Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([C:19]4[CH:45]=[CH:44][C:22]([CH2:23][N:24]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:25](=[O:35])[C:26]5[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=5)=[CH:21][CH:20]=4)[N:15]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.[Cl-].[Na+].O>[NH2:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]([N:24]([CH2:36][C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:23][C:22]2[CH:21]=[CH:20][C:19]([C:16]3[N:15]=[C:14]([C:11]4[CH:12]=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=5)=[CH:9][CH:10]=4)[O:18][N:17]=3)=[CH:45][CH:44]=2)=[O:35])=[CH:27][CH:28]=1
Reactant: Cc1ccc(-c2ccc(-c3nc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc([N+](=O)[O-])cc5)cc4)no3)cc2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2ccc(-c3nc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc(N)cc5)cc4)no3)cc2)cc1
Temperature: 65 °C
Yield: 100 %

Procedure:
Prepared using General Procedure 5. To a stirred solution of tert-butyl 2-(N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)-4-nitrobenzamido)acetate INT-58 (7.25 g, 12.0 mmol) in THF (30 mL) was added water (10 mL) and sodium dithionite (6.26 g, 36.0 mmol) and then heated to 65° C. for 3 h. The reaction mixture was allowed to cool to room temperature and then diluted with brine (300 mL) and extracted into EA (300 mL) and THF (250 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. The solid was dried under vacuum for 18 h to afford 7.17 g (100%.) of tert-butyl 2-(4-amino-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-59 as a pale yellow powder. LCMS-ESI (m/z) calculated for C35H34N4O4: 574; found 519 [M-t-Bu+H]+, tR=3.12 min (Method 10).
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:9]([CH2:15][CH3:16])[C@H:10]([OH:14])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>O.ClCCl>[CH:24]1([NH:27][C:11](=[O:12])[C@@H:10]([OH:14])[C@@H:9]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:15][CH3:16])[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: CC[C@@H]([C@H](O)C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CC[C@@H]([C@H](O)C(=O)NC1CC1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of argon, (2S,3S)-3-(dibenzylamino)-2-hydroxypentanoic acid (5.85 g, 18.7 mmol, Eq: 1.00), cyclopropanamine (2.13 g, 2.62 ml, 37.3 mmol, Eq: 2) were combined with dichloromethane (100 ml) to give a light yellow solution. At 0° C. HOBt (4.29 g, 28.0 mmol, Eq: 1.5), EDC (5.37 g, 28.0 mmol, Eq: 1.5) and N-methylmorpholine (3.78 g, 4.1 ml, 37.3 mmol, Eq: 2) were added to the reaction. The reaction was stirred overnight at RT. The reaction mixture was poured into water (150 ml) and extracted with dichloromethane. The organic layer was back-extracted with water. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 70 g, 0% to 60% ethyl acetate in heptane). The title compound was obtained as a light brown crystalline (4.42 g, 67.2%, MS (m/e)=353.3 [M+H+]).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:19]=[CH:18][C:10]([CH:11]=[N:12][C@@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])=[CH:9][CH:8]=1.CO.C(OCC)(=O)C>[Pt].O>[CH3:17][C@H:13]([NH:12][CH2:11][C:10]1[CH:18]=[CH:19][C:7]([O:6][CH2:5][C:4]2[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)[C:14]([NH2:16])=[O:15]
Reactant: C[C@H](N=Cc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Agent: [Pt]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](NCc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
An autoclave is loaded with (S)-2-[4-(3-fluorobenzyloxy)benzylidene-amino]propanamide (16.0 g; 0.053 mol), prepared as described above, and wet (50% H2O) Pt/C 5% (1.7 kg: Engelhard S.r.l., Rome, Italy) and methanol (90 mL) is added thereto. The autoclave is purged from air with nitrogen and then hydrogen is introduced at 5.0 bars. The reaction is kept at 5.0 bar and at 35° C. for 1 hour. After cooling to room temperature and elimination of the catalyst by filtration, the solvent is distilled off under reduced pressure until a residue of approximately 30 g is obtained. To this residue a mixture of ethyl acetate (150 mL) and H2O (110 mL) is added and the heterogeneous mixture is heated to 40° C., until two clear phases are obtained. These two phases are separated and the aqueous layer is extracted with 50 mL of ethyl acetate at 40° C. The organic phases are collected and evaporated to dryness. The procedure is repeated twice by adding every time 90 mL of ethyl acetate to make the product anhydrous. 95 mL of n-heptane are then added slowly and under stirring to the residue. The mixture is then maintained under stirring for 3 hours at 20° C. The solid formed is collected by filtration, washed with n-hetpane (15 mL) and dried under reduced pressure to give 15.2 g (94.8% yield) of safinamide with a HPLC purity of 99.8 (area %, see Example 17A) and a content of (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide lower than 0.005% by weight measured by HPLC (see Example 17B).
Reaction SMILES: CC(C)=O.Cl[C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[H][H].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>CO.CC(O)=O.C(Cl)Cl.O=[Pt]=O>[CH:9]1([CH:12]2[CH2:13][CH2:14][CH:15]([C:18]([CH3:19])=[O:20])[CH2:16][CH2:17]2)[CH2:8][CH2:7][CH2:6][CH2:11][CH2:10]1
Reactant: CC(=O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Reactant: [H][H]
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Pt]=O
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)C1CCC(C2CCCCC2)CC1
Yield: 80 %

