Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].Cl[C:12]1[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=[O:20].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.[Cu]I.C(O)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C:16]1[CH:15]=[CH:14][NH:13][C:12](=[O:20])[CH:17]=1
Reactant: OCc1ccc(Cl)cc1Cl
Reactant: Clc1cc(I)ccn1
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O=CO
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1cc(OCc2ccc(Cl)cc2Cl)cc[nH]1
Temperature: 105 °C
Reaction time: 96 h
Yield: 23.9 %

Procedure:
A suspension of (2,4-dichlorophenyl)methanol (4.10 g, 23.2 mmol), 2-chloro-4-iodopyridine (5.05 g, 21.1 mmol), Cs2CO3 (8.94 g, 27.4 mmol), CuI (4.01 g, 21.1 mmol) and 1,10-phenanthroline (760 mg, 4.22 mmol) in toluene (20 mL) was degassed by bubbling N2 through the suspension for 15 min. The suspension was put under N2, and heated at 105° C. for 18 h. The suspension was cooled, EtOAc (50 mL) was added, and the resulting suspension was passed through a plug of SiO2. The resulting solution was concentrated under reduced pressure. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. A suspension of the white solid and NH4OAc (6.13 g, 79.5 mmol) in 1:1 HCO2H/H2O (40 mL) was heated at reflux with stirring for 4 d. The solution was cooled and concentrated under reduced pressure. The resulting residue was made basic with saturated NaHCO3 solution and the resulting suspension was filtered. The solid was washed with H2O and dried under reduced pressure. Flash chromatography on silica gel ((1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) afforded 1.36 g (24%) of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.16 (br s, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.61 (d, J=8.1, 1H), 7.50 (dd, J=8.4, 2.1 Hz, 1H), 7.26 (d, J=7.2 Hz, 1H), 5.91 (dd, J=7.5, 2.7 Hz, 1H), 5.81 (d, J=2.4 Hz, 1H), 5.10 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C(=O)([O-])[O-].[K+].[K+].O.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:15]([N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCOCCO
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: OCCOCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 50 g (475.56 mmol) of 2-(2-amino-ethoxy)-ethanol and 144.6 g (1.046 mol) of potassium carbonate in 600 ml of ethanol/60 ml of water is heated to 60° C. 178.95 g (1.046 mol) of benzyl bromide is instilled in this mixture within 1 hour and then refluxed for 2 hours. It is concentrated by evaporation in a vacuum, the residue is taken up with 1 l of dichloromethane and filtered off from the salts. The filtrate is concentrated by evaporation in a vacuum and purified by flash chromatography on silica gel. (Mobile solvent: dichloromethane/hexane/acetone: 10/5/1)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccno2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccno2)cc1

