Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:24])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([NH:20][CH2:21][CH2:22][OH:23])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]>CO.[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[O:24])=[CH:12][C:13]=1[NH:20][CH2:21][CH2:22][OH:23]
Reactant: Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])c(NCCO)c2)cc1C
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc(N)c(NCCO)c2)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-(3,4-dimethyl-phenyl)-3-(2-hydroxyethylamino)-4-nitro-benzamide (70 mg) in MeOH (20 mL) was added 10% Pd/C (10 mg). The reaction mixture was stirred under H2 balloon at room temperature for 16 h. The reaction mixture was filtered through celite, washed with MeOH. The filtrate was concentrated under reduced pressure to give 4-amino-N-(3,4-dimethyl-phenyl)-3-(2-hydroxy-ethylamino)-benzamide as a grey solid; MS (m/z) 300 (M+1); 1H NMR (DMSO-d6, 400 MHz) δ 9.54 (s, 1H), 7.51 (s, 1H), 7.45 (d, 1H), 7.18 (d, 1H), 7.04 (d, 2H), 6.57 (d, 1H), 5.12 (s, 2H), 4.69 (t, 1H), 4.50 (t, 1H), 3.65 (q, 2H), 3.19 (q, 2H), 2.20 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [CH2:1]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]1[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH3:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl>[CH2:1]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]1[O:12][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([CH3:24])[CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1(C(=O)OCC)CCCC1O
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCC1(C(=O)OCC)CCCC1OC(=O)c1cccc(C)c1

Procedure:
6.05 grams (0.025 mol) of ethyl 1-n-hexyl-2-hydroxy-cyclopentane carboxylate obtained in Example 17 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 3.05 ml (0.0375 mol) of pyridine was slowly added, then 4.99 ml of 3-methyl-benzoyl chloride was dropwise added. Then the procedure as described in Example 23 was followed, to give 10.01 g of brown liquid. MS: m/e 361(M++1), 360(M+′), 315(M+—OCH2CH3), 287(M+—CO2CH2CH3), 276, 241(M+—CH3C6H4CO), 225(M+—CH3C6H4CO2), 195, 151, 140, 119(base), 118, 91, 77.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][C:10](OCC)=[O:11])#[N:2].[BH4-].[Na+]>C(O)C>[OH:11][CH2:10][CH2:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CCOC(=O)Cc1cnccc1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccncc1CCO
Yield: 36.3 %

Procedure:
Ethyl 2-(4-cyanopyridin-3-yl)acetate (2.3 g, 12.10 mmol) was reacted with NaBH4 (919 mg, 24.21 mmol) and ethanol (20 mL) at room temperature for 72 hours to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 650 mg of the product.
Reaction SMILES: C([N:3](C=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:6])=O.[ClH:17].C(O)C>>[ClH:17].[NH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:6]
Reactant: COc1ccccc1C(=O)CN(C=O)C=O
Agent: Cl
Solvent: CCO
Product: COc1ccccc1C(=O)CN
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 2-(diformyl-amino)-2′-methoxyacetophenone (3.28 g) and 5% hydrogen chloride-ethanol solution (37 ml) was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether. To the powder was again added 5% hydrogen chloride-ethanol solution and the mixture was stirred at room temperature for one day, and the mixture was concentrated under reduced pressure. The residue was washed with diethyl ether and ethyl acetate to obtain 2-amino-2′-methoxyacetophenone hydrochloride (2.91 g) as colorless solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[C:16]#[N:17])(=O)=O.[CH3:20][C:21]([CH3:26])=[CH:22]B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.CCOC(C)=O>[N+:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH:20]=[C:21]([CH3:26])[CH3:22])[C:8]=1[C:16]#[N:17])([O-:15])=[O:14]
Reactant: CC(C)=CB(O)O
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)=Cc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Yield: 61.3 %

