Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:10]([O:14][CH3:15])(=[O:13])[C:11]#[CH:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>C(#N)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][CH:12]=[CH:11][C:10]([O:14][CH3:15])=[O:13]
Reactant: Oc1cc(F)cc(F)c1
Reactant: C#CC(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: C1CCOC1
Product: COC(=O)C=COc1cc(F)cc(F)c1
Reaction time: 1 h
Yield: 102.6 %

Procedure:
A solution of 3,5-difluorophenol (35.5 g, 273 mmol) and methyl propiolate (25.0 mL, 300 mmol) in acetonitrile (109 mL) was added to a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M commercial solution, 109 mL, 109 mmol) at room temperature over a period of 2 hours. After complete addition of the solution, the mixture was stirred for 1 hour. The reaction mixture was diluted with toluene (350 mL) and the organic mixture was washed twice with water (250 mL×2), dried over magnesium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on amino gel (hexane:ethyl acetate=3:2 as an eluent) to afford the title compound as a yellow solid (60.0 g, quant, 1:1 mixture of cis- and trans-isomers).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH:7]2[CH2:12][CH2:11][C:10]3([C:20]4[C:15](=[CH:16][CH:17]=[N:18][CH:19]=4)[C:14](=[O:21])[O:13]3)[CH2:9][CH2:8]2)[NH:4][N:3]=1.[CH2:22](Cl)[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[N:3]([CH2:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[N:4]=[C:5]([CH:7]2[CH2:12][CH2:11][C:10]3([C:20]4[C:15](=[CH:16][CH:17]=[N:18][CH:19]=4)[C:14](=[O:21])[O:13]3)[CH2:9][CH2:8]2)[CH:6]=1
Reactant: Nc1cc(C2CCC3(CC2)OC(=O)c2ccncc23)[nH]n1
Reactant: O=C(CCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(C2CCC3(CC2)OC(=O)c2ccncc23)nn1CC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
3-Amino-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazole (180 mg, 0.633 mmol), phenacyl chloride (150 mg, 0.94 mmol) and potassium carbonate (180 mg, 1.27 mmol) were stirred overnight at room temperature in N,N-dimethylformamide (10 mL). The mixture was stirred for further 1 hour at 80° C. The reaction solution was cooled down to room temperature and ethyl acetate was added thereto. The reaction solution was washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to remove the solvent. The residue was separated and purified by a silica gel column chromatography (C-300, methanol:chloroform=1:50 to 1:30) to obtain the title compound (26.5 mg, 10.4%) as a cis and trans mixture.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:35]=[CH:34][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[CH2:29]Cl)=[CH:23][C:22]=3[O:32][CH3:33])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].C1COCC1.[CH2:41]([NH:43][CH2:44][CH3:45])[CH3:42].[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]/[C:49]([OH:51])=[O:50]>CC(C)=O.C(OCC)C>[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]/[C:49]([OH:51])=[O:50].[CH2:1]([O:3][C:4]1[CH:35]=[CH:34][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[CH2:29][N:43]([CH2:44][CH3:45])[CH2:41][CH3:42])=[CH:23][C:22]=3[O:32][CH3:33])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)CCl)cc1OC
Reactant: CCNCC
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)CN(CC)CC)cc1OC
Reaction time: 15 h