Procedure:
To a solution of 5-(4-methylphenyl)-isoxazole (17 g) and N-bromosuccinimide (19 g) in tetrachloromethane (500 ml) under nitrogen, bisbenzoyl peroxide (0.43 g) is added, and the mixture heated on reflux over night. The solvent is evaporated, and the residue purified by flash chromatography (silica gel, hexane/ethyl acetate 4:1) to give pure 5-(4- bromomethylphenyl)-isoxazole.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5]O.[C:20]1(=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[NH:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1.O.C(#N)C>[O:30]=[C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[N:21]1[CH2:5][CH:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:2]([F:19])([F:18])[F:1]
Reactant: O=C(NC(CO)CC(F)(F)F)OCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC(CN1C(=O)c2ccccc2C1=O)CC(F)(F)F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 1.58 g of rac-benzyl (4,4,4-trifluoro-1-hydroxybutan-2-yl)carbamate (Example 43A, 5.70 mmol, 1 equivalent), 0.84 g of 1H-isoindole-1,3(2H)-dione (phthalimide, 5.70 mmol, 1 equivalent) and 2.24 g of triphenylphosphine (8.54 mmol, 1.5 equivalents) were dissolved in 28 ml of THF, and 1.84 g of di-tert-butyl (E)-diazene-1,2-dicarboxylate (DIAD, 8.54 mmol, 1.5 equivalents) were added at RT. The mixture was stirred at RT for 30 min and then a water/acetonitrile mixture was added. Purification by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.1% TFA) gave 1.92 g (79% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([C:37](O)=[O:38])=[CH:31]2.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>CN(C)C=O.O>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:37]([C:32]2[NH:33][C:34]3[C:30]([CH:31]=2)=[CH:29][C:28]([Cl:27])=[CH:36][CH:35]=3)=[O:38])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-({4-[2-(Heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (400 mg) obtained in Example 303-2 and 5-chloro-1H-indole-2-carboxylic acid (196 mg) were dissolved in N,N-dimethylformamide (5 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (211 mg) and hydroxybenzotriazole (HOBT) (168 mg) were successively added thereto, and the mixture was stirred at room temperature for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and ether was added to the residue to give the title compound as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([O:24][CH3:25])[N:9]=1.[CH2:26]([N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][C:30]1=[O:39])[C:27]#[CH:28].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:28]#[C:27][CH2:26][N:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31][C:30]3=[O:39])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([O:24][CH3:25])[N:9]=1
Reactant: COC1N=C(c2ccccc2F)c2cc(I)ccc2-n2c(C)nnc21
Reactant: C#CCN1C(=O)CCc2ccccc21
Solvent: ClCCl
Solvent: CCO
Product: COC1N=C(c2ccccc2F)c2cc(C#CCN3C(=O)CCc4ccccc43)ccc2-n2c(C)nnc21

Procedure:
The title compound was prepared by coupling rac-6-(2-fluorophenyl)-8-iodo-4-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepine with 3,4-dihydro-1-(2-propynyl)-2(1H)-quinolinone under the conditions used in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. The combined clean fractions were evaporated and the residue was crystallized from ethyl acetate/ether to give colorless crystals of rac-1-{3-[6-(2-fluorophenyl)-4-methoxy-1-methyl-4H[1,2,4]triazolo[4,3-a][1,4] benzodiazepin-8-yl]-2-propynyl}-3,4-dihydro-2(1H)-quinolinone with m.p. 155°-160°. These crystals contained 0.33 molar equivalents of water.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:16]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:15]=3[O:14][C:13]=2[CH:30]=1.[CH2:31](Br)[C:32]#[CH:33]>C(O)CCC>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:33][C:32]#[CH:31])[CH2:21][CH2:20]3)[C:16]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:15]=3[O:14][C:13]=2[CH:30]=1
Reactant: COc1ccc2c(c1)Oc1ccc(C)cc1C(N1CCNCC1)C2
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: C#CCN1CCN(C2Cc3ccc(OC)cc3Oc3ccc(C)cc32)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.8 G. of sodium carbonate are added to a solution of 10 g. of 1-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-piperazine in 55 ml. of butanol and then a solution of 2.5 ml. of propargyl bromide in 20 ml. of butanol is added dropwise. Then, the mixture is stirred for 20 hours at room temperature and the solvent is removed by distillation under reduced pressure. After working-up in an analogous manner to that described in Example 13, there is isolated crude 1-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-4-(2-propynyl)-piperazine in the form of an oil. The dihydrochloride, prepared in ethanol and recrystallized from methanol/ether, melts at 210°-212° C. (with decomposition).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[CH:1]1([CH2:7][C:8]([Cl:14])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To cyclohexylacetic acid (23a) (89, 56.25 mmol) in DCM (160 mL) at room temperature was added the oxalyl chloride (6.4 mL, 73.14 mmol) and 2 drops of DMF. The reaction mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure to give cyclohexylacetyl chloride.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([N:11]=[C:12]=[O:13])=[CH:4][C:3]=2[O:2]1.[F:14][C:15]([F:33])([F:32])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][OH:31])[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.[Cl:34]C1C=CC(N2CCN(CCCO)CC2)=CC=1>C1(C)C=CC=CC=1>[ClH:34].[F:33][C:15]([F:14])([F:32])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][CH2:30][O:31][C:12](=[O:13])[NH:11][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:10][CH2:1][O:2][C:3]=4[CH:4]=3)[CH2:26][CH2:27]2)[CH:19]=[CH:20][CH:21]=1
Reactant: OCCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: O=C=Nc1ccc2c(c1)OCCO2
Reactant: OCCCN1CCN(c2ccc(Cl)cc2)CC1
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(Nc1ccc2c(c1)OCCO2)OCCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 68.7 %

