Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:20]=1.Br[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[O:29][CH3:30].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CC(O)(C)C>[N+:17]([C:15]1[CH:14]=[CH:13][C:10]2[C:11](=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=4[O:29][CH3:30])=[CH:20][C:6]=3[O:7][CH2:8][C:9]=2[CH:16]=1)([O-:19])=[O:18]
Reactant: COc1cc(F)ccc1Br
Reactant: Nc1ccc2c(c1)OCc1cc([N+](=O)[O-])ccc1C2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COc1cc(F)ccc1Nc1ccc2c(c1)OCc1cc([N+](=O)[O-])ccc1C2=O
Temperature: 100 °C

Procedure:
In accordance with general method Z, 0.70 g (2.60 mmol) of (6), 0.55 g (2.68 mmol) of 2-bromo-5-fluoroanisole, 2 spatula tips of Pd(OAc)2, 0.10 g of 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (phosphine ligand), 0.50 g of KOt-Bu, 2.0 ml of t-BuOH are weighed out and dissolved in 10 ml of toluene (anhydrous). The mixture is refluxed at 100° C. under an argon atmosphere for 4 h. The crude product is purified by chromatography over silica gel with MC/EtOH (98/2). Yield: 0.07 g (0.01%); melting point: 222.3° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:37]1[CH:41]=[C:40]([CH2:42]O)[CH:39]=[N:38]1)=O)(C)(C)C>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[CH2:42][C:40]1[CH:41]=[N:37][NH:38][CH:39]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Reactant: CC(C)(C)OC(=O)n1cc(CO)cn1
Product: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 48.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 82 using 5-benzyloxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (2.98 g) and 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)pyrazole (1.83 g) as starting materials, 5-benzyloxy-N-(4-methoxyphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.74 g) was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])=[N:5][N:4]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=2)C=CC=CC=1.N12CCCCC1C=NCCC2.Cl>O1CCOCC1.O>[CH3:35][O:34][C:32]1[CH:31]=[C:30]([O:36][CH3:37])[N:29]=[C:28]([NH:27][C:26]([NH:18][S:15]([CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:6]2[O:7][C:3]([S:2][CH3:1])=[N:4][N:5]=2)(=[O:17])=[O:16])=[O:25])[N:33]=1
Reactant: CSc1nnc(-c2ccccc2CS(N)(=O)=O)o1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Cc2ccccc2-c2nnc(SC)o2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
To a solution containing 0.62 g of the sulfonamide prepared in Example 3 contained in 10 ml of p-dioxane was added 0.6 g of phenyl(4,6-dimethoxy pyrimidin-2-yl)carbamate followed by dropwise addition of 0.33 g of 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU). The solution was stirred at room temperature for two hours then diluted with about 100 ml of water. The clear solution was acidified with concentrated hydrochloric acid (red to litmus paper), to give a viscous oil. The oil was triturated by decanting off the aqueous solvent and stirring the oil residue in about 5 ml of acetonitrile. After filtering the suspension, the solid residue was washed with 1×5 ml of warm ethyl acetate to give 0.26 g of the subject compound; m.p. 174°-177° C.
Reaction SMILES: ClCCl.Cl[C:5]1[S:6][CH:7]=[C:8]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[CH2:25][O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:11])[N:9]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.O>[C:33]1([C:5]2[S:6][CH:7]=[C:8]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]3[CH2:25][O:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:11])[N:9]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2csc(Cl)n2)C(COc2cccnc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2csc(-c3ccccc3)n2)C(COc2cccnc2)C1
Temperature: 80 °C

Procedure:
[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (7 mg, 0.009 mmol) was added to a mixture of tert-butyl 4-(2-chlorothiazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (77 mg, 0.18 mmol), benzeneboronic acid (43 mg, 0.35 mmol) and sodium carbonate (37 mg, 0.35 mmol) in toluene (4 mL), 1,4-dioxane (1 mL), and water (1 mL). The reaction mixture was heated to 80° C. overnight. Upon cooling to room temperature, the reaction mixture was filtered through Celite®, concentrated under reduced pressure, and purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). This gave 74.9 mg (72%) of the TFA salt of the desired product. LC-MS: RT=8.74 min, [M+H]+=481.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=O)[CH2:8][CH2:7][CH2:6]2.[BH4-].[Na+].O>C(O)C.C1(C)C=CC=CC=1.C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][CH2:7][CH:8]=[CH:9]2
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)CCC=C2
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.9 %

