Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH:5]=[C:6]([C:13]([CH3:15])=O)[C:7]([O:9]CCCl)=[O:8])#[N:2].[NH2:20]/[C:21](/[CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])=[CH:22]\[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(OCC)(=O)C>[C:1]([C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH:5]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])[NH:20][C:13]([CH3:15])=[C:6]1[C:7]([OH:9])=[O:8])#[N:2]
Reactant: CC(=O)C(=Cc1ccccc1C#N)C(=O)OCCCl
Reactant: CCOC(=O)/C=C(\N)C(OCC)OCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)O)C1c1ccccc1C#N
Yield: 82.5 %

Procedure:
A mixture of 2-chloroethyl 2-(2-cyanobenzylidene)acetoacetate (4.72 g) and ethyl 3-amino-4,4-diethoxycrotonate (4.06 g) was heated for 3 hours at 100°~105° C. with stirring. After cooling, the reaction mixture was dissolved in ethyl acetate, and the solution was washed twice with an aqueous solution of sodium chloride and then dried over magnesium sulfate. After removal of the solvent under reduced pressure, the residual oil was chromatographed over silica gel with a mixture of benzene and ethyl acetate (5:1 V/V) to give 2-chloroethyl ester of 4-(2-cyanophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid (5.81 g).
Reaction SMILES: C([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C@@H:26]([CH2:30][CH2:31][CH2:32][NH:33][CH:34]2[C:43]3[N:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH2:37][CH2:36][CH2:35]2)[C:27]([OH:29])=[O:28])=[O:24])=[CH:19][N:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(OC(C)(C)C)=O.[ClH:44].O1CCOCC1>CO>[ClH:44].[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C@@H:26]([CH2:30][CH2:31][CH2:32][NH:33][CH:34]2[C:43]3[N:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH2:37][CH2:36][CH2:35]2)[C:27]([OH:29])=[O:28])=[O:24])=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)N[C@@H](CCCNC2CCCc3cccnc32)C(=O)O)cn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(N[C@@H](CCCNC1CCCc2cccnc21)C(=O)O)c1ccc(CNCc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
The compound obtained in Example 12-5 (26.8 mg) was dissolved in methanol (0.5 ml), and 4 mol/l hydrochloric acid/dioxane solution (0.5 ml) was added. The mixture was stirred for 4.5 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was purified by silica gel column chromatography (1 g, chloroform/methanol/water=7/3/0.5). The obtained product was added with an aqueous solution of hydrochloric acid and concebtrated, and then azeotropically distilled with water. The resulting solid was washed with ether to obtain a hydrochloride of the title compound (25.8 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:31]2[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=2)[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:39][C:40]1[CH:45]=[CH:44][C:43](OB(O)O)=[CH:42][CH:41]=1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:31]2[CH:36]=[CH:35][C:34]([C:43]3[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN(c2ccc(Br)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cs1
Reactant: OB(O)Oc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN(c2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cs1
Yield: 89.5 %

Procedure:
2-{[4-(2-{(4-Bromophenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (1.2 g) synthesized in Example 256-1 and 4-fluorophenylboric acid (0.31 g) were dissolved in dioxane (10 mL) and 2 mol/L sodium carbonate (5 mL), tetrakis(triphenylphosphine)palladium (0.11 g) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1 to 2:1) to give the title compound (1.1 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][N:12]=[C:11]3[NH2:18])[CH:5]=[CH:6][CH:7]=1.[N:19]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[C:20]=[O:21]>CN(C)C=O>[NH2:18][C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:20]([NH:19][CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:21])[CH:7]=[CH:6][CH:5]=3)[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: Nc1cccc(-c2ccc3ncnc(N)c3c2)c1
