Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH:19]1[CH2:29][CH2:28][CH2:27][CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20]1>CC#N>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:19]2[CH2:29][CH2:28][CH2:27][CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20]2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
4-Chlorobenzyl chloride (6.42 g, 39.9 mmol) and iPr2NEt (7.74 g, 40.0 mmol) were added to a solution of ethyl nipecotate (6.29 g, 40.0 mmol) in CH3CN (15 mL). The reaction mixture was stirred at 70° C. for 1.5 h. The solvent was removed under reduced pressure. Saturated aqueous NaHCO3 (50 mL) was added to the residue and the mixture was extracted with EtOAc (100 mL). The organic phase was washed with saturated aqueous NaHCO3 and brine, and dried over Na2SO4. The solvent was removed under reduced pressure to afford ethyl 1-(4-chlorobenzyl)nipecotate as a red yellow oil (11.025 g, 97.8%) used without further purification. The purity was determined by RPLC/MS (97%); ESI/MS m/e 382.2 (M++H, C15H21ClNO2).
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5](N(C(OC(C)(C)C)=O)NC(OC(C)(C)C)=O)[CH:4]=1)#[N:2].C(C1SC([N:31]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=CC=1)=O>>[C:1]([C:3]1[S:7][C:6]([N:31]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc(C=O)s1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1csc(C#N)c1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc(C#N)s1
Yield: 75 %

Procedure:
Following the same procedure as described for compound 12 (step 2, scheme 2, example 1c) except using 19 (935 mg, 2.73 mmol) instead of 11 to provide compound 20 (692 mg, 75%) as a yellow solid. LRMS (ESI): calc. 339.1; found 340.2 (MH)+.
Reaction SMILES: O1C2(CCCCC2)[NH:2]1.[CH3:9][NH:10][C@@H:11]([CH3:20])[C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13].[ClH:21]>CCOCC.CO>[ClH:21].[CH3:9][N:10]([C@@H:11]([CH3:20])[C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:13])[NH2:2]
Reactant: C1CCC2(CC1)NO2
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C[C@@H]([C@H](O)c1ccccc1)N(C)N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-oxa-2-azaspiro[2.5]octane (0.60 g, 5.3 mmol) in ether (20 ml) a solution of (1R*,2S*)-2-methylamino-1-phenyl-1-propanol (0.86 g, 5.3 mmol) in ether (5 ml) was added. The reaction mixture was stirred at room temperature for 30 minutes then evaporated to dryness. 5% Hydrochloric acid (30 ml) was added to the residue and the mixture was stirred at ambient temperature for 1 h. The mixture was washed with Et2O (2×30 ml), made alkaline with Na2CO3 under ice-cooling and extracted with EtOAc (3×50 ml). The combined EtOAc extracts were dried and evaporated to give a solide residue which was dissolved in methanol (5 ml) and converted to the crystalline hydrochloride salt by using 22% ethanolic hydrogen chloride (2 ml) and diethyl ether. Crystals were filtered off and recrystallized from methanol/diethyl ether.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.O[CH2:21][C@H:22]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N+:42]([O-:44])=[O:43])(=[O:35])=[O:34])[C@@H:23]1[CH2:27][C@@H:26]([CH2:28][CH2:29][CH3:30])[C:25](=[O:31])[O:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N+:42]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[S:33]([N@:32]1[CH2:21][CH:22]1[C@H:23]1[O:24][C:25](=[O:31])[C@H:26]([CH2:28][CH2:29][CH3:30])[CH2:27]1)(=[O:35])=[O:34])([O-:44])=[O:43]
Reactant: CCC[C@@H]1C[C@@H]([C@H](CO)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reaction time: 0.17 h
Yield: 73.2 %