Procedure:
The methylketone starting material for Example 60 in the table below was prepared from trans-4-(4-chlorophenyl)cyclohexyl-1-ethanone (1 g, 4.2 mmol) in two steps. Hydrogenation of the aromatic ring with concomitant reduction of the aromatic ketone to the alcohol and concomitant hydrogenolysis of the carbon-chlorine bond was accomplished using hydrogen gas (H2 pressure=50 psi) in a resealable glass pressure vessel equipped with a manometer and pressure valve. The reaction was stirred under H2 pressure for 2 days in MeOH:AcOH (1:1; 6 mL) using PtO2 (200 mg) as the catalyst to effect the desired transformation. Filtration through Celite® and evaporative workup gave the crude alcohol product (900 mg) which was used as-is in the preparation of the corresponding ketone by oxidation with PCC (6.3 mmol, 1.5 eq), the reaction being effected by stirring overnight in DCM containing molecular sieves (about 100 mg) at RT. The [4-(cyclohexyl)-cyclohexyl]methylketone product (700 mg) was isolated after workup and filtration through a silica gel column to remove impurities.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6]([NH2:15])([C:12]([OH:14])=[O:13])[CH2:7]2.C(N(CC)CC)C.[C:23](=O)([O:39]N1C(=O)CCC1=O)[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>C(#N)C.O>[C:23]([CH:7]1[C:8]2[C:3](=[C:2]([Cl:1])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][C:6]1([NH2:15])[C:12]([OH:14])=[O:13])([O:24][CH2:25][CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:39]
Reactant: NC1(C(=O)O)CCc2c(Cl)cccc2C1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: NC1(C(=O)O)CCc2c(Cl)cccc2C1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.7 %

Procedure:
A mixture of racemic 5-chloro-2-aminotetraline-2-carboxylic acid (402 mg, 1.78 mmole), triethylamine (0.38 ml, 2.73 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 904 mg, 2.68 mmole) in acetonitrile (20 ml) and water (20 ml) was stirred at room temperature for two days. TLC analysis of the reaction after two days indicated the presence of starting material amino acid. 9-fluorenylmethyl succinimidyl carbonate (0.12 g) and triethylamine (0.1 ml) was added and the mixture was stirred at room temperature for another day. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH˜3 with 10% aqueous citric acid solution, and the white emulsion extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 3→6→8% methanol/methylene chloride) to give racemic Fmoc-5-chloro-2-aminotetraline-2-carboxylic acid (540 mg, 68% yield) as a white solid. HRMS (EI): C26H22ClNO4 (M) calc. 447.1237, observed: 447.1234.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[CH:11]=1)[NH:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]2.[OH-].[Li+].Cl.C(OCC)C>CO.O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[CH:11]=1)[NH:8][CH:7]([C:13]([F:15])([F:16])[F:14])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Br)cc(Br)c2NC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: O=C(O)C1=Cc2cc(Br)cc(Br)c2NC1C(F)(F)F
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Ethyl 6,8-dibromo-2-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylate (732.0 mg, 1.70 mmol) was suspended in methanol-tetrahydrofuran-water (5 mL, 7:2:1). Lithium hydroxide (214 mg, 5.108 mmol) was added and the mixture was gently heated to reflux for two hours. The reaction was cooled to room temperature and 1 N aqueous hydrochloric acid added until pH=1. The organic solvent was removed in vauco to afford a suspension of a crude yellow solid. Diethyl ether (50 mL) was added, and the solution was washed with water (2×50 mL), saturated ammonium chloride (2×50 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 6,8-dibromo-2-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid (633.0 mg, 1.52 mmol) as a yellow solid (89% yield): 1H NMR (CD3OD3, 300 MHz)7.07 (s, 1H), 7.57 (d, 1H, J=2.0 Hz), 7.39 (d, 1H, J=2.0 Hz), 5.26 (m, 1H). Anal. Calcd for C11H6Br2F3NO3: C, 32.95; H, 1.51; N, 3.49. Found: C, 32.88; H, 1.51; N, 3.46.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:12][C@@H:13]([C:15]([NH2:17])=[O:16])[CH3:14].CCN(C(C)C)C(C)C.CCOC(C)=O>CS(C)=O.O>[Br:1][C:2]1[CH:9]=[C:8]([NH:12][C@H:13]([CH3:14])[C:15]([NH2:17])=[O:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H](N)C(N)=O
Reactant: N#Cc1ccc(F)cc1Br
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](Nc1ccc(C#N)c(Br)c1)C(N)=O
Yield: 69 %