Procedure:
A suspension of 2-cyano-3-nitrophenyl trifluoromethanesulfonate (Example 129d) (4.80 g; 16.21 mmol), 2-methyl-1-propenylboronic acid (2.43 g; 24.32 mmol), tetrakis(tiphenylphosphine)palladium(0) (1.87 g; 1.62 mmol), sodium carbonate (1.89 g; 17.83 mmol) and water (33.0 mL) in dimethoxyethane (DME) (132.0 mL) was heated at reflux for 4 h, under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water (100 mL) and EtOAc (250 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3×100 mL). The combined extract was washed with brine and dried with anhydrous MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using gradient hexanes to hexanes/EtOAc (7:3), to give 2.01 g (61%) of the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.19-8.23 (m, 1H), 7.83-7.93 (m, 2H), 6.45 (broad s, 1H), 1.95-1.98 (m, 3H), 1.75-1.79 (m, 3H).
Reaction SMILES: [C:1]([Si:5]([CH3:32])([CH3:31])[O:6][CH2:7][C@H:8]([NH:10][C:11](=[O:30])[N:12]([CH2:21][C:22]1[C:23](Cl)=[N:24][C:25]([Cl:28])=[N:26][CH:27]=1)[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>O1CCCC1>[C:1]([Si:5]([CH3:31])([CH3:32])[O:6][CH2:7][C@H:8]([N:10]1[C:23]2=[N:24][C:25]([Cl:28])=[N:26][CH:27]=[C:22]2[CH2:21][N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:11]1=[O:30])[CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCc1ccc(N(Cc2cnc(Cl)nc2Cl)C(=O)N[C@H](C)CO[Si](C)(C)C(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1ccc(N2Cc3cnc(Cl)nc3N([C@H](C)CO[Si](C)(C)C(C)(C)C)C2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of (R)-3-[2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-1-(2,4-dichloro-pyrimidin-5-yl-methyl)-1-(4-ethyl-phenyl)-urea (380 mg, 0.76 mmol) (from Example 38d supra) in tetrahydrofuran (10 mL) was treated at room temperature with potassium tert-butoxide (160 mg, 1.14 mmol) (Aldrich). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue (395 mg, yellow oil) was purified by flash chromatography to give (R)-1-[2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-7-chloro-3-(4-ethyl-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a colorless oil. (Yield 102 mg, 30%).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][O:12][C:13](=[O:25])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:15]=1[CH3:24]>ClCCl>[CH3:11][O:12][C:13](=[O:25])[C:14]1[C:15]([CH3:24])=[C:16]([O:22][CH3:23])[CH:17]=[C:18]([O:20][CH3:21])[C:19]=1[CH:3]=[O:4]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(OC)cc(OC)c1C
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1c(C)c(OC)cc(OC)c1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 340 ml of N,N-dimethylformamide in 1 l of dichloromethane were added slowly 404 ml of phosphoryl chloride. The solution was stirred for 1.5 h at room temperature, and then, a solution of 618 g of 3,5-dimethoxy-2-methylbenzoic acid methyl ester in 200 ml of dichloromethane was added within 10 min. The mixture was heated for 72 h at reflux temperature. After cooling, the mixture was slowly poured into 3 l of ice-water and subsequently extracted with 3.6 l of dichloromethane. The organic layer was washed with 2 l of saturated sodium carbonate solution and twice with 2 l of water. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The solid residue was triturated in 3 l of ethyl acetate at 60° C., and after cooling, 1.5 l of hexane were added. The solid was isolated by filtration to yield 646 g of 2-formyl-3,5-dimethoxy-6-methylbenzoic acid methyl ester, m.p. 164°-165° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([Cl:21])(=[O:20])=[O:19].[Cl:22]C1C=CC(C(O)=O)=CC=1>>[Cl:22][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([Cl:21])(=[O:20])=[O:19]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: COc1ccc(C(=O)c2ccc(F)c(S(=O)(=O)Cl)c2)cc1
Product: COc1ccc(C(=O)c2ccc(Cl)c(S(=O)(=O)Cl)c2)cc1

Procedure:
The title compound is prepared as described above for 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride, starting with 4-chloro-benzoic acid.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=O)[CH3:8])[CH3:3].[CH3:12][C:13]([CH3:15])=[O:14]>CCOCC>[CH3:8][C:7]([CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])=[CH:9][CH:10]=[CH:12][C:13](=[O:14])[CH3:15]
Reactant: CC(C)=CCCC(C)=CC=O
Reactant: CC(C)=O
Solvent: CCOCC
Product: CC(=O)C=CC=C(C)CCC=C(C)C
Temperature: 67.5 °C
Yield: 91 %