Procedure:
To a solution of 5.01 g (24.3 mmol) of 6,7-dimethoxy-1-tetralone (Aldrich Chemical Co.) in 100 mL of ethanol was added 0.932 g (24.6 mmol) of NaBH4, and the mixture was stirred for 14 hours at room temperature. Most of the solvent was removed by evaporation, and to the residue was added 150 mL of methylene chloride and 50 mL of water. The aqueous layer was separated and reextracted with methylene chloride, then the organic extracts were combined and washed with brine, dried over MgSO4, and concentrated to leave an orange oily residue. The crude intermediate product was dissolved in 100 mL of refluxing toluene, to which was added 48 mg of p-toluenesulfonic acid, and the solution was heated at reflux for 30 min. The reaction was cooled to room temperature and 50 mL of water was added. The aqueous layer was extracted with ethyl acetate, and the organic extracts were combined, washed with brine, dried over MgSO4, and concentrated to leave an orange oil. This was dissolved in methylene chloride, which was washed with saturated sodium bicarbonate solution, water, dried and concentrated to afford 4.34 g of the title product (94% yield). NMR (CDCl3) δ:6.67 (s, 1H), 6.60 (s, 1H), 6.38 (d, 1H, J=10 Hz), 5.94(dt, 1H, J=4 Hz, J=10 Hz), 3.88 (s, 3H), 3.86 (s, 3H), 2.73 (t, 2H, J=8 Hz), 2.32-2.24 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29](C(O[Si](C(C)C)(C(C)C)C(C)C)=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([CH2:3][NH:4][C:5]([C:7]1([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[CH:22][CH:21]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: CC(C)[Si](OC(=O)N1CCN(c2ccc(-c3ccccc3SC3(C(=O)NCC#N)CCCCC3)cc2)CC1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#CCNC(=O)C1(Sc2ccccc2-c2ccc(N3CCNCC3)cc2)CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a 0° C. solution of triisopropylsilyl 4-{2′-[(1-{[(cyanomethyl)amino]carbonyl}-cyclohexyl)sulfanyl][1,1′-biphenyl]-4yl}-1-piperazinecarboxylate (35 mg, 0.055 mmol) in THF (8 mL) was added TBAF (1 M in THF, 0.08 mL). The solution was stirred at 0° C. for 20 min, then partitioned between EtOAc and saturated aq. NaHCO3. The organic phase was washed with water and brine, then dried over MgSO4 and concentrated and placed under vacuum for 6 h to give N-(cyanomethyl)-1-{[4′-(1-piperazinyl)[1,1 ′-biphenyl]-2-yl]sulfanyl}cyclohexanecarboxamide. MS (+APCI) m/z 435 (M+1, 40), 351 (100), 318 (45).
Reaction SMILES: O.[OH-].[Li+].C(OC([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:30]=[C:29]([CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[CH2:39][C:40](OC)=[O:41])[C:28]([C:44]([F:47])([F:46])[F:45])=[CH:27][N:26]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=O)(C)(C)C.O[N:49]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CO.O.CC(C)=O.CN(C=O)C>[NH2:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25]3[N:30]=[C:29]([CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[CH2:39][C:40]([NH2:49])=[O:41])[C:28]([C:44]([F:47])([F:46])[F:45])=[CH:27][N:26]=3)=[CH:22][CH:23]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CO
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCC(N)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium hydroxide mono hydrate (43.0 mg, 1.03 mmol) was added to a suspension of methyl 2-(2-(2-(2-((4-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I78) (211 mg, 0.344 mmol) in THF (10 mL), MeOH (1.0 mL) and water (1.5 mL) and the resulting mixture was stirred at room temperature for 16 hours. The organics were removed in vacuo then 2 M aqueous NaOH solution (100 mL) was added. The resulting solution was extracted with EtOAc (2×100 mL), then the combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to yield a white solid. The solid was dissolved in dry THF (10 mL) and dry DMF (2 mL) under an atmosphere of nitrogen. To this solution were added 1-hydroxybenzotriazole (72 mg, 0.53 mmol), EDCI (101 g, 0.529 mmol) and N,N-diisopropylethylamine (246 μL, 1.41 mmol) and the resulting mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (203 mg, 2.12 mmol) was added in one portion and the reaction was stirred at room temperature for 3 days. The volatiles were removed in vacuo and the residue was taken up in EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (70 mL). The combined organic layers were washed with water (2×100 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo to give a yellow solid which was dissolved in a small amount of acetone and precipitated with petroleum benzine 40-60° C. to yield the title compound (I79) (138 mg, 65%) as a yellow solid; NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 7.56 (d, J=8.9 Hz, 2H), 7.44 (s, 1H), 7.27-7.12 (m, 4H), 6.96-6.81 (m, 4H), 3.58 (d, J=12.7 Hz, 2H), 3.50 (s, 2H), 3.15-2.93 (m, J=15.2, 6.3 Hz, 4H), 2.67 (t, J=12.0 Hz, 2H), 1.79 (d, J=11.4 Hz, 2H), 1.55-1.42 (m, 2H), 1.39 (s, 9H). LCMS Method C: rt 5.30 min; m/z 599 [M+H]+.
Reaction SMILES: [CH2:1]([CH:5]([CH2:9][CH:10]=[CH2:11])[C:6](O)=[O:7])[CH:2]([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([CH:5]([CH2:9][CH:10]=[CH2:11])[CH2:6][OH:7])[CH:2]([CH3:4])[CH3:3]
Reactant: C=CCC(CC(C)C)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(CO)CC(C)C
Reaction time: 1 h