Reactant: O=C=NC1CCCC1
Solvent: CN(C)C=O
Product: Nc1ncnc2ccc(-c3cccc(NC(=O)NC4CCCC4)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a 4 mL screw-cap vial was added 6-(3-aminophenyl)quinazolin-4-amine (35 mg; 0.15 mmol) followed by dimethylformamide (0.5 mL) and isocyanatocyclopentane (1.1 equiv., 0.16 mmol, 18 mg). The reaction was stirred at room temperature overnight. The following morning the crude reaction mix was directly purified by reverse phase HPLC, yielding 19 mg of desired product. 1H NMR (400 MHz, DMSO) δ 8.51-8.45 (d, J=1.8 Hz, 1H), 8.45-8.40 (s, 1H), 8.40-8.37 (s, 1H), 8.03-7.95 (dd, J=8.7, 1.9 Hz, 1H), 7.95-7.76 (s, 2H), 7.76-7.70 (d, J=8.7 Hz, 1H), 7.43-7.28 (m, 3H), 6.33-6.20 (d, J=7.2 Hz, 1H), 4.04-3.90 (dd, J=13.4, 6.7 Hz, 1H), 1.93-1.80 (m, 2H), 1.74-1.46 (m, 4H), 1.46-1.32 (m, 2H). LCMS M/Z (M+H)=348.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:24])[N:16]([CH3:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:25]#[N:26].[CH:27]1([NH2:30])[CH2:29][CH2:28]1>CS(C)=O.CCOC(C)=O>[C:25]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:24])[N:16]([CH3:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9]2)=[N:7][C:2]=1[NH:30][CH:27]1[CH2:29][CH2:28]1)#[N:26]
Reactant: NC1CC1
Reactant: CN(C(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C(=O)N[C@@H]1CCCN(c2cnc(C#N)c(NC3CC3)n2)C1)c1ccccc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
(R)-3-(1-(6-Chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methyl-1-phenylurea (513, 100 mg) was dissolved in 4 mL DMSO in a sealed tube. To it was added cyclopropylamine (210 μL, 3 mmol) and the mixture was stirred in 70° C. bath for 16 hours. It was diluted with 60 mL EtOAc, washed with water ×2, concentrated in vacuo to afford crude (R)-3-(1-(5-cyano-6-(cyclopropylamino)pyrazin-2-yl)piperidin-3-yl)-1-methyl-1-phenylurea (514). It was dissolved in 4 mL MeOH and 2 mL DMSO. To it were added one NaOH solid pellet (about 50-100 mg) and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 45 min, diluted with 10 mL MeCN, stirred for 5 min, concentrated on rotavap. The residue was treated with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-3-(cyclopropylamino)-5-(3-(3-methyl-3-phenylureido)piperidin-1-yl)pyrazine-2-carboxamide (515) as HCl salt (74 mg, 67% yield). LC-MS (ESI): m/z (M+1) 410.3. UV: λ=283, 317, 369 nm.
Reaction SMILES: [Cl:1][C:2]1[C:3](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:5]([S:14]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH3:28])([CH3:27])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[C:6]([CH:13]=1)[O:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].Br[C:39]1[C:44]([C:45]#[N:46])=[CH:43][C:42]([C:47]([F:50])([F:49])[F:48])=[N:41][CH:40]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:13]=[C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([S:14]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH3:27])([CH3:28])[CH2:19][CH2:18]2)(=[O:15])=[O:16])=[CH:4][C:3]=1[C:39]1[C:44]([C:45]#[N:46])=[CH:43][C:42]([C:47]([F:49])([F:50])[F:48])=[N:41][CH:40]=1
Reactant: CC1(C)CCN(S(=O)(=O)c2cc(B3OC(C)(C)C(C)(C)O3)c(Cl)cc2OCCCCO)c2ccccc21
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)CCN(S(=O)(=O)c2cc(-c3cnc(C(F)(F)F)cc3C#N)c(Cl)cc2OCCCCO)c2ccccc21
Temperature: 100 °C
Yield: 35.5 %

Procedure:
