Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH3:17])[CH3:16])=[C:10]([F:18])[C:9]=2[F:19])[CH2:4]1.[C:20]1([C:26]2[O:30][C:29]([C:31](OCC)=[O:32])=[N:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:16][N:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:5]2[CH2:6][N:3]([C:31]([C:29]3[O:30][C:26]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:27][N:28]=3)=[O:32])[CH2:4]2)=[C:9]([F:19])[C:10]=1[F:18])[CH3:17]
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Reactant: CN(C)Cc1ccc(OC2CNC2)c(F)c1F
Agent: Cl
Product: CN(C)Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)c(F)c1F
Yield: 15.7 %

Procedure:
Using a similar protocol as described in Example 36 employing 39A (0.32 g, 1.00 mmol) and ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.24 g, 1.10 mmol) as starting materials afforded 65 mg (15%) of 39 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.27 (s, 6H), 3.46 (s, 2H), 4.39 (dd, 1H), 4.65 (dd, 1H), 4.82 (m, 1H), 5.13 (m, 2H), 6.52 (t, 1H), 7.04 (t, 1H), 7.54 (t, 2H), 7.60 (t, 1H), 8.16 (d, 2H), MS (APCI+) m/z 415 [M+H]+, LC purity: 89%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step A was prepared from {3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13b, and benzenesulfonyl chloride following the method described in Example 3, Step B 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.60 (m, 1H), 8.49 (m, 1H), 7.87 (m, 4H), 7.61-7.51 (m, 3H), 7.26-7.08 (m, 3H), 6.75 (m, 1H), 6.63 (m, 1H), 6.58 (m, 1H), 4.38 (s, 2H), 4.34 (s, 2H), 4.31 (s, 2H), 1.47 (s, 9H); MS 546 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[F:23])[CH2:11][CH2:10]2)[N:5]=[C:4]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C(OCC)(=O)C>[Cl:22][C:18]1[C:17]([F:23])=[C:16]([CH:21]=[CH:20][CH:19]=1)[C:15]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:6]2[CH:7]=[C:2]([N:31]3[CH2:35][CH2:34][CH2:33][C:32]3=[O:36])[CH:3]=[C:4]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[N:5]=2)[CH2:10][CH2:11]1)=[O:24]
Reactant: O=C(c1cccc(Cl)c1F)N1CCN(Cc2cc(Br)cc(Nc3nccs3)n2)CC1
Reactant: O=C1CCCN1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(c1cccc(Cl)c1F)N1CCN(Cc2cc(N3CCCC3=O)cc(Nc3nccs3)n2)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 25.5 mg of 4-bromo-6-((4-(3-chloro-2-fluorobenzoyl)piperazin-1-yl)methyl)-N-thiazol-2-ylpyridin-2-amine obtained in Example 81 in 1 mL of 1,4-dioxane was added 0.011 mL of pyrrolidin-2-one, 32 mg of potassium phosphate, 8.7 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and 7.8 mg of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, successively. The reaction solution was stirred at 100° C. for 3 hours. The reaction solution was cooled, diluted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo and the resulting residue was purified by a reversed phase medium pressure liquid chromatography [ODS-AS-360-CC (manufactured by YMC company), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The obtained fraction was diluted with ethyl acetate, washed with saturated sodium bicarbonate, and then dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo to give the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:20])([F:19])[F:18])[N:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)[O:25][B:24](B2OC(C)(C)C(C)(C)O2)[O:23]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:18][C:17]([F:20])([F:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([B:24]([OH:25])[OH:23])=[C:3]2[CH:10]=[N:9]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: FC(F)(F)c1ccccc1-n1ncc2c(I)ccnc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1ccnc2c1cnn2-c1ccccc1C(F)(F)F

Procedure:
To a 48 mL pressure bottle containing Intermediate 76A (535 mg, 1.32 mmol) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (500 mg, 1.97 mmol), potassium acetate (520 mg, 5.30 mmol), and anhydrous DMSO (10 mL). The reaction mixture was flushed with argon, treated with PdCl2(dppf).CH2Cl2 (60 mg, 0.082 mmol), and heated to 105° C. for 1.25 h to give the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[C:15]=2[C:23]#[N:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=2[C:23]#[N:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc([N+](=O)[O-])c2C#N)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2C#N)CC1

