Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1>>[CH3:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:30][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: Cc1cccc(CBr)c1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: Cc1cccc(CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)c1

Procedure:
Compound 133 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-(bromomethyl)-3-methylbenzene and conditions outlined in procedure V. LCMS: 406 [M+H]; Rt=1.02 min.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][CH2:6][CH2:7][NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[C:21]([N+:23]([O-:25])=[O:24])=[CH:20][CH:19]=[C:18]3[CH3:26])=[CH:14][CH:13]=[CH:12][CH:11]=2.[C:27](O)(=[O:30])[CH2:28][CH3:29]>>[ClH:3].[C:27]([O:5][CH2:6][CH2:7][NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[C:21]([N+:23]([O-:25])=[O:24])=[CH:20][CH:19]=[C:18]3[CH3:26])=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:30])[CH2:28][CH3:29]
Reactant: O=S(Cl)Cl
Reactant: CCC(=O)O
Reactant: Cc1ccc([N+](=O)[O-])c2c(NCCO)c3ccccc3nc12
Product: CCC(=O)OCCNc1c2ccccc2nc2c(C)ccc([N+](=O)[O-])c12
Product: Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 68 %

Procedure:
Thionyl chloride (10 ml) is added to a stirred, cooled to −20° C. propionic acid (50 ml) and at the same temperature 9-(2-hydroxyethylamino)-4-methyl-1-nitroacridine (0.55 g) is added in portions, and the mixture is stirred at room temperature for 20 hours. The reaction mixture is distilled off under reduced pressure, washed several times with 10% aqueous sodium bicarbonate and water, dried under vacuum, and crystallized from absolute methanol-ethanol hydrogen chloride solution to give 9-(2-propionoxyethylamino)-4-methyl-1-nitroacridine hydrochloride with 68% yield, m.p. 228-230° C., anal. C19H19N3O4Cl(C,H,N). 1H NMR (d6DMSO): δ 1.20(t, 3H, H-3″), 2.0(q, 2H, H-2″), 2.8(s, 3H, CH3), 3.9(t, 2H, H-1), 4.0(t, 2H, H-2′), 7.4(t, 1H, H-7), 7.5(d, 1H, J=7.8 Hz, H-3), 7.6(d, 1H, J=8.3 Hz, H-6), 8.0(t, 1H, H-5), 8.4(m, 1H, H-8).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6](C(Cl)=O)=[CH:5][CH:4]=1.[CH3:12][Mg]Br.[Cl-].[NH4+].C([O:20][CH2:21][CH3:22])(=O)C>O1CCCC1.CCCCCC>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:21]([CH3:22])([OH:20])[CH3:12])=[CH:5][CH:4]=1
Reactant: C[Mg]Br
Reactant: CCOC(C)=O
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 4-chloromethylbenzoyl chloride (40 g) in tetrahydrofuran (400 ml) was added dropwise methylmagnesium bromide (3M, tetrahydrofuran solution) (70 ml) under ice-cooling and the mixture was stirred at 0° C. for 4 hr. The reaction mixture was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated to give a yellow oil. The oil was subjected to silica gel column chromatography (developing solvent; hexane:ethyl acetate=9:1) to give an orange oil. The oil was subjected to silica gel column chromatography (developing solvent; hexane:ethyl acetate=4:1) to give the title compound (10 g) as a pale-brown oil, m.p.=101-103° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.N1C=CC=CC=1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(Cl)Cl.O>[C:9]([O:8][C:7]([NH:6][C@H:3]1[CH2:4][CH2:5][N:1]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:2]1)=[O:13])([CH3:10])([CH3:12])[CH3:11]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (4.2 g, 22 mmol) in methylene chloride (49 mL) was cooled at 0° C. and treated with pyridine (2.2 mL, 29 mmol) and benzyl chloroformate (3.8 mL, 29 mmol). The mixture was stirred at 0° C. for 30 minutes and then warmed to ambient temperature and stirred for 4 hours. The reaction mixture was diluted with water (100 mL) and methylene chloride (100 mL), the organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 40 g, ISCO, 1-100% ethyl acetate in heptanes) to afford the title compound as a white solid, which was used in the next step without any further purification (5.2 g, 73%).
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[SH:6][C:7]1[C:8]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:9]=2[S:10][C:11]=1[C:12]([NH2:14])=[O:13].C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[NH2:14][C:12]([C:11]1[S:10][C:9]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:8]=2[C:7]=1[S:6][CH2:2][C:3]([OH:5])=[O:4])=[O:13]
Reactant: COc1ccc2sc(C(N)=O)c(S)c2c1
Reactant: O=C(O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2sc(C(N)=O)c(SCC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
Bromoacetic acid (72 mg, 0.52 mmol) is added to a room temperature solution of 3-mercapto-5-methoxybenzo[b]thiophene-2-carboxamide (50 mg, 0.21 mmol) in 3 mL of THF followed by NaHCO3 (219 mg, 2.60 mmol) and the reaction mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with ethyl acetate and washed with 1N HCl and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane provides [[2-(aminocarbonyl)-5-methoxybenzo[b]thien-3-yl]thio]acetic acid in 54% yield; mp=126°-127° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:14]=2[O:22][CH3:23])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]>[CH2:1]([N:8]1[C:12]([C:13]2[C:14]([O:22][CH3:23])=[CH:15][CH:16]=[CH:17][C:18]=2[NH2:19])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc([N+](=O)[O-])c1-c1nnnn1Cc1ccccc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: COc1cccc(N)c1-c1nnnn1Cc1ccccc1
Reaction time: 18 h
Yield: 94.8 %

