Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:23]C)[N:13]2[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[C:9]([NH2:25])[N:8]=1)[CH2:3][O:4][CH3:5].Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:25][C:9]1[N:8]=[C:7]([O:6][CH:2]([CH3:1])[CH2:3][O:4][CH3:5])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: COCC(C)Oc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COCC(C)Oc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
To a solution of 2-{[1-methyl-2-(methoxy)ethyl]oxy}-8-(methoxy)-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (260 mg) in dry methanol (10 ml) at room temperature and under nitrogen was added 4.0M hydrogen chloride in 1,4-dioxane (4.0 ml). The reaction was left to stir at room temperature for 3 hours. The reaction was neutralised by the addition of 2.0M sodium hydroxide solution and concentrated in vacuo. The residue was taken up in water (15 ml) and the solid filtered and washed with water (2×5 ml). The solid was dried en vacuo (60° C.) for 30 minutes. This afforded the title compound as an off-white solid (70 mg).
Reaction SMILES: C1(N=C=S)C=CC=CC=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+:22]1([CH2:28][CH2:29][N:30]=[C:31]=[N:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:27]COCC1.CNC1[C:42](N)=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45]C=1>N1C=CC=CC=1>[CH3:27][N:22]1[C:28]2[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][C:29]=2[N:30]=[C:31]1[NH:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: S=C=Nc1ccccc1
Solvent: c1ccncc1
Product: Cn1c(Nc2ccccc2)nc2cc([N+](=O)[O-])ccc21
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of phenyl isothiocyanate (1.58 ml, 13.2 mmol) and 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (6.6 g, 15.6 mmol) was stirred in pyridine (20 ml) at 90° C. After 2 hours, N1-methyl-4-nitro-benzene-1,2-diamine was added and the reaction was heated overnight. The reaction was cooled and concentrated to a red solid. This was dissolved in EtOAc and washed with water. The organic layer was dried over MgSO4 and concentrated to a red solid. This was stirred in MeOH, filtered, and dried to give the title compound as an orange solid (1.97 g, 62%). 1H NMR (300 MHz, d6-DMSO) δ 8.23 (s, 1H), 8.17 (d, J=1.8 Hz, 1H), 8.02 (dd, J=8.7 and 2.1 Hz, 1H), 7.89 (d, J=8.1 Hz, 2H), 7.50 (d, J=8.7 Hz, 1H), 7.36 (m, 2H), 7.02 (m, 1H), 3.79 (s, 1H) ppm. MS (ESI) m/z=269 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][C:14](O)=O)#[CH:2].CCN(C(C)C)C(C)C.[NH2:26][C:27]1[C:28](=[O:40])[N:29]([CH3:39])[C:30](=[O:38])[N:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:32]=1[NH2:33]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][C:14]1[NH:26][C:27]2[C:28](=[O:40])[N:29]([CH3:39])[C:30](=[O:38])[N:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:32]=2[N:33]=1)#[CH:2]
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: C#Cc1ccc2cncc(CC(=O)O)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#Cc1ccc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(6-Ethynyl-isoquinolin-4-yl)-acetic acid (58 mg, 0.28 mmol) is dissolved in DMF (1 ml) and O-(7-azabenzotriazo-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.125 g, 0.33 mmol) and Hunig's base (0.180 ml, 1.03 mmol) are added, followed by a solution of 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (58 mg, 0.28 mmol) in DMF (0.7 ml). The reaction is stirred at room temperature for 2 hours. The solvent is evaporated and the residue purified by flash column chromatography (30:1 dichloromethane-methanol elution). The intermediate is dissolved in methanol (2 ml) and water (2.75 ml) added, followed by 4M aqueous sodium hydroxide (0.25 ml). The reaction is heated at 40° C. for 2 hours, then stirred for 16 hours at ambient temperature. The solvent is evaporated and the crude product purified by flash column chromatography (30:1 dichloromethane-methanol elution) to afford 8-(6-ethynyl-isoquinolin4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione, [MH]+ 388.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](Br)[CH:27]=1>ClCCl>[Br:25][C:26]1[CH:27]=[C:28]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)c1ccc2c(c1)CCNC2=O