Procedure:
4-(2-Cyano-3-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (12.172 g, 36.6 mmol) from step 1 was dissolved in ethanol (300 ml) in a Parr flask. The flask was flushed with N2, and Pd/C (1.3 g) was added. The solution was treated with H2 on a Parr apparatus at 30 psi overnight. The mixture was filtered through celite, then washed with EtOAc. After concentration, the residue was purified by flash chromatography to give 4-(3-amino-2-cyano-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. (7.585 g, 69%) MS: (M+H)+ 303.2.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([Cl:25])[N:17]=1.O>C1COCC1>[Cl:25][C:18]1[N:17]=[C:16]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([F:3])=[CH:5][C:6]=2[C:11]([F:12])([F:13])[F:14])[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1
Reactant: Nc1ccc(F)cc1C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccc(F)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
Sodium hydride (0.124 g, 5.18 mmol) was added to a chilled (0° C.) solution of 4-fluoro-2-(trifluoromethyl)aniline (0.464 g, 2.59 mmol) in THF (1 mL) and stirred for 30 min. 2,6-Dichloro-3-nitropyridine (0.500 g, 2.59 mmol) was then added and the reaction mixture stirred at 80° C. for 18 h. Water was added to quench excess sodium hydride and volatile solvents were removed under reduced pressure. The product was then extracted into DCM, solvent removed under reduced pressure, and the residue purified by preparative HPLC to give the title compound (0.624 g). LCMS m/z=336.0 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 6.87 (d, J=8.6 Hz, 1H), 7.34 (td, J1=8.4 Hz, J2=3.0 Hz, 1H), 7.43 (dd, J1=8.4 Hz, J2=3.0 Hz, 1H), 7.94 (dd, J1=9.0 Hz, J2=5.0 Hz, 1H), 8.49 (d, J=8.6 Hz, 1H), 10.26 (br s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[S:15][CH2:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:20]=[CH:19][N:18]=1)=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:38])C=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[S:15]([CH2:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:20]=[CH:19][N:18]=1)=[O:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)n1c(SCc2nccc(OCCCOC)c2C)nc2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)n1c(S(=O)Cc2nccc(OCCCOC)c2C)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
0.6 g of 1-ethoxycarbonyl-2-{4-(3-methoxypropoxy)-3-methylpyridine-2-yl}methylthiobenzimidazole was dissolved in 20 ml of dichloromethane to obtain a solution. 0.4 g of m-chloroperbenzoic acid was added to the solution at -45° C. After one hour, 0.3 g of triethylamine and 20 ml of a saturated aqueous solution of sodium hydrogencarbonate were added to the resulting mixture. The obtained mixture was stirred at a room temperature for 30 minutes. The dichloromethane layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate twice, dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain a residue. This residue was purified by silica gel column chromatography to obtain 0.21 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][C@@H:26]2[OH:34])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:36](Cl)(=[O:38])[CH3:37]>>[CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:36](=[O:38])[CH3:37])[C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][C@@H:26]2[OH:34])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H]2c3ccccc3C[C@@H]2O)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@@H]2c3ccccc3C[C@@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: {2′-[((1R,2S)-2-hydroxy-indan-1-ylamino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[CH:7]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[F:27].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[F:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])[N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: O=C(Nc1cn2cc(O)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cn2cc(Oc3ccc([N+](=O)[O-])cc3F)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
To a solution of N-(6-hydroxyimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (30 g, 138 mmol) and 1,2-difluoro-4-nitrobenzene (24.2 g, 152 mmol) in dimethyl sulfoxide (180 mL) was added cesium carbonate (58.5 g, 180 mmol), and the mixture was stirred at room temperature for 5 hr under an argon atmosphere. Water (1080 mL) was added to the reaction mixture, and the mixture was stirred for 20 min. The precipitate was collected by filtration and washed with water and ethyl acetate. After air drying for one day, the mixture was dried under reduced pressure at 100° C. for 5 hr to give the title compound (46.5 g, 95%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].OO.C(N(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O)CN(CC([O-])=O)CC([O-])=[O:18].[Na+].[Na+].[Na+].[Na+].[Na+].S(=O)(=O)(O)O>C(O)(=O)C>[CH3:8][C:7]1[C:6](=[O:18])[CH:5]=[C:4]([CH3:9])[C:3](=[O:10])[C:2]=1[CH3:1]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CCN(CC(=O)[O-])CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Yield: 84 %

Procedure:
A solution of 13.6 g (100 mmol) of 2,3,6-trimethylphenol in 40 ml of acetic acid and 62.3 g (550 mmol) of 30% by weight aqueous hydrogen peroxide were simultaneously added dropwise to a stirred solution of 0.68 g (2.0 mmol) of iron 5,14-dihydrodibenzo[b,i][5,9,14,18]tetraaza[14]annulene, 2.52 g (2.0 mmol) of a 40% by weight aqueous solution of a pentasodiumdiethylenetriaminepentaacetate and 0.5 ml of concentrated sulfuric acid in 50 ml of acetic acid at 40° C. with cooling. The reaction mixture was then subjected to steam distillation. The distillate was extracted by shaking with methylene chloride. The organic phase was shaken with aqueous sodium bicarbonate solution and then with water, separated from the aqueous phase, dried over magnesium sulfate, filtered and concentrated to a yellow oil, which slowly solidifed. 12.6 g (84%) of 2,3,5-trimethyl-p-benzoquinone were obtained in the form of yellow oily crystals.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=O)C(F)(F)F)[CH2:16][CH2:15]2)[CH:10]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH2:9]1)=[O:7].CI>C(Cl)(Cl)Cl>[F:40][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[CH:10]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[CH2:9]2)=[O:7])[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1
Reactant: Cc1ccc(C2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC2N2CCN(C(=O)C(F)(F)F)CC2)cc1
Solvent: CI
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC2N2CCN(C)CC2)cc1