Procedure:
A mixture of 3,4-ethylenedioxyphenylisocyanate (2.0 mmol) (produced as in Example 16) and 3-[4-(3-trifluoromethyl-phenyl) -1-piperazinyl]propanol (580 mg; 2.0 mmol) in toluene (30 ml) was refluxed for 16 h. To the crude product was added 3-[4-(4-chlorophenyl)-1-piperazinyl]propanol (510 mg; 2.0 mmol) in toluene (30 ml) and refluxed for 16 h. The solvent was evaporated and the residue resuspended in ethyl acetate, filtered and evaporated to dryness. The residue was submitted to flash chromatography on silica gel 60 eluting with toluene/ethyl acetate (1:1) graduated to toluene/ethyl acetate (1:3). The product was taken up in ethanol, which was treated with hydrogen chloride in ether to give 690 mg of the title compound. M.p. 242°-245° C. MS (70 eV): m/z 465 (34%, M+), 450 (11), 288 (25), 265 (21), 243 (100), 177 (61), 70 (79).
Reaction SMILES: C(C1C=C(NC(=O)C2C=CC(C3CCNCC3)=CC=2)C=CC=1)(C)(C)C.Cl[C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][N:28]=1.[C:36]([C:40]1[CH:41]=[C:42]([NH:46][C:47]([C:49]2[CH:54]=[CH:53][C:52]([N:55]3[CH2:60][CH2:59][N:58](C4C=CC(C(O)=O)=CC=4)[CH2:57][CH2:56]3)=[C:51](F)[CH:50]=2)=[O:48])[CH:43]=[CH:44][CH:45]=1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([C:40]1[CH:41]=[C:42]([NH:46][C:47]([C:49]2[CH:54]=[CH:53][C:52]([N:55]3[CH2:60][CH2:59][N:58]([C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][N:28]=4)[CH2:57][CH2:56]3)=[CH:51][CH:50]=2)=[O:48])[CH:43]=[CH:44][CH:45]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cn4)CC3)cc2)c1

Procedure:
6-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperazin-1-yl}-nicotinic acid was synthesized from N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and 6-chloro-nicotinic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C28H31N3O3 (m/e) 457, obsd 458 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[CH2:8]2)[CH2:4][CH2:3]1.C(O)C.[ClH:28].N>CCOCC.[Zn]>[ClH:28].[ClH:28].[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH2:8]1
Reactant: CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1ccccc12
Agent: Cl
Agent: N
Agent: [Zn]
Solvent: CCO
Solvent: CCOCC
Product: CN1CCC2(CC1)CN(c1ccccc1N)c1ccccc12

Procedure:
A large excess, about 20-25 g, of zinc dust is added portionwise to a vigorously stirring solution, at about 0° C., of 10.7 g of 1'-methyl-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine] (Example 15), in a combined solvent of 75 ml of ethanol and 5 ml of concentrated hydrochloric acid. After total addition, an additional 15 ml of concentrated hydrochloric acid is carefully added to maintain the temperature of the reaction mixture below 70° C. The reaction mixture is basified with concentrated ammonia, and the alkaline mixture is filtered and concentrated to dryness. The residue is partitioned between 400 ml of methylene dichloride and 400 ml of 10% sodium hydroxide. The organic portion is successively washed thrice with 400 ml portions of 10% sodium hydroxide and then once with a 400 ml portion of water, dried and concentrated to dryness, leaving a black glassy product. The product is converted to its hydrochloride in ether which is recrystallized from a methanol-ether mixture to leave the salt, mp 243° C., dec. of 1-(2-aminophenyl)-1'-methylspiro[indoline-3,4'-piperidine]-dihydrochloride.
Reaction SMILES: C=O.[CH2:3]([NH2:9])[CH:4]([OH:8])[C:5]([OH:7])=[O:6].[Cl:10][C:11]1[S:15][C:14]([C:16](Cl)=[O:17])=[CH:13][CH:12]=1.[C:19](=O)([O-])O.[Na+]>[OH-].[Na+].CC(C)=O.O>[Cl:10][C:11]1[S:15][C:14]([C:16]([N:9]2[CH2:3][CH:4]([C:5]([OH:7])=[O:6])[O:8][CH2:19]2)=[O:17])=[CH:13][CH:12]=1
Reactant: O=C([O-])O
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: NCC(O)C(=O)O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C1CN(C(=O)c2ccc(Cl)s2)CO1
Temperature: 25 °C

