Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C@@H:4](C(CCC)=O)[CH2:5][C@H:6]([C:14]([O:16]C)=[O:15])[N:7]2N.[OH-:23].[Li+]>O1CCCC1.O>[C:14]([C@H:6]1[CH2:5][C@H:4]([NH:7][C:6]([CH2:5][CH2:4][CH3:3])=[O:23])[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[NH:7]1)([OH:16])=[O:15]
Reactant: CCCC(=O)[C@H]1C[C@H](C(=O)OC)N(N)c2cc(Cl)cc(Cl)c21
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(=O)N[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of trans-5,7-dichloro-2-methoxycarbonyl-4-n-propylcarbonyl-amino-1,2,3,4-tetrahydroquinoline (0.70 g, 0.493 mmol) in a mixture of tetrahydrofuran (15 ml) and water (5 ml) was added aqueous lithium hydroxide (1.1 ml of a 0.50M solution, 0.55 mmol) and the resulting mixture was stirred at room temperature for 20 h. The organic solvent was then removed under vacuum and the aqueous residue was diluted with dilute sodium bicarbonate solution (50 ml) then washed with ethyl acetate (1×30 ml). The aqueous phase was separated, acidified with dilute hydrochloric acid and extracted with ethylacetate (2×50 ml). The combined extracts were washed with brine (1×50 ml), dried (MgSO4) and evaporated to give a solid which was triturated with diethyl ether to give the title compound as colourless crystals (0.123 g) m.p. 174°-176° C. (dec). δ (DMSO, 360 MHz) δ 0.85 (3H, t, J=7.4 Hz, COCH2CH2CH3), 1.48-1.64 (3H, m, CHACHBHCCHD) and COCH2CH2CH3), 2.04 (2H, t, J=7.2 Hz, COCH2CH2CH3), 2.16 (1H, dm, J=13.1 Hz, CHACHBHCCHD), 3.82 (1H, dd, J=12.6 and 2.8 Hz, CHACHBHCCHD), 5.01 (1H, m, CHACHBHcCHDNHCO) 6.64 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.76 (1H, s, ArNH), 6.87 (1H, d, J=2.1 Hz, 6-H or 8-H), 8.10 (1H, d, J=7.2 Hz, --CHDNHCO--); m/e 330 (M+), 198 (100%, M-NHCOCH2CH2CH3, CO2H and H); Found C, 50.09; H, 4.78; N, 8.41; C14H16Cl2N2 03.0.2H2O requires C, 50.22; H, 4.94; N, 8.37%.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH2:5]1)=[O:3].[CH3:16][NH2:17]>O1CCCC1.O>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH:6]1[CH2:7][N:4]([C:2]([NH:17][CH3:16])=[O:3])[CH2:5]1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2cccc(Cl)c2)C1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2cccc(Cl)c2)C1
Reaction time: 16 h
Yield: 39.1 %

Procedure:
A solution of 1-chlorocarbonyl-3-(3-chlorophenoxy) azetidine (0.01275 mole) in 20 ml of tetrahydrofuran was treated with 4 ml (0.05 mole) of 40% aqueous methylamine and stirred for 16 hr. The reaction mixture was diluted with water until an oil began to separate, then extracted with 3×50 ml of benzene. The combined extracts were dried over magnesium sulfate and concentrated to a solid which was recrystallized from benzene/ligoin to yield 1.2 g (40.0%) of fine white crystals, m.p. 140°-141° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[C:19]([Cl:20])=[C:18]([CH3:21])[S:17][C:15]=2[N:16]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[C:19]([Cl:20])=[C:18]([CH3:21])[S:17][C:15]=2[N:16]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1Cl
Reactant: NCc1ccc(F)cc1
Product: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
Following the procedure of Example 1, the reaction of 4-fluorobenzylamine with 2,4,5-trichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2,5-dichloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[O:24][CH3:25])[NH:20][C:19](=[O:26])[CH2:18][CH2:17]3)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[F:36]>CN(C)C=O>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[CH2:28][N:20]1[C:21]2[C:16](=[CH:15][C:14]([C:6]3[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:12])[F:13])=[C:4]([F:3])[CH:5]=3)=[C:23]([O:24][CH3:25])[CH:22]=2)[CH2:17][CH2:18][C:19]1=[O:26]