A mixture of 4-[5-Chloro-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-butan-1-ol (270.0 mg, 0.49 mmol), 5-bromo-2-trifluoromethyl-isonicotinonitrile (112 mg, 0.45 mmol), Pd(Ph3P)4 (57 mg, 0.05 mmol) and Na2CO3 (286 mg, 2.7 mmol) in dioxane (4 mL) and water (0.4 mL) was degassed with N2 for 5 min. The reaction vessel was sealed and then heated at 100° C. for 16 hrs. The mixture was then partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was washed with brine (2×10 mL), dried over MgSO4, filtered and concentrated to give a material which was purified by TLC plates eluting with 30% acetone in hexanes to give 5-[2-chloro-5-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(4-hydroxy-butoxy)-phenyl]-2-trifluoromethyl-isonicotinonitrile 11-1 as a white solid (95 mg). MS: 594.2 (M+H)+; tR=2.94 min (method 1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[CH2:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:14]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>CCO.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[CH2:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:14]1=[N:31][OH:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCc2ccccc2C1Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CC2C(=NO)CCc3ccccc32)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 1-(3-benzyloxy-4-nitrobenzyl)-3,4-dihydro-1H-naphthalen-2-one (600 mg, 1.55 mmol), hydroxylamine hydrochloride (160 mg, 2.32 mmol) and sodium acetate (254 mg, 3.10 mmol) in 6 mL EtOH/H2O (2:1) is refluxed for 2 h. The solution is cooled to RT and extracted with CH2Cl2. The organic layer is washed with water, brined and dried over MgSO4. The solvent is removed under reduced pressure and the residue is purified by flash chromatography with CH2Cl2 to give the title compound as a yellow liquid. (M+1)+=403.
Reaction SMILES: CSC.B.[CH2:5]1[CH2:15][C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.C1([C@@H]2[C@@H](C3C=CC=CC=3)ON(C)B2)C=CC=CC=1>C1COCC1>[C@H:13]1([OH:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:15]1
Reactant: O=C1CCCc2ccccc21
Agent: B
Agent: CN1B[C@H](c2ccccc2)[C@@H](c2ccccc2)O1
Solvent: C1CCOC1
Solvent: CSC
Product: O[C@@H]1CCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Borane dimethylsulfide complex (2M in THF, 7.0 mL, 0.014 moles) was added over 45 minutes at ambient temperature to a solution of α-tetralone (2.92 g, 0.02 moles) and the title compound of Example 1 (247 mg, 0.001 moles) in THF (80 mL). The reaction mixture was stirred for 15 minutes (at which time thin layer chromatography indicated complete consumption of α-tetralone) and then cooled to 0° C. and quenched with methanol 27 mL). The quenched solution was allowed to warm to ambient temperature, with stirring, for 16 hours. The solvents were removed in vacuo and the residue was redissolved with methylene chloride (50 mL) and pH4 phosphate buffer (50 mL). The phases were separated and the organic phase was washed with water (50 mL), treated with MgSO4 and filtered. The solvent was removed in vacuo to afford 2.93 (99%) of -(R)-(+)-1,2,3,4-tetrahydro-1-naphthol as a white solid. HPLC with a chiral support demonstrated that the product had a 94% e.e.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[N:5][C:6]2[CH2:7][CH2:8][N:9]([C:13]([C:15]34[CH2:22][CH2:21][CH2:20][CH:19]3[CH2:18][C:17](=O)[CH2:16]4)=[O:14])[CH2:10][C:11]=2[CH:12]=1.[C:26]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Na].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[C:26]1([CH:32]2[CH2:33][CH2:34][N:35]([CH:17]3[CH2:16][C:15]4([C:13]([N:9]5[CH2:8][CH2:7][C:6]6[N:5]=[CH:4][C:3]([C:2]([F:25])([F:24])[F:1])=[CH:12][C:11]=6[CH2:10]5)=[O:14])[CH:19]([CH2:20][CH2:21][CH2:22]4)[CH2:18]3)[CH2:36][CH2:37]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1CC2CCCC2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(N1CCc2ncc(C(F)(F)F)cc2C1)C12CCCC1CC(N1CCC(c3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)hexahydropentalen-2(1H)-one (0.175 g, 0.497 mmol) in DCE (4.3 mL) was added 4-phenylpiperidine (0.080 g, 0.50 mmol). The reaction mixture was stirred at ambient temperature for about 2 h then sodium triacetoxyborohydide (0.158 g, 