starting from 3-{2-[4-(7-Chloro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D18) and methanesulfonyl chloride.
Reaction SMILES: C([O:3][CH:4]([O:12][CH2:13][CH3:14])[CH2:5][C:6](=[CH2:11])[C@H:7](O)[CH2:8][OH:9])C.Cl>>[CH2:13]([O:12][C@@H:4]1[O:3][C@H:7]([CH2:8][OH:9])[C:6](=[CH2:11])[CH2:5]1)[CH3:14].[CH2:13]([O:12][C@H:4]1[O:3][C@H:7]([CH2:8][OH:9])[C:6](=[CH2:11])[CH2:5]1)[CH3:14]
Reactant: C=C(CC(OCC)OCC)[C@H](O)CO
Agent: Cl
Product: C=C1C[C@@H](OCC)O[C@@H]1CO
Product: C=C1C[C@H](OCC)O[C@@H]1CO

Procedure:
reacting the product of step e with 10% HCl in a suitable solvent for 30 minutes to form (2S-cis)-tetrahydro-5-ethoxy-3-methylene-2-furanmethanol and (2S-trans)-tetrahydro-5-ethoxy-3-methylene-2-furanmethanol.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1>ClCCl>[N+:7]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:9][CH:10]=1)[CH2:17][CH2:16][CH2:15][CH2:14]2)([O-:8])=[O:6]
Reactant: c1ccc2c(c1)CCCC2
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
To a suspension of 85% nitronium tetrafluoroborate (52 g, 0.333 mol) in dichloromethane (500 mL) was added dropwise a solution of tetralin (40 g, 0.303 mol) in dichloromethane (400 mL) over 45 min at 0° C. The mixture was stirred for 30 min at 0° C. and quenched by addition of ice-water (700 mL). The organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 30:1~5:1 hexane/toluene to give 14.15 g of the title compound: 1H NMR (CDCl3) δ7.91 (s, 1H), 7.88 (d, 1H, J=7.6 Hz), 7.17 (d, 1H, J=7.6 Hz), 2.84 (m, 4H), 1.83 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[CH:14]=2)[N:8]([CH2:24][C:25]([O:27]CC)=[O:26])[N:7]=1)=[O:5])[CH3:2].[Li+].[OH-].Cl>O1CCCC1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:16]=[C:15]([F:23])[CH:14]=2)[N:8]([CH2:24][C:25]([OH:27])=[O:26])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cn1nc(C(=O)OCC)cc1OCc1cc(F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(OCc2cc(F)cc(C(F)(F)F)c2)n(CC(=O)O)n1
Temperature: 25 °C

Procedure:
To an ice cold solution of 1-ethoxycarbonylmethyl-5-(3-fluoro-5-trifluoromethyl-benzyloxy)-1H-pyrazole-3-carboxylic acid ethyl ester (2) in 1 mL of tetrahydrofuran and 0.2 mL of water was added 0.21 mL (0.21 mmol) of 1 M LiOH solution, and the mixture was allowed to warm up to rt for 2 h. The reaction mixture was then acidified with 0.25 mL (0.25 mmol) of 1 M HCl solution, and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, and concentrated to give 58.5 mg (0.150 mmol) of 1-carboxymethyl-5-(3-fluoro-5-trifluoromethyl-benzyloxy)-1H-pyrazole-3-carboxylic acid ethyl ester (3) as crude product.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][C:6]=1[F:14].[Al+3].[Cl-].[Cl-].[Cl-].[C:19]1([O:25][CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCl>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([C:22]2[CH:23]=[CH:24][C:19]([O:25][CH3:26])=[CH:20][CH:21]=2)=[O:10])=[CH:7][C:6]=1[F:14]
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccc(OCCBr)c(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(OCCBr)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.2 %