Procedure:
2.95 ml of a solution of diethyl azodicarboxylate in toluene (40%) (6.48 mmol) was added to a solution of 2.01 g of N-{(S)-2-hydroxy-1-[(2S,4R)-5-oxo-4-propyltetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in Example (116f) (5.4 mmol) and 1.7 g of triphenylphosphine (6.48 mmol) in tetrahydrofuran (54 ml) under ice-cooling over five minutes, and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/acetone=5/1) to obtain 1.4 g of the title compound (yield: 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[C:3]=1[N+:12]([O-:14])=[O:13].O1CCC[CH2:16]1.C[Si](C=[N+]=[N-])(C)C>CO>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[C:4]([CH3:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: C1CCOC1
Reactant: Cc1c(C(=O)O)ccc(N)c1[N+](=O)[O-]
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccc(N)c([N+](=O)[O-])c1C
Yield: 55 %

Procedure:
4-Amino-2-methyl-3-nitrobenzoic acid (1.87 g, 9.54 mmol) was solubilized in methanol (100 mL) and tetrahydrofuran (100 mL) and was treated with (trimethylsilyl)diazomethane solution (5.3 mL, 10.5 mmol, 2.0M in diethyl ether). After the reaction was shown to be complete, the mixture was concentrated and the residue was purified via column chromatography (silica gel, 5:1 hexanes/ethyl acetate) to give 1.10 g (55% yield) of methyl 4-amino-2-methyl-3-nitrobenzoate. 1H NMR (400 MHz, d6-DMSO): 7.73 (d, 1H), 6.75 (d, 1H), 6.51 (broad s, 2H), 3.75 (s, 3H), 2.37 (s, 3H). MS (EI) for C9H10N2O4: 210 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[C:13]1[NH:14][C:15](=[O:26])[C:16]2[N:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:17]=2[N:18]=1)[CH3:2].[OH-].[Na+]>C(O)C>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:13]2[NH:14][C:15](=[O:26])[C:16]3[N:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:17]=3[N:18]=2)[CH:6]=1
Reactant: CCCc1ccnc2c(=O)[nH]c(-c3cc([N+](=O)[O-])ccc3OCC)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1ccnc2c(=O)[nH]c(-c3cc(N)ccc3OCC)nc12
Yield: 71.5 %

Procedure:
Stannous chloride dihydrate (2.48 g, 0.011 mol) was added to a stirred solution of 2-(2-ethoxy-5-nitrophenyl)-8-n-propylpyrido[3,2-d)pyrimidin-4(3H)-one (Example 10; 0.78 g, 0.0022 mol) in ethanol (10 ml) and the mixture was heated under reflux for 2 hours, allowed to cool, basified to pH 11 by the addition of 10% aqueous sodium hydroxide solution, and then extracted with methanol:dichloromethane (1:9, 3×50 ml). The organic extracts were combined, dried (MgSO4) and evaporated under vacuum, then the residue was chromatographed on silica gel (12 g) using a methanol in dichloromethane elution gradient (0-2% methanol). Trituration of the product with hexane:ethyl acetate gave the title compound as a colourless solid (0.51 g, 71%), m.p. 156-158° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[C:31]([C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1)([CH3:34])([CH3:33])[CH3:32].CN(C=O)C>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:41][C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:36]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(NC(=O)c1coc(Oc2cccc(C(C)(C)C)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 182.4 %

Procedure:
In a 5 ml glass tube were placed 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (40 mg, 0.10 mmol), K2CO3(17 mg, 0.12 mmol), 3-tert-butyl phenol (18 mg, 0.12 mmol), DMF (1 mL), and a magnetic stir bar. The vial was sealed with septum and placed into the Microwave cavity. The vial was irradiated in a Microwave synthesizer at 130° C. for 10 min. The reaction mixture was diluted with EtOAc, and washed with saturated ammonium chloride and water. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (gradient 12% to 100% EtOAc in n-hexane) to give title compound (90 mg, 80%).
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1)(=O)=O)([O-])=O.CN1CCOCC1.[N:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[C:53]([OH:55])=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C=O)C>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)[C:53](=[O:55])[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][N:47]=2)=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccccn1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(c1ccccn1)N(Cc1ccc(CNCc2ccccn2)cc1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 131.1 %

