Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.S(Cl)([Cl:15])=O>O>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Cl)cc1F
Reactant: O=S(Cl)Cl
Solvent: O
Product: O=C(Cl)c1cc(F)c(Cl)cc1F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
38.5 g 4-chloro-2,5-difluorobenzoic acid (0.2 mole) was placed in a 250 mL, 3-necked roundbottom flask equipped with a magnetic stirbar, a thermometer, and a water-cooled condenser. 238 g thionyl chloride was added in one lot. The mixture was stirred and heated on a water bath. At about 58°-60° C. the solid dissolved with evolution of gas and formation of foam. The mixture was stirred and maintained at 60° C. until all the solid dissolved - about 30 minutes. It was then heated in a boiling water bath to reflux and held there for 2 hours.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11](=[O:15])OCC)=[N:2]1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.O>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11]([N:26]2[CH2:25][CH2:24][N:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[F:16])[CH2:28][CH2:27]2)=[O:15])=[N:2]1
Reactant: CCOC(=O)Nc1n[nH]c2ccccc12
Reactant: Fc1ccccc1N1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1n[nH]c2ccccc12)N1CCN(c2ccccc2F)CC1
Temperature: 100 °C
Yield: 54.2 %

Procedure:
Ethyl 1H-indazol-3-ylcarbamate (81 mg) and 1-(2-fluorophenyl)piperazine (Aldrich Co., 47 mg) were dissolved in dimethylformamide (2 ml), and the mixture was stirred with heating at 100° C. for 11 hr. After allowing to cool, water was added to the reaction mixture, and the precipitated solid was collected by filtration and dried to give 4-(2-fluorophenyl)-1-piperazinecarboxylic acid (1H-indazol-3-yl)amide (48 mg, yield 57%).
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16](O)=[O:17])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2].C[N:21]1CCOCC1.ClC(OCC)=O>O1CCCC1.C(Cl)Cl>[C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([NH2:21])=[O:17])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Reactant: CN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(N)=O)NC1=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid (0.30 g, 1.05 mmol) is dissolved in tetrahydrofuran (5.0 mL). 4-Methylmorpholine (0.14 mL, 1.05 mmol) is then added, and the reaction is cooled to -20° C. Ethyl chloroformate (0.1 mL, 1.05 mmol) is then added, and the reaction is stirred at -20° C. for 30 minutes. The reaction is then filtered, and the filtrate is concentrated to give a yellow oil. This oil is dissolved in methylene chloride (20.0 mL), and anhydrous ammonia gas is bubbled through the solution for 1 hour. The bubbling is stopped, and the reaction is stirred an additional 1 hour. The solvent is evaporated, and the residue is partitioned between ethyl acetate and water. The aqueous layer is extracted several times with ethyl acetate, the combined organic layers are dried (Na2SO4), and the solvent is evaporated to give trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxamide, MS:M+1=287.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].[OH-].[Na+]>C(O)(=O)C>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:12][CH2:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CCc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)CCNc1ccc(CC)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 4-ethyl aniline (10.0 g) in acetic acid (25 mL) was added ethyl acrylate (10.8 g). The mixture was heated to 80° C. for 2 hours. Additional ethyl acrylate (1.0 mL) was added, and the mixture was again heated to 80° C. for 1 hour. The mixture was allowed to cool to room temperature and stir for two days. Sodium hydroxide (8N) was added until the pH equaled 9. The mixture was partitioned between dichloromethane and water and the combined organics were washed once with 1N sodium hydroxide, once with brine, dried with sodium sulfate, filtered, and concentrated. The mixture was chromatographed using a 20% ethyl acetate in heptane solvent solution. A mixture of the mono and di ester product (19.5 g) were obtained (1:1 mixture). MS (ESI+) for C13H19NO2 m/z 221.99 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:38])([CH3:37])[O:11][Si:12]([O:29][Si:30]([CH3:36])([CH3:35])[CH2:31][CH2:32][CH2:33][OH:34])([O:21][Si:22]([CH3:28])([CH3:27])[CH2:23][CH2:24][CH2:25][OH:26])[O:13][Si:14]([CH3:20])([CH3:19])[CH2:15][CH2:16][CH2:17][OH:18]>N1C=CC=CC=1>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:37])([CH3:38])[O:11][Si:12]([O:29][Si:30]([CH3:35])([CH3:36])[CH2:31][CH2:32][CH2:33][O:34][S:2]([CH3:1])(=[O:4])=[O:3])([O:13][Si:14]([CH3:19])([CH3:20])[CH2:15][CH2:16][CH2:17][O:18][S:2]([CH3:1])(=[O:4])=[O:3])[O:21][Si:22]([CH3:28])([CH3:27])[CH2:23][CH2:24][CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(CCCO)O[Si](O[Si](C)(C)CCCO)(O[Si](C)(C)CCCO)O[Si](C)(C)CCCO
Solvent: c1ccncc1
Product: C[Si](C)(CCCOS(C)(=O)=O)O[Si](O[Si](C)(C)CCCOS(C)(=O)=O)(O[Si](C)(C)CCCOS(C)(=O)=O)O[Si](C)(C)CCCOS(C)(=O)=O

