Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1([CH2:32][CH2:33][CH2:34][CH3:35])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([CH:27]=C)=[CH:26][C:20]=3[S:19](=[O:30])(=[O:29])[N:18]=2)[C:6]1=[O:31])[CH2:2][CH2:3][CH3:4].I([O-])(=O)(=O)=[O:37].[Na+]>O1CCOCC1.O.C(O)(C)(C)C.[Cl-].[NH4+].[Os](=O)(=O)(=O)=O>[CH2:32]([C:5]1([CH2:1][CH2:2][CH2:3][CH3:4])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([CH:27]=[O:37])=[CH:26][C:20]=3[S:19](=[O:30])(=[O:29])[N:18]=2)[C:6]1=[O:31])[CH2:33][CH2:34][CH3:35]
Reactant: C=Cc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3cc(F)ccc3C(CCCC)(CCCC)C1=O)N2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(C=O)ccc3N2)=C(O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.3 %

Procedure:
A solution of the compound of Example 21A (52 mg, 0.10 mmol) in dioxane (2 mL) and water (200 μL) was treated with a solution of osmium tetroxide in t-butanol (2.5% (wt/vol), 200 μL) and sodium periodate (45 mg, 0.21 mmol) followed by stirring at ambient temperature for 24 h. The mixture was diluted with water and saturated ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic layer washed with water and saturated NaCl solution. Drying (Na2SO4) and concentration in vacuo afforded the title compound (47 mg, 90%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 0.51 (m, 2H) 0.69 (t, J=7.35 Hz, 6 H) 0.90 (m, 2 H) 1.10 (m, 4 H) 1.92 (m, 2 H) 2.15 (m, 2 H) 7.52 (m, 1 H) 7.73 (m, 3 H) 8.11 (dd, J=8.64, 1.65 Hz, 1 H) 8.40 (d, J=1.47 Hz, 1 H) 10.03 (s, 1 H) 14.38 (s, 1 H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:10]([O:12][C:13](=[O:16])[CH2:14]Br)[CH3:11]>CN(C=O)C>[CH2:10]([O:12][C:13](=[O:16])[CH2:14][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11]
Reactant: CCOC(=O)CBr
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccccc1
Yield: 80.1 %

Procedure:
10.8 g (0.098 mol) of benzenethiol in 70 mL of DMF at 0° C., were treated with 4.31 g (0.108 mol, 1.1 eq) of NaH (55% in oil) over 40 min. 17.19 g (0.103 mol, 1.05 eq) of bromo-acetic acid ethyl ester were added, and stirring was continued over night. The reaction mixture was partitioned between aqueous NH4Cl and EtOAc, dried over Na2SO4, filtered and evaporated, to afford 15.4 g (80%) of phenylsulfanyl-acetic acid ethyl ester as a colorless oil, MS: 197 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([NH:6][C:7]1([C:17]([O:19]CC)=O)[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)=[O:5].[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]2([CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)[C:17]1=[O:19]
Reactant: CCOC(=O)C1(NC(=O)CNC)CCc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CC(=O)NC2(CCc3ccccc3C2)C1=O
Temperature: 80 °C
Yield: 61.4 %

Procedure:
A solution of ethyl 2-(N-methylaminoacetylamino)tetralin-2-carboxylate (290 mg, 1.0 mmol) in a 1 N aqueous sodium hydroxide solution (2 ml)-tetrahydrofuran (10 ml) was stirred for 13 hours while heating at 80° C. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate. This solution was washed by sequential additions of water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 150 mg (61%) of the title compound as a crude crystal, a portion of which was then recrystallized from chloroform-isopropyl ether.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([NH:15][CH3:16])[N:3]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:25])[CH2:19]1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>CC#N.O>[CH3:16][NH:15][C:4]1[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:7]=[C:2]([NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:35])([F:36])[F:37])=[O:25])[CH2:19]2)[N:3]=1
Reactant: CNc1nc(Cl)nc(N2CCN(C)CC2)n1
Reactant: NC1CCCC(C(=O)NCc2ccccc2C(F)(F)F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc(NC2CCCC(C(=O)NCc3ccccc3C(F)(F)F)C2)nc(N2CCN(C)CC2)n1
Temperature: 80 °C
Yield: 1.8 %