Procedure:
To a stirred solution of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (209 mg, 0.39 mmol) in dry DMF (1 mL) was added N-methylmorpholine (0.5 mL, 4.45 mmol), picolinic acid (64 mg, 0.52 mmol), 1-hydroxybenzotriazole (57 mg, 0.42 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (85 mg, 0.44 mmol). The reaction mixture was allowed to stir at room temperature for further 18 hours and then concentrated. The residue was diluted with ethylacetate (300 mL) and washed with saturated aqueous NaHCO3, then brine, dried (Na2SO4) and evaporated. Purification of the crude material by column chromatography on silica gel (1.5×20 cm, 50:50 EtOAc/CH2Cl2) gave the desired amide (237 mg, 94%) as a yellow oil.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:28][CH3:29])=[N:19][N:20]3[CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[C:33]([CH2:35][C:36](O)=[O:37])[N:32]=[CH:31]1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:28][CH3:29])=[N:19][N:20]3[CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:16][CH:15]=2)[CH2:11][CH2:12][N:13]1[C:36](=[O:37])[CH2:35][C:33]1[N:32]=[CH:31][NH:30][CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1nn(C2CCCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Reactant: O=C(O)Cc1c[nH]cn1
Product: CCc1nn(C2CCCC2)c2cc(N3CCN(C(=O)Cc4c[nH]cn4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 50 %

Procedure:
Prepared using the same procedure described in Example 189 from (S)-6-(3-Benzyl-piperazin-1-yl)-1-cyclopentyl-3-ethyl-1H-indazole and (1H-imidazol-4-yl)-acetic acid to afford the title compound as colorless solid (66 mg, 50%). LC/MS (Method B) 2.68 min, [M+1]+ 497.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]=[C:9]([CH2:11][O:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:10][C:6]=2[CH:5]=1)([O-])=O.C(OCC)(=O)C>[Pd].C(O)C>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[N:8]=[C:9]([CH2:11][O:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:10][C:6]=2[CH:5]=1
Reactant: O=C(OCc1nc2ccc([N+](=O)[O-])cc2s1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc2nc(COC(=O)c3ccccc3)sc2c1
Yield: 96.2 %

Procedure:
10 g of the 6-nitro-2-benzoyloxymethylbenzothiazole obtained in the Preparation Example 3 was dissolved in a solution comprising a mixture of ethyl acetate and ethanol (1:1) and hydrogenated in the presence of 1 g of a palladium/carbon catalyst for 10 h. After the completion of the reaction, the catalyst was removed by filtration through Celite and the filtrate was concentrated under reduced pressure to give 8.7 g of the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.C1C(=O)N([Br:30])C(=O)C1.O>C(#N)C>[Br:30][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]=[C:10]3[C:2]([CH3:22])([CH3:1])[C:3]4[C:8]([C:9]3=[CH:21][C:20]2=1)=[CH:7][CH:6]=[CH:5][CH:4]=4
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccccc13
Solvent: O
Solvent: CC#N
Product: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(Br)cc13
Reaction time: 4 h

Procedure:
66.5 g (234.6 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]-fluorene are initially introduced in 1000 ml of acetonitrile. A solution of 41.7 g (234.6 mmol) of NBS in 500 ml of CH3CN is subsequently added dropwise at −15° C. with exclusion of light, allowed to come to RT and stirred at this temperature for a further 4 h. 150 ml of water are subsequently added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot hexane and filtered off with suction. Yield: 47.5 g (131 mmol), 55.9% of theory, purity according to 1H-NMR approx. 97%.
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[N:7]=1)=[O:5])C.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>>[CH2:21]([N:23]([CH2:24][CH3:25])[C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[N:7]=1)=[O:5])[CH3:22]
Reactant: CCNCC
Reactant: CCOC(=O)c1nc(-c2cccc3ccccc23)no1
Product: CCN(CC)C(=O)c1nc(-c2cccc3ccccc23)no1