Procedure:
Tetrakis(bromopropyldimethylsiloxy)silane was synthesized by the following reactions starting from tetrakis(dimethylsiloxy)silane. Thus, allyloxytrimethylsilane was reacted with tetrakis(dimethylsiloxy)silane in the presence of a platinum 1,1,3,3-tetramethyl-1,3-divinyldisiloxane complex as catalyst to produce tetrakis(trimethylsiloxypropyldimethylsiloxy)silane, from which the trimethylsiloxy group was subsequently eliminated by the action of excess methanol to give tetrakis(hydroxypropyldimethylsiloxy)silane. Methanesulfonyl chloride was then reacted in pyridine with the tetrakis(hydroxypropyldimethylsiloxy)silane to give tetrakis(methanesulfonyloxypropyldimethylsiloxy)silane, which was subsequently reacted with sodium bromide in DMF to give tetrakis(bromopropyldimethylsiloxy)silane:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:27])[N:8]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:37][C:38]([Cl:45])([Cl:44])[CH2:39][O:40][C:41](Cl)=[O:42]>C1COCC1>[Cl:37][C:38]([Cl:45])([Cl:44])[CH2:39][O:40][C:41](=[O:42])[NH:27][C:7]1[N:8]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3cnn(CCN4CCOCC4)c3c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc3cnn(CCN4CCOCC4)c3c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.1 %

Procedure:
A solution of Intermediate 24a (134 mg, 0.36 mmol) was formed in THF (10 mL). DIPEA (125 μL, 0.72 mmol) was added followed by the dropwise addition of a solution of 2,2,2-trichloroethylchloroformate (50 μ□L, 0.36 mmol) in THF (2 mL). The mixture was stirred at RT for 4 h, then partitioned between EtOAc/water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification by FCC, using 0-10% MeOH in EtOAc, gave the title compound (200 mg, 99%) as a colourless film. LCMS (Method 4): Rt 2.59, m/z 543, 545 [MH+].
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:15]=[C:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23]>C(#N)C>[C:9]1([NH:8][CH2:15][CH:16]2[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]2=[O:23])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: C=C1CCC(=O)NC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(CNc2ccccc2)C(=O)N1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
30 ml absolute triethylamine and 2.75 ml freshly distilled aniline were added to a solution of 1.25 g 3-methylene piperidine-2,6-dione (M. J. Wanner and G. -J. Koomen, Tetrahedron Lett. 1992, 33, 1513-1516) in 100 ml acetonitrile and the mixture was stirred for 16 h at 80° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=5)[CH:20]=4)[OH:15])=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccc(Cl)cc2)nn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5ccc(Cl)cc5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(4-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([N:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]3)=[CH:16][CH:15]=2)[CH:13]=1.Cl[C:48]([O:50][CH2:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:49]>>[CH3:53][C:52]([CH3:55])([CH3:54])[CH2:51][O:50][C:48]([N:44]1[CH2:45][CH2:46][N:41]([C:38]2[CH:39]=[CH:40][C:35]([C:32]3[CH:31]=[CH:30][C:29]([CH2:28][C:11]4[N:12]([C:14]5[CH:15]=[CH:16][C:17]([N:20]6[CH2:21][C:22](=[O:27])[NH:23][S:24]6(=[O:26])=[O:25])=[CH:18][CH:19]=5)[CH:13]=[C:9]([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])[N:10]=4)=[CH:34][CH:33]=3)=[CH:36][CH:37]=2)[CH2:42][CH2:43]1)=[O:49]
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCNCC5)cc4)cc3)cc2)S(=O)(=O)N1
Reactant: CC(C)(C)COC(=O)Cl
Product: CC(C)(C)COC(=O)N1CCN(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)CC1

Procedure:
5-{4-[4-(2,4-Dichloro-phenyl)-2-(4′-piperazin-1-yl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (20 mg, 0.03 mmol) was treated as described in general procedure U using neopentyl chloroformate (9 mg, 0.06 mmol) to give 4-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-piperazine-1-carboxylic acid 2,2-dimethyl-propyl ester.
Reaction SMILES: [CH3:1][N:2]([S:26]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)(=[O:28])=[O:27])[C:3]1[CH:4]=[C:5]([O:21][C:22]([F:25])([F:24])[F:23])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C[N:36](C)CCCN=C=NCC.CN(C)C=O>O>[CH3:1][N:2]([S:26]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)(=[O:28])=[O:27])[C:3]1[CH:4]=[C:5]([O:21][C:22]([F:24])([F:25])[F:23])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH2:36])=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CN(c1cc(OC(F)(F)F)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cc(OC(F)(F)F)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.9 %