Procedure:
1.00 mL (5.84 mmoles) of citral (purchased from Aldrich Chemical Co., Milwaukee, Wis.), 20 mL of acetone (HPLC-grade, purchased from Aldrich Chemical Co.), and 1.66 g of alumina (weakly acidic, activated, Brockmann I, 150 mesh, Aldrich catalog #26,774-0) were added to a 200 mL glass pressure bottle containing a Teflon-coated spin bar. After sweeping the bottle briefly with a stream of nitrogen gas, the bottle was closed; and the mixture was subsequently heated at 65-70° C. (external oil bath temperature) for 20 hours. After cooling the mixture to room temperature, the product was isolated by dilution of the reaction mixture with 160 mL of 3:1 (v/v) ether: dichloromethane and removal of the alumina by filtration through a small pad of Hyflo Super-Cel® filtering aid. For large-scale reactions, fractional distillation of this filtrate would be the only requirement to complete the process of isolating the product. For convenience in a small-scale reaction, the filtrate was washed three times with 140 mL portions of 5% (w/v) aqueous sodium chloride to remove 4-hydroxy-4-methyl-2-pentanone (formed in minor amounts by the self-aldol condensation of acetone), then dried over anhydrous magnesium sulfate, and filtered. Removal of the ether and dichloromethane by evaporation at reduced pressure and subsequent evaporative ("Kugelrohr oven") distillation afforded 1.03 g (91% yield) of the named unsaturated ketone: boiling point 102-110° C. (bath temperature, 0.40 mm). The identity and purity of this compound was ascertained by IR and proton NMR analysis (recorded at 400 MHz). The latter spectrum exhibited a multiplet at δ 7.42 (C-4 vinyl H), a doublet (J=14.8 Hz) at δ 6.08 (C-3 vinyl H), a doublet (J=12 Hz) at δ 6.004 (C-5 vinyl H), a multiplet at δ 5.09 (C-9 vinyl H), a singlet at δ 2.27 (CH3C=O), and signals for three vinyl methyl groups at δ 1.90 (CH3 bonded to C-6), 1.676, and 1.606.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)COC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a mixture of ethyl 2-hydroxyacetate (2 g, 20 mmol, TCI) and 3,4-dihydro-2H-pyran (3.2 g, 40 mmol, Alfa) in 40 mL of CH2Cl2 was added PPTS (500 mg, 2 mmol, Aldrich) in portions at rt. The mixture was stirred at rt for 4 hours. The reaction mixture was then washed with brine, and the organic layer was separated and the combined organic phases were dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) petroleum ether/EtOAc) to give the desired compound as colorless oil (3.01 g, 81%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1Br)(=[O:3])[CH3:2].[CH3:27][C:28]1[C:32](B(O)O)=[C:31]([CH3:36])[O:30][N:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:32]1[C:28]([CH3:27])=[N:29][O:30][C:31]=1[CH3:36])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnccc1Br
Reactant: Cc1noc(C)c1B(O)O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnccc1-c1c(C)noc1C

Procedure:
By carrying out the operation analogously to example 177, starting from 4-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation II, and 3,5-dimethyl-4-isoxazoleboronic acid, the desired product is obtained in the form of a pink powder (yield=30%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.S(=O)(=O)(O)O.[N+:16]([O-])([O-:18])=[O:17].[K+].N.Cl>>[N+:16]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][NH:2][CH2:1]2)=[CH:6][CH:7]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: c1ccc2c(c1)CCNC2
Agent: Cl
Agent: N
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2c(c1)CNCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
1,2,3,4-Tetrahydroisoquinoline (50 g; 1 equiv.) was added at 0° C., in the course of 90 minutes, to 185 ml of sulfuric acid, and the reaction mixture was stirred for 30 minutes at 0° C. Potassium nitrate (40.7 g; 1.2 equiv.) was then added in portions, and stirring was carried out for 15 hours at room temperature. When the conversion was complete, the reaction mixture was shaken on 500 g of ice and adjusted to pH 8-9 with ammonia solution. Extraction with chloroform was then carried out 3 times, and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in IPA (500 ml) and cooled to 0° C., and hydrochloric acid (2 equiv.) was added. The resulting solid was filtered out and recrystallised from methanol. 7-Nitro-1,2,3,4-tetrahydroisoquinoline (35 g; 52.3%) was obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([S:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:14](Cl)(=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH3:13][S:12][C:11]1[C:2]([NH:1][C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: CSc1ccc2ncccc2c1N
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1c(SC)ccc2ncccc12