Procedure:
The solution of 4-chloro-N-methyl-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (30.0 mg, 0.084 mmol, 1 equivalent) and 3-amino-N-(2-(trifluoromethyl)benzyl) cyclohexanecarboxamide as TFA salt (103 mg, 0.248 mmol, 2.95 equivalents) in CH3CN/H2O (1/1, 2 ml) was adjusted to pH 9-10 with 1N NaOH. The resulting solution was heated at 80° C. for 16 hours. The solvent was removed under vacuo to give the crude product, which was purified with RP-HPLC (Luna 5μ, C8(2), 100×21 mm, 10-50% CH3CN/H2O, 0.1% TFA, 25 min) to give the final compound (0.94 mg, 1.8%). MS (ES+): m/e 507.17 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=O)C.O.[NH2:21][NH2:22]>C(O)C>[CH2:16]([N:15]([CH2:18][CH3:19])[C:13]1[CH:12]=[CH:11][C:9]2[CH:10]=[C:6]([C:4]([NH:21][NH2:22])=[O:3])[O:7][C:8]=2[CH:14]=1)[CH3:17]
Reactant: NN
Reactant: CCOC(=O)c1cc2ccc(N(CC)CC)cc2o1
Solvent: O
Solvent: CCO
Product: CCN(CC)c1ccc2cc(C(=O)NN)oc2c1
Temperature: 25 °C
Yield: 97 %

Procedure:
Equimolar amounts of 6-diethylaminobenzofuran-2-carboxylic acid ethyl ester (Example 3) and hydrazine hydrate are boiled under reflux for three hours in solution in ethanol and after cooling to ambient temperature stirred for another twelve hours. The reaction mixture is poured into ice-water and the precipitate is suction filtered and washed with water. After recrystallization from alcohol the hydrazide is obtained in colorless crystals having a melting point of 127° to 129°C in a yield of 97%. (N: calculated 16.99, found 17.1). It dissolves in alcohol to give a colorless solution with a strong blue fluorescence.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([OH:9])[CH:4]=1)[NH2:2].[CH3:10][CH2:11][CH2:12][C:13](=O)[CH2:14][CH2:15][CH3:16]>>[CH3:10][CH2:11][CH2:12][C:13](=[N:2][NH:1][C:3]1[N:8]=[CH:7][N:6]=[C:5]([OH:9])[CH:4]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(=O)CCC
Reactant: NNc1cc(O)ncn1
Product: CCCC(CCC)=NNc1cc(O)ncn1

Procedure:
10.0 g (79.3 mmol) 6-hydrazinopyrimidin-4-ol (CAS-No: 29939-37-5) were transformed in analogy to intermediate example 1c using heptan-4-one to give after working up and purification 13.5 g (77%) of the title compound.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:28](=[O:30])[CH3:29])[N:23]([CH2:25][CH:26]=[CH2:27])[CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:18][CH2:19][C:20]1[N:21]=[C:22]([C:28](=[O:30])[CH3:29])[N:23]([CH2:25][CH:26]=[CH2:27])[CH:24]=1
Reactant: C=CCn1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1C(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCn1cc(CO)nc1C(C)=O
Reaction time: 1 h

Procedure:
The compound (0.750 g) obtained in (2) was dissolved in THF (50 mL), followed by addition of TBAF (1.0 M THF solution, 1.79 mL) under stirring, and the stirring was continued for 1 hour. The reaction solution was concentrated, and the resulting residue was purified by flash chromatography (ethyl acetate/hexane=5%-÷100%) using amino column (product name: Hi-Flash Column 3 L, manufactured by Yamazen Corporation), washed with ethyl acetate/hexane, and subsequently dried to afford the title compound (0.280 g).
Reaction SMILES: Br[C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:23]([CH3:25])[CH3:24])[NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:37][C:38]([F:50])([F:49])[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O>COCCOC>[F:30][C:28]1[CH:27]=[CH:26][C:3]([O:4][CH2:5][C:6]([N:8]([CH:23]([CH3:25])[CH3:24])[NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[O:39][C:38]([F:37])([F:50])[F:49])[CH:29]=1
Reactant: COCCOc1ccc(C(=O)NN(C(=O)COc2ccc(F)cc2Br)C(C)C)cc1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCCOc1ccc(C(=O)NN(C(=O)COc2ccc(F)cc2-c2ccccc2OC(F)(F)F)C(C)C)cc1
Yield: 54.4 %