0.745 mmol) and acetic acid (0.043 mL, 0.74 mmol) were added. The reaction mixture was then stirred at ambient temperature for about 18 h. Saturated aqueous sodium bicarbonate was added to the reaction mixture and the product was extracted into DCM (3×10 mL). The solvent was removed under reduced pressure and the crude material was purified by RP-HPLC to provide [2-(4-phenyl-piperidin-1-yl)-hexahydro-pentalen-3a-yl]-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone as a mixture of four diastereomers (0.075 g). RP-HPLC (Table A, Method c) Rt 2.05 min; m/z: (M+H)+498. In addition, the diastereomers were separated using a two-step chiral HPLC method (Step 1: Diastereomer separation: Isocratic using 85% heptane, 7.5% methanol, 7.5% ethanol with 0.2% diethylamine on a Daicel OD-H column (20×250 mm) at 35 deg C. and 12 mL/min flow rate (UV wavelength monitored=265 nm). Step 2: Enantiomer separation: 10-70% gradient over 19 min of isopropanol in heptane with 0.2% diethylamine on a Daicel AD-H column (20×250 mm) at 35 deg C. and 16 ml/min flow rate (UV wavelength monitored=265 nm)) to provide the four enantiomers—the absolute configuration of each compound was not determined Isomer 1: RP-HPLC (Table A, Method d) Rt 12.66 min. Isomer 2: RP-HPLC (Table A, Method d) Rt 13.57 min. Isomer 3: RP-HPLC (Table A, Method d) Rt 8.46 min Isomer 4: RP-HPLC (Table A, Method d) Rt 11.76 min.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[N:11]=[C:10]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[NH:9][N:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl.Cl.N1C=NC=N1.C(N(CC)CC)C.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:34][N:35]([CH3:39])[C:36]([N:9]1[C:10]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:11][C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[N:8]1)=[O:37]
Reactant: CC(C)(C)c1n[nH]c(SCc2ccccn2)n1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)n1nc(C(C)(C)C)nc1SCc1ccccn1

Procedure:
Ten g of 3-t-butyl-5-(pyrid-2-yl-methylthio)-1H-1,2,4-triazole dihydrochloride, 0.5 g (4.1 mmole) of 1,2,4-triazole dihydrochloride, 0.5 g (4.1 mmole) of 4-dimethylaminopyridine, 10 g (100 mmole) of triethylamine, 3.5 g of dimethylcarbamoyl chloride and 100 ml of THF were refluxed for two hours. The mixture was concentrated in vacuo, and partitioned between ether and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the solvent was removed in vacuo to yield 1-dimethylcarbamoyl-3-t-butyl-5-(pyrid-2-yl-methylthio)-1H-1,2,4triazole, an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([CH2:17][NH:18][C@H:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](O)=[O:21])=[C:11]2[C:10]([C:27]([O:29][CH3:30])=[O:28])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:41]2[CH:42]=[CH:43][CH:44]=[N:45][C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CN1CCOCC1>C1COCC1>[CH:40]1([NH:45][C:20](=[O:21])[C@H:19]([NH:18][CH2:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]=[C:10]([C:27]([O:29][CH3:30])=[O:28])[C:11]=23)[C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)O)C(C)(C)C)c12
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)NC3CCCC3)C(C)(C)C)c12
Temperature: 43 °C
Reaction time: 36 h

Procedure:
To (R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-3,3-dimethylbutanoic acid was added THF (2 mL), HATU (94 mg, 0.246 mmol), cyclopentanamine (70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg, 0.822 mmol). The suspension was stirred at 43° C. for 36 h to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C26H38N4O5, 487; found, 487.6.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([CH2:23][CH2:24]Cl)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]1>CC#N>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([CH2:23][CH2:24][N:28]3[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2CCCl)c2cnccc12