Reactant: COc1cc2c(cc1-c1ccc(C(F)(F)F)c(F)c1)CCC(=O)N2
Reactant: Fc1ccc(CBr)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1-c1ccc(C(F)(F)F)c(F)c1)CCC(=O)N2Cc1ccc(F)cc1F
Yield: 52 %

Procedure:
To a suspension of 95% sodium hydride in anhydrous N,N-dimethylformamide (2 mL) at room temperature in a dry flask equipped with an inlet of dry nitrogen was added a solution of 6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one, prepared a shown above (53 mg, 0.10 mmol) in N,N-dimethylformamide (1 mL) with stirring. The reaction mixture was stirred for 30 minutes, followed by addition of 1-(bromomethyl)-2,4-difluorobenzene (207 mg, 1.0 mmol), and the reaction mixture stirred overnight. The reaction was followed by LCMS and stirring was continued as needed until the starting material was consumed. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (5 mL) with stirring, concentrated under reduced pressure, diluted with ethyl acetate (20 mL) and dilute aqueous ammonium chloride (10 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL), and the combined organic phase was successively washed with 2N sodium carbonate (20 mL), 30% aqueous ammonium chloride (20 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a crude mixture that was purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford 1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (25 mg, 0.05 mmol, 52%). LCMS mz 466.0 (M+H), 487.9 (M+Na), anal HPLC>98% in purity. 1H NMR (400 MHz; CDCl3) δ7.58 (t, J=7.8 Hz, 1H); 7.34 (m, 2H); 7.21 (m, 1H); 7.10 (s, 1H); 6.80-6.89 (m, 2H); 6.57 (s, 1H); 5.24 (s, 2H); 3.70 (s, 3H); 2.94 (m, 2H); 2.81 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:14][C:15]2[CH:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[NH:17][N:16]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:23][C:24](OC(C)=O)=[O:25]>C1COCC1.O>[Br:1][C:2]1[C:3]([NH:14][C:15]2[CH:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[N:17]([C:24](=[O:25])[CH3:23])[N:16]=2)=[N:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Brc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2Br)cc1C1CC1
Reaction time: 14 h
Yield: 67.3 %

Procedure:
To the mixture of 5-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenylpyrimidin-4-amine (200 mg, 0.56 mmol, 1.0 eq) in THF (8 mL) and water (5 mL) was added a solution of Ac2O (0.18 mL, 1.68 mmol, 3.0 eq) in THF (2 mL). The reaction mixture was stirred for 14 hours and water was added. The mixture was filtered and the solid was washed with water and dried by co-evaporated with ethanol to give 1-(3-(5-bromo-2-phenylpyrimidin-4-ylamino)-5-cyclopropyl-1H-pyrazol-1-yl)ethanone (150 mg, 67%). LC-MS (m/z)=398.0, 400.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH:15]([C:17](=[O:20])[CH2:18][CH3:19])[CH3:16].Cl>CN(C=O)C>[OH:9][B:8]1[C:4]2[CH:3]=[C:2]([O:1][CH:15]([C:17](=[O:20])[CH2:18][CH3:19])[CH3:16])[CH:11]=[CH:10][C:5]=2[CH2:6][O:7]1
Reactant: CCC(=O)C(C)Br
Reactant: OB1OCc2ccc(O)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)C(C)Oc1ccc2c(c1)B(O)OC2
Temperature: 0 °C
Reaction time: 24 h
Yield: 38 %

Procedure:
H181 (150 mg, 1.0 mmol) was dissolved in DMF (6.0 mL) and cooled to 0° C. with ice bath. To this solution under nitrogen were added in sequence NaH (60% in mineral oil, 160 mg, 4.0 mmol) and 2-bromopentan-3-one (660.12 mg, 4.0 mmol). The reaction mixture was stirred for 1 d then treated with 1.0 M HCl (10.0 mL). After extraction with ethyl acetate, the organic phase was washed with water and brine, and dried over anhydrous Na2SO4. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound (88.9 mg, 38% yield). 1H NMR (400 MHz, CDCl3): δ 7.21 (d, J=8.1 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 6.98 (dd, J=8.4 & 2.7 Hz, 1H), 5.00 (s, 2H), 4.67 (q, J=6.8 Hz, 1H), 2.73-2.61 (m, 1H), 2.49-2.39 (m, 1H), 1.47 (d, J=6.8 Hz, 3H) and 0.99 (t, J=7.2 Hz, 3H) ppm; Mp: 72-74° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]1.C(N(C(C)C)CC)(C)C.[CH2:18]([O:20][C:21](=[O:42])[C@H:22]([CH3:41])[CH2:23][C@H:24]([N:38]=[C:39]=[O:40])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[CH3:19]>CN(C=O)C>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:28]=[CH:27][C:26]([CH2:25][C@@H:24]([NH:38][C:39]([N:1]2[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]2)=[O:40])[CH2:23][C@H:22]([C:21]([O:20][CH2:18][CH3:19])=[O:42])[CH3:41])=[CH:31][CH:30]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)N=C=O
Reactant: O=C(O)c1cc[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)n1ccc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a vigorously stirred 1:1 mixture of methylene chloride/8% aqueous NaHCO3 (8 mL) at 0° C. is added triphosgene (28.4 mg, 0.096 mmol). After stirring the mixture at 0° C. for 5 minutes, (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (100 mg, 0.287 mmol) is added and stirring is continued for 15 minutes. The organic phase is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to furnish (2R,4S)-5-biphenyl-4-yl-4-isocyanate-2-methyl-pentanoic acid ethyl ester. Next, to a solution of 1H-pyrazole-3-carboxylic acid (32.2 mg, 0.287 mmol) in DMF (1 mL) is added diisopropylethylamine (0.05 mL, 0.287 mmol). After 15 min a solution of the above (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester in DMF (1 mL) is added dropwise and the mixture is stirred at room temperature for 18 hours. The mixture is purified by preparative HPLC using a gradient of 10% MeCN to 100% MeCN (0.1% TFA). Lyophilization of the appropriate fractions furnishes the title compound. HPLC Retention time 1.5 minutes (condition A); MS 450.3 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (d, J=7.07Hz, 3H), 1.10 (t, 3H), 1.86 (t, 2H), 2.52 (m, 1H), 2.85 (m, 1H), 2.98 (m, 1H), 3.98 (q, 2H), 4.11 (m, 1H), 6.85 (d, J=2.65Hz, 1H), 7.28 (d, J=8.08Hz, 2H), 7.33 (t, 1H), 7.44 (t, 2H), 7.57 (d, J=8.21Hz, 2H), 7.63 (d, J=7.33Hz, 2H), 8.29 (d, J=2.65Hz, 1H), 8.58 (d, J=9.22Hz, 1H), 13.33 (s, broad, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:10]1[N:11]=[C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:39]=[CH:38][CH:37]=[CH:36][C:27]=4[O:28][CH:29]([CH2:33][CH2:34][CH3:35])[C:30]([NH2:32])=O)=[CH:20][C:18]=3[CH:19]=2)[S:13][CH:14]=1)([CH3:9])([CH3:8])[CH3:7]>CN(C)C=O>[C:6]([C:10]1[N:11]=[C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:39]=[CH:38][CH:37]=[CH:36][C:27]=4[O:28][CH:29]([CH2:33][CH2:34][CH3:35])[C:30]#[N:32])=[CH:20][C:18]=3[CH:19]=2)[S:13][CH:14]=1)([CH3:7])([CH3:8])[CH3:9]
Reactant: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(N)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCC(C#N)Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
Phosphorus oxychloride (245 mg) was dissolved in dimethylformamide (2 ml) and the solution was ice-cooled. To this solution was added 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy]pentanamide (510 mg), and the mixture was stirred for two hours at room temperature. The reaction mixture was concentrated, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}pentanenitrile (453 mg).