Procedure:
A solution of 4-(2-methoxy-ethoxy)-benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (202 mg, 0.42 mmol) in DME (5 ml)/2M Na2CO3 (0.731 ml, 1.46 mmol) was with 2-trifluoromethoxyphenylboronic acid (129 mg, 0.63 mmol) and Pd[PPh3]4 (96.5 mg, 0.084 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 45-60% ethyl acetate/hexane gradient to afford the product as a solid (129 mg, 55%). MS m/e 565.55 (M+H+)
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[C:15]2[CH:16]=[C:17]([CH3:21])[CH2:18][CH2:19][CH2:20][C:14]=2[CH:13]=[CH:12][CH:11]=1)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:21][C:17]1[CH2:18][CH2:19][CH2:20][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:9][OH:8])[C:15]=2[CH:16]=1
Reactant: CC1=Cc2c(cccc2CO[Si](C)(C)C(C)(C)C)CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1=Cc2c(CO)cccc2CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl(8-methyl-6,7-dihydro-5H-benzo[a]cyclohepten-1-ylmethoxy)dimethylsilane (5.594 g, 18.49 mmol) in tetrahydrofuran (50 ml) was added a solution (22.2 ml, 22.2 mmol) of 1.0 M tetrabutylammonium fluoride in tetrahydrofuran at room temperature and the mixture was stirred at room temperature for 15 min. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to give the objective substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][C:20]([CH2:25][CH3:26])([CH2:23][OH:24])[CH2:21][OH:22]>>[OH:22][CH2:21][C:20]([NH:19][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])([CH2:23][OH:24])[CH2:25][CH3:26]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: CCC(N)(CO)CO
Product: CCC(CO)(CO)NC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(1,1-Bis-hydroxymethyl-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.33 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.47 mmol of 2-amino-2-ethyl-propane-1,3-diol. LC/MS [5.93 min; 460 (M+1)]
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[SH:26][C:27]1[S:28][CH:29]=[N:30][N:31]=1.[H-].[Na+].C(O)(=O)C>CN(C)C=O.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([S:26][C:27]4[S:28][CH:29]=[N:30][N:31]=4)[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Reactant: Sc1nncs1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Sc4nncs4)nc32)c(=O)[nH]c1=O
Temperature: 55 °C
Reaction time: 16 h

Procedure:
To a mixture of the product from example 44 step (viii) (0.20 g) and 2-mercapto-1,3,4-thiadiazole (0.120 g) in dry dimethylformamide (2 ml) was added 60% sodium hydride (0.041 g). The mixture was stirred for 16 h then heated at 55° C. for 24 h. The reaction mixture was diluted with water and neutralised by the addition of acetic acid. The aqueous was extracted with dichloromethane and the combined organic extracts were dried (MgSO4). The solvent was removed under reduced pressure and the residue purified by flash chromatography eluting with dichloromethane/5% ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12](=[O:20])[N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:21]([O:23]CCCC)=[CH2:22].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:21]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12](=[O:20])[N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:23])[CH3:22]
Reactant: C=COCCCC
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C(C)=O)cc(C(=O)OC)c1
Temperature: 122 °C

Procedure:
A mixture of methyl 3-bromo-5-(dipropylcarbamoyl)benzoate (342 mg, 1.0 mmol), 1-(vinyloxy)butane (200.4 mg, 0.26 mL, 2.0 mmol), palladium acetate (6.68 mg, 0.030 mmol), DPPP (27.2 mg, 0.066 mmol) and potassium carbonate (166 mg, 1.2 mmol) in DMF (2.5 mL) and H2O (0.3 mL) in a Smith process vial was heated at 122° C. in microwave for 3 h. The reaction mixture was cooled down to RT and hydrolyzed by addition of 5% HCl slowly. The reaction mixture was worked up by extraction with ethyl acetate and concentration under vacuum. The crude mixture was purified by reverse phase prep HPLC to give the title compound: HPLC retention time: 1.805 min (method A). MS (ESI) (M+H)+ 306.26.
Reaction SMILES: Br[C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:31])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1.[CH:38]1(B(O)O)[CH2:40][CH2:39]1>>[CH:38]1([C:2]2[CH:33]=[CH:32][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][C:12]([CH:16]=[C:17]5[S:21][C:20]([N:22]6[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][OH:30])[CH2:26][CH2:27]6)=[N:19][C:18]5=[O:31])=[CH:13][CH:14]=4)[CH:9]=[N:8]3)=[C:4]([C:34]([F:35])([F:37])[F:36])[CH:3]=2)[CH2:40][CH2:39]1
Reactant: OB(O)C1CC1
Reactant: O=C1N=C(N2CCN(CCO)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Br)cc2C(F)(F)F)c1
Product: O=C1N=C(N2CCN(CCO)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C3CC3)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Cyclopropyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-one and cyclopropyl boronic acid following General Procedure F.
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+:8].[C:9](=[O:11])=[O:10]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[K+:8]
Reactant: O=C=O
Reactant: [O-]c1ccccc1
Agent: [K+]
Product: O=C([O-])c1ccc(O)cc1