Reactant: Brc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C)c1ccc2c(c1)CCN(c1cccc(Br)c1)C2=O
Temperature: 150 °C
Yield: 67.8 %

Procedure:
6-Dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (762 mg, 4.01 mmol), cuprous iodide (153 mg, 0.802 mmol) and potassium carbonate (554 mg, 4.01 mmol) were deposited in a sealed type vessel. 6 mL DMSO and 1,3-dibromobenzene (1.89 g, 8.02 mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 24 hours. Cuprous iodide (153 mg, 0.802 mmol) was added and the mixture was heated at 150° C. for an additional 24 hours. This was diluted with dichoromethane and filtered through a pad of celite. The filtrate was partitioned between dichloromethane and 5% aq. ammonium hydroxide. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 100% ethyl acetate/hexanes) to yield 2-(3-Bromo-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (939 mg, 2.72 mmol). MS (ESI) 345.0 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][C:8]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:7]=2[CH2:6]1)=[N+]=[N-]>[Pd]>[O:9]1[CH:5]([CH2:4][NH2:1])[CH2:6][C:7]2[CH:17]=[CH:16][C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:8]1=2
Reactant: [N-]=[N+]=NCC1Cc2ccc3c(c2O1)CCCC3
Agent: [Pd]
Product: NCC1Cc2ccc3c(c2O1)CCCC3
Yield: 67 %

Procedure:
Treatment of (±)-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-ylmethyl 4-methylbenzenesulfonate (2.05 g, 5.72 mmol) with sodium azide (0.929 g, 14.30 mmol) generally according to the procedure described for Intermediate 24 gave (±)-2-(azidomethyl)-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan. Treatment of the azide with palladium on carbon (10 wt. %, 0.094 g) generally according to the procedure described for Example 2 afforded 0.917 g (67%) of (±)-1-(2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp>220° C. (dec.); Anal. calcd. for C13H17NOHCl.0.1H2O: C, 64.15; H, 7.50; N, 5.75. Found: C, 64.41; H, 7.64; N, 5.67.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19]C(=O)OC(C)(C)C)[CH3:12])[N:4]=1.FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[CH3:12])[N:4]=1
Reactant: COc1cc(OC)nc(C(C)c2ccccc2NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)nc(C(C)c2ccccc2N)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product of stage (b) above (5.0 g) was added to trifluoroacetic acid (25 ml) and the resulting solution was stirred at room temperature for 3 hours. The solution was evaporated and the residue was triturated with diisopropyl ether and cooled in a solid carbon dioxide-acetone bath. The solid was filtered and washed with diisopropyl ether to give 3.5 g of the desired product, mp 136°-139° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:13]=[C:12]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([F:28])[CH:20]=3)[N:15]=2)[CH:11]=[CH:10][C:9]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35].Cl.[CH3:37][O:38][C:39](=[O:42])[CH2:40][NH2:41].CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1.CN(C=O)C>[CH3:7][C:8]1[CH:13]=[C:12]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:41][CH2:40][C:39]([O:38][CH3:37])=[O:42])=[O:24])=[C:21]([F:28])[CH:20]=3)[N:15]=2)[CH:11]=[CH:10][C:9]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35]