Procedure:
1-Benzyl-5-(2-methoxy-6-nitrophenyl)-1H-tetrazole (Intermediate 14, 0.14 g) was dissolved in ethanol (5 mL) under a nitrogen atmosphere. Platinum on carbon (10%, 0.01 g) was added and the nitrogen atmosphere was replaced by hydrogen. The mixture was stirred for 18 hours and then filtered through celite. The filtrate was evaporated to dryness to give the title compound as a brown gum (0.12 g).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[C:15](=[O:20])N(OC)C)=[O:7])([CH3:4])[CH3:3].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[CH:22]1>>[C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[C:15]([C:22]1[O:21][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=1)=[O:20])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C1CN(C)CCN1C(=O)OC(C)(C)C
Reactant: c1ccc2occc2c1
Product: CN1CCN(C(=O)OC(C)(C)C)C(C(=O)c2cc3ccccc3o2)C1
Yield: 52 %

Procedure:
The title compound (1.81 g, 52%) was prepared from (RS)-2-(methoxy-methyl-carbamoyl)-4-methyl-piperazine-1-carboxylic acid dimethyl-ethyl ester, D54 (2.9 g, 10.1 mmol) and benzofuran (0.74 g, 10.1 mol) using the method of Description 2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[CH:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=O.S(=O)(O)[O-].[Na+]>CO>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:9]1[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Nc1ccccc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Yield: 19 %

Procedure:
A mixture of 1,2-diaminobenzene (6.59 g), methyl 4-formylbenzoate (10.0 g) and sodium bisulfite (6.60 g) in methanol (500 mL) is stirred at reflux for 6 hours. The mixture is filtered and the solvent evaporated to leave a yellow solid. This solid is recrystallized from ethyl acetate/ethanol to give 2.92 g of the title compound as an oil-white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Cl[CH:10]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18].O>C1(C)C=CC=CC=1>[C:1]1([O:7][CH:10]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Clc1ccc(C(Cl)c2cccnc2)c(Cl)c1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(C(Oc2ccccc2)c2cccnc2)c(Cl)c1