Procedure:
Parahydroxybenzoic acid has been used for manufacturing a wide variety of products including liquid crystalline polymers and preservatives for cosmetics and medicines. Generally, parahydroxybenzoic acid is prepared by a method in which phenol is reacted with potassium hydroxide to give potassium phenoxide, and the obtained potassium phenoxide is reacted with carbon dioxide under pressure to give potassium parahydroxybenzoate and then, parahydroxybenzoic acid is isolated by means of aciding out procedure, i.e. by adding a mineral acid to the salt.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[N:1]1([CH2:7][CH2:8][C:9]([Cl:15])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCN1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-piperidin-1-yl-propionic acid (472 mg, 3 mmol) in DCM (15 mL) at 0° C. was added oxalyl chloride (4.5 mmol) followed by one drop of DMF. After stirring for 2 hours at rt, the solvent was removed to give 3-piperidin-1-yl-propionyl chloride as a white solid. To a solution of 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine (347 mg, 2.55 mmol) in DCM (10 mL) was added TEA (1 eq.) and 1-piperidinepropionic acid chloride. The mixture was stirred at rt for overnight. The reaction was diluted with DCM, washed with NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 230 mg of 3-piperidin-1-yl-1-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepin-4-yl)-propan-1-one as a light brown gel.
Reaction SMILES: [CH2:1]([NH:4][C@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].C([Li])CCC.[NH2-].[Li+].[C:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[CH:21]=[CH:22][CH:23]=[CH2:24]>O1CCCC1>[CH2:1]([N:4]([C@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@H:22]([CH:23]=[CH2:24])[CH2:21][C:20]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:2]=[CH2:3]
Reactant: C=CCN[C@H](C)c1ccccc1
Reactant: C=CC=CC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [Li]CCCC
Agent: [NH2-]
Solvent: C1CCOC1
Product: C=CCN([C@H](C=C)CC(=O)OC(C)(C)C)[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A solution of (R)-N-allyl-α-methylbenzylamine (24) (1.78 g, 11.1 mmol) in anhydrous tetrahydrofuran (20 ml) was cooled to -78° C. and 1.6M butyllithium (6.00 ml, 9.5 mmol) was added dropwise via a syringe. The resulting orange lithium amide solution was stirred at -78° C. for 1 hour. A solution of t-butyl pentadienoate (25) (1.137 g, 7.4 mmol) in anhydrous tetrahydrofuran (15 ml) was then added via a cannula and the solution was stirred for a further 1 hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and the solution was allowed to warm to room temperature. Ethyl acetate (50 ml) was added, followed by brine (10 ml). The organic layer was separated, dried (magnesium sulphate) and filtered and the solvent evaporated under reduced pressure to afford a pale yellow oil. This was purified by flash chromatography on silica gel [ethyl acetate/petroleum ether (1:49)] to afford the title compound (Rf 0.25) as a colourless oil (1.97 g, 85%). δH (300 MHz; CDCl3) 7.40-7.19 (5H, m, Ph), 5.94-5.74 (2H, m, CH2 =CHCH and NCH2CH=CH2), 5.16-5.00 (4H, m, CH2 =CHCH and NCH2CH=CH2), 4.02 (1H, q, J=6.8, PhCHCH3), 3.90 (1H, app. q, J=7.1, NCHCH2), 3.15 (2H, d, J=6.1, NCH2CH=CH2), 2.41 (1H, dd, J=6.4 and 14.5, CH2CO2), 2.31 (1H, dd, J=14.5 and 8.3, CH2CO2), 1.42 (9H, s, (CH3)3C), 1.39 (3H, d, J=6.8, PhCHCH3).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][C:25]([F:28])([F:27])[F:26])[CH:15]=[CH:16][CH:17]=2)[N:7]=1)=[O:5])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.[OH-].[Na+].O>[CH3:11][C:9]1[N:8]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][C:25]([F:28])([F:26])[F:27])[CH:15]=[CH:16][CH:17]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(C)n(-c2cccc(-c3ccccc3OC(F)(F)F)c2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)O)nn1-c1cccc(-c2ccccc2OC(F)(F)F)c1