Procedure:
5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole (30.9 g.) was heated under reflux in an excess of diethylamine (35.6g.) for 1.5 hr. The mixture was cooled and evaporated under reduced pressure to give a solid which was recrystallised from methanol yielding title compound (29.3 g.), m.p. 101.5°-102.5°, λmax. (EtOH) 302 nm. (ε 9,700), νmax. (CHBr3) 1662 cm.-1 (CONEt2).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccccc2)C1=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 898 %

Procedure:
To a solution of 40 mg (0.098 mmol) of 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 1, Step F) in 0.5 mL of dry dimethylformamide at room temperature under nitrogen was added 5 mg of 60% sodium hydride oil dispersion (3 mg NaH, 0.13 mmol, 1.3 eq). After 5 minutes, 0.013 mL of benzyl bromide (19 mg, 0.11 mmol, 1.1 eq) was added and the mixture stirred for 1 hour at room temperature, then added to 20 mL of ethyl acetate and washed with water (2×) and brine. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (1:1) to afford 44 mg (0.88 mmol, 90%) of product. 1H NMR (200 MHz, CDCl3): 1.37 (s,3H), 1.38 (s,3H), 1.73 (m,1H), 2.3-2.6 (m,5H), 4.48 (m,1H), 4.80 (d,15 Hz,1H), 5.07 (br s,2H), 5.23 (d,15 Hz,1H), 5.62 (br s,1H), 6.67 (br d,7 Hz,1H), 7.1-7.4 (m,14H). FAB-MS: calculated for C30H33N3O4 499; found 500 (M+H,100%).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([NH:20][NH:21]C(OC(C)(C)C)=O)=[O:19])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1>C(OCC)(=O)C.CO>[ClH:1].[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([NH:20][NH2:21])=[O:19])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1
Reactant: COc1cc(/C=C/C(=O)NNC(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(/C=C/C(=O)NN)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (3 mL) was added to a solution of tert-butyl N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazinecarboxylate (668 mg) in ethyl acetate (5 mL) and methanol (1 mL), and the reaction solution was stirred at room temperature for two hours. The solid precipitated in the reaction solution was collected by filtration and washed with diethyl ether to obtain 658 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][C@@H:9]([CH3:11])[C@:8]([C:13]#[CH:14])(O)[C:7]([CH3:16])([CH3:15])[CH2:6]1)(=[O:3])[CH3:2].O>CC1C=CC=CC=1C.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([O:4][C@H:5]1[CH2:6][C:7]([CH3:15])([CH3:16])[C:8]([C:13]#[CH:14])=[C:9]([CH3:11])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: C#C[C@]1(O)[C@H](C)C[C@@H](OC(C)=O)CC1(C)C
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1C
Product: C#CC1=C(C)C[C@@H](OC(C)=O)CC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
121.6 g of crude (1R,4S,5R)-4-ethynyl-4-hydroxy-3,3,5-trimethylcyclohexyl acetate (prepared according to Example 9) were dissolved in 1 l of o-xylene under argon in a sulphonation flask having a water separator. The mixture was treated with 7.9 g of copper(II)sulphate and boiled and stirred intensively for 2 hours under reflux and with the separation of water. The reaction mixture was subsequently cooled to room temperature and the insoluble copper sulphate was filtered off (rinsing with 400 ml of hexane). The filtrate was washed with 400 ml of water and with 400 ml of semi-saturated sodium bicarbonate solution The wash solutions were back-extracted twice with 300 ml of hexane each time. The organic phases were dried over sodium sulphate and filtered. The filtrate was concentrated to a volume of about 200-300 ml in a rotary evaporator at 80 Torr and 40°-60° C. bath temperature. Distillation of the residual xylene solution in a high vacuum gave at about 83° C./0.19- 0.09 Torr 96.5 g of (R)-4-ethynyl-3,5,5-trimethyl-3-cyclohexen-1-yl acetate (purity 98.1%) as a colourless oil; boiling point 78-82° C./0.14 Torr. The chemical yield amounted to 93% based on (4R,6R)-4-hydroxy-2,2,6-trimethylcyclohexanone.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:37])=O>CN(C)C=O>[Cl:37][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C(c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2)(C(F)(F)F)C(F)(F)F)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C(c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2)(C(F)(F)F)C(F)(F)F)cc1

