Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:15]1=[O:37])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:15]1=[O:37])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=c1c2cc(F)c(Cl)nc2n(-c2ccc(C(F)(F)F)cc2)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccc(C(F)(F)F)cc2)c(=O)n1OCc1ccccc1
Yield: 85.6 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(4-trifluoromethylphenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example U-2, 0.19 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.18 g of the title compound as a solid, mp 231-233° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:13]2[C:12]3[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=3[C:10](=[O:18])[O:9][C:8]=2[CH:7]=[C:6]([CH3:19])[CH:5]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>CS(C)=O.O>[CH3:19][C:6]1[CH:5]=[C:4]([O:3][CH2:20][CH:22]2[CH2:23][O:24]2)[C:13]2[C:12]3[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=3[C:10](=[O:18])[O:9][C:8]=2[CH:7]=1
Reactant: Cc1cc(O)c2c3c(c(=O)oc2c1)CCCC3
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(OCC2CO2)c2c3c(c(=O)oc2c1)CCCC3
Reaction time: 0.08 h

Procedure:
To a stirred solution of NaOH (4.0 g. 0.1 mol) in dimethylsulfoxide (DMSO) (250 ml) and water (250 ml), was added 7,8,9,10-tetrahydro-1-hydroxy-3-methyl-6-oxo-6H-dibenzo[b,d]pyran (20.0 g. 0.087 mol) and the mixture stirred for 5 minutes, then treated with epichlorohydrin (50 ml). After 5 hours the mixture was cooled in a ice bath for 30 minutes and the precipitated solid collected by filtration, washed with water and dried to give 7,8,9,10-tetrahydro-3-methyl-1-(oxiranylmethoxy)-6-oxo-6H-dibenzo[b,d]pyran as a white solid, m.p. 164°-165° C. An analytical sample recrystallized from methanol melted at 165°-166° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[CH:17][CH:16]=[N:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:7]=1.[F:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:28]=1[NH:27][N:26]=[C:25]2[NH2:29]>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH:29][C:25]2[C:24]3[C:28](=[C:20]([F:19])[CH:21]=[CH:22][CH:23]=3)[NH:27][N:26]=2)[C:3]2[CH:18]=[CH:17][CH:16]=[N:15][C:4]=2[N:5]=1
Reactant: Clc1ccccc1-c1nc(Cl)c2cccnc2n1
Reactant: Nc1n[nH]c2c(F)cccc12
Product: Fc1cccc2c(Nc3nc(-c4ccccc4Cl)nc4ncccc34)n[nH]c12

Procedure:
Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[2,3-d]pyrimidine (100 mg, 0.36 mmol) and 7-Fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (93 mg, 46% yield). HPLC-Method A, Rt 3.04 min; 1H NMR (DMSO, 500 MHz): δ 13.67 (1H, s), 11.40-11.25 (1H, bs), 9.35-9.25 (2H, m), 7.95 (1H, m), 7.80-7.47 (5H, m), 7.35(1H, m), 7.15 (1H, m); MS (m/z), MH+391.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:14])=O.CN(C)C=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)cc1
Reaction time: 0.25 h

Procedure:
A slurry of 22.5 g. (0.15 mole) of 4-methoxybenzoic acid in benzene at reflux is treated with 12.5 ml. (0.15 mole) of thionyl chloride and 1 ml. of N,N-dimethyl formamide. After stirring for 15 minutes the solution is evaporated and cooled to provide 4-methoxybenzoyl chloride as a yellow solid. The solid is dissolved in carbon disulfide and added to 20 g. (0.15 mole) of aluminum chloride slurried in 200 ml. of carbon disulfide. To this mixture is added 30 g. (0.15 mole) of 2,6-di(t-butyl)phenol. After stirring for 2 hours at room temperature, the resulting mixture is poured into a dilute hydrochloric acid-ice mixture, then extracted with three portions of dichloromethane. The organic layer is dried, then evaporated to provide a residue which is recrystallized twice from a benzene-hexane mixture to provide 4-(4-methoxybenzoyl)-2,6-di(t-butyl)phenol, m.p. 141°-142.5° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:23][CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:30][C:29]([CH3:32])([CH3:31])[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=2)=[CH:22][CH:23]=1)=[O:33]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: CC(C)(C)C(=O)Nc1ccc(O)cc1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1ccc(OCCOc2ccc(NC(=O)C(C)(C)C)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and N-(4-hydroxy-phenyl)-2,2-dimethyl-propionamide via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid. MS (ES) for C23H29NO6 [M+H]+: 416.4.
Reaction SMILES: [C:1]1([CH3:15])[C:2]([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.C(N(CC)CC)C>CS(C)=O>[C:1]1([CH3:15])[C:2]([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1Nc1nc(CO)cs1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccccc1Nc1nc(C=O)cs1