Reactant: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)cc1C
Reactant: COC(=O)CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(C)c3)n2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
Oxalyl chloride (63.46 μL; 0.75 mmol) was added to suspension of example 4 (97.10 mg; 0.25 mmol) and DMF (0.50 μL; 0.01 mmol) in DCM (10 mL) and the resulting mixture was stirred at RT for 1 hour. The solution was then evaporated to dryness, the residue taken up in THF (3 mL) and then added to a mixture of glycine methyl ester hydrochloride salt (FLUKA; 50110; 31.39 mg; 0.25 mmol) and DIEA (189.56 μL; 1.10 mmol) in THF (2 mL). The reaction mixture was stirred at RT for 2 hours, filtered through a SPE NH2 column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound as a yellow oil (99 mg; 86%). 1H NMR (DMSO-d6, 300 MHz) δ 8.95-8.90 (m, 1H), 8.18 (br s, 1H), 8.10-8.04 (m, 2H), 7.98 (dd, J=10.8, 1.3 Hz, 1H), 7.93-7.88 (m, 1H), 7.40-7.27 (m, 4H), 7.15-7.12 (m, 1H), 4.07 (d, J=5.5 Hz, 2H), 3.69 (s, 3H), 2.14 (s, 3H), 2.04 (s, 3H). LC/MS (Method B): 458.5 (M−H)−, 460.3 (M+H)+. HPLC (Method A) Rt 5.57 min (Purity: 99.2%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)[CH:5]=3)=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:13][CH:14]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(F)cc2)cn1
Yield: 10 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluorophenyl)-isoxazole (73 mg, 0.3 mmol) was converted, using 4-fluorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (10 mg, 10%) which was obtained as an off-white solid. MS: m/e=338.7[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Si:20]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]O)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Si:20]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:11]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCO
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
In toluene (30 ml) was dissolved the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (0.94 g, 3.1 mmol) obtained in Example 5, followed by the addition of 5-(t-butyldimethylsilyloxy)-1-pentanol (1.1 ml, 4.6 mmol) and cyanomethylenetri-n-butylphosphorane (1.0 g, 4.1 mmol). The resulting mixture was heated under reflux for 14 hours under an argon atmosphere. The reaction mixture was allowed to cool down and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=15:1), whereby the title compound (1.4 g, 87%) was obtained as a colorless oil.
Reaction SMILES: [Na].[C:2]([O:8][CH3:9])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[CH2:10]([C:15]1[C:16](=[O:20])[CH2:17][CH2:18][CH:19]=1)[CH2:11][CH2:12][CH2:13][CH3:14].[Cl-].[Na+]>C(O)(=O)C.CO>[CH2:10]([C:15]1([CH:3]([C:2]([O:8][CH3:9])=[O:7])[C:4](=[O:5])[CH3:6])[CH2:19][CH2:18][CH2:17][C:16]1=[O:20])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCC1=CCCC1=O
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCC1(C(C(C)=O)C(=O)OC)CCCC1=O
Reaction time: 48 h
Yield: 70.5 %

Procedure:
750 ml of absolute methanol was introduced into a 2 liter flask. 17.3 g of sodium were added thereto. 580 g of methyl acetoacetate and 456 g of 2-pentyl-cyclopent-2-en-1-one were then added and the mixture was allowed to stand for 48 hours at the ambient temperature. The reaction product was neutralised with 45 g of acetic acid and then poured into 3 liters of a 10% aqueous sodium chloride solution. The product was then worked up as described in Example 1 (a). There were thus obtained 567 g (yield = 70%) of 2-n-pentyl-(1-carbomethoxy-2-oxopropyl)-1-cyclopentanone having: nD20 = 1.4702, d420 = 1.0545.