Procedure:
4.1 1.48 ml (19.9 mmol) of 37% aqueous formaldehyde solution are added to a solution of 2.00 g (19.0 mmol) of DL-isoserine in 10 ml of 1N aqueous sodium hydroxide solution. The resultant solution is left at 5° C. for 18 hours. A solution of 3.46 g (19.1 mmol) of 5-chlorothiophenecarbonyl chloride in 10 ml of acetone is added dropwise to this solution at an internal temperature of 0-5° C. During the dropwise addition, the pH is held at a value above 7 by addition of solid sodium hydrogencarbonate. When the addition is complete, the mixture is allowed to warm to room temperature, water is added, and the mixture is extracted with tert-butyl methyl ether. The aqueous phase is acidified using 1N HCl and extracted with tert-butyl methyl ether. This organic phase is dried over sodium sulfate and evaporated, giving 3-(5-chlorothiophene-2-carbonyl)oxazolidine-5-carboxylic acid as a colourless solid; ESI 262. 4.2 479 mg (2.50 mmol) of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (DAPECI) are added to a solution of 500 mg (1.91 mmol) of 3-(5-chlorothiophene-2-carbonyl)oxazolidine-5-carboxylic acid and 367 mg (1.91 mmol) of 4-(4-aminophenyl)morpholin-3-one in 5 ml of dimethylformamide (DMF), and the mixture is stirred at room temperature for 18 hours. The reaction mixture is added to saturated sodium hydrogencarbonate solution, and the precipitate formed is filtered off, giving N-[4-(3-oxomorpholin-4-yl)phenyl]-3-(5-chlorothiophene-2-carbonyl)oxazolidine-5-carboxamide (“A5”) as a colourless solid; ESI 436.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[C:6]([F:16])[C:5]([F:17])=[C:4]([F:18])[C:3]=1[F:19].[CH:20](OCC)(OCC)OCC.C(OC(=O)C)(=O)C.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[F:1][C:2]1[C:7]([C:8]([C:10](=[CH:20][NH:40][CH:37]2[CH2:39][CH2:38]2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[C:6]([F:16])[C:5]([F:17])=[C:4]([F:18])[C:3]=1[F:19]
Reactant: NC1CC1
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
70.5 g of ethyl pentafluorobenzoylacetate (0.25 mol), 66.6 g of triethyl orthoformate (0.45 mol) and 77.4 g of diacetyl oxide (0.72 mol) were stirred at 150° C. for 2.5 hours. Fractions having a lower boiling point were evaporated under reduced pressure. To the residue was added 250 ml of anhydrous ethanol. 14.5 g of cyclopropylamine (0.25 mol) was added to the solution under cooling of ice water and the reaction was then carried out at room temperature for 2 hours. The resultingt mixture was filtered under suction. The residue was re-crystallized from a mixture of petroleum ether and cyclohexane to yield 62.8 g (0.18 mol) of ethyl 2-(pentafluorobenzoyl)-3-cyclopropylaminoacrylate in 72.0% yield, mp 88-91° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[C:37]([NH:44][NH2:45])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].CN(C=O)C>C(Cl)Cl.CCOC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH:45][NH:44][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:22])=[CH:23][CH:24]=3)=[C:8]([C:12]([F:13])([F:14])[F:15])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)cc1