Procedure:
A mixture of {2-[7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (210 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (90 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (120 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr. 1H-1,2,3-Benzotriazol-1-ol-ammonia complex (150 mg) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (190 mg) were added to the reaction mixture, and the mixture was further stirred at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was purified by preparative HPLC to give the title compound (90 mg, yield 43%) as pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give pale-yellow prism crystals. melting point 186-187° C. MS: 519 (MH+).
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH3:4].N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]([O:11][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH3:4]
Reactant: CCCCCCC(C)(O)CC
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCC(C)(CC)OC(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
40.0 G. (0.25 mole) of 3-methylnonan-3-ol, 20. g. of pyridine and 60 ml. of toluene are combined and cooled to 5° C. under agitation. To the resulting solutin is added, under agitation, over a period of 1 to 2 hours while maintaining the reaction temperature between 5°-15° C., a solution of 35.15 g. (0.25 mole) of benzoyl chloride, dissolved in 30 ml. of toluene. The source of cooling is removed and the reaction mixture is agitated overnight, permitting the temperature of the reaction mixture to rise to room temperature (25°-30° C.). After completion of the reaction, the formed pyridine hydrochloride is removed by successive washings with 100 ml. of warm water. The solvent is removed by distillation and the desired ester is rectified by fractional distillation in a vacuum, preferably at 1 mm.
Reaction SMILES: CO[N:3]=[C:4]1[C:12]2[C:7](=[C:8]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.N>CO.[Ni]>[N:13]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:7]=2[CH2:6][CH2:5][CH:4]3[NH2:3])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CON=C1CCc2c1cccc2N1CCCCC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NC1CCc2c1cccc2N1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Piperidin-1-ylindan-1-one O-methyloxime (4.33 g, 17.7 mmol) was added to a mixture of 20% ammonia in methanol (200 mL) and Raney 2800 nickel (43 g) in a stainless steel autoclave. The reactor was sealed and flushed with nitrogen, and then it was pressurized with hydrogen (60 psi). The mixture was stirred at ambient temperature for 90 minutes. The Raney nickel was filtered off, washed with methanol and the filtrate was concentrated. Obtained 4-piperidin-1-ylindan-1-yl-amine (3.81 g, 99%) as a yellow oil. MS (DCI/NH3) m/z: 217.13 [M+H]+. 1H NMR (DMSO-d6) δ: 1.51 (m, 3H), 1.62 (m, 4H), 1.77 (s, 2H), 2.28 (m, 1H), 2.62 (m, 1H), 2.80 (m, 3H), 2.94 (m, 2H), 4.14 (t, 1H), 6.71 (d, 1H), 6.95 (d, 1H), 7.09 (t, 1H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([C:17]2(O)[CH:22]=[CH:21][NH:20][C:19](=[O:23])[NH:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]>C(O)C>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[N:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(C2(O)C=CNC(=O)N2)cc1OC1CC2CCC1C2
Solvent: CCO
Product: COc1ccc(-c2cc[nH]c(=O)n2)cc1OC1CC2CCC1C2
Temperature: 25 °C
Yield: 31.5 %

Procedure:
The hydroxy pyrimidinone of Example 60 (0.2 g, 0.61 mmol) is dissolved in 5 ml ethanol, treated with 2.5 ml 1N HC1 and refluxed for 6 hours. The reaction is cooled to room temperature, quenched with water and the product extracted 3x ethyl acetate. The organics are washed, dried, filtered and concentrated in vacuo to yield a crude substance which is crystallized from ethyl acetate to give 60 mg (31.5%) of the pyrimidinone as a crystalline solid. This material is a 7:3 mixture of endo-exo bicycloalkyl isomers.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.C(OC([NH:19][C@H:20]([CH2:28][N:29]([CH3:39])[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])[C@@H:21]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[OH:22])=O)(C)(C)C>CCO.CCOCC>[NH2:19][C@H:20]([CH2:28][N:29]([CH3:39])[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])[C@@H:21]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[OH:22]
Reactant: CN(C[C@@H](NC(=O)OC(C)(C)C)[C@H](O)C1CCCC1)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CCO
Product: CN(C[C@@H](N)[C@H](O)C1CCCC1)C(=O)OCC[Si](C)(C)C

