Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:8]1[O:12][N:11]=[C:10]([CH2:13]O)[CH:9]=1)([O:4][CH2:5][C:6]#[CH:7])[CH3:3].S(Cl)([Cl:17])=O>ClCCl>[Cl:17][CH2:13][C:10]1[CH:9]=[C:8]([C:2]([CH3:3])([O:4][CH2:5][C:6]#[CH:7])[CH3:1])[O:12][N:11]=1
Reactant: O=S(Cl)Cl
Reactant: C#CCOC(C)(C)c1cc(CO)no1
Solvent: ClCCl
Product: C#CCOC(C)(C)c1cc(CCl)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.20 g of {5-[1-methyl-1-(2-propynyloxy)ethyl]isoxazol-3-yl}methanol was dissolved in 5 ml of dichloromethane, and 0.5 ml of thionyl chloride was then added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain 0.21 g of 3-(chloromethyl)-5-[1-methyl-1-(2-propynyloxy)ethyl]isoxazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.O>O1CCOCC1.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>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH:5]=[C:4]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:3]=2)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(N3CCCCC3)cc(Cl)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(-c2cc(N3CCCCC3)cc(Nc3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 60 %

Procedure:
To a solution of (6′-chloro-3,4,5,6-tetrahydro-2H[1,4′]bipyridinyl-2′-yl)-(4-trifluoromethoxyphenyl)-amine (200 mg, 0.53 mmol) in 1,4-dioxane (8 mL) were added potassium carbonate (148 mg, 1.06 mmol), and tetrakis(triphenylphosphine)palladium(0) (62 mg, 0.053 mmol), followed by 4-fluorophenyl boronic acid (150 mg, 1.6 mmol). This reaction mixture was refluxed for 8 hours, after which time water was added (10 mL) to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum. The resulting product was purified through column chromatography using 230-400 mesh silica gel (15% ethyl acetate in petroleum ether) to afford the desired compound as colorless gummy mass (130 mg, yield 60% ).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8]([O:14][CH2:15][CH2:16][O:17][C:18](ON1C(=O)CCC1=O)=[O:19])(=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12]>>[OH:4][CH2:3][C@@H:2]([NH:1][C:18]([O:17][CH2:16][CH2:15][O:14][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:19])[C:5]([OH:7])=[O:6]
Reactant: N[C@H](CO)C(=O)O
Reactant: CCCCC(=O)OCCOC(=O)ON1C(=O)CCC1=O
Product: CCCCC(=O)OCCOC(=O)N[C@H](CO)C(=O)O
Yield: 72.9 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (504 mg, 4.8 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl pentanoate (1.1 g, 4.0 mmol) were reacted to provide 809 mg (73% yield) of the title compound (31) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.80 (m, 1H), 6.26 (br s, 1H), 5.50 (br s, 1H), 4.40 (m, 1H), 4.02 (m, 1H), 3.85 (m, 1H), 2.36 (m, 2H), 1.60 (m, 2H), 1.47 (d, 3H), 1.37 (m, 2H), 0.91 (t, 3H). MS (ESI) m/z 295.19 (M+NH4)+; 300.08 (M+Na)+; 272.12 (M−H)−.