Procedure:
9.7 g (0.02 mol) of 2-(4-carboxyphenyl)-2-[4-(4-nitrophenoxy)phenyl]hexafluoropropane were suspended in 47 cm3 of thionyl chloride, a few drops of dimethylformamide were added, and the mixture was refluxed until evolution of gas was no longer observed. The thionyl chloride was removed by distillation, and the residue was recrystallized from acetonitrile.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=[O:2].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O:3][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:2]
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A mixture of 2-carboxybenzaldehyde (15.00 g, 0.100 moles), benzyl bromide (20.52 g, 0.120 moles) and potassium carbonate (41.46 g, 0.300 moles) in 250 ml of acetone under nitrogen in a 500 ml round-bottom flask equipped with a magnetic stirrer was refluxed for 6 hours and then stirred at room temperature overnight. The mixture was then filtered through Celite and the filtrate concentrated in vacuo to remove the acetone. The remaining yellow oil was dissolved in ether (200 ml) and this solution washed with saturated sodium bicarbonate solution (1×50 ml), saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 20.4 g of the product as a yellow oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)(=[O:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1.CO>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)(=[O:3])[CH3:2]
Reactant: COc1cccc(C2=C(OC(C)=O)c3ccc(OC)cc3CC2)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: C1COCCO1
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2OC(C)=O)c1

Procedure:
A solution was prepared of 52.7 g (162 mmol) of 1-acetyloxy-2-(3-methoxyphenyl)-6-methoxy-3,4-dihydronaphthalene and 36.9 g (162 mmol) of DDQ in 500 mL of p-dioxane. The solution was heated to reflux for two hours under a nitrogen atmosphere. The reaction was allowed to cool and the solvent removed by evaporation. The residue was extracted by stirring in CHCl3 for sixteen hours, then filtering to remove the insoluble material. The CHCl3 extract was further purified by chromatography on a silica gel column eluted with CHCl3. This resulted in a red oil, which was suspended in MeOH and crystallized at −70° C. This yielded 46.5 g of the title compound as a low melting solid.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:23][N:24]1[C:28]2=[N:29][CH:30]=[C:31]([C:33]([OH:35])=O)[CH:32]=[C:27]2[C:26]([CH3:36])=[N:25]1.[NH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44]>CN(C)C=O>[CH3:23][N:24]1[C:28]2=[N:29][CH:30]=[C:31]([C:33]([NH:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:35])[CH:32]=[C:27]2[C:26]([CH3:36])=[N:25]1
Reactant: Cc1nn(C)c2ncc(C(=O)O)cc12
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: Cc1nn(C)c2ncc(C(=O)NCCNC(=O)OC(C)(C)C)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Hydroxybenzotriazole (3.55 g) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (4.45 g) were added to a solution of 1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (4.00 g) in N,N-dimethylformamide (40 ml) with ice cooling. The mixture was stirred for 30 minutes at room temperature, and then t-butyl (2-aminoethyl)carbamate (3.65 ml) was added thereto and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The organic phase was washed with 10% citric acid solution, 4% sodium bicarbonate solution and a saturated saline solution. The product was dried under sodium sulfate anhydrous and concentrated under reduced pressure to give t-butyl {2-[(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbonyl)amino]ethyl}carbamate (4.02 g, Y.:57%) as colorless crystals.