Procedure:
Following a procedure similar to that described in Preparation 44, the desired compound was prepared from 6.12 g of 2-(o-toluidino)thiazole-4-ylmethanol, 13.2 g of a sulfur trioxide pyridine complex, 12 ml of triethylamine and 210 ml of dimethyl sulfoxide, as pale brown prismatic crystals having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:19][CH2:20]O>>[CH2:19]([O:12][C:11]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)=[O:13])[CH3:20]
Reactant: CCO
Reactant: O=C(O)c1cc2ccc(Cl)cc2[nH]1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Temperature: 120 °C

Procedure:
6-Chloro-1H-indole-2-carboxylic acid (2.59 g, 13.4 mmol) was dissolved in EtOH (75 mL) and conc. H2SO4 (1 mL) was added. The reaction was heated to 120° C. overnight then submitted to aqueous workup to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]2[CH2:23][CH2:24][CH:25]=[CH:26][N:14]2[C:13]1=[O:27].S(=O)(=O)(O)O.[CH:33]([OH:35])=[O:34]>C(OCC)(=O)C.CCCCCC.C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]2[CH2:23][CH2:24][CH2:25][C@@H:26]([C:33]([OH:35])=[O:34])[N:14]2[C:13]1=[O:27]
Reactant: O=C1[C@@H](N2C(=O)c3ccccc3C2=O)Cc2ccccc2C2CCC=CN12
Reactant: O=CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: O=C(O)[C@@H]1CCCC2c3ccccc3CC(N3C(=O)c4ccccc4C3=O)C(=O)N21
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Combine (S)-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,6,7,8,12b-hexahydro-6-oxopyrido[2,1-a][2]benzazepine (67 mg, 0.19 mmol) and sulfuric acid (2.0 mL, 95-98%) in a pressure vessel. Add 96% formic acid (400 μL) and quickly seal the vessel. After 18 hours, open the vessel cautiously and add ice-cold water (5 mL). Extract the reaction mixture repeatedly with chloroform. Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 2/1/0.01 ethyl acetate/hexane/acetic acid to give the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([Cl:9])=[CH:5][N:4]=1.S(Cl)([Cl:13])(=O)=O>ClCCl>[Cl:13][CH2:1][S:2][C:3]1[N:8]=[CH:7][C:6]([Cl:9])=[CH:5][N:4]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CSc1ncc(Cl)cn1
Solvent: ClCCl
Product: ClCSc1ncc(Cl)cn1
Yield: 82 %

Procedure:
2-Methylthio-5-chloropyrimidine (75 mmol) and sulfuryl chloride (104 mmol) were heated together in refluxing dichloromethane (100 ml) for 3 h. Evaporation of the mixture left a solid which was recrystallized from ethanol; yield 82%, m.p. 78° C. 1H NMR (CDCl3): 5.20 (SCH2), 8.54 (H-4, H-6).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[O:16][C:15]([C:17](=[NH:21])OCC)=[CH:14][CH:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].CO[CH:24](OC)[CH2:25][NH2:26].CO>Cl>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[O:16][C:15]([C:17]3[NH:21][CH:24]=[CH:25][N:26]=3)=[CH:14][CH:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCOC(=N)c1ccc(-c2ccc(OC)c(OC)c2)o1
Reactant: COC(CN)OC
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2ccc(-c3ncc[nH]3)o2)cc1OC
Yield: 28.3 %