Procedure:
0.55 g of the compound obtained in step A) above was mixed at 20° C. with 20 ml of THF and 10 ml of diethylamine. The reaction mixture was left to stand for 15 hours and then concentrated under vacuum. The residue was taken up with water, extracted with AcOEt and washed with 1N HCl and with water; it was dried over Na2SO4 and the solvent was evaporated off under vacuum. The residue is chromatographed on silica using DCM and then DCM/AcOEt (95/5; v/v) as the eluent to give 0.5 g of a wax, which was converted to a salt with 0.1 g of fumaric acid in 20 ml of acetone. The salt obtained is soluble in ethyl ether. m=0.2 g. M.p.=124° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([NH2:7])=[N:4][N:3]=1.[H-].[Na+].[N+](C1C=CC([O:19][C:20]([N:22]2[CH2:25][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[F:39])=[CH:29][N:28]=3)[CH2:23]2)=O)=CC=1)([O-])=O>CN(C=O)C>[CH3:1][C:2]1[O:6][C:5]([NH:7][C:20]([N:22]2[CH2:23][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[F:39])=[CH:29][N:28]=3)[CH2:25]2)=[O:19])=[N:4][N:3]=1
Reactant: Cc1nnc(N)o1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(-c3ccccc3F)cn2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc(NC(=O)N2CC(Oc3ccc(-c4ccccc4F)cn3)C2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
To a solution of 5-Methyl-[1,3,4]oxadiazol-2-ylamine (31 mg, 0.31 mmol, [Cas. No. 52838-39-8]) in DMF (3 mL) at 0° C. was added sodium hydride (20 mg, 0.5 mmol, 60% disp. in mineral oil). After stirring at 0° C. for 15 min. a solution of 3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid 4-nitro-phenyl ester (102 mg, 0.25 mmol) in DMF (4 mL) was added dropwise. After stirring for 16 hrs at ambient temperature the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (50 mL) and washed sequentially with sat. aqueous sodium hydrogen carbonate solution (2×50 mL) then sat. sodium chloride solution (50 mL). Mixture dried over magnesium sulphate and filtered. Filtrate solvents were removed in vacuo and the residue was purified by preparative HPLC to give the title compound (10 mg, 11%)
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[C:16]([C:17]2[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)=[CH:15][C:10]2[NH:11][C:12](=[O:14])[S:13][C:9]=2[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[C:36]#[CH:37]>O>[F:6][C:7]1[C:16]([C:17]2[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)=[CH:15][C:10]2[N:11]([CH2:37][C:36]#[CH:35])[C:12](=[O:14])[S:13][C:9]=2[CH:8]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc3[nH]c(=O)sc3cc2F)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCn1c(=O)sc2cc(F)c(-c3ccc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To 10 ml of DMF, 0.4 g (1.2 mmol) of 3-(6-fluoro-benzothiazolin-2-on-5-yl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone, 0.18 g (1.3 mmol) of potassium carbonate and 0.15 g (1.3 mmol) of propargyl bromide were added, followed by heating and stirring at 70° C. for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.32 g (yield: 72%) of the desired product. Melting point: 150-151° C. 1H-NMR (300 MHz, CDCl3) δ value: 2.30(1H,t), 3.73(3H,s), 4.73(2H,d), 6.80(1H,d), 7.27(1H,d), 7.45(1H,d), 7.56(1H,d)ppm.
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(OC(C=C([NH:36][CH2:37][C:38]([O-])=[O:39])C)=O)C.[Na+].[K+].[Br-]>>[NH2:36][CH2:37][C:38]([NH:1][CH:2]([C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)[C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:12])([CH3:13])[S:11][C@H:7]12)=[O:4])=[O:39]
Reactant: CCOC(=O)C=C(C)NCC(=O)[O-]
Reactant: CC1(C)S[C@@H]2C(NC(=O)C(N)c3ccc(O)cc3)C(=O)N2C1c1nnn[nH]1
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Product: CC1(C)S[C@@H]2C(NC(=O)C(NC(=O)CN)c3ccc(O)cc3)C(=O)N2C1c1nnn[nH]1
Yield: 45 %