Reaction SMILES: [Cl-].[CH:2]1([CH2:9][NH2+:10][CH2:11][CH2:12]Cl)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[N:25]=[C:26]=[S:27]>>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[N:25]=[C:26]1[N:10]([CH2:9][CH:2]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:11][CH2:12][S:27]1
Reactant: ClCC[NH2+]CC1CCCCCC1
Reactant: COc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Product: COc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC1CCCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cycloheptylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methoxy-4-nitrophenyl isothiocyanate to give 2-(2-methoxy-4-nitrophenylimino)-3-(cycloheptylmethyl)-1,3-thiazolidine.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][O:9][N:10]=[C:6]2[CH2:5][CH:4]([O:11][CH2:12][O:13][CH3:14])[CH:3]1[O:15][C:16]([O:18][CH3:19])=[O:17].N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C(Cl)Cl.C(OCC)C>[Si:25]([O:1][CH:2]1[CH:7]2[CH2:8][O:9][N:10]=[C:6]2[CH2:5][CH:4]([O:11][CH2:12][O:13][CH3:14])[CH:3]1[O:15][C:16]([O:18][CH3:19])=[O:17])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: COCOC1CC2=NOCC2C(O)C1OC(=O)OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOCC
Product: COCOC1CC2=NOCC2C(O[Si](C)(C)C(C)(C)C)C1OC(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
4-Hydroxy-5-methoxycarbonyloxy-6-(methoxymethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole (275 mg) was dissolved in 10 ml of methylene chloride, and 200 mg of imidazole and 226 mg of tert-butyldimethylsilyl chloride were added, followed by stirring the mixture overnight at room temperature. The reaction mixture was diluted with diethyl ether, and washed with dilute hydrochloric acid, a sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution in sequence. The organic layer was dried over anhydrous sodium sulfate, and concentration was effected under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 285 mg of 4-(tert-butyldimethylsilyloxy)-5- methoxycarbonyloxy-6-(methoxymethoxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following property (yield 73%).
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([SH:14])[N:8]=1.[H-].[Na+].Cl[CH:18]([CH3:28])/[CH:19]=[CH:20]/[C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH2:26]([N:23]([CH2:24][CH3:25])[C:21](=[O:22])/[CH:20]=[CH:19]/[CH:18]([S:14][C:9]1[N:8]=[C:7]([NH2:6])[CH:12]=[C:11]([Cl:13])[N:10]=1)[CH3:28])[CH3:27]
Reactant: CCN(CC)C(=O)/C=C/C(C)Cl
Reactant: Nc1cc(Cl)nc(S)n1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)/C=C/C(C)Sc1nc(N)cc(Cl)n1
Reaction time: 15 h

Procedure:
To (E)-N,N-Diethyl-4-hydroxy-2-pentenamide (0.67 g, 3.93 mmol) in methylene chloride cooled to -15° C. in a flame dried flask is added dichlorotriphenylphosphorane (1.40 g, 4.33 mmol). The reaction is warmed to ambient temperature, quenched by addition of ice (10 ml), extracted with methylene chloride (3×20 ml), washed with saline (30 ml), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (75/25). The appropriate fractions are combined (Rf =0.48, TLC, hexane/ethyl acetate, 25/75) and concentrated in vacuo to give (E)-4-chloro-N,N-diethyl-2-pentenamide. 4-Amino-6-chloro-2-mercaptopyrimidine mesylate (0.56 g, 2.19 mmol) is dissolved in DMF (4 ml) and sodium hydride (0.12 g, 4.82 mmol) at ambient temperature followed by the addition of (E)-4-chloro-N,N-diethyl-2-pentenamide (0.41 g, 2.19 mmol). The reaction is stirred for 15 hours, quenched with excess water, extracted with ethyl acetate (3×25 ml). The extracts are combined, washed with saline (25 ml), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with a gradient of hexane/ethyl acetate (80/20-60/40). The appropriate fractions are combined (Rf =0.27, TLC, hexane/ethyl acetate, 25/75) and concentrated in vacuo to give the title compound, mp 152-153° C.