Reactant: OC1CCNC1
Solvent: CC#N
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2CCN2CCC(O)C2)c2cnccc12
Yield: 6 %

Procedure:
A solution of 1-{[5-chloro-1-(2-chloroethyl)-1H-benzimidazol-2-yl]methyl}-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (110 mg, 0.26 mmol) and 3-pyrrolidinol (1 mL) in CH3CN (2 mL) was heated at 150° C. for 1 hour under microwave irradiation. The resulting mixture was concentrated in vacuo and the residue was purified by column chromatography (MeOH:DCM=3:25) to afford the title product as a grey solid (8 mg, yield: 6%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]([CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[C:27]1[CH:32]=[CH:31][C:30](OS(C(F)(F)F)(=O)=O)=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:30]1[CH:31]=[CH:32][C:27]([N:26]([C:21]2[N:20]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:28][CH:29]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: O=S(=O)(Oc1ccc(N(c2ncccn2)C2CCOCC2)cc1)C(F)(F)F
Product: COC(=O)C(C/C=C/c1ccc(N(c2ncccn2)C2CCOCC2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 59.2 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (164.0 mg) was reacted with trifluoromethanesulfonic acid 4-[pyrimidin-2-yl-(tetrahydropyran-4-yl)amino]phenyl ester (220.0 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(pyrimidin-2-yl-(tetrahydro-pyran-4-yl)-amino)phenyl]pent-4-enoic acid methyl ester (178.5 mg). Column chromatography (silica gel, eluent: chloroform/cyclohexane=1/2→chloroform) and thin layer chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate=1/1) were used for purification.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH:18]([OH:20])[CH3:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH:18]([O:20][C:35](=[O:37])[CH3:36])[CH3:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)OC(C)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1

Procedure:
A solution of 0.026 g (0.057 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-hydroxyethyl)pyrrolidine (diastereomer 2, Example 18), 0.027 mL (0.28 mmol) of acetic anhydride, 0.046 mL of pyridine and 3.4 mg of DMAP in 2 mL of THF was stirred at rt for 18 h. The reaction mixture was concentrated and purified by chromatography (silica, hexanes:ethylacetate:(2N NH3 in MeOH), 15:15:1) to give the title compound as white solid. 1H NMR (CDCl3) δ (key peaks) 7.89-7.90 (m, 3H), 7.47-7.54 (m, 4H), 7.19 and 7.09 (d of d, 2H, J=6.0, 8.5 Hz), 6.99 and 6.94 (t, 2H, J=8.5 Hz), 5.04-5.20 (m, 1H1), 1.34 and 1.09 (d, 3H, J=6.5 Hz), Mass Spectrum (ESI) m/e=503 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C>O1CCCC1.CCCCCC>[CH:9]1([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([B:17]([OH:20])[OH:18])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: Brc1ccc(CC2CC2)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(CC2CC2)cc1
Temperature: -70 °C

Procedure:
1-Bromo-4-(cyclopropylmethyl)benzene (2.11 g) was dissolved in anhydrous tetrahydrofuran (20 ml) and cooled to −70° C. under an argon atmosphere. A 1.25M solution of n-butyl lithium in hexane (8.8 ml) was added at such a rate that the temperature did not exceed −65° C. with stirring, which was maintained for a further 30 minutes. Trimethyl borate was added slowly keeping the temperature below −60° C. and the reaction mixture was stirred for a further 1.5 hours at −70° C. After warming to −5° C., the reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (50 ml) and the organic phase was separated. The aqueous layer was extacted with ethyl acetate (2×30 ml) and combined organic phases were dried (MgSO4) and evaporated to give 4-(cyclopropylmethyl)phenylboronic acid (1.52 g); 1H NMR (d6-DMSO): 0.2 (d, 2H), 0.5 (d, 2H), 0.9-1.07 (m, 1H), 2.5 (partly obscured by DMSO), 7.2 (d, 2H), 7.7 (d, 2H); mass spectrum (−ve ESP) 175 (M−H)−.