Procedure:
2-isobutyl-4-pentenoic acid (J. Am. Chem. Soc. 115, 1993, 8669) (13 g, 83 mmol) was dissolved in tetrahydrofuran (80 mL), and the solution was added dropwise to a tetrahydrofuran (80 mL) mixed solution of lithium aluminum hydride (3.4 g, 90 mmol) under ice cooling. The mixture was stirred at this temperature for 1 hour. Then, water (3.4 mL), a 15% aqueous sodium hydroxide solution (3.4 mL), and water (10.2 mL) were added thereto in this order, and the mixture was stirred overnight. After removal of insoluble matter, the filtrate was concentrated to obtain the compound of interest as an oil substance (4.9 g, 42%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:14]([NH2:17])[CH2:15][NH2:16].[BH4-].[Na+].Cl>CO.O1CCCC1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:16][CH2:15][CH2:14][NH2:17])[CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NCCN
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(NCCN)c1ccc(S(C)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
4′-(Methylsulfonyl)acetophenone (1.0 g) and ethylenediamine (908 mg) were dissolved in methanol (10 ml), and the solution was heated at 50° C. for 3 hours. The reaction mixture was added with a suspension of sodium borohydride (286 mg) in tetrahydrofuran (50 ml), and then added with methanol (6 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was made acidic with 1 N hydrochloric acid, and then the solvent was evaporated under reduced pressure. The mixture was added with distilled water and potassium carbonate and thereby neutralized, then the mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=10:1:0.1) to obtain the title compound (553 mg).
Reaction SMILES: C(OC(=O)[N:7]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:8][C@@H:9]([C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH2:31]([O:30][NH:7][CH2:8][C@@H:9]([C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:20][CH2:21]1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)CN(OCc3ccccc3)C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(C(=O)[C@H](CNOCc3ccccc3)CC(C)C)CC2)cc1
Yield: 122.2 %