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>C(Cl)Cl>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:18][CH2:19][N:20]([C:30](=[O:31])[N:29]([CH3:33])[CH3:28])[CH2:21][CH2:22]3)[CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCNCC2)CCO1
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCN(C(=O)N(C)C)CC2)CCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To 4-amino-5-chloro-2-methoxy-N-[{4-(4-piperidinylmethyl)-2-morpholinyl}methyl]-benzamide (Example 23) (1.0 g) and a solution of TEA (0.53 ml) in methylene chloride (20 ml) was added dropwise dimethylcarbamoyl chloride (0.30 g) under ice-cooling. After completion of addition, the internal temperature of the reaction solution was warmed to room temperature, and the solution was stirred for 3 hours. The reaction solution was washed with water, then brine, and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=30/1) to give the titled compound (1.1 g) as a white solid. Melting point 179-180° C. (recrystallized from EA)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[CH:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].CCN(CC)CC.[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>CN(C=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[C:28][C:38]([N:37]([CH3:41])[CH3:36])=[O:39])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: C#CCC(NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2)C(=O)OC(C)(C)C
Reactant: CN(C)C(=O)Cl
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C12CC3CC(CC(C(=O)NC(CC#CC(=O)N(C)C)C(=O)OC(C)(C)C)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound from Step A of Example 49 (0.389 g, 1 mmol) was dissolved in dry DMF (5 mL) with dichlorobis(diphenylphosphine)palladium (II) (0.02 eq), CuI (0.02 eq), Et3N (0.4 eq, 3 mL), and N,N-dimethylcarbamyl chloride (1.0 eq, 92 μL). The reaction mixture was stirred overnight at room temperature and then at 70° C. for 1 hour. The mixture was filtered through a pad of Celite and the solvent removed under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc/hexanes, 2:3) to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[NH2:10][C:11]1[NH:15][N:14]=[N:13][N:12]=1>O1CCCC1.C(N(CC)CC)C.C(Cl)(=O)OCC>[NH:12]1[C:11]([NH:10][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[N:15][N:14]=[N:13]1
Reactant: O=C(O)c1cnccn1
Reactant: Nc1nnn[nH]1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1nnn[nH]1)c1cnccn1

Procedure:
To a suspension of 1.50 g of pyrazine-2-carboxylic acid in 50 ml of tetrahydrofuran, 1.85 ml of triethylamine and 1.27 ml of ethyl chlorocarbonate were added dropwise successively at 0° C. under stirring. After stirring for 30 minutes at 0° C., 1.35 g of 5-amino-1H-tetrazole was added to the mixture, and the reaction mixture was stirred for 28.5 hours at room temperature. The precipitate was collected by filtration, and washed with dilute hydrochloric acid affording 2.05 g as colorless crystals, which was recrystalized from dimethylsulfoxide giving colorless crystals, m.p. 291°-296 ° C. (decomp.).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.ClS([N:19]=[C:20]=[O:21])(=O)=O.O>C(#N)C>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[N:9]2[C:20]([NH2:19])=[O:21])=[CH:5][CH:4]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Cc2ccc(C(F)(F)F)cc2N1
Solvent: CC#N
Solvent: O
Product: NC(=O)N1C(=O)Cc2ccc(C(F)(F)F)cc21
Reaction time: 0.75 h
Yield: 9.4 %

Procedure:
To a slurry of 6-trifluoromethyl-2-oxindole (8.0 g, 0.04 mole) in acetonitrile (80 ml) was added chlorosulfonyl isocyanate (6.65 g, 0.047 mole) and the mixture stirred for 45 minutes. Water (100 ml) was then added and the aqueous mixture stirred for one hour. The precipitate which formed was filtered off and recrystallized from acetonitrile to give 0.92 g of title product. Extraction of the filtration from the aqueous reaction mixture with ethyl acetate (300 ml) followed by drying the extract over MgSO4 and then evaporating it under reduced pressure gave additional product. Recrystallization from acetonitrile gave additional (2.2 g) product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:35]=[C:36]([NH2:40])[CH:37]([CH3:39])[CH3:38]>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:40]=[C:36]([CH:37]([CH3:39])[CH3:38])[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: CC(C)C(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.70 mmol) in dichloromethane (30 ml) was treated with 1,1′-carbonyldiimidazole (272 mg, 1.70 mol) and the solution was stirred at room temperature for 1 hour. The N′-hydroxy-2-methylpropanimidamide (Monatsh.Chem.; 113; 1982; 781-792) (174 mg, 1.70 mmol) was then added and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and the residue was heated neat at 120° C. under a nitrogen atmosphere for 18 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane to afford the title compound as a colourless oil (250 mg).