Procedure:
The title compound is prepared in 45% yield from 6-(2-amino-2-[p-hydroxyphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and sodium N-(2-ethoxycarbonyl-1-methylvinyl)-2-aminoacetate, using the procedure of Example XC. The product has m.p. 173°-188° C. (dec.) IR (KBr disc): 1785 cm-1 (β-lactam). NMR (DMSO-d6): 7.55-7.10 ppm (m, 2H), 7.00-6.00 ppm (m, 2H), 5.75-5.40 ppm (m, 3H), 5.10 ppm (s, 1H), 3.65 ppm (m, 2H), 1.55 ppm (s, 3H), 0.95 ppm (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.C(#N)C.CCN(C(C)C)C(C)C.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>O>[Cl:8][C:6]1[CH:7]=[C:2]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:3]2[N:4]([CH:9]=[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:11]=2)[N:5]=1
Reactant: CCOC(=O)Cc1cn2nc(Cl)cc(Br)c2n1
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)Cc1cn2nc(Cl)cc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 28a (1.80 g, 5.66 mmol) was placed in a 20 mL vial equipped with a stir bar and then ACN (11 mL) was added. Once the mixture was homogeneous, DIEA (1.79 mL, 10.3 mmol) was added. Morpholine (0.601 mL, 6.90 mmol) was added and then the reaction was stirred at rt for 3 h during which time the entire solution solidified. The solid was broken up and additional ACN (2 mL) was added. The reaction was stirred for an additional 2 h at rt. The reaction was poured into water (50 mL) and the resulting precipitate was isolated by filtration. The solid was washed with water (2×20 mL) and then dried under reduced pressure to afford compound 28b. 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.73 (s, 1H), 6.05 (s, 1H), 4.20 (q, J=7.1 Hz, 2H), 3.97-4.05 (m, 4H), 3.86-3.93 (m, 4H), 3.79 (s, 2H), 1.28 (t, J=7.2 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C14H17ClN4O3: 325.1 (M+H). Found: 325.1.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[C:20]1([CH:26]2[CH:33]3[CH2:34][CH:29]4[CH2:30][CH:31]([CH2:35][CH:27]2[CH:28]4[CH2:36][C:37](O)=[O:38])[CH2:32]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:20]1([CH:26]2[CH:33]3[CH2:34][CH:29]4[CH2:30][CH:31]([CH2:35][CH:27]2[CH:28]4[CH2:36][C:37]([N:12]2[CH2:13][CH:14]4[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]4)[CH2:11]2)=[O:38])[CH2:32]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)CC1C2CC3CC(C2)C(c2ccccc2)C1C3
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1C3CC4CC(C3)C(c3ccccc3)C1C4)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Triethylamine 1.00 ml was added in a methylene chloride 30 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 815 mg, and stirred at 0° C. for 30 min. 4-phenyl-2-adamantyl acetic acid 774 mg and WSC 1.65 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 16.5 hours. The reaction mixture was washed with 1N hydrochloric acid and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-(4-phenyl-2-adamantylacetyl)1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 229 mg and refluxed under heating for I hour. The reaction mixture was cooled, then added water and 2.5N sodium hydroxide thereto, and removed the insoluble material by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of flash column chromatography (Merck, silica gel 60: 230-400 mesh, chloroform) to obtain the product. Yield: 878 mg (Yield 78%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].S1C=CN=C1C1C=CC(CNS(C2C=NC=CC=2)(=O)=O)=CC=1.[S:56]1[C:60]([CH2:61]O)=[CH:59][C:58]2[CH:63]=[CH:64][CH:65]=[CH:66][C:57]1=2>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:61][C:60]2[S:56][C:57]3[CH:66]=[CH:65][CH:64]=[CH:63][C:58]=3[CH:59]=2)[NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:19])[N:10]=1)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2cccnc2)n1
Reactant: OCc1cc2ccccc2s1
Agent: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2cc3ccccc3s2)NS(=O)(=O)c2cccnc2)n1
Yield: 93.1 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 2-(a) except for using tert-butyl(tert-butoxycarbonyl{6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetate (126 mg, 0.263 mmol) obtained in Reference Example 12-(d) in place of N-[4-(thiazol-2-yl)benzyl]pyridin-3-ylsulfonamide, and using benzo[b]thiophen-2-ylmethanol (43.2 mg, 0.263 mmol) in place of tert-butyl[tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate to afford the title compound (153 mg) as a slightly yellow liquid. (Yield: 93%)
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1I)([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[C:25](=[O:27])=[O:26].[OH-].[Na+]>C(OCC)C.O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[C:25]([OH:27])=[O:26])([CH3:3])[CH3:2]
Reactant: O=C=O
Reactant: CC(C)c1cccc(C(C)C)c1I
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)c1cccc(C(C)C)c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a solution of 5.09 g (17.7 mmol) of 2, 6-diisopropylphenyl iodide in 70 ml of dry ethyl ether was dropwise added 1.6M solution of n-butyllithium in hexane (11.1 ml, 17.8 mmol) at -20° C. The reaction mixture was allowed to warm at 0° C., stirred for 1 hour and poured onto about 100 g of pulverized dry ice. The mixture was allowed to warm gradually to room temperature, mixed with 50 ml of water and the aqueous layer was made alkaline with aqueous sodium hydroxide. The organic layer was separated, and the aqueous layer was washed with ethyl ether, acidified With conc. hydrochloric acid and extracted with ethyl ether. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent evaporated to give 2.53 g of 2, 6-diisopropylbenzoic acid as white solid.
Reaction SMILES: [C:1]([OH:9])(=O)[C@H:2]([CH2:4][C:5](O)=[O:6])[OH:3].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C(C)C)C=CC=CC=1>O>[CH2:10]([N:17]1[C:5](=[O:6])[CH2:4][C@H:2]([OH:3])[C:1]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)C[C@H](O)C(=O)O
Reactant: NCc1ccccc1
Solvent: CC(C)c1ccccc1
Solvent: O
Product: O=C1C[C@H](O)C(=O)N1Cc1ccccc1
Yield: 39.6 %