Procedure:
A solution of 2-bromo-4-fluorobenzonitrile (200 mg, 1.00 mmol), D-alanine amide hydrochloride (148 mg, 1.19 mmol) and DIEA (0.620 mL, 3.56 mmol) in DMSO (3 mL) was stirred at 100 C for 18 h. EtOAc and water were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silicsa gel column, eluted first with 30% EtOAc in hexane, then with 100% EtOAc to give (R)-2-(3-bromo-4-cyanophenylamino)propanamide (185 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([F:39])[CH2:18][N:19]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[S:20]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH3:53]>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([F:39])[CH2:18][N:19]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH3:53])=[CH:34][CH:33]=3)[S:20]([C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: COCCOCCBr
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N(CC(F)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCCOc1ccc(N(CC(F)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 43 %

Procedure:
A solution of the product of Step 3 (15.9 mg, 0.023 mmol), potassium carbonate (13.6 mg, 0.098 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (8.5 mg, 0.041 mmol) in dimethylformamide (1.0 ml) was heated at 70° C. overnight. The reaction was diluted with EtOAc and washed with water several times, then brine. Column chromatography in 100% DCM (+0.2% TEA)-1% MeOH/DCM (+0.2% TEA) gave the pure product. Yield=43%.
Reaction SMILES: [CH3:1]N(CCN(C)C)C.C([Li])(CC)C.[CH2:14]([N:16]([CH2:26][CH3:27])[C:17](=[O:25])[O:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH3:15].IC>C1COCC1.[Cl-].[Na+].O>[CH2:26]([N:16]([CH2:14][CH3:15])[C:17](=[O:25])[O:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[CH3:1])[CH3:27]
Reactant: CCN(CC)C(=O)Oc1cccnc1
Reactant: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Oc1cnccc1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To the cooled (-78° C.) solution of TMEDA (516.5 mg, 4.40 mmol) in anhydrous THF (10 mL) was slowly added sec-butyl lithium (1.3 M, 3.38 mL, 4.40 mmol), and the resultant solution was stirred at -78° C. for 10 minutes. 3-Pyridyl diethylcarbamate (776 mg, 4.0 mmol) in THF (3 mL) was slowly added, and the mixture was stirred at -78° C. for 30 minutes. Iodomethane (275.4 μL, 4.40 mmol) was then added, and the mixture was stirred for two hours. Brine (1 mL) was added, and the mixture was slowly warmed up to room temperature. The organic layer was decanted, and the residue washed with ethyl acetate (3×5 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel eluting with hexane/EtOAc (1:2 and 0:1) to provide 765 mg (92% yield) of the title compound. TLC Rf 0.28 (1:2 hexane/EtOAc). MS (DCI/NH3) m/e 209 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.34 (s, 1H, ArH), 8.32 (d, J=6.9 Hz, 1H, ArH), 7.16 (d, J=69 Hz, 1H, ArH), 3.48 (q, J=7.5 Hz, 2H, NCH2), 3.41 (q, J=7.5 Hz, 2H, NCH2), 1.28 (t, J=7.5 Hz, 3H, CH3), 1.22 (t, J=7.5 Hz, 3H, CH3).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][C@H:9]([CH3:11])[CH2:8][CH2:7][C@H:6]1[C:12]([OH:14])=O)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[C:1]([O:4][CH:5]1[CH2:10][CH:9]([CH3:11])[CH2:8][CH2:7][CH:6]1[C:12]([Cl:18])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@H](C)CC[C@H]1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)OC1CC(C)CCC1C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1R,2S,4R)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid (109 mg, 0.54 mmol) in dichloromethane (2.7 ml) was added oxalyl chloride (545 ul, 1.09 mmol) followed by 1 drop of dimethylformamide. The reaction mixture was stirred for 4 h at room temperature. The solvents were then removed to obtain 119 mg (99%) of (1R*,2S*, 4R*)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid chloride. NMR 1H (CDCl3, 400 MHz): 5.45 ppm (s, 1H); 2.46-2.42 ppm (m, 1H); 2.02 ppm (s, 3H); 2.02-1.96 ppm (m, 1H); 1.91-1.76 ppm (m, 3H); 1.70-1.61 ppm (m, 1H); 1.16-1.08 ppm (m, 1H); 0.99-0.88 ppm (m, 1H); 0.87 ppm (d, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[O:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35].C([Li])CCC>O1CCCC1.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]([N:32]1[CH2:33][CH2:34][O:30][C:31]1=[O:35])=[O:15]
Reactant: O=C1NCCO1
Reactant: O=C(O)/C=C/c1ccc2ccccc2c1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(/C=C/c1ccc2ccccc2c1)N1CCOC1=O
Reaction time: 1 h