Reaction SMILES: [ClH:1].O1CCOCC1.[C:8]12([CH2:18][CH2:19][N:20]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:21]([C@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3C(OC(C)(C)C)=O)=[O:22])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>>[ClH:1].[C:8]12([CH2:18][CH2:19][N:20]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:21]([C@H:23]3[CH2:27][CH2:26][CH2:25][NH:24]3)=[O:22])[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]([CH2:16]3)[CH2:15]1)[CH2:17]2
Reactant: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Next, 4 N hydrogen chloride/dioxane (20 ml, 81 mmol) was added to (R)-1-(t-butoxycarbonyl)-2-pyrrolidinecarboxylic acid N-[2-(1-adamantyl) ethyl]-N-pentylamide (1.8 g, 4.0 mmol) under ice-cooling, then the temperature was raised to room temperature, and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give 1.5 g (quantitatively) of (R)-2-pyrrolidinecarboxylic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide hydrochloride as a noncrystalline solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[CH3:30][C:31]1[N:32]=[CH:33][C:34]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:35][CH:36]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCCCC4)CC3)cc2n1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCC(N5CCCCC5)CC4)cc3n2)cn1

Procedure:
1′-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-[1,4′]bipiperidinyl (Example 24) was reacted with 2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine in General Procedure A. Purification on silica yielded 132. NMR (CDCl3): 1.62 m, 10H, 5×CH2), 1.70 (m, 2H, CH2), 2.13 (t, 2H, CH2, J=11.07 Hz), 2.36 (m, H, CH), 2.58 (m, 2H, CH2), 2.66 (s, 3H, CH3), 3.06 (d, 2H, CH2, J=11.5 Hz), 3.83 (s. 2H, CH2), 3.90-3.92 (m, 4H, 2×CH2), 4.06-4.08 (m, 4H, 2×CH2), 7.25 (d, H, ArH, J=8.1 Hz), 7.31 (s, H, ArH), 8.58 (dd, H, ArH, J=2.14 Hz, 8.09 Hz), 9.52 (d, H, ArH, J=1.9 Hz). MS: (ESI+): MH+=493.45
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[CH3:14][NH2:15]>>[CH3:14][NH:15][C:3](=[O:2])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5]
Reactant: CN
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Product: CNC(=O)[C@@H](N)Cc1ccccc1
Yield: 82 %

Procedure:
Hydrochloride salt of (2S,5S)-5-benzyl-2-tert-butyl-3-methyllimidazolidin-4-one (1): To a solution of ethanolic MeNH2 (8.0 M, 50 ml) was added (S)-phenylalanine methyl ester (23.0 g, 130 mmol). The resulting solution was stirred at room temperature until the amino ester was judged to be consumed by TLC analysis. The resulting solution was then concentrated to provide (S)-phenylalanine N-methyl amide (18 g, 82% yield) as a white solid. To a flask containing (S)-phenylalanine N-methyl amide (8.9 g, 50 mmol) was added THF (100 ml), trimethylacetaldehyde (5.4 g, 50 mmol), FeCl3 (1.7 g, 10 mmol) and 4Å MS (5.0 g). The resulting mixture was stirred at room temperature for 36 h, then washed with H2O (3×100 mL). The combined organics were concentrated and the resulting residue was treated with HCl (27 mL, 1N in ether). The resulting heterogeneous mixture was filtered to removed the undesired trans isomer.HCl salt and the resulting solution was concentrated. The residue was recrystallized (9:1 pentane/CH2Cl2) to provide the product (1) as a crystalline solid (2.88 g, 23% yield, >99% ee). IR (film) 3343, 2958, 1605, 1028 cm−1; 1H NMR (300 MHz, CDCl3) δ7.31−7.17 (m, 5H, ArH), 4.04 (s, 1H, NCHN), 3.72−3.65 (m, 1H, CHCH2), 3.13 (dd, J=4.1, 13.7 Hz, 1H, CH2), 2.92 (dd, J=7.7, 13.7 Hz, 1H, CH2), 2.90 (s, 3H, NCH3), 0.82 (s, 9H, C(CH3)3); 13C NMR (75 MHz, CDCl3) δ175.3, 138.0, 129.8, 128.7, 126.8, 82.7, 77.8, 77.4, 76.9, 59.7, 38.6, 35.4, 31.0, 25.7; [α]D=−39.6 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC using a Chiralpak OD-H and OD guard column (3.0% i-PrOH/hexanes, 1 mL/min); (5S) isomer tr=16.7 min, (5R) isomer tr=20.1 min.