Procedure:
A mixture of 50.0 g (0.373 mole) (S)-malic acid (Ia), 41 ml (0.373 mole) benzyl amine and 250 ml cumene was heated with an internal temperature of 155° C. for 2.5 h on a water separator, during which time 12 ml water were separated. An oily phase formed during cooling off which slowly crystallized. The cumene was decanted off thereafter and the residue crystallized out of 220 ml EtOH. 30.3 g (39.6%) (S)-1-benzyl-3-hydroxy-2,5-pyrrolidinedione (IIa) were isolated in the form of colorless crystals.
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[C:11]([O:13]C)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26]O>[Pd]>[CH3:26][N:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:10]([C:11]([OH:13])=[O:12])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1
Reactant: CO
Reactant: COC(=O)C(=Cc1ccc(OC)c(OC)c1)NC(=O)c1ccccc1
Agent: [Pd]
Product: COc1ccc(C[C@@H](C(=O)O)N(C)C(=O)c2ccccc2)cc1OC
Yield: 95 %

Procedure:
Methyl α-benzoylamino-3,4-dimethoxycinnamate (20 g) was treated with 10% palladium on carbon (2 g) in methanol (400 mL) under a hydrogen atmosphere (1 atm.) for 3 days. The reaction mixture was then filtered and the solvent stripped to yield the title compound (18.90 g, 95%); MP 106°-107° C.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](=[O:22])[C:20]#[N:21])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:29])[C:26](Cl)=[O:27].C(N(C(C)C)C(C)C)C>C(O)(=O)C.[Pd].ClCCl>[CH3:23][O:24][C:25](=[O:29])[C:26]([NH:21][CH2:20][C:19]([C:10]1[C:11]2[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:9]=1)=[O:22])=[O:27]
Reactant: COc1cccc2c(C(=O)C#N)cn(CC3CCCCC3)c12
Reactant: COC(=O)C(=O)Cl
Agent: [Pd]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: COC(=O)C(=O)NCC(=O)c1cn(CC2CCCCC2)c2c(OC)cccc12
Reaction time: 14 h
Yield: 45 %

Procedure:
To a solution of (1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-oxoacetonitrile (975 mg, 3.29 mmol) in acetic acid (40 ml) under nitrogen was added 10% palladium on charcoal (90 mg). The reaction was placed under a hydrogen atmosphere and stirred for 14 h. The reaction mixture was then filtered through a pad of dicalite. The dicalite was washed with acetic acid and the combined filtrate evaporated to leave a red oil. The red oil was taken up in dichloromethane (50 ml) and to this was added methylchlorooxoacetate (0.393 ml, 4.28 mmol) followed by N-ethyldiisopropylamine (1.7 ml, 9.87 mmol) dropwise. The reaction was stirred for 1 h and poured into a separating funnel. The organics were washed sequentially with 2M aqueous hydrochloric acid (50 ml), 5% aqueous sodium carbonate (50 ml) and brine (50 ml). The organics were dried over sodium sulfate, filtered and the solvent removed in vacuo to leave a brown oil. The oil was purified by flash chromatography using dichloromethane followed by 66% (v/v) diethyl ether in heptane to afford N-[(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-2-oxo-ethyl]oxalamic acid methyl ester (573 mg, 1.48 mmol) as a yellow/brown solid.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][CH2:22][CH2:23]O.CN1C=CN=C1.[O:31]1CCCC1>>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]([CH:22]([OH:31])[CH3:23])[CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: OCCNc1ccccn1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: Cn1ccnc1
Product: CC(O)N(c1ccccn1)C(c1ccccc1)c1ccccc1
Reaction time: 72 h
Yield: 62 %