Procedure:
A mixture of 52.0 g (0.167 mole) of ethyl 5-(3,4-dimethoxyphenyl)-2-furimidate hydrochloride, 19.3 g (0.184 mole) of aminoacetaldehyde dimethyl acetal and 800 ml of anhydrous methanol was heated to reflux with dissolution. The solution was refluxed for 5 hours and the solvent was then removed on the Calab evaporator yielding a residual oil which was stirred in 800 ml of 3N HCl for ca. 20 hours at a temperature of 70°. The resulting solid was washed in refluxing acetic acid, filtered hot and dried at 100° to yield 14.5 g (28%) of 2-[5-(3,4-dimethoxyphenyl)-2-furyl]imidazole hydrochloride. An analytical sample was prepared by washing a sample a second time in refluxing acetic acid and drying in the vacuum piston at the temperature of refluxing water, m.p. 288°-289°.
Reaction SMILES: [OH:1][C:2]1C=CC(C2C(=O)C3C(=C(C)C(O)=CC=3)OC=2)=CC=1OC.C(OC(=O)C)(=O)C.[C:30]([O:33][C:34]1[CH:55]=[CH:54][C:37]([C:38]2[C:47](=[O:48])[C:46]3[C:41](=[C:42]([CH3:53])[C:43]([O:49][C:50](=[O:52])[CH3:51])=[CH:44][CH:45]=3)[O:40][CH:39]=2)=[CH:36][CH:35]=1)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([O:33][C:34]1[CH:55]=[CH:54][C:37]([C:38]2[C:47](=[O:48])[C:46]3[C:41](=[C:42]([CH3:53])[C:43]([O:49][C:50](=[O:52])[CH3:51])=[CH:44][CH:45]=3)[O:40][CH:39]=2)=[CH:36][C:35]=1[O:1][CH3:2])(=[O:32])[CH3:31]
Reactant: CC(=O)Oc1ccc(-c2coc3c(C)c(OC(C)=O)ccc3c2=O)cc1
Reactant: COc1cc(-c2coc3c(C)c(O)ccc3c2=O)ccc1O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc(-c2coc3c(C)c(OC(C)=O)ccc3c2=O)ccc1OC(C)=O

Procedure:
4′,7-Diacetoxy-3′-methoxy-8-methylisoflavone was prepared from 4′,7-dihydroxy-3′-methoxy-8-methylisoflavone (0.42 g, 1.4 mmol), acetic anhydride (2.6 ml) and pyridine (0.5 ml) as described for 4′,7-diacetoxy-8-methylisoflavone. Yield: (0.4 g, 74%) m.p. 209° C. 1H NMR (CDCl3): δ 2.22 (s, 3H, CH3), 2.32, 2.39 (each s, 3H, OCOCH3), 3.89 (s, 3H, OMe), 7.07-7.11 (m, 2H, ArH), 7.13 (d, 1H, J 8.6 Hz, H6), 7.32 (d, 1H, J 1.5 Hz, ArH), 8.09 (s, 1H, H2), 8.18 (d, 1H, J 8.7 Hz, H5).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=S)=[CH:11][N:10]=[CH:9][N:8]=1)[CH3:2].[S]>[Hg]=O.O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[N:13][C:12]2[C:7]1=[N:8][CH:9]=[N:10][CH:11]=2)[CH3:2]
Reactant: CCOCCNc1ncncc1NC(=S)NC1CCN(Cc2ccccc2)CC1
Agent: O=[Hg]
Agent: [S]
Solvent: C1CCOC1
Product: CCOCCn1c(NC2CCN(Cc3ccccc3)CC2)nc2cncnc21
Reaction time: 2 h
Yield: 79.3 %

Procedure:
A mixture of 22.4 parts of N-[4-[(2-ethoxyethyl)amino]-5-pyrimidinyl]-N'-[1-(phenylmethyl)-4-piperidinyl]thiourea, 17.3 parts of mercury(II) oxide, 0.1 parts of sulfur and 270 parts of tetrahydrofuran was stirred for 2 hours at reflux temperature. The reaction mixture was filtered while hot over diatomaceous earth. The filtrate was evaporated and the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 16.3 parts (79.3%) of 9-(2-ethoxyethyl)-N-[1-(phenylmethyl)-4-piperidinyl]-9H-purin-8-amine as a residue (compound 11).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8].[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][C:26]1[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=1
Reactant: O=C(CC(=O)Nc1ccc(O)c(F)c1)Nc1ccc(F)cc1
Reactant: OB(O)c1ccncc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CC(=O)Nc1ccc(Oc2ccncc2)c(F)c1)Nc1ccc(F)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 20.9 %