Procedure:
A solution of tert-butyl(benzyloxy)((2S)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-4-methylpentyl)carbamate (134 mg; 0.25 mmol; 1.0 eq.) and HCl 4M in dioxan (0.938 mL, 15 eq.) in DCM (1 mL) was stirred overnight at room temperature. The solvents were evaporated to give the title product as a yellow oil (130 mg, 100%). HPLC, Rt: 2.9 min (purity: 95.9%). M+(LC-MS (ESI)): 426.4.
Reaction SMILES: [F:1][C:2]([F:28])([CH:13]1[CH2:18][CH2:17][CH:16]([CH:19]2[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)[O:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([F:12])[CH:5]=1.[H-].[Na+].Cl/[CH:32]=[CH:33]/[C:34]([F:37])([F:36])[F:35].O>CN1C(=O)CCC1>[F:12][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[O:11]/[CH:32]=[CH:33]/[C:34]([F:37])([F:36])[F:35])[O:3][C:2]([F:1])([F:28])[CH:13]1[CH2:14][CH2:15][CH:16]([CH:19]2[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]2)[CH2:17][CH2:18]1
Reactant: CCCC1CCC(C2CCC(C(F)(F)Oc3cc(F)c(O)c(F)c3)CC2)CC1
Reactant: FC(F)(F)/C=C/Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCC1CCC(C2CCC(C(F)(F)Oc3cc(F)c(O/C=C/C(F)(F)F)c(F)c3)CC2)CC1
Temperature: 130 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
4-(Difluoro(4′-propyl-[1,1′-bi(cyclohexane)]-4-yl)methoxy)-2,6-difluorophenol (3.0 g, 7.45 mmol) prepared by known methods and sodium hydride (55%) (0.325 g, 7.45 mmol) were stirred in NMP (N-methylpyroridone) at 60° C. for 30 minutes. (E)-1-Chloro-3,3,3-trifluoro-1-propene (2.43 g, 18.6 mmol) was then added to the reaction solution, and the mixture was stirred at 130° C. for 24 hours. The reaction solution was poured into water, which was extracted with toluene. The combined organic layers were washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off with an evaporator and the residue was purified by silica gel chromatography and then by recrystallization to give (E)-4-((3,5-difluoro-4-((3,3,3-trifluoro-1-propen-1-yl)oxy)phenoxy)difluoromethyl)-4′-propyl-1,1′-bi(cyclohexane) (56% yield).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[C:31]#[N:32])[NH2:27]>C(O)C>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])[N:27]=[CH:3][CH:4]=1
Reactant: N#Cc1cccc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Solvent: CCO
Product: N#Cc1cccc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)c1
Yield: 21 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 3-hydrazino-benzonitrile in ethanol as solvent according to the method described for Example 1 in 21% yield. MS: M=424.1 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:19][CH:18]([OH:20])[CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18](=[O:20])[CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCC(O)CN1C(=O)OCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C1CC[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1