Procedure:
To a solution of 4-(2-bromoethoxy)-3-fluorobenzoyl chloride (1.07 g, 3.80 mmol) and anhydrous AlCl3 (1.01 g, 7.60 mmol) in dry dichloromethane (18 mL) was added anisole (822 mg, 7.60 mmol) in 2 mL dichloromethane at 0° C. After stirring at rt for 6 h, the mixture was poured into 3 N HCl and extracted with dichloromethane twice. The extracts were combined, washed with sat. NaHCO3 and brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 5/1) to give 1.05 g (77% yield) of the subtitle compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.8 Hz, 2H), 7.58 (d, J=11.6 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.03 (dd, J=8.0 Hz, 8.4 Hz, 1H), 6.98 (d, J=9.2 Hz, 2H), 4.44 (t, J=6.4 Hz, 2H), 3.90 (s, 3H), 3.70 (t, J=6.4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=3)[N:11]=[C:10]([C:21]([O:23]CC)=[O:22])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=3)[N:11]=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(C#N)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: N#Cc1cccc(-n2nc(C(=O)O)cc2-c2cccc(Cl)c2)c1
Reaction time: 6 h

Procedure:
The preparation of the title compound takes place starting from the compound of Example 61A in analogy to the synthesis of the compound of Example 71A but with stiffing for 6 hours. 470 mg of the title compound with 77% purity are obtained.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH3:7][O:8][CH:9](OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][CH2:2][C@@H:3]1[CH2:4][O:5][C@@H:7]([O:8][CH3:9])[O:6]1
Reactant: OCC(O)CBr
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CO[C@@H]1OC[C@@H](CBr)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
To a solution of 3-bromo-1,2-propanediol (6.0 g, 38.7 mmol) in benzene (90 mL) was added trimethylorthoformate (4.23 mL, 38.7 mmol, 1 eq.) and p-toluenesulfonic acid (pTSA, few crystals). The mixture was stirred for 20 hr at 85°-90° C., then cooled to room temperature and benzene was removed under reduced pressure. The crude material was obtained in 96% yield (7.26 g) as a mixture of cis and trans isomers in a 1:1 ratio.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[C:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:12]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (5 g, 29 mmol), 1-acetylpiperazine (29 mmol), and K2CO3 (4.0 g, 29 mmol) in DMF (20 mL) was stirred at 120° C. for 4 h. The reaction mixture was cooled to room temperature and poured into ice cold water (100 mL). The crude solid product was collected by filtration, air dried, and purified by flash chromatography (silica gel, 4×15 cm, eluted with CHCl3) to yield the product as orange crystals.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([NH2:7])=[O:6])#[N:3].[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]([C:15]2[C:24]([CH3:25])=[CH:23][C:18]([CH2:19][N:20]=[N+:21]=[N-:22])=[CH:17][C:16]=2[CH3:26])=[O:14])=[CH:11][CH:10]=1.C(O)(=O)C>C(O)C>[NH2:3][C:2]1[N:20]([CH2:19][C:18]2[CH:17]=[C:16]([CH3:26])[C:15]([C:13](=[O:14])[C:12]3[CH:27]=[CH:28][C:9]([Cl:8])=[CH:10][CH:11]=3)=[C:24]([CH3:25])[CH:23]=2)[N:21]=[N:22][C:4]=1[C:5]([NH2:7])=[O:6]
Reactant: N#CCC(N)=O
Reactant: Cc1cc(CN=[N+]=[N-])cc(C)c1C(=O)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(Cn2nnc(C(N)=O)c2N)cc(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.8 %

Procedure:
A stirred, 60° solution of sodium (105 mg, 4.55 mmol) in absolute ethanol (11.4 ml) was treated in one portion with 2-cyanoacetamide (382 mg, 4.55 mmol), kept 5 minutes, and treated in one portion with a solution of 4-(4-chlorobenzoyl)-3,5-dimethylbenzyl azide (1.05 g, 3.50 mmol) in absolute ethanol (4 ml). The mixture was refluxed 1 hour, cooled to ambient temperature, acidified with glacial acetic acid (577 μl, 605 mg, 9.10 mmol), and evaporated almost to dryness under vacuum. The residue was refluxed briefly with methanol (7 ml), cooled to ambient temperature, and filtered. The solid product was washed four times with small volumes of methanol, washed three times with water, and dried under vacuum at 40° C. to provide 870 mg (65%) 5-amino-1-(4-[4-chlorobenzoyl]-3,5-dimethylbenzyl)-1,2,3-triazole-4-carboxamide, m.p. 208°-209° C.
Reaction SMILES: [Na].[NH2:2][C:3]1[N+:8]([O-:9])=[C:7]([NH2:10])[CH:6]=[C:5](Cl)[N:4]=1.[CH2:12]([OH:14])[CH3:13]>>[NH2:2][C:3]1[N+:8]([O-:9])=[C:7]([NH2:10])[CH:6]=[C:5]([O:14][CH2:12][CH3:13])[N:4]=1
Reactant: CCO
Reactant: Nc1cc(Cl)nc(N)[n+]1[O-]
Agent: [Na]
Product: CCOc1cc(N)[n+]([O-])c(N)n1
Temperature: 120 °C