Procedure:
N1-(3-Fluoro-4-hydroxyphenyl)-N3-(4-fluorophenyl)malonamide (31 mg, 0.10 mmol), copper(II) acetate (27 mg, 0.15 mmol), pyridin-4-ylboronic acid (25 mg, 0.20 mmol), and pyridine (16 μL, 0.20 mmol) were placed in a pressure tube in that order. The tube was charged with methylene chloride (0.5 mL) and sealed. The reaction was stirred at 120° C. for 5 h. The reaction mixture was filtered through silica gel using 5% methanol/ethyl acetate. After concentration, the crude product was purified by prep HPLC. The appropriate fraction was concentrated to remove methanol and the resulting aqueous solution was made basic with saturated NaHCO3 solution (5 mL). The aqueous solution was extracted with EtOAc (3×10 mL) and the combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The product was treated with 4N HCl in dioxane and concentrated. Lyophilization with water gave the title compound (8 mg, 21%) as a yellow solid. 1H NMR (CD3OD) δ 8.31 (d, 2H, J=6.1 Hz), 7.72 (dd, 1H, J=12.7, 2.4 Hz), 7.49-7.46 (m, 2H), 7.27-7.25 (m, 1H), 7.15 (t, 1H, J=8.8 Hz), 6.97 (t, 2H, J=8.7 Hz), 6.85 (dd, 2H, J=5.1, 1.2 Hz), 3.46 (s, 2H); MS(ESI+) m/z 384.21 (M+H)+.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COC(=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1N1CCN(Cc2ccccc2)CC1
Temperature: 150 °C
Yield: 58 %

Procedure:
To a 250 mL pressure bottle equipped with magnetic stirring was added methyl 2-fluorobenzoate (Lancaster Synthesis Inc.) (3.0 g, 20 mmol), 1-benzylpiperazine (Aldrich) (3.8 g, 22 mmol) and K2CO3 (3.0 g, 22 mmol) in DMF (100 mL) The mixture was heated at 150° C. for 12 h. After cooling to RT the reaction was diluted with EtOAc (100 mL) and H2O was added. The organic layer was separated and washed with H2O, brine, dried over Na2SO4, filtered and concentrated in vacuo to afford a brown oil. The crude material was purified by column chromatography (4:1 hexanes-EtOAc) to give the title compound as a white foam (3.6 g). MS (ESI, pos. ion) m/z: 311 (M+H). Calc'd for C19H22N2O2: 310.17.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:12]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Br:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc(C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc(CBr)cc1
Temperature: 80 °C
Yield: 81 %

Procedure:
Into a reaction flask equipped with a mechanical stirrer, thermometer and reflux apparatus was charged 75 grams (0.5 moles) of p-methylphenyl acetate prepared in Part A, 88 grams (0.5 moles) of N-bromosuccinimide, 300 milliliters of carbon tetrachloride and 1.0 gram of benzoyl peroxide. The resulting reaction mixture was carefully heated to 80° C. with a mantle, at which temperature, slight reflux ensued along with an exothermic reaction. Reflux was carefully maintained for 40 minutes and then 200 milliliters of carbon tetrachloride was gradually added to the reaction flask and the reaction mixture was then cooled to 25° C. (total time from onset of reflux was 50 minutes). The reaction mixture was filtered on a Buchner funnel and after the collected solid (succinimide) was washed four times with 100 milliliters of carbon tetrachloride, the total carbon tetrachloride solution (filtrate and washes) was stripped on a rotary evaporator. The resulting residue was distilled at reduced pressure (0.4 torr) to give a total of 92.8 grams of the desired product, whose nuclear magnetic resonance (NMR) spectrum was consistent with bromination of the aromatic methyl group: 2.13δ, singlet, CH3O; 4.28, singlet, BrCH2 --; and 6.97, quartet, aromatic protons.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:14]([CH2:16][C:17]([O:19]CC)=[O:18])#[N:15].N1CCCCC1>C(O)C>[C:14]([C:16](=[CH:1][C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1)[C:17]([OH:19])=[O:18])#[N:15]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C=C(C#N)C(=O)O)cc(OC)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
To a solution of 2 g (11.0 mmol) of syringaldehyde and 1.2 ml (11.3 mmol) of ethyl cyanoacetate in 30 ml of ethanol was added 2 ml of piperidine, and the mixture was stirred at room temperature for 16 hours. The solution was evaporated under reduced pressure, subsequently the residue was acidified by adding 1N hydrochloric acid and extracted with 200 ml of ethyl acetate. The organic layer was washed with water, and concentrated under reduced pressure. A formed precipitate was washed with ethanol, and then dissolved in a mixed solvent of tetrahydrofuran and methanol (30 ml, 20 ml). To the solution was added potassium hydroxide solution (3.0 g/30 ml), and the mixture was stirred at room temperature for 1.5 hours. A 100 ml of water and 50 ml of ethyl acetate was added to the solution for separation of each layer. An aqueous layer was acidified with conc. hydrochloric acid, and a formed precipitate was filtrated to give 1.4 g (yield 51.1%) of objective α-cyano-3,5-dimethoxy-4-hydroxycinnamic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:24]=[C:25]([NH2:30])[CH:26]=[CH:27][C:28]=4[CH3:29])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[C:31]([O:35][N:36]([CH2:40][C:41](O)=[O:42])[C:37]([CH3:39])=[O:38])([CH3:34])([CH3:33])[CH3:32].Cl.CN(C)CCCN=C=NCC.CO>C(Cl)Cl.CN(C)C=O.CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:31]([O:35][N:36]([CH2:40][C:41]([NH:30][C:25]1[CH:26]=[CH:27][C:28]([CH3:29])=[C:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH2:16][C:13]3[CH:12]=[CH:11][C:10]([S:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[CH:15][CH:14]=3)[CH2:18][CH2:19]2)[CH:24]=1)=[O:42])[C:37]([CH3:39])=[O:38])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(=O)N(CC(=O)O)OC(C)(C)C
Reactant: COc1ccc(Sc2ccc(CN3CCC(c4cc(N)ccc4C)CC3)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Sc2ccc(CN3CCC(c4cc(NC(=O)CN(OC(C)(C)C)C(C)=O)ccc4C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 49.7 %