Procedure:
To a stirred solution of (E)-3-(2-naphthyl)prop-2-enoic acid (10 g, 0.05 mole) at −78° C., was added triethylamine (8.42 ml, 0.06 mole) and pivaloyl chloride (7.5 ml, 0.06 mole). Stirring was continued for 1 hour. To a stirred solution of oxazolidinone (5.14 g, 0.06 mole) in dry tetrahydrofuran (200 ml) at −78° C. was added slowly n-butyl lithium (1.6M in hexanes, 38 ml, 0.06 mole). Stirred for 1 hour. The suspension of the mixed anhydride was transferred into the oxazolidinone anion by means of a canula maintaining the temperature below −60° C. The resulting reaction mixture was stirred for 2 hours. Water was added cautiously and the reaction extracted with ethyl acetate. The solvent was washed with brine, dried and evaporated to dryness in-vacuo. Chromatography on flash silica using ethyl acetatehexane (1:1) gave 3-[(E)-3-naphthalen-2-ylprop-2-enoyl]-1,3-oxazolidin-2-one as a white solid, M/e 268 (M+H).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH2:23][CH2:24][CH3:25])[N:11]=[C:12]2[C:21]=1[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:14]=[C:13]2[NH2:22]>CN(C=O)C.ClCCl>[CH3:1][S:2][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH2:23][CH2:24][CH3:25])[N:11]=[C:12]2[C:21]=1[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:14]=[C:13]2[NH2:22]
Reactant: C[S-]
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCCCSC
Temperature: 80 °C
Yield: 100.2 %

Procedure:
Sodium thiomethoxide (0.3 g, 3.79 mmol) was added to a solution of 1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (1.0 g, 3.16 mmol) in 15 mL of DMF and heated for 3 hours at 80° C. The reaction mixture was allowed to cool to ambient temperature, diluted with dichloromethane, and washed with water. The aqueous layer was extracted with several additional portions of dichloromethane and the combined organic layers were washed with water, washed with brine, dried over magnesium sulfate, and concentrated to afford 1.04 g of 1-(4-methylthiobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:10][C:11]([CH3:13])=O>CO>[C:11](=[N:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([CH3:13])[CH3:10]
Reactant: COc1ccc(N)cn1
Reactant: CC(C)=O
Solvent: CO
Product: COc1ccc(N=C(C)C)cn1
Yield: 80.6 %

Procedure:
To a solution of 5-amino-2-methoxypyridine (18 g, 161 mmol) in methanol (80 mL) was added acetone (20 mL, 177 mmol). The reaction was heated at reflux for 24 hours and the volatiles were concentrated in vacuo to provide 21.3 g of isopropylidene-(6-methoxy-pyridin-3-yl)-amine. 1H NMR (CDCl3) δ 7.59 (d, 1H) 7.31 (m, 1H), 6.70 (d, 1H), 3.91 (s, 3H), 2.20 (s, 3H), 1.85 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][C:10]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:2]=1>C(OCC)(=O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH:10]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:2]=1
Reactant: CCOC(=O)C=C(CCCCOC1CCCCO1)CCCc1cccnc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(CCCCOC1CCCCO1)CCCc1cccnc1