Procedure:
A solution of TsOH (36.8 mg, 0.194 mg) in 1.0 mL EtOH (1 mL) was added to (1R,2R)-2-(t-butoxycarbonylamino)-1-cyclopentyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-1-ol (68.2 mg, 0.164 mmol) in 3.0 mL Et2O (3 mL). The solvent was removed under reduced pressure at 60° C. and the residue maintained at this temperature for 1 h. The residue was taken up into CH2Cl2 (50 mL), washed with 1 N aq NaOH and brine, and dried over Na2SO4. Removal of the solvent left (1R,2R)-2-amino-1-cyclopentyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-1-ol which was used without purification.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][N:11]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]2)=[O:21])[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:41]>>[Cl:41][C:17]1[CH:18]=[CH:19][C:14]([C@H:13]2[C@H:9]([NH:7][CH3:6])[CH2:10][N:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[O:21])[CH2:12]2)=[CH:15][CH:16]=1
Reactant: ClCCl
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)cc1
Yield: 98 %

Procedure:
To a solution of rac-[(3S,4R)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (0.86 g, 1.61 mmol) in CH2Cl2 (12 ml) was added TFA (3 ml) at RT. Stirring was continued over night. The reaction mixture was then concentrated under vacuo, the crude dissolved in CH2Cl2, washed with aq.NaHCO3 and the organic phase dried over Na2SO4. Purification by flash chromatography (SiO2, CH2Cl2/MeOH 95:5) yielded 0.68 g (98%) of the title compound as a white solid. ES-MS m/e: 401.3 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].C(O[C:27](=N)[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])C.C(=O)([O-])O.[Na+]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:27]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: CCOC(=N)CC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Yield: 95.1 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (200 mg, 0.646 mmol) in ethanol (5 mL) was added ethyl 3-ethoxy-3-iminopropionate (190 mg, 0.969 mmol), and this was heated to reflux for 2 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with ethyl acetate. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The crystals obtained were purified by silica gel column chromatography to yield the title compound (249 mg, 95% yield) as gray crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:39][CH2:40][C:41]#[N:42].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[C:41]([CH2:40][CH2:39][N:19]1[CH2:20][CH2:21][CH:16]([C:14]([N:12]2[CH2:13][CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH:10]([N:22]([CH3:37])[C:23](=[O:36])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:25]=3)[CH2:11]2)=[O:15])[CH2:17][CH2:18]1)#[N:42]
Reactant: N#CCCBr
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(CCC#N)CC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
To a solution of N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (50 mg, 0.090 mmol) in dichloromethane (1 mL) was added 3-bromopropionitrile (11 μL, 0.13 mmol) and an aqueous saturated solution of sodium carbonate (1000 μL). The resulting suspension was stirred for 18 h at ambient temperature. After the addition of dichloromethane (1 mL) and further 3-bromopropionitrile (11 μL, 0.13 mmol) it was stirred for 6 h at 40° C. After diluting with ethyl acetate (10 mL) the mixture was washed with an aqueous solution of sodium carbonate (10 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:(ethyl acetate:triethylamine=95:5):methanol=20:80:0:0 to 0:0:90:10) afforded the title compound (51 mg, 93%) as an light brown foam. MS m/e: 611.2 [M]+.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C:14]2[C:13](=[O:15])[CH:12]=[CH:11][C:10](=[O:16])[C:9]=2[CH2:8][C@H:7]([CH2:17][CH3:18])[O:6]1)(=[O:3])[CH3:2].C(O[CH:23]=[CH:24][CH:25]=[CH2:26])(=O)C>C1(C)C=CC=CC=1>[O:16]=[C:10]1[C:9]2[CH2:8][C@H:7]([CH2:17][CH3:18])[O:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C:14]=2[C:13](=[O:15])[C:12]2[C:11]1=[CH:23][CH:24]=[CH:25][CH:26]=2
Reactant: C=CC=COC(C)=O
Reactant: CC[C@H]1CC2=C(C(=O)C=CC2=O)[C@H](NC(C)=O)O1
Solvent: Cc1ccccc1
Product: CC[C@H]1CC2=C(C(=O)c3ccccc3C2=O)[C@H](NC(C)=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the starting quinone from step 1 herein (56 mg; 0.22 mmol) in toluene (50 ml) was added 1-acetoxy-1,3-butadiene (30 μl; 11 eq). The mixture was stirred overnight at room temperature and was then concentrated and applied to a column of silica gel using 1-15% acetone in benzene to elute the product which was then recrystallized from dichloromethane:pentane affording the title compound as a yellow solid (10 mg; 15%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7]1([S:13](Cl)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[OH-].[Na+]>[C:7]1([S:13]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Yield: 95 %

Procedure:
N-benzenesulfonylalanine was prepared by mixing equimolar quantities of alanine and benzenesulfonyl chloride at 60° C. in aqueous sodium hydroxide (200 mol%). A 95% yield was obtained. The method is set out in the previously mentioned book "Chemistry Of The Amino Acids".