Procedure:
Diphenylmethyl bromide (0.1 mol; 24.75 g) was dissolved in 25 ml of tetrahydrofuran and placed in a flask together with N-pyridylethanolamine (0.05 mole-6.9 g) and 0.5 ml of catalytic N-methylimidazol, and then left for 72 hours in a dryer at temperature of 65° C. The product of this reaction was purified on a column filled with silica gel 60 of a particle size 70-230 mesh. Methanol gradient in methylene chloride was used as an eluting phase. Then the fractions containing the product of the reaction (N-pyridyl-N-[diphenylmethyl]aminoethanol) were isolated and combined. The excess of solvent was evaporated. The compound was characterized by means of the 1HNMR and 13CNMR spectra, presented in FIG. 9. 19.03 g were obtained (a yield of 62%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]([S:17]([CH3:16])(=[O:19])=[O:18])[S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc(Br)cc1)S(C)(=O)=O
Temperature: 0 °C

Procedure:
4-bromoaniline (500 mg, 2.91 mmol) and triethylamine (1215 μl, 8.72 mmol) were placed in a dry flask and dichloromethane (1.45 ml) was then added. The solution was cooled to 0° C. for 20 minutes. Methanesulfonyl chloride (226 μl, 2.91 mmol) was then added dropwise and the solution was allowed to warm to room temperature overnight. It was quenched with water and aqueous sodium bicarbonate, and extracted using ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was conducted via silica gel chromatography (0-100% ethyl acetate in hexanes) to yield the title compound. 1H NMR (600 MHz, d6-DMSO): δ 7.63 (d, 2H), 7.38 (d, 2H), 3.42 (s, 6H).
Reaction SMILES: [CH:1](OCC)=[O:2].C[O-].[Na+].[CH:9]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)([CH3:11])[CH3:10]>C(OCC)C>[CH:9]([CH:12]1[CH2:17][CH:16]([CH:1]=[O:2])[C:15](=[O:18])[CH2:14][CH2:13]1)([CH3:11])[CH3:10]
Reactant: CCOC=O
Reactant: CC(C)C1CCC(=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)C1CCC(=O)C(C=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl formate (6 mmol) in diethyl ether (2 ml) was added dropwise to a suspension of sodium methoxide (6 mmol) and 4-isopropyl-cyclohexanone (3 mmol) in absolute diethyl ether (3 ml) and after complete evolution of the gas the reaction mixture was stirred overnight at room temperature. The solid formed was filtered off, washed with diethyl ether and dried in a high vacuum. The product was obtained as a slightly yellow solid. tR 2.26; MS (pos. Ion.) m/z 169.32 [M+H]+. (J. Org. Chem. 2000, 65(21), 7145-7150).
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][NH2:6])#[N:2].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([OH:17])[CH3:16]>>[C:15]([N:5]([CH2:4][CH2:3][C:1]#[N:2])[N:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:17])[CH3:16]
Reactant: CCO
Reactant: N#CCCNN
Reactant: O=Cc1ccccc1
Product: CC(=O)N(CCC#N)N=Cc1ccccc1

Procedure:
10-2 moles of (2-cyanoethyl)hydrazine are added to a solution containing 10-2 moles of benzaldehyde in 20 ml of ethanol. The reaction is left under reflux for 30 minutes. At the end of the reaction, the mixture is cooled. After evaporation of the solvents, the product obtained is in the form of an extremely unstable oil. The crude reaction yield is 81%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:11](Br)[CH:12]=[CH2:13].Cl[C:16]([N:18]1[C@H:23]([CH3:24])[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C@@H:19]1[CH3:32])=[O:17]>>[CH3:24][C@H:23]1[CH2:22][NH:21][CH2:20][C@@H:19]([CH3:32])[N:18]1[C:16]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([O:10][CH2:13][CH:12]=[CH2:11])[CH:8]=[CH:9][C:2]=1[F:1])=[O:17]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Reactant: C=CCBr
Reactant: OCc1cc(O)ccc1F
Product: C=CCOc1ccc(F)c(COC(=O)N2[C@H](C)CNC[C@@H]2C)c1

Procedure:
2-Fluoro-5-(2-propenyl)oxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate was prepared from 2-fluoro-5-hydroxybenzyl alcohol, allyl bromide and 1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine according to the methods described for Examples 54 and 121 to give the product as a yellow oil (8.4%); HPLC (XTERRA, 50/80, 220 nm) 95.7% (2.87 min); NMR δH (400 MHz, DMSO-d6) 1.183(6H, d, J 6.5 Hz), 2.673(4H, m), 3.294(2H, bs), 3.910(2H, m), 4.572(2H, m), 5.078(2H, s), 5.252(1H, m), 5.371(1H, m), 6.022(1H, m), 6.948(2H, m) and 7.138(1H, t, J 9.5 Hz).