Reaction SMILES: C(=O)([S:3][CH2:4][C@@H:5]([NH:10][C:11]1[C:16]([F:17])=[CH:15][N:14]=[C:13]([Cl:18])[N:12]=1)[C:6]([CH3:9])([CH3:8])[CH3:7])C.C[O-].[Na+]>CO>[Cl:18][C:13]1[N:12]=[C:11]([NH:10][C@@H:5]([C:6]([CH3:8])([CH3:7])[CH3:9])[CH2:4][SH:3])[C:16]([F:17])=[CH:15][N:14]=1
Reactant: CC(=O)SC[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[C@@H](CS)Nc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a nitrogen-purged solution of (S)—S-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutyl ethanethioate, 76a, (1.00 g, 3.27 mmol) in methanol (20 mL) was added NaOMe (1.457 mL of 25% solution in MeOH, 6.540 mmol) and the solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in water (25 mL) and slowly acidified with 2N HCl to give a white precipitate that was extracted twice with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure to afford 0.85 g of the desired product as a pale beige color solid: LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 264.92 (M+H) RT=3.32 min.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:8](C(OC)=O)=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].S(Cl)(Cl)=O>CCO.O.C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(=O)OC)c2ccc(Br)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccnc2cc(Br)ccc12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of 750 mg (2.31 mmol) of dimethyl 7-bromo-2,4-quinolinedicarboxylate in a mixture of 20 mL of EtOH, 10 mL THF and 4 mL of H2O was added 925 mg (23.1 mmol) of NaOH. The mixture was stirred at 50° C. An additional 10 mL of THF and 15 mL of H2O were added after 5 min. After 30 min total at 50° C., the solution was concentrated to ⅓ volume and the pH was adjusted to 4.0 with 1.0 N HCl (aq) followed by the addition of 100 mL of H2O. The resulting solids were collected by suction filtration, washed with H2O and dried. The solids were then added to 10 mL of diphenyl ether and the mixture stirred at 215° C. for 20 min. Upon cooling, 20 mL of hexanes was added and the resulting solids were collected by suction filtration, washed with hexanes and dried. The solids were then suspended in 20 mL of MeOH and 505 μL (6.90 mmol) of thionyl chloride was added. The mixture was refluxed for 1 hr, then an additional 505 μL (6.90 mmol) of thionyl chloride was added. After an additional 1 hr of refluxing, the solvent was evaporated. The residue was diluted with EtOAc then washed with saturated Na2CO3 (aq) and brine then dried over Na2SO4. Concentration of the solution yielded 320 mg (52%) of methyl 7-bromo-4-quinolinecarboxylate as a beige solid. 1H NMR (400 MHz, CDCl3): δ 9.01 (d, J=4 Hz, 1H), 8.70 (d, J=9 Hz, 1H), 8.35 (s, 1H), 7.92 (d, J=4 Hz, 1H), 7.75-7.72 (m, 1H), 4.03 (s, 3H). ESI-LCMS m/z 267 (M+H)+.
Reaction SMILES: Cl[CH:2]([C:8](=[O:10])[CH3:9])[CH:3](OC)OC.Cl.[C:12]([NH2:15])(=[NH:14])[CH3:13].C([O-])(=O)C.[Na+]>O1CCOCC1>[C:8]([C:2]1[N:14]=[C:12]([CH3:13])[NH:15][CH:3]=1)(=[O:10])[CH3:9]
Reactant: CC(=N)N
Reactant: COC(OC)C(Cl)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)c1c[nH]c(C)n1
Yield: 75.2 %

Procedure:
A mixture of 1.66 g (10 mmole) 2-chloro-1,1-dimethoxy-3-butanone, 1.43 g (15 mmole) acetamidine hydrochloride and 2.05 g (25 mmole) sodium acetate in 50 ml dioxane is heated at reflux for 24 hours. The dioxane is evaporated in vacuo and the residual oil is flash chromatographed on silica gel (40:60 ethyl acetate/hexane, 40 mm) to obtain three fractions. The third fraction, a white solid (1.121 g) was rechromatographed (40 mm, acetone) to afford 933 mg (75.1%) of product as white solid which is pure as judged by its NMR spectrum in CDCl3 and by TLC on silica gel (one spot, 1:9 methanol/chloroform).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.Cl.[NH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C>CN1C(=O)CCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:8])[N:14]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]2=[O:10]
Reactant: CCOC(=O)CCN
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN1C(=O)c2ccc(C)cc2C1=O