Procedure:
1 gm of phenol is added to 100 ml of toluene in a 250 Erlenmeyer flask equipped with a refluxing condensor. 0.26 gm sodium is added and the system is heated at reflux until the sodium has dissolved. The system is then allowed to come to room temperature. At this time, 2.50 gm of alpha-chloro-2,4-dichloro-alpha-(3-pyridyl)toluene in 30 ml of toluene is added over 1 hour. The system is then heated at reflux for 6 hours. The system is added to water and the product extracted in the organic phase. The toluene is removed by stripping to give the 3-pyridyl-2,4-dichlorophenylcarbinol phenylether.
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[S:16][C:17]([C:35]([F:38])([F:37])[F:36])=[CH:18][C:19]=1[C:20]1[N:33]([CH3:34])[C:23]2=[N:24][CH:25]=[C:26]([S:28][C:29]([F:32])([F:31])[F:30])[CH:27]=[C:22]2[N:21]=1)C.[S:39]([O-:43])([O-])(=[O:41])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:39]([C:15]1[S:16][C:17]([C:35]([F:37])([F:38])[F:36])=[CH:18][C:19]=1[C:20]1[N:33]([CH3:34])[C:23]2=[N:24][CH:25]=[C:26]([S:28][C:29]([F:30])([F:32])[F:31])[CH:27]=[C:22]2[N:21]=1)(=[O:43])=[O:41])[CH3:11]
Reactant: O=S([O-])([O-])=S
Reactant: CCSc1sc(C(F)(F)F)cc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1sc(C(F)(F)F)cc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.12 g of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to 3 ml of a solution of 0.1 g of 2-(2-ethylthio-5-trifluoromethylthiophen-3-yl)-3-methyl-6-trifluoromethylthio-3H-imidazo[4,5,b]pyridine in chloroform under ice cooling, and the mixture was stirred for 2 hours and at room temperature for 1 hour. A 10% aqueous sodium thiosulfate solution was poured into the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.09 g of 2-(2-ethylsulfonyl-5-trifluoromethylthiophen-3-yl)-3-methyl-6-trifluoromethylthio-3H-imidazo[4,5,b]pyridine (Compound of Present Invention (8)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:20])[CH2:11][C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.OP(O)(O)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][C:10](=[O:20])[NH:9]2)=[CH:7][CH:8]=1.[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:11][C:10](=[O:20])[NH:9]2
Reactant: COc1cccc(NC(=O)CC(=O)c2ccccc2)c1
Agent: O=P(O)(O)O
Solvent: O
Product: COc1ccc2c(-c3ccccc3)cc(=O)[nH]c2c1
Product: COc1cccc2[nH]c(=O)cc(-c3ccccc3)c12
Temperature: 25 °C

Procedure:
A mixture of N-(3-methoxyphenyl)benzoylacetamide (5.8 g), o-phosphoric acid (30 mL of 85% acid in H2O) and H2O (30 mL) was heated at 100°-110° C. for 6 hr. After cooling to r.t., H2O (50 mL) was added and the precipitate that formed was collected by filtration. The title compound was thus obtained as a mixture with the regioisomeric product, 5-methoxy-4-phenyl-2-quinolinone, and used as such.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12].Cl.C1COCC1>O>[CH:3]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])=[O:2]
Reactant: COC(OC)c1cc(Oc2cccc(C#N)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(Oc2ccc([N+](=O)[O-])c(C=O)c2)c1
Temperature: 25 °C