Procedure:
5-Amino-6-methylthioquinoline, prepared as described in Example 34, and commercially available oleoyl chloride were coupled to give the title compound according to the procedure described in Example 25. Mass psectrum m/e: 454.3 (M+).
Reaction SMILES: [N+](C1C=CC([N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:11](=[O:13])[O-])=CC=1)([O-])=O.C(N(CC)C(C)C)(C)C.[NH2:35][C@@H:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:37][OH:38]>ClCCl>[OH:38][CH2:37][C@@H:36]([NH:35][C:11]([NH:10][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1)=[O:13])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C([O-])N(c1ccc(-c2ccncc2)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: N[C@H](CO)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2ccncc2)cc1)N[C@H](CO)c1ccccc1
Reaction time: 20 h
Yield: 81.6 %

Procedure:
To a solution of 4-nitrophenyl[4-(4-pyridinyl)phenyl]carbamate (7.50 g) and N,N-diisopropylethylamine (5.84 mL) in dichloromethane (150 mL) was added (2S)-2-amino-2-phenylethanol (4.60 g) at ambient temperature and the mixture was stirred at the same temperature for 20 hours. The resulting mixture was concentrated in vacuo and then water (45 mL) and ethyl acetate (45 mL) was added to the residue. The precipitated solid was collected by filtration and washed with water (30 mL×5) to obtain yellow crystals. The crystals were triturated with ethyl acetate (30 mL) to give 1-[(1S)-2-hydroxy-1-phenylethyl]-3-[4-(4-pyridinyl)phenyl]urea (6.1 g) as a slightly yellow crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C:11]1[N:12]([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19](C(=O)C3C=CC=CC=3)[CH2:18][C:17]2([CH3:35])[CH3:34])[CH:13]=[N:14][CH:15]=1)=O.[F-].[Na+].O>C1COCC1>[CH3:34][C:17]1([CH3:35])[CH:16]([N:12]2[C:11]([CH2:9][OH:8])=[CH:15][N:14]=[CH:13]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH2:18]1
Reactant: COC(=O)c1cncn1C1c2ccccc2N(C(=O)c2ccccc2)CC1(C)C
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CNc2ccccc2C1n1cncc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
LiAlH4 (26 mg, 0.68 mmol) is carefully added to a solution of 3-(1-benzoyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester (101 mg, 0.26 mmol) in THF (10 mL) at 0° C. The resulting mixture is warmed up to room temperature. After overnight, NaF and water are added at 0° C. Then the reaction mixture is warmed up to room temperature and stirred until the grey suspension turned to off white color. The mixture is filtered and the filtrate is concentrated and taken up into ethyl acetate and washed with brine, and dried over anhydrous sodium sulfate. After concentration, the residue is purified by flash chromatography and gives the title compound (23 mg, 34.5% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.81 (s, 3 H), 1.08 (s, 3 H), 2.68 (br. s., 1 H), 2.97 (d, J=12.1 Hz, 1 H), 3.19 (d, J=12.1 Hz, 1 H), 4.22 (br. s., 1 H), 4.73 (s, 2 H), 5.11 (s, 1 H), 6.54-6.61 (m, 2 H), 6.87 (s, 1 H), 6.92 (d, J=7.3 Hz, 1 H), 7.08 (t, J=8.3 Hz, 1 H), 7.28 (s, 1 H). HRMS: calculated for C15H20N3O: 258.1606. Found: 258.1615.
Reaction SMILES: [C:1]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[CH:10]=[C:11](O)[C:12]([NH:14][C@H:15]([C:23](=[O:25])[NH2:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([C:5]1[O:9][CH:8]=[N:7][C:6]=1/[CH:10]=[C:11]1/[C:12](=[O:13])[NH:14][C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23](=[O:25])[NH:24]/1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ocnc1C=C(O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)c1ocnc1/C=C1\NC(=O)[C@H](Cc2ccccc2)NC1=O