Procedure:
1.8 g of sodium are dissolved in 100 ml of ethanol. 10 g of 2,4-diamino-6-chloropyrimidine 3-oxide are added. The reaction mixture is refluxed until the starting material has disappeared and is heated to 120° C. in an autoclave for 7 hours. It is returned to ambient temperature and the insoluble material is filtered off and washed with ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([CH2:21][CH3:22])[CH:3]=1.Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br.C(N(CC)C(C)C)(C)C.CN1CCCC1>C(OCC)(=O)C>[CH2:8]([C:6]1[CH:7]=[C:2]([N:1]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=[C:4]([CH2:21][CH3:22])[C:5]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:9]
Reactant: BrCCOCCBr
Reactant: CCc1cc(N)cc(CC)c1NS(=O)(=O)c1ccc(C)cc1
Agent: CN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCc1cc(N2CCOCC2)cc(CC)c1NS(=O)(=O)c1ccc(C)cc1
Temperature: 180 °C
Yield: 91 %

Procedure:
A mixture of N-(4-amino-2,6-diethyl-phenyl)-4-methyl-benzenesulfonamide (70 mg), bis-(2-bromoethyl)ether (33 μL), N,N-diisopropyl-ethylamine (115 μL) and N-methylpyrrolidine (0.3 mL) was heated to 180° C. for 20 minutes in a sealed microwave process vial. The mixture was diluted with ethyl acetate (20 mL), washed with brine (30 mL) and saturated aqueous potassium carbonate (30 mL), and dried over sodium sulfate. The organic phase was concentrated in vacuo to furnish 78 mg (91%) of the title compound. LC-MS (m/z) 389 (MH+); tR=2.77, (UV, ELSD) 57%, 98%. The crude product was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH2:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[CH2:19][CH3:20]>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:24]2[CH:25]=[CH:26][C:21]([CH2:18][CH2:19][CH3:20])=[CH:22][CH:23]=2)[CH:5]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: CCCc1ccc(B(O)O)cc1
Product: CCCc1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)cc1
Yield: 30 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 4-propylphenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (52 mg, 30%) which was obtained as a white solid. MS (ESI): m/e=344.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:24])=[CH:4][C:5]([OH:23])=[C:6]([C:8](=[O:22])[CH2:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])=[CH:12][CH:11]=2)[CH:7]=1.[C:25](OC(=O)C)(=O)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[OH:24])[O:23][C:25]([CH3:26])=[C:9]([C:10]1[CH:21]=[CH:20][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])=[CH:12][CH:11]=1)[C:8]2=[O:22]
Reactant: N#CCCCOc1ccc(CC(=O)c2cc(Cl)c(O)cc2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccc(OCCCC#N)cc1

Procedure:
This compounds was synthesised in the same manner as described above. 4-{4-[2-(5-Chloro-2,4-dihydroxy-phenyl)-2-oxo-ethyl]-phenoxy}-butyronitrile (0.62 g, 1.8 mmol), acetic anhydride (1.0 ml), potassium carbonate (1 g, 7.2 mmol). 4-[4-(6-Chloro-7-hydroxy-2-methyl-4-oxo-4H-chromen-3-yl)-phenoxy]-butyronitrile was obtained as a white solid (0.55 g, 82.7%) Rf 0.6 ethyl acetate/hexane (70/30).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[N:14]=[C:15]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]([C:28]2[CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-:42])=[O:41])[CH:35]=3)[C:32]([C:43]([O:45][CH3:46])=[O:44])=[C:31]([CH3:47])[NH:30][C:29]=2[CH3:48])=[O:27])[S:16][CH:17]=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH3:12][C:13]1[N:14]=[C:15]([S:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]([C:28]2[CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-:42])=[O:41])[CH:35]=3)[C:32]([C:43]([O:45][CH3:46])=[O:44])=[C:31]([CH3:47])[NH:30][C:29]=2[CH3:48])=[O:27])=[O:9])[S:16][CH:17]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCSc2nc(C)cs2)C1c1cccc([N+](=O)[O-])c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCS(=O)c2nc(C)cs2)C1c1cccc([N+](=O)[O-])c1
Yield: 65 %