Procedure:
A mixture of 3-(3-dimethoxymethyl-4-nitro-phenoxy)-benzonitrile (0.068 mol) in water (55 mL) was stirred at room temperature, and then 12N HCl (55 mL) and THF (140 mL) were added, and the reaction mixture was stirred overnight at room temperature. The mixture was stirred in H2O and extracted with diisopropyl ether. The organic layer was separated, washed with a 10% NaHCO3 solution, separated again, dried, filtered off and the solvent was evaporated. The obtained residue was stirred in diisopropyl ether, and then the desired product was filtered off and dried to yield the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([CH3:10])=[N:3]1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:16]([CH:19]=1)[C:17]#[N:18].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:17]([C:16]1[CH:19]=[C:12]([NH:11][C:7]([C:5]2[C:4]([CH3:10])=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:8])[CH:13]=[CH:14][C:15]=1[O:20][CH2:21][C:22]([CH3:24])([CH3:23])[CH3:25])#[N:18]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: Cc1nn(C)cc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nn(C)cc1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
1,3-Dimethylpyrazole-4-carboxylic acid (0.6 g), 5-amino-2-neopentyloxybenzonitrile (0.9 g), triethylamine (1.0 g) and diethyl cyanophosphate (1.0 g) were added to dimethylformamide (10 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (0.5 g), melting point: 193–194° C.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[O:14][C:15]4[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][C:16]=4[N:17]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:26]([NH2:28])[CH3:27].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1.ClCCl>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[O:14][C:15]4[CH:21]=[CH:20][C:19]([C:22]([NH:28][CH2:26][CH3:27])=[O:23])=[CH:18][C:16]=4[N:17]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN
Reactant: O=C(O)c1ccc2oc(N3CCC(N4CCCCC4)CC3)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)c1ccc2oc(N3CCC(N4CCCCC4)CC3)nc2c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
2-(1,4′-Bipiperidin-1′-yl)benzo[d]oxazole-5-carboxylic acid (Example 95A, 40 mg, 0.121 mmol), ethanamine hydrochloride (15 mg, 0.182 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (55 mg, 0.146 mmol) were combined in tetrahydrofuran (3 mL). Triethylamine (51 μL, 0.364 mmol) was added and the mixture was stirred at 45° C. overnight. The reaction mixture was diluted with dichloromethane, washed with a 1 N aqueous solution of sodium hydroxide, and absorbed on silica gel. The crude mixture was purified with silica gel chromatography eluting with a gradient of methanol in dichloromethane (3-18%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.25 (t, J=7.29 Hz, 3 H) 1.39-1.51 (m, 2 H) 1.52-1.75 (m, 7 H) 1.96 (d, J=12.89 Hz, 2 H) 2.44-2.61 (m, J=4.75 Hz, 4 H) 3.01-3.15 (m, 2 H) 3.43-3.58 (m, 2 H) 4.29-4.41 (m, 2 H) 6.01 (s, 1 H) 7.21-7.28 (m, 1 H) 7.50 (dd, J=8.31, 1.86 Hz, 1 H) 7.66 (d, J=1.36 Hz, 1 H); MS (ESI+) m/z 357.0 (M+H)+.
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH2:16]([NH2:20])[CH2:17][CH2:18][NH2:19]>>[CH:2]1[C:11]2[C:6](=[C:7]([S:12]([NH:19][CH2:18][CH2:17][CH2:16][NH2:20])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: NCCCN
Agent: Cl
Product: NCCCNS(=O)(=O)c1cccc2cnccc12
Yield: 81.1 %

Procedure:
According to the method of Reference Example 2, a reaction was performed by using isoquinoline-5-sulfonyl chloride hydrochloride (20 g) and 1,3-propylenediamine (22.2 g) to obtain the title compound (16.3 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.CS(O)(=O)=O.[N-:17]=[N+]=[N-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:17][CH2:6][CH2:5]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2cc(F)ccc21
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NCCc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a solution of 5-fluoro-2,3-dihydro-1H-inden-1-one (4.5 g, 29.97 mmol) in dichloromethane (50 ml) was added methanesulfonic acid (40 ml). This was followed by the addition of sodium azide (2.73 g, 42.0 mmol) in several batches with stirring over 2 hours at 0° C. The reaction mixture was then quenched with aqueous sodium hydroxide and extracted with dichloromethane (2×100 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 10%-100% ethyl acetate in petroleum ether to afford 6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-one as a white solid (2.5 g, 51%); (ES, m/z): [M+H]+ 166; 1H NMR (300 MHz, CDCl3): δ 8.11 (dd, J=6.0, 8.7 Hz, 1H), 7.07-7.00 (m, 1H), 6.94 (dd, J=2.4, 8.7 Hz, 1H), 6.57 (br s, 1H), 3.61 (t, J=6.6, 2H), 3.03 (t, J=6.6, 2H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].O.[C:6]1(C)[CH:11]=[CH:10][C:9](S(O)(=O)=O)=[CH:8][CH:7]=1.C1C=CC=CC=1>O>[CH2:2]1[CH2:1][O:4][CH2:9][CH:10]([CH2:11][CH2:6][CH:7]=[CH2:8])[O:3]1
Reactant: OCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C=CCCC1COCCO1
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 5-oxy-1-hexene (9.8 g.), ethylene glycol (18.6 g.), p-toluene sulfonic acid monohydrate (1.56 g.) and benzene (250 ml.) is heated at reflux under a Dean-Stark water separator. After 2 hrs., the reaction mixture is washed with water and the organic layer is separated, dried with magnesium, and evaporated in vacuo. Distillation of the residue gives 5-ethylenedioxy-1-hexene (90% yield) b.p. 34°-37°/1.5 mm. nmr (CDCl3)δ: 1.27 (s, CH3), 1.5-2.4 (m, CH2 --CH2); 2.83 (s, --O--CH2 --CH2 --O); 4.80-6.1 (m, CH2 =CH--). IR (film)μ: 6.06 (CH2 =CH--).
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.[CH2:13](Cl)[CH:14]=[CH2:15]>CN(C=O)C>[CH2:15]([N:6]1[C:2](=[O:12])[C:3]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:4]2[C:5]1=[O:7])[CH:14]=[CH2:13]
Reactant: C=CCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)c2ccccc2C1=O