Procedure:
The effect of the amount of acid catalyst and reaction time was evaluated. (S,Z)-3-[(5-tert-Butyloxazol-4-yl)methylene]-6-benzylpiperazine-2,5-dione was prepared by reacting 3-(5-tert-Butyloxazol-4-yl)-N-((S)-1-carbamoyl-2-phenylethyl)-2-hydroxyacrylamide with various amounts of p-toluenesulfonic acid for various times. Enantiomeric excess of the product was determine by chiral HPLC using a CHIRALCEL OD column eluted with n-Hexane:Ethanol (5:1). The reaction conditions, product yields, and enantiomeric excess is present is Table 4.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH3:27])=[CH:14][CH:13]=2)[CH:11]=1)=[O:6].[C:28]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])([CH3:30])[CH3:29].N1C=CN=C1.CN(C)C=O>[Cl-].[Na+].O>[Si:32]([O:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH3:27])=[CH:14][CH:13]=2)[CH:11]=1)=[O:6])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:34])[CH3:33]
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)NCCO)cn2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)NCCO[Si](C)(C)C(C)(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
A mixture of N-(2-hydroxyethyl)-1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazole-4-carboxamide prepared in Example 66 (0.500 g), tert-butylchlorodimethylsilane (0.303 g), imidazole (0.273 g) and N,N-dimethylformamide (5.0 mL) was stirred overnight at room temperature. The reaction mixture was diluted with brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=1:1) to give the titled compound (0.550 g) as a colorless solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:14]1([CH2:17][NH:18][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)[CH2:16][CH2:15]1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: NCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(NCC2CC2)cc1C(F)(F)F
Temperature: 20 °C
Yield: 99.1 %

Procedure:
A mixture of 4-fluoro-2-(trifluoromethyl)benzonitrile (9.45 g, 50 mmol), 1-cyclopropylmethanamine (5.0 g, 70 mmol), and potassium carbonate (10 g) was stirred for 12 hours in acetonitrile (50 mL) at 55° C. The mixture was cooled to 20° C., filtered, and the filter-cake was washed with acetonitrile (3×25 mL). The filtrate was concentrated under vacuum to obtain 11.9 g (99%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=8.6 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 6.65 (dd, J=8.6, 2.4 Hz, 1H), 4.62 (bs, 1H), 3.02 (d, J=7.1 Hz, 2H), 1.09 (m, 1H), 0.61 (m, 2H), 0.27 (m, 2H).
Reaction SMILES: [CH2:1]([N:4]([CH:10]([CH3:16])[CH:11](OC)[O:12]C)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].O.[Cl-].[Na+]>C(O)=O>[CH2:1]([N:4]([CH:10]([CH3:16])[CH:11]=[O:12])[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCN(C(=O)OCC)C(C)C(OC)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: C=CCN(C(=O)OCC)C(C)C=O

Procedure:
182 g (0.787 mol) of ethyl N-allyl-N-(1,1-dimethoxyprop-2-yl)-carbamate in 1.5 1 of water are heated under reflux for three hours with 80 ml of formic acid. The mixture is saturated with sodium chloride, the organic phase is separated off and the aqueous phase is extracted twice with 500 ml of methylene chloride each time. The organic solutions are washed with saturated sodium hydrogen carbonate solution until neutral, dried over magnesium sulphate and concentrated, and the residue is distilled.
Reaction SMILES: C1(N2C(=O)C3=CNC4C=[CH:15][C:16]([N:19]5[CH2:24]CN[CH2:21][CH2:20]5)=CC=4C3=N2)C=CC=CC=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:35]2[NH:34][CH:33]=[C:32]3[C:38](=[O:49])[N:39]([C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[N:40]=[C:31]3[C:30]=2[CH:29]=1.CN1CCNCC1>>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([N:39]2[C:38](=[O:49])[C:32]3=[CH:33][NH:34][C:35]4[CH:36]=[CH:37][C:28]([N:27]5[CH2:21][CH2:20][N:19]([CH3:24])[CH2:16][CH2:15]5)=[CH:29][C:30]=4[C:31]3=[N:40]2)=[CH:46][CH:45]=1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)cc3c-2nn1-c1ccccc1
Reactant: COc1ccc(-n2nc3c4cc(N)ccc4[nH]cc-3c2=O)cc1
Agent: CN1CCNCC1
Product: COc1ccc(-n2nc3c4cc(N5CCN(C)CC5)ccc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure for 7a using 6c and 1-methylpiperazine. 1H-NMR (DMSO-d6) δ (ppm): 3.25 (4H, br), 3.45 (3H, s), 3.50 (4H, br), 3.75 (3H, s), 7.00 (1H, d, J=9.06 Hz), 7.40 (1H, m), 7.48 (1H, br), 7.68 (1H, d, J=9.06 Hz), 7.92 (1H, d, J=8.79 Hz), 8.05 (2H, d, J=8.79 Hz), 8.56 (1H, br), 9.12 (1H, br). m/z 390.4 (MH+).