Procedure:
To a stirred solution of 3-(1-{[4-(4-methoxyphenylthio)phenyl]methyl}(4-piperidyl))-4-methylphenylamine (121 mg, 0.289 mmol) in CH2Cl2/dimethylformamide (2.00/0.200 mL) was added 2-[(tert-butoxy)-N-methylcarbonylamino]acetic acid (54.6 mg, 0.289 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (111 mg, 0.578 mmol) and 4-dimethylaminopyridine (5.00 mg). The reaction mixture was stirred at room temperature for 10 h, then partitioned between CH2Cl2 (10 mL) and saturated NaHCO3 solution (10 mL) and the organic phase was separated and washed with water (10 mL), then brine (10 mL), dried over MgSO4 and concentrated in vacuo to give the crude product. Purification by flash column chromatography (eluent: CH2Cl2 then 3% methanol in CH2Cl2) gave 2-[(tert-butoxy)-N-methylcarbonylamino]-N-[3-(1-{[4-(4-methoxyphenylthio)phenyl]methyl}(4-piperidyl))-4-methylphenyl]acetamide (84.7 mg, 50.1% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.[CH2:22]([NH:29][CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[CH2:22]([N:29]([CH3:30])[C:10](=[O:12])[C@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][CH:14]=[CH2:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=CC[C@H](C(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: CNCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC[C@H](C(=O)N(C)Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h

Procedure:
A solution of 4.8 g (19.6 mmol) of 2-(S)-(3,4-dichlorophenyl)-4-pentenoic acid in 50 mL of CH2Cl2 and 10 drops of DMF was cooled in an ice bath and 1.8 mL of oxalyl chloride was added. The solution was stirred for 15 min after gas evolution had ceased. The mixture was concentrated in vacuo and the residue was diluted with 50 mL of CH2Cl2. The solution was cooled in ice bath as 2.6 mL (20.4 mmol) of N-benzyl-methyl amine and 1.7 mL (21 mmol) of pyridine were added. After stirring for 1 h at ice bath temperature the solution was diluted with CH2Cl2 and washed with water, 1.2N HCl and brine. The solution was dried over Na2SO4 and concentrated to give N-benzyl-N-methyl-2(S)-(3,4-dichlorophenyl)-4-pentenoamide as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[CH:16]=[O:17].C[O-].[Na+].[C:21](O)(=[O:23])C.C(Cl)Cl>CO>[CH:16]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]=1[O:23][CH3:21])=[O:17]
Reactant: CC(=O)O
Reactant: COC(=O)c1cc(C=O)c(Cl)nc1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(C=O)c(OC)nc1C(=O)OC
Temperature: 90 °C
Reaction time: 15 h
Yield: 63 %

Procedure:
A solution of dimethyl 6-chloro-5-formylpyridine-2,3-dicarboxylate (1.0 g, 0.0039 mol) in methanol (10 mL) is added to sodium methoxide (0.42 g, 0.0078 mol) in methanol (2 mL). The resulting mixture is stirred for 15 hours at 90° C. After cooling to room temperature, the reaction mixture is acidified to pH 3.0 with acetic acid. The reaction is poured into methylene chloride, washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title compound (0.62 g, 63%) as an orange oil, identified by IR and NMR spectral analyses.