Procedure:
Dissolve 1 -benzyloxycarbonyl-5-hydroxy-(S)-pipecolic acid (prepared from 5-hydroxy-(S)-pipecolic acid in 2N sodium hydroxide solution treated with benzylchlorformate in diethyl ether) in acetone and treat with Jones reagent to obtain 1-benzyloxycarbonyl-5-keto-(S)-pipecolic acid. Then esterify in methanol to give the respective methyl ester.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:42])[CH2:6][O:7][C:8]1[CH:13]=[C:12]([S:14]CCC(OCC(CC)CCCC)=O)[C:11]([NH:28][C:29](=O)[C:30]2[CH:35]=[CH:34][C:33]([O:36]CC3CC3)=[CH:32][CH:31]=2)=[CH:10][N:9]=1)(=[O:3])[CH3:2].[O-]CC.[Na+].FC(F)(F)C(O)=O>C1COCC1>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([C:29]2[S:14][C:12]3[CH:13]=[C:8]([O:7][CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:42])[N:9]=[CH:10][C:11]=3[N:28]=2)=[CH:31][CH:32]=1
Reactant: CCCCC(CC)COC(=O)CCSc1cc(OC[C@H](C)NC(C)=O)ncc1NC(=O)c1ccc(OCC2CC2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)COc1cc2sc(-c3ccc(O)cc3)nc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A mixture of 2-ethylhexyl 3-((2-(((2S)-2-acetamidopropyl)oxy)-5-((4-(cyclopropylmethoxy)benzoyl)amino)pyridin-4-yl)sulfanyl)propanoate (740 mg), sodium ethoxide (20% ethanol solution, 840 mg) and THF (10 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C., trifluoroacetic acid (0.475 mL) was added thereto, the obtained mixture was stirred at 70° C. for 1 hr. The reaction mixture was cooled to 0° C., and the precipitate was collected by filtration, and washed with diisopropyl ether. The obtained residue was dissolved in trifluoroacetic acid (5 mL), and the obtained solution was stirred at 70° C. for 1 hr. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (379 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][C:7]([CH2:8][NH:9][C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=4)=[O:32])=[CH:25][CH:24]=3)([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O>C1COCC1.[Pd]>[NH2:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][NH:33][C:31]([CH2:30][O:29][C:26]2[CH:25]=[CH:24][C:23]([C:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]([NH:9][CH2:8][C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:45][CH:44]=4)=[O:11])=[CH:15][CH:16]=3)([CH3:22])[CH3:21])=[CH:28][CH:27]=2)=[O:32])=[CH:40][CH:39]=1
Reactant: CC(C)(c1ccc(OCC(=O)NCc2ccc([N+](=O)[O-])cc2)cc1)c1ccc(OCC(=O)NCc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(c1ccc(OCC(=O)NCc2ccc(N)cc2)cc1)c1ccc(OCC(=O)NCc2ccc(N)cc2)cc1
Yield: 64.7 %

Procedure:
1.8 g of 2,2-bis-[4-(4-nitrobenzylamino)carbonylmethoxyphenyl]propane are dissolved in 300 ml of THF and, after addition of 0.5 g of palladium charcoal (10%), are hydrogenated in a bypass apparatus until the starting compound can no longer be detected (TLC). After the catalyst has been filtered off with suction, the filtrate is concentrated to dryness in vacuo and the residue is chromatographed through a silica gel column using a mixture of dichloromethane/ethanol, 95:5. The chromatographically pure fractions are combined and concentrated, and the residue is dried under high vacuum. 1.05 g of the title compound are obtained in the form of a solidified foam.
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[S:29](=[O:33])(=[O:32])([OH:31])[OH:30]>C(O)(C)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[S:29]([O-:33])([O-:32])(=[O:31])=[O:30]
Reactant: O=S(=O)(O)O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC(C)O
Product: O=S(=O)([O-])[O-]
Temperature: 80 °C
Reaction time: 22 h

Procedure:
Sitagliptin (5 g) and isopropanol (75 mL) are charged into a round-bottom flask and the mixture is heated to about 80° C. for about 15 minutes to obtain a clear dissolution. Sulfuric acid (1.2 g) is added and the reaction mixture is refluxed for about 1 hour. The reaction mixture is cooled to about 30° C. and stirred for about 22 hours. The separated solid is filtered, washed with isopropanol (5 mL), and dried under reduced pressure at about 40° C. for about 1.5 hours to afford the title compound. (Yield: 6.0 g; MC: 0.84% w/w; HPLC purity: 99.98%)
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][C:8]=1Cl>C(O)C>[CH3:4][O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][C:8]=1[NH:3][CH2:1][CH3:2]
Reactant: CCN
Reactant: COC(=O)c1ccc(C)nc1Cl
Solvent: CCO
Product: CCNc1nc(C)ccc1C(=O)OC

Procedure:
To a cold solution of 5.4 g. (0.12 mole) of anhydrous ethyl amine in 5 ml. of ethanol was added 11.1 g. (0.06 mole) of 2-chloro-6-methylnicotinic acid methyl ester. The mixture was heated in a glass autoclave over a steam bath for 5 hours. The mixture was then evaporated in a rotary evaporator and the residue was added to 100 ml. of water and was basified with concentrated ammonium hydroxide. The mixture was then extracted with 100 ml. of chloroform. The chloroform layer was dried over magnesium sulfate, filtered and was evaporated to give 2-ethylamino-6-methylnicotinic acid methyl ester as an oil which was used without further purification.