Procedure:
The title compound, MS: m/e=514.4 (M+H+), [α]58920=−25.92, [α]54620=−32.60, [α]43620=−71.06, [α]36520=−152.15 (c=0.1196, chloroform), was prepared in accordance with the general method of example 102 from (−)-(1-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-p-tolyl-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone and methyl iodide.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].Br[C:26]1[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][N:27]=1>>[F:32][C:31]1[C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[O:11])=[N:27][CH:28]=[C:29]([F:33])[CH:30]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1cnc(Br)c(F)c1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(F)cc2F)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone and 2-bromo-3,5-difluoropyridine. ESI-MS (m/z): 440 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=N)[CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)[CH3:2].CC[O:33]C(C)=O>O>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=N)CCCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Solvent: O
Product: CCOC(=O)CCCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 100 °C

Procedure:
400 mg (0.89 mmol) trans-4-{4-[Methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-butyrimidic acid ethyl ester were suspended in 10 ml water and heated to 100° C. for 2.5 h. EtOAc was added, and the inorganic phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and evaporated to give 355 mg (89%) trans-4-{4-[Methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-butyric acid ethyl ester as yellow oil, MS: 452 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][C:14]=2[F:24])[N:5]=1)(=[O:3])[CH3:2].CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>C(#N)C>[CH3:27][N:28]([CH3:30])[CH:29]=[CH:2][C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][C:14]=2[F:24])[N:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(C)=O)c1=O
Solvent: CC#N
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(=O)C=CN(C)C)c1=O
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 3-acetyl-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxypyridazin-4(1H)-one (600 mg), N,N-dimethylformamide dimethyl acetal (3 mL) and acetonitrile (3 mL) was stirred at 80° C. for 12 hr, allowed to be cooled to room temperature, and stirred for 12 hr. The precipitate was collected by filtration, and washed with diisopropyl ether to give the title compound (600 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]4[C:24](=[O:50])[N:25]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[N:26]([CH2:29][C@H:30]([O:32][C:33](=[O:43])[CH2:34][NH:35]C(OC(C)(C)C)=O)[CH3:31])[C:27]=4[CH3:28])=[O:22])=[N:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[ClH:51]>CCOC(C)=O>[ClH:51].[NH2:35][CH2:34][C:33]([O:32][C@H:30]([CH3:31])[CH2:29][N:26]1[C:27]([CH3:28])=[C:23]([C:21](=[O:22])[NH:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:19][N:18]=2)[C:24](=[O:50])[N:25]1[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[O:43]
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CNC(=O)OC(C)(C)C)n(-c5ccccc5)c4=O)nc3)ccnc2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CN)n(-c5ccccc5)c4=O)nc3)ccnc2c1
Yield: 76 %

Procedure:
The title compound was prepared according to the procedure described in Example 1 Step 3 by using (R)-1-(4-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-ylcarbamoyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydropyrazol-1-yl)propan-2-yl2-(tert-butoxycarbonyl amino)acetate (100 mg, 0.146 mmol) and a saturated HCl solution in EtOAc (3 mL). The title compound was crystallized in MeOH/EtOAc (20 mL, v/v=1:5) to afford the title compound as a white solid (84.2 mg, 76%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]2[N:10]=[CH:11][CH:12]=[C:8]2[N:7]=[C:6]([S:13][CH3:14])[C:5]=1[C:15]#[N:16].CN(C=O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([NH:3][C:4]1[N:9]2[N:10]=[CH:11][CH:12]=[C:8]2[N:7]=[C:6]([S:13][CH3:14])[C:5]=1[C:15]#[N:16])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CSc1nc2ccnn2c(N)c1C#N
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccnn2c(NCc2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.2 %

Procedure:
100 mg of sodium hydride (60%) was added to 500 mg of 7-amino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile and 8 ml of DMF, followed by stirring at room temperature for about 10 minutes, and then 420 mg of benzyl bromide was added thereto, followed by stirring at about 50° C. for about 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, about 50 ml of water was added thereto, and the precipitated crystals were collected by filtration, washed with water and dried to obtain crude crystals. The crude crystals were purified by silica gel column chromatography to obtain 570 mg of 7-benzylamino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compound No. 2) having a melting point of 165° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:14](=[O:16])[CH3:15])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Ni]>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:14](=[O:16])[CH3:15])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(=Cc1ccc(O)cc1)C(C)=O
Agent: [Ni]
Product: CCOC(=O)C(Cc1ccc(O)cc1)C(C)=O