Procedure:
Phthalimide potassium salt can be alkylated with allyl chloride in DMF to produce N-allylphthalimide. Under the Heck reaction conditions (Patel et al. 1977), N-allylphthalimide reacted with aryl bromide to give N-cinnamyl phthalimide. Upon treatment with hydrazine, cinnamyl amine was obtained from N-cinnamyl phthalimide (FIG. 28).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH3:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC1(C(=O)OCC)CCCC1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1(C(=O)OCC)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h
Yield: 109.7 %

Procedure:
Ethyl 2-hydroxy-1-n-propyl-cyclopentane carboxylate (6.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.67 ml) was slowly added, then benzoyl chloride (5.33 ml, 0.045 mol) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 10.00 g of yellow liquid, MS: m/e 305(M+″+1), 304(M+), 259, 230, 199, 182, 153, 105(base), 77.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[C:5]([N+:13]([O-])=O)[CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16]>C(O)C.[Pd]>[NH2:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3](=[O:16])[N:2]([CH3:1])[C:10]2([CH3:12])[CH3:11]
Reactant: CN1C(=O)c2c([N+](=O)[O-])cccc2C1(C)C
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)c2c(N)cccc2C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
20 mg of 5% Pd/C was cautiously added to a solution of 2,3,3-trimethyl-7-nitroisoindolin-1-one (Compound 148B, 0.15 g, 0.68 mmol) in ethanol (5 mL), and stirred under hydrogen atmosphere at room temperature overnight. The reaction mixture was and concentrated to remove ethanol to provide 80 mg of pure the title compound (62%). 1H NMR (CDCl3, 500 MHz): δ1.36 (s, 6H), 3.58 (s, 3H), 3.60 (brs, 2H), 6.58 (d, J=8.0 Hz, 1H), 6.69 (d, J=7.0 Hz, 1H), 6.84 (dd, J=7.0, 8.0 Hz, 1H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[Cl:19][C:20]1[CH:25]=[C:24]([N:26]=C=O)[CH:23]=[C:22]([Cl:29])[CH:21]=1.[N:30]1[S:31][N:32]=[C:33]2[C:38]([NH2:39])=[CH:37][CH:36]=[CH:35][C:34]=12>>[N:30]1[S:31][N:32]=[C:33]2[C:38]([NH:39][C:16]([C@@H:9]3[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]3[C:6]([NH:26][C:24]3[CH:25]=[C:20]([Cl:19])[CH:21]=[C:22]([Cl:29])[CH:23]=3)=[O:7])=[O:18])=[CH:37][CH:36]=[CH:35][C:34]=12
Reactant: Nc1cccc2nsnc12
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Product: CON=C1C[C@@H](C(=O)Nc2cccc3nsnc23)N(C(=O)Nc2cc(Cl)cc(Cl)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 1,3-dichloro-5-isocyanatobenzene, and 2,1,3-benzothiadiazol-4-amine the title compound was obtained in 55% purity by LC/MS. MS(ESI+): m/z=479.6.