Procedure:
A solution of m-chloroperbenzoic acid (0.156g, 0.001 mol) in dichloromethane (5mL) was added to a solution of 3-[6-(4-methylthiazol-2-yl) thiohexyloxy-carbonyl]-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine (18) (0.545 g, 0.001 mol) in dichloromethane (10 mL) at room temperature with agitation. Stirring under the same conditions was maintained for 2 h. The excess peracid was decomposed by 10% solution of sodium sulfite. The organic layer was separated and washed with 5% sodium bicarbonate solution in order to extract m-chlorobenzoic acid, followed by washing with water and drying over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residual oil was purified by elution from a silica gel column using chloroform-hexane (8:2, v/v) as eluant to give 3-[6-(4-methylthiazol-2-yl)sulfinylhexyloxycarbonyl]-5-methoxycarbonyl-2,6-dimethyl-4-(3- nitrophenyl)-1,4-dihydropyridine (65%) as colorless prisms, mp 81°-83° C. IR (KBr) 3365 (NH) 1695 and 1652 (CO2R) 1033 (SO)cm-1, NMR (CDCl3) 1.22-1.74 (m, 8H, (CH2)4), 2.36 (S, 6H, Me-2, Me-6) 2.52 (S, 3H, Me-HEt),3.02-3.22 (m, 2H, CH2 --SO), 3.68 (S, 3H, CO2Me), 3.96-4.14 (m, 2H, CH2 --O), 5.12 (S, 1H, H-4), 6.56 (S, 1H, H-HEt), 7.26 (S, 1H, NH), 7.38-8.14 (m, 4H, H-2', H-4', H-5', H-6'). Analysis found: C, 55.75; H, 5.64; N, 7.35; S, 11.30. Required: C, 55.66; H, 5.56; N, 7.48; S, 11.42 (C26H31N3O7S2). ##STR7##
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.C([Li])CCC.[CH2:12]([N:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=[O:26])=[CH:24][C:19]=2[N:18]=[N:17]1)[CH2:13][CH2:14][CH3:15]>CCCCCC.O(CC)CC>[CH2:12]([N:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]([C:2]3[CH:6]=[CH:5][S:4][CH:3]=3)[OH:26])=[CH:24][C:19]=2[N:18]=[N:17]1)[CH2:13][CH2:14][CH3:15]
Reactant: Brc1ccsc1
Reactant: CCCCn1nnc2cc(C=O)ccc21
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCn1nnc2cc(C(O)c3ccsc3)ccc21
Temperature: 0 °C
Yield: 58.9 %

Procedure:
To a stirred and cooled (-78° C.) solution of 7.2 parts of 3-bromothiophene in 70 parts of 1,1'-oxybisethane were added 30 parts of a 1-butyllithium solution 1.6M in hexane. After stirring for 20 minutes at this low temperature, a solution of 6 parts of 1-butyl-1H-benzotriazole-5-carboxaldehyde in 1,1'-oxybisethane was added to the previous mixture. The reaction mixture was stirred for 2 hours at -78°~-'° C. The whole was poured into 200 parts of ice water and the product was extracted three times with 56 parts of 1,1'-oxybisethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 5 parts (58.9%) of 1-butyl-α-(3-thienyl)-1H-benzotriazole-5-methanol; mp. 80° C. (int. 58).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:23])([F:24])[F:25])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][CH2:34][OH:35])=[O:5]
Reactant: NCCO
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Product: O=C(NCCO)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.33 h
Yield: 43 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 40 mg, 0.093 mmol), 2-aminoethanol (8.52 mg, 0.139 mmol), HATU (45.9 mg, 0.121 mmol), and 4-methylmorpholine (37.6 mg, 0.372 mmol) were added to a vial. It was stirred for 20 min and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.1 min) to provide (R/S)-2-hydroxy-N-(2-hydroxyethyl)-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (20 mg, 0.040 mmol, 43.2% yield): LCMS=474.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.46 (1 H, s), 8.12 (2 H, d, J=8.35 Hz), 7.50-7.73 (7 H, m), 5.13 (1 H, s), 3.58-3.69 (2 H, m), 3.35-3.40 (2 H, m); HPLC peak RT=6.8 min (Method A).