Procedure:
According to the procedure of Liebigs Ann. Chem. (1980), 9, 1392, 2-(4-hydroxy-benzyl)-3-oxo-butyric acid ethyl ester was prepared from 2-acetyl-3-(4-hydroxy-phenyl)-acrylic acid ethyl ester, Raney-nickel, hydrogen.
Reaction SMILES: [C:1]([CH:5]([CH:21]1[CH2:24][C:23](=[O:25])[C:22]1(Cl)Cl)[C:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[O:7][SiH3:8])([CH3:4])([CH3:3])[CH3:2].C(OCC)C>C(O)(=O)C.[Zn]>[C:1]([CH:5]([CH:21]1[CH2:22][C:23](=[O:25])[CH2:24]1)[C:6]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[O:7][SiH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(C1CC(=O)C1(Cl)Cl)C(O[SiH3])(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)C(C1CC(=O)C1)C(O[SiH3])(c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 44 %

Procedure:
Zinc dust (15.7 g, 0.24 mol) was added to a solution of 3-(tert-butyl-diphenyl-siloxyethyl)-2,2-dichlorocyclobutanone (17 g, 0.04 mol) in glacial acetic acid (68 mL) at room temperature. The reactants were heated at 60° C. for 1 hr, after which time dry diethyl ether was added to the cooled products, which were then filtered. The residue was washed with diethyl ether and the combined filtrate and washings were concentrated under reduced pressure. The residue was dissolved in CH2Cl2, which was washed with saturated NaHCO3 twice and water once. The organic phase was dried over MgSO4 and the solvent was evaporated to give an oily product, which was purified by silica gel flash chromatography (Hexane: EtOAc=12:1) to give a colorless oil (6.2 g, 43.7%). 1H NMR (CDCl3, 400 MHz): δ 1.06 (s, 9H), 1.82-1.87 (m, 2H), 2.48-2.60 (m, 1H), 2.65-2.71 (m, 2H), 3.07-3.14 (m, 2H), 3.69-3.73 (t, J=6.0, 6.4, 2H), 7.37-7.46 (m, 6H), 7.65-7.73 (m, 4H). 13C NMR (CDCl3, 100 MHz): δ 19.37, 26.76, 27.06, 39.02, 52.87, 62.87, 127.91, 129.88, 129.92, 133.86, 208.89. IR (neat) νmax 2957, 2930, 2857, 1784, 1472, 1428, 1388, 1112, 822, 739, 702.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])=[CH:17][CH:16]=1)C1C=CC=CC=1.CO[CH:30](OC)[CH2:31][NH2:32]>C(O)C>[NH:32]1[CH:31]=[CH:30][N:26]=[C:25]1[CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:20][CH:19]=1
Reactant: N#CCCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: COC(CN)OC
Solvent: CCO
Product: NCCCCc1ccc(OCCCc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 23.2 %

Procedure:
Compound 2 (0.156 g, 0.425 mmol) was dissolved in anhydrous ethanol (10 mL). To the solution was bubbled anhydrous HCl gas for 3 min. The reaction vessel was sealed and the mixture was stirred at room temperature for 48 h, and then concentrated to dryness under vacuum. The resulting residue was dissolved in anhydrous methanol (5 mL). To the newly formed solution was added 2,2-dimethoxyethylamine (0.097 mL, 0.891 mmol) in one portion. After stirring at room temperature overnight, temperature was raised to reflux which was maintained for another 3 h before the mixture was cooled to ambient temperature. Solvent was removed under vacuum and the residue was treated with 1.2 N HCl aqueous solution at 80° C. for 2 hours. The mixture was then cooled to ambient temperature again and neutralized to pH˜9 with powder K2CO3. Water was completely removed under vacuum and the residue was dissolved in methanol. The methanol solution was loaded onto silica gel, and the product was eluted with a mixture of concentrated ammonium hydroxide/MeOH/CH2Cl2 (1.8:18:81.2, v/v), affording the product 21 (27 mg, 23% overall yield) as an off-white solid. 1H NMR (300 MHz, CD3OD): δ 1.60 (m, 4H), 2.14 (m, 2H), 2.56 (t, 2H), 2.76 (t, 2H), 2.86 (t, 2H), 3.94 (t, 2H), 6.79 (d, 2H), 6.91 (s, 2H), 7.08 (d, 2H). m/z (APCI): 274 [C16H23N3O+H]+.