Temperature: 130 °C
Yield: 80.4 %

Procedure:
A solution of 4-methylphthalic anhydride (21.3 g, 0.13 mol), ethyl 3-aminopropionate hydrochloride (20.2 g, 0.13 mol), and triethylamine (19 mL) in NMP was stirred at ambient temperature for 3 days, and heated to 130° C. for 3 hours. The mixture was diluted with water (300 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with 1N hydrochloric acid (2×50 mL), sodium bicarbonate solution (2×50 mL), dried (MgSO4), and concentrated to give 27.3 g yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22]
Reactant: Ic1ccccn1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1ccccn1
Yield: 44.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (453 mg, 2.21 mmol) and 2-(but-3-ynyl)isoindoline-1,3-dione (400 mg, 2.01 mmol, Example 189(B)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 70:30) to yield 250 mg (0.90 mmol, 45%) of 2-(4-(pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione as.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][CH2:24][N:25]3C(=O)C4=CC=CC=C4C3=O)[CH2:18]1)=[O:16])[CH2:7][CH2:6]2.CN>>[NH2:25][CH2:24][CH2:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:15]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)=[O:16])[CH2:18]1
Reactant: COc1cc2c(cc1OC)CN(C(=O)N1CCCC(CCN3C(=O)c4ccccc4C3=O)C1)CC2
Agent: CN
Product: COc1cc2c(cc1OC)CN(C(=O)N1CCCC(CCN)C1)CC2
Yield: 95.8 %

Procedure:
(±)-6,7-Dimethoxy-2-[(3-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoqinoline hydrochloride (3.19 g) was desalted by a customary method, and a conventional alkylation reaction was carried out using an acetonitrile solution (30 ml) of the residue, 2.85 g of N-(2-bromoethyl)phthalimide and 1.55 g of potassium carbonate to give 3.83 g of (±)-6,7-dimethoxy-2-{[3-(2-phthalimidoethyl)piperidyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline. Then, 3.83 g of (±)-6,7-dimethoxy-2-{[3-(2-phthalimidoethyl)piperidyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline was deprotected by a customary method using 45 ml of a methanolic solution containing 40% of methylamine to give 2.67 g of (±)-2-{[3-(2-aminoethyl)piperidyl]carbonyl}-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline as a yellow foamy substance.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([F:16])([F:15])[C:4]([F:14])([F:13])[C:5]([F:12])([F:11])[C:6]([F:10])([F:9])[CH2:7][CH3:8].FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[I:25].C=C>>[F:1][C:2]([F:17])([F:18])[C:3]([F:15])([F:16])[C:4]([F:13])([F:14])[C:5]([F:11])([F:12])[C:6]([F:10])([F:9])[CH2:7][CH2:8][I:25]
Reactant: CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: C=C
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI

Procedure:
1,1,1,2,2,3,3,4,4,5,5-Undecafluoroheptane (CF3CF2CF2CF2CF2CH2CH3) may be prepared by reaction of 1,1,1,2,2,3,3,4,4,5,5-undecafluoro-5-iodo-pentane with ethylene to give 1,1,1,2,2,3,3,4,4,5,5-undecafluoro-7-iodo-heptane followed by zinc reduction in an acid such as HCl or acetic acid.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:25])[CH:4]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1)[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:6]=1[F:15]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH3:1][S:2][C:3](=[NH:25])[C:4](=[N:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=1)[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:6]=1[F:15]
Reactant: COc1cc(OC)c(F)c(C(Nc2ccc(C#N)cc2)C(=N)SC)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(F)c(C(=Nc2ccc(C#N)cc2)C(=N)SC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
After adding 4.95 g of manganese dioxide to a solution of 2.05 g of 2-(4-cyanophenylamino)-2-(2-fluoro-3,5-dimethoxyphenyl)thioacetimidic acid methyl ester in 100 ml of ethyl acetate, the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through celite, and the celite was washed with 500 ml of ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The title compound (2.01 g) was obtained as a light yellow solid.