Procedure:
A solution of ethyl-5-methyl-1-[2′-(trifluoromethoxy)-1,1′-biphenyl-3-yl]-1H-pyrazole-3-carboxylate (0.39 g, 1 mmol) (from EXAMPLE 3) in a mixture of MeOH (5 ml) and 2N NaOH (2 ml) was refluxed for 16 hours. The reaction was then cooled, diluted with water, acidified with 10% citric acid and extracted with ethylacetate. The organic phase was washed with water, dried (sodium sulfate) and concentrated in vacuo to give the titled product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=3)[S:10][C:3]=12.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([O-:19])=[O:18].C([O-])([O-])=O.[K+].[K+].O(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[CH3:16][N:14]1[CH:15]=[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:26][C:23]3[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=3)[CH:8]=2)[N:12]=[CH:13]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: Cn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4)c3s2)c1
Temperature: 190 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A mixture of 224 (950 mg, 3.81 mmol), 4-nitrophenol (795 mg, 5.72 mmol), K2CO3 (1.05 g, 7.62 mmol) and Ph2O (5 mL) was stirred at 190° C. for 2 h in a sealed tube, cooled and treated with additional amount of 4-nitrophenol (795 mg, 5.72 mmol). The mixture was stirred for another hour at the same conditions, cooled to room temperature and diluted with DCM. The DCM solution was extracted with 2N HCl; the aqueous phase was collected, basified with concentrated ammonium hydroxide solution (pH˜11) and extracted with EtOAc. The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 225 (860 mg, 64% yield) as an orange solid. MS (m/z): 353.1(M+1).
Reaction SMILES: [C:1]([C:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:10](O)(=O)[CH3:11]>CC(C)=O>[C:1]([C:5]1[CH:9]=[C:8]2[C:7](=[C:10]([CH3:11])[CH2:2][C:1]2([CH3:4])[CH3:3])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC=CC1
Reactant: CC(=O)O
Solvent: CC(C)=O
Product: CC1=C2C=C(C(C)(C)C)C=C2C(C)(C)C1
Reaction time: 18 h

Procedure:
In a 1000 ml five neck flask, 24.97 g (204 mmol) of tert-butylcyclopentadiene and 399.04 g of acetone were placed. In an ice water bath, 82.1 g (1.15 mol) of pyrolydine was dropwise added, followed by stirring for 18 hours under reflux. In an ice water bath, 70.91 g (1.18 mol) of acetic acid was dropwise added. From the resulting crude product, the solvent was distilled off under reduced pressure (150 torr, 40° C.), and the resulting product was washed with water, a 5% acetic acid solution, a saturated sodium hydrogen carbonate aqueous solution and a saturated saline solution, followed by drying over magnesium sulfate. After the solvent was distilled off, the remainder was purified by vacuum distillation, whereby 23.4 g of 5-tert-butyl-1,1,3-trimethyl-1,2-dihydropentalene represented by the following formula [1] was obtained. Identification was carried out by a 1H-NMR spectrum and a GC-mass spectrometry spectrum (GC-MS). The results of the measurement are given below.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.[CH3:39][NH:40][CH2:41][CH2:42][CH2:43][CH3:44]>C1(C)C=CC=CC=1>[CH2:41]([N:40]([CH3:39])[CH2:11][CH2:10][N:9]([CH3:8])[C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCCNC
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)c2ccc([N+](=O)[O-])cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCN(C)CCN(C)c1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-[methyl-(4-nitro-phenyl)-amino]-ethyl ester TFA salt (74 mg, 0.21 mmol) in toluene (1 mL) is added triethylamine (50 μL) and N-methylbutylamine (75 μL, 0.63 mmol). The mixture is shaken in 70° C. block shaker overnight. The reaction mixture is concentrated and purified by reverse phase high performance liquid chromatography to give N-butyl-N,N′-dimethyl-N′-(4-nitro-phenyl)-ethane-1,2-diamine as a di-TFA salt (71 mg, 68%).