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]>CO>[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:2])=[O:28]
Reactant: O=C(O)CCCCCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)CCCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
p-Toluenesulfonic acid monohydrate (0.28 g, 1.45 mmol) was added to a solution of the above 14-hydroxy-tetradecanoic acid (7.10 g, 29.1 mmol) in methanol (150 mL) and the resulting solution was stirred at room temperature for 3 days. Methanol was removed under reduced pressure; the residue was dissolved in ethyl acetate (170 mL); washed with 5% aqueous solution of sodium carbonate (3×50 mL) and brine (25 mL); dried over anhydrous magnesium sulfate and evaporated in vacuo to give methyl 14-hydroxy-tetradecanoate as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][S:13](Cl)(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]=[C:25]1[CH2:30][NH:29][CH2:28][CH2:27][NH:26]1>ClCCl.N1C=CC=CC=1>[CH2:17]([CH:11]([CH2:12][S:13]([N:29]1[CH2:28][CH2:27][NH:26][C:25](=[O:24])[CH2:30]1)(=[O:15])=[O:14])[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CNCCN1
Reactant: O=C(OCc1ccccc1)C(Cc1ccccc1)CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1CN(S(=O)(=O)CC(Cc2ccccc2)C(=O)OCc2ccccc2)CCN1
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To the resultant compound from Example 11C (320.5 mg, 0.908 mmol)in dichloromethane (5 mL) at -10° C. was added 2-oxopiperazine (140 mg, 1.40 mmol, Yu et. al. J. Med. Chem.1900, 31, 1435) in pyridine (2 mL). After 30 min at -10° C. and 30 min at ambient temperature, the solvent was evaporated and the residue was partitioned between ether and 0.5M H3PO4. The organic layer was washed with 0.5M H3PO4, saturated NaHCO3 solution and brine, and then was dried over MgSO4 and evaporated. Chromatography of the residue on silica gel with 2% methanol in chloroform afforded 237.1 mg (63%) of the desired product as a foam: TLC (5% methanol/95% chloroform) Rf =0.26; 1H NMR (CDCl3) 7.43-7.07 (m, 10H), 5.97 (br, 1H), 5.12 (d, 1 H), 5.08 (d, 1H), 3.82 (d, 1H), 3.78 (d, 1H), 3.55 (dd, 1H), 3.43-3.17 (m, 5H), 3.07 (dd, 1H), 3.01 (dd, 1H), 2.87 (dd, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[O-:12][CH2:13][CH3:14].[Na+].C(O)C>CN(C)C=O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([O:12][CH2:13][CH3:14])[N:10]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOc1nc(Cl)ccc1C(N)=O
Temperature: 15 °C
Reaction time: 0.67 h
Yield: 95 %

Procedure:
Refer to synthesis of D46 for preparation of 2,6-dichloro-nicotinamide (1). Freshly prepared sodium ethoxide solution in ethanol (12.1 mL of 2.17 M, 26.2 mmol) was slowly added over 10 min to a solution of 1 (5.01 g, 26.2 mmol) in dimethylformamide (30 mL) at 15° C. [Note: a water bath was used to maintain reaction temperature around 14-16° C.; sodium ethoxide was prepared from reaction of Na solid (1.50 g, 65.2 mmol) with anhydrous EtOH (30.0 mL)]. Upon completion of sodium ethoxide addition, the reaction was stirred for 40 min at 14-16° C. [Note: An aliquout (0.3 mL) of reaction was concentrated. A 1H NMR of aliquout recorded in d6-DMSO showed ˜98% conversion to desired 2]. The reaction was poured into water (500 mL) and extracted with EtOAc (3×400 mL). All organics were combined, dried over Na2SO4, filtered and concentrated to give the title compound as a light gray solid (5.20 g, 95% purity as established by 1H NMR). The title compound was carried forward without further purification. 1H NMR 400 MHz (d6-DMSO) δ 8.16 (d, J=8.2 Hz, 1H), 7.76 (br s, 1H), 7.57 (br s, 1H), 7.17 (d, J=7.8 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[OH:17])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:24]([O:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)=[C:10]([OH:17])[CH:11]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1ccc(Oc2cccc(F)n2)c(O)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(Oc2cccc(F)n2)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.4 %

Procedure:
To a solution of 2-[(6-fluoropyridin-2-yl)oxy]-5-(hydroxymethyl)phenol (0.42 mmol; 104 mg) under argon, in anhydrous DMF (0.8 mL), were added K2CO3 (0.5 mmol; 68 mg), DMAP (0.08 mmol; 12 mg), and acetic anhydride (0.41 mmol; 0.04 mL). The reaction was stirred at room temperature overnight. After dilution with ethyl acetate (4 mL), the organic phase was washed with saturated NaHCO3 (3*3 mL), dried (MgSO4), concentrated in vacuo, purified by preparative TLC (dichloromethane) to yield the title compound as a clear oil (3 mg; 0.01 mmol; 3%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[F:17][CH:18]([F:28])[C:19]1[C:23]([C:24](Cl)=[O:25])=[CH:22][N:21]([CH3:27])[N:20]=1>N1C=CC=CC=1>[F:28][CH:18]([F:17])[C:19]1[C:23]([C:24]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:4]2[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=2)=[O:25])=[CH:22][N:21]([CH3:27])[N:20]=1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: Nc1ccccc1-c1cc(F)c(F)c(F)c1