Procedure:
A mixture of 4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid (synthesis is described in PCT/US2010/024035) (1 equiv.), EDCI (1 equiv.), and BocNHNH2 (1 equiv.), in DCM and DMF (1:1) is stirred at 25° C. overnight, followed by an aqueous/EtOAc workup. Purification if necessary by column chromatography on silica gel to give the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][CH:12]([CH3:16])[CH2:13]2)[C@H:9]1[CH2:17][NH2:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]2[N:26]([C:27]=1[C:28](O)=[O:29])[CH:25]=[CH:24][S:23]2>>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][CH:12]([CH3:16])[CH2:13]2)[C@H:9]1[CH2:17][NH:18][C:28]([C:27]1[N:26]2[C:22]([S:23][CH:24]=[CH:25]2)=[N:21][C:20]=1[CH3:19])=[O:29])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC1C[C@H]2CN(C(=O)OC(C)(C)C)[C@H](CN)[C@H]2C1
Reactant: Cc1nc2sccn2c1C(=O)O
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2CC(C)C[C@H]2CN1C(=O)OC(C)(C)C

Procedure:
prepared by reaction of (1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]-octane-3-carboxylic acid tert.-butyl ester with commercially available 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[NH:12][N:13]=[C:8]3[C:9]2=[C:4]([CH2:5][CH:6]([CH3:23])[N:7]3[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:3]=1.[C:24]1([C@H:30]([NH:32][C:33]([NH2:35])=[O:34])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:7]2[CH:6]([CH3:23])[CH2:5][C:4]3[N:3]=[C:2]([NH:35][C:33]([NH:32][C@@H:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:31])=[O:34])[CH:11]=[C:10]4[NH:12][N:13]=[C:8]2[C:9]=34)=[CH:16][CH:17]=1
Reactant: COc1ccc(CN2c3n[nH]c4cc(Cl)nc(c34)CC2C)cc1
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(CN2c3n[nH]c4cc(NC(=O)N[C@H](C)c5ccccc5)nc(c34)CC2C)cc1
Temperature: 100 °C

Procedure:
7-chloro-3-(4-methoxybenzyl)-4-methyl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine (150 mg, 0.263 mmol), (R)-1-(1-phenylethyl)urea (64.7 mg, 0.394 mmol), cesium carbonate (257 mg, 0.788 mmol) and BrettPhos pre-catalyst (23.8 mg, 0.026 mmol) were charged in a 1 dram vial, evacuated and backfilled with nitrogen and taken in 1,4-dioxane (1.4 mL). The mixture was heated at 100° C. for 1 hour before it was diluted with DCM, washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-80% EtOAc-hexanes) gave 1-(3-(4-methoxybenzyl)-4-methyl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-((R)-1-phenylethyl)urea. MS ESI calc'd. for C26H28N6O2[M+H]+ 699. found 699.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]1[C:18](=[O:19])[CH2:17][CH:16]([C:20]([CH3:22])=[CH2:21])[CH2:15][CH:14]=1>ClC1C=CC=CC=1.O1CCOCC1>[CH:17]1[C:16]([CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=[C:13]([CH3:12])[C:18]=1[OH:19]
Reactant: C=C(C)C1CC=C(C)C(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: Clc1ccccc1
Product: Cc1ccc(C(C)C)cc1O
Temperature: 180 °C
Yield: 85 %

Procedure:
A mixture of p-toluenesulfonic acid (1.4 g) and carvone (11.3 g) in chlorobenzene/1,4-dioxane (4:1 by volume; 75 mL) was heated at 180° C. for 35 min, then rapidly cooled using the cold-finger, and extracted with 10% NaOH solution (3×100 mL). The combined aqueous extract was washed with CH2Cl2 (2×100 mL), neutralized by dropwise addition of conc H2SO4, and extracted with CH2Cl2 (3×100 mL). The organic extract was washed with sat NaHCO3 (100 mL), dried with MgSO4, and concentrated in vacuo to give carvacrol (9.6 g; 85%).