Procedure:
A solution of 1.385 g of ethyl 3-[3-(3-pyridyl)-propyl]-7-(2-tetrahydropyranyloxy)-hept-2-enoate in 30 mL ethyl acetate is hydrogenated in a Parr apparatus at 3 atmospheres pressure and room temperature in the presence of 5% Pd/C catalyst for 13 hours to yield ethyl 3-[3-(3-pyridyl)-propyl]-7-(2-tetrahydropyranyloxy)-heptanoate; NMR (CDCl3): delta 2.2 (ddd,2H).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.N1C=CC=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][O:33][C:34](Cl)=[O:35])=[C:27]([N+:37]([O-:39])=[O:38])[CH:26]=1.CC(O)C.N#N>C(Cl)Cl>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][O:33][C:34]([O:7][CH2:6][C@H:5]2[O:8][C@@H:1]([N:9]3[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]3=[O:11])[CH2:2][C@@H:3]2[OH:4])=[O:35])=[C:27]([N+:37]([O-:39])=[O:38])[CH:26]=1
Reactant: O=C(Cl)OCCc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: N#N
Solvent: CC(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC(=O)OCCc3ccc(Cl)cc3[N+](=O)[O-])O2)c(=O)[nH]c1=O
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
Thymidine (150 mg, 0.62 mmol) was co-evaporated with pyridine (2×5 ml, pro analysi quality, additionally dried over molecular sieve 4 Å), dissolved in pyridine and cooled to -30° C. A solution of 2-(4-chloro-2-nitrophenyl)ethoxycarbonyl chloride (255 mg, 0.97 mmol) in CH2Cl2 (3 ml, dist. over CaH2) was added dropwise thereto for 5 min. After being stirred for 4 h in conditions of i-PrOH/N2 cooling (-30° to -15° C.), the mixture was diluted with CH2Cl2 (30 ml) and washed with H2O (30 ml). The aqueous phase was post-extracted with CH2Cl2 (2×30 ml). The combined organic phases were dried over MgSO4, filtered and co-evaporated with toluene (4×10 ml) and CH2Cl2 (20 ml). The crude product was purified by column chromatography (SiO2 15×3 cm, solvent: CH2Cl2 /MeOH 100:7 700 ml). 5'-O-(2-(4-chloro-2-nitrophenyl)ethoxycarbonyl)thymidine (219 mg, 75% ) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH2:10]Br)[CH:7]=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[CH2:14][CH3:15].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[CH:26]=C.C(=O)([O-])[O-].[K+].[K+].C(N(CCCC)CCCC)CCC.Cl>CN(C=O)C.C1(P([Pd-2](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8](/[CH:10]=[CH:26]/[C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[Cl:18])[CH:7]=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[CH2:14][CH3:15]
Reactant: C=Cc1ccc(Cl)cc1Cl
Reactant: CCC(=O)Nc1ccc(CBr)cc1C(=O)OC
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: CCC(=O)Nc1ccc(/C=C/c2ccc(Cl)cc2Cl)cc1C(=O)OC
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-bromomethyl-2-propionylamino-benzoic acid methyl ester (172 mg, 0.60 mmol), 2,4-dichloro-1-vinyl-benzene (125 mg, 0.72 mmol), potassium carbonate (100 mg, 0.66 mmol), tri-butyl amine (160 μl, 0.66 mmol) and bis(tri-phenyl-phosphino)palladium (II) di-chloride in DMF (3 ml) was heated to 130° C. After 30 minutes, the reaction mixture was allowed to reach room temperature, acidified with 2 M HCl and the resulting precipitate collected by filtration, washed with water and dried under vacuum to give crude 5-[(E)-2-(2,4-dichloro-phenyl)-vinyl]-2-propionylamino-benzoic acid methyl ester. This was hydrolyzed in ethanol (3 mL) and 1.0 M NaOH (3 mL) overnight and then acidified with 1.0 M HCl. The resulting precipitate was collected by filtration, washed with water and dried under vacuum (136 mg, 62% total yield). 1H-NMR (DMSO-d6) δ 1.14 (t, 3H), 2.43 (q, 2H), 7.32 (d, 1H), 7.37 (d, 1H), 7.44 (dd, 1H), 7.63 (d, 1H), 7.87-7.91 (m, 1H), 8.17 (d, 1H), 8.57 (d, 1H), 11.19 (s, 1H), 13.80 (bs, 1H)