Solvent: c1ccncc1
Product: Cn1cc(C(=O)Nc2ccccc2-c2cc(F)c(F)c(F)c2)c(C(F)F)n1
Temperature: 45 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
9.55 kg 3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl-amine (I) were dissolved in 51.4 kg and 6 kg pyridine were added. The mixture was stirred at 45° C. and 8.3 kg 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride (II) were dosed during one hour. Due to the exothermic nature of the reaction, the temperature raised to 55° C. Post-reaction by stirring for 1 hour at 55° C. followed. Three extractions at 85° C. with 16 liter hydrochloric acid (5%), 14 liter sodium hydrogen carbonate (8%), and 14 liter deionized water followed. The resulting clear solution in toluene was cooled from 85° C. with a rate of 10° C. per hour to 0° C. Around 75° C., the first turbidity was observed, and at 75° C. and 73° C., respectively, the batch was seeded with 10 g 3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (III) each (>98% form B). The resulting slurry was filtered at 0° C. over a process filter and the filter cake was washed with 10 kg toluene at 0° C. After drying in the drying cabinet at 80° C. and 20 mbar for 12 hours, 13.5 kg 3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide (III) of >99.5% purity (GC, HPLC, NMR) was isolated. Using powder diffractometry (PXRD) and Fourier-Transform solid state infrared spectrometry (FT-IR) it was proven that the material consists to >98% of form B.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:27])([CH2:24][CH2:25][CH3:26])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:27])([CH2:24][CH2:25][CH3:26])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=4)(=[O:37])=[O:36])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCCC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Product: CCCC1(C)C(=O)N(C2CCN(S(=O)(=O)c3cccc(C)c3)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4-methyl-2-piperidin-4-yl-4-propyl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B8*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.C[O:39][C:40](=[O:43])[CH2:41][NH2:42]>CN(C1C=CN=CC=1)C>[CH3:32][C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([C:26]([NH:42][CH2:41][C:40]([OH:39])=[O:43])=[O:27])[CH:24]=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)O)cc2s1
Reactant: COC(=O)CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)NCC(=O)O)cc2s1
Yield: 91.3 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-6-carboxylic acid (175 mg, 0.387 mmol), DMAP (142 mg, 1.16 mmol), EDC (111 mg, 0.580 mmol), and glycine methyl ester hydrochloride (73 mg, 0.580 mmol) are reacted and hydrolyzed in a sequence analogous to Example 5 to afford the title compound (180 mg, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:23][C:21](=[CH2:22])[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8](=[O:12])[O:9][C:10]=2[CH:11]=1)=[O:24]
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)Oc1ccc2ccc(=O)oc2c1
Temperature: 15 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
40 g (247 mmol) of 7-hydroxy-coumarin (umbelliferone) were suspended in 700 ml of tetrahydrofuran and treated in succession with 38 ml (271 mmol) of triethylamine and 0.603 g (5 mmol) of 4-dimethylaminopyridine (DMAP). 28.4 g (271 mmol) of methacryloyl chloride were added dropwise to the suspension, cooled to about 15° C., in the course of 30 minutes. The reaction batch was stirred at room temperature for 4 hours and subsequently filtered over a thin silica gel layer. The silica gel layer was rinsed thoroughly with THF. After evaporation of the solvent the crude product was dissolved in about 300 ml of dichloromethane and treated with 1.5 l of ethanol. The dichloromethane was again removed on a rotary evaporator. The product crystallized from the remaining ethanolic solution overnight in a refrigerator. It was filtered off, dried and recrystallized once again from 1.1 l of ethanol according to the described procedure. Filtration and drying at 40° C. in a water-jet vacuum gave 42.9 g of 2-oxo-2H-1-benzopyran-7-yl 2-methyl-acrylate as white crystals. λmax. (in CH2Cl2)=312.6 nm (ε=9610 l/mol cm) and 282.3 nm (ε=11450 l/mol cm).
Reaction SMILES: [C:1]1([S:7]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:30]=[CH:31][CH:32]=1)[O:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][CH2:19][CH:20]([NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[CH3:21])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:1]1([S:7][N:22]([CH:20]([CH3:21])[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][C:12]3[CH:30]=[CH:31][CH:32]=[C:10]([Cl:9])[CH:11]=3)=[CH:15][CH:16]=2)[C:23](=[O:27])[O:24][CH2:25][CH3:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClSc1ccccc1
Reactant: CCOC(=O)NC(C)COc1ccc(Oc2cccc(Cl)c2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)N(Sc1ccccc1)C(C)COc1ccc(Oc2cccc(Cl)c2)cc1

Procedure:
A solution of 4 g of phenylsulfenyl chloride in 10 ml of toluene is added dropwise at 0°-5° C. in the course of 20 minutes to a solution of 9 g of ethyl 2-[4-(3-chlorophenoxy)phenoxy]-1-methylethylcarbamate in 30 ml of pyridine, with stirring, and the mixture is stirred for a further 15 hours at room temperature. Most of the pyridine and toluene is then distilled off in vacuo at a temperature of lower than 45° C., and the residue is poured into 300 ml of ice-water and extracted repeatedly with ether. The combined ether phases are first washed with cold, dilute hydrochloric acid and then with water, the mixture is dried over sodium sulfate, and the solvent is distilled off completely. The residue is purified further by chromatography on silica gel (eluent: n-hexane/diethyl ether, 19:1), by which process ethyl N-phenylthio-2-[4-(3-chlorophenoxy)phenoxy]-1-methylethylcarbamate is obtained as a colourless oil, nD20 : 1.5810.
Reaction SMILES: CON(C)[C:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5].[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1)[CH3:14]>C1COCC1>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([C:4]([C:6]2[S:7][CH:8]=[CH:9][C:10]=2[CH3:11])=[O:5])=[CH:17][CH:16]=1)[CH3:14]
Reactant: CON(C)C(=O)c1sccc1C
Reactant: CCc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)c2sccc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of N-methoxy-N,3-dimethylthiophene-2-carboxamide (52) (J. Med. Chem., 2001, 44, 863) (5.00 g, 27.0 mmole) in THF (30 mL) was added 4-ethylphenylmagnesium bromide (0.5M in THF, 108 mL, 54.0 mmole) at 0° C. The resulting solution was stirred at ambient temperature overnight. The reaction mixture was quenched by adding MeOH (20 mL) and concentrated in vacuo. The crude residue was purified on Biotage® purification apparatus to yield the compound 53 (4-ethylphenyl)(3-methylthiophen-2-yl)methanone (4.42 g, 19.2 mmole, 71%) as brown oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=[O:5].[OH-:14].[Na+]>>[OH:14][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Reactant: [OH-]
Agent: [Na+]
Product: O=Cc1c(O)cccc1C(F)(F)F
Temperature: 80 °C

Procedure:
A mixture of 2-fluoro-6-trifluoromethylbenzaldehyde (25 g) and aqueous sodium hydroxide solution (0.5 M; 866 ml) was stirred and heated at 80° C. under nitrogen for 43 hours. The cooled solution was washed with ether (2×350 ml), acidified with concentrated hydrochloric acid, then extracted with ether (2×500 ml). The combined extracts were dried over magnesium sulphate and the solvent removed in vacuo. The residue was purified by flash chromatography over silica eluting with a 95:5 mixture of dichloromethane and methanol. Appropriate fractions were combined and the solvent removed in vacuo to give 2-hydroxy-6-trifluoromethylbenzaldehyde (6.2 g) as an oil.