Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:23]=[CH:22][C:8]([CH:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]/[C:11]/2=[N:20]\[OH:21])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:24](Br)(=[O:26])[CH3:25].C(N(CC)CC)C>ClCCl>[C:24]([O:21]/[N:20]=[C:11]1/[C:10](=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:22]=2)[C:19]2[C:14]([CH2:13][CH2:12]/1)=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:26])[CH3:25]
Reactant: CC(=O)Br
Reactant: CS(=O)(=O)c1ccc(C=C2/C(=N/O)CCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O/N=C1\CCc2ccccc2C1=Cc1ccc(S(C)(=O)=O)cc1
Yield: 60.2 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one oxime (25 mg, 0.076 mmol) and acetylbromide (0.017 ml, 0.23 mmol) were added into dichloromethane (2.0 ml). Then, at room temperature triethylamine (0.032 ml, 0.23 mmol) was added, stirred for an hour so as to complete the reaction. Afterward, an organic layer was separated by blending water, washed again with water and saturated brine, and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and made to crystal by using a mixed organic solvent (diethylether/isopropanol/n-hexane=1/1/5, v/v/v). As a result, 16.9 mg of the present compound (productive yield 60%) was obtained as a white solid crystal.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([NH:20][CH3:21])=[O:19])=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.CC(O)=O.O>>[NH2:1][C:2]1[C:3]([C:18]([NH:20][CH3:21])=[O:19])=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1nc(C2CCC3(CC2)OCCO3)ccc1N
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)c1nc(C2CCC(=O)CC2)ccc1N
Temperature: 75 °C

Procedure:
A mixture of 3-Amino-6-(1,4-dioxaspiro[4.5]dec-8-yl)-N-methylpyridine-2-carboxamide (Compound 232C, 0.160 g, 0.549 mmol) in AcOH (1.0 mL, 18 mmol) and H2O (0.2 mL, 10 mmol) was warmed to 75° C. for 2.5 hours, after which, the reaction was cooled and concentrated in vacuo. The residue was taken up in water and basified with a saturated aqueous solution of K2CO3. This mixture was extracted three times with DCM and the combined organic layers were dried over Na2SO4, filtered and concentrated to a brown tar. This was taken up in DCM, treated with silica and concentrated and loaded into a sample cartridge. The product was isolated after purification on an ISCO Combiflash unit (eluting with 0-4% MeOH/DCM) as 53 mg of a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 1.97-2.13 (m, 4H), 2.26 (dt, J=14.40, 2.02 Hz, 2H), 2.52-2.59 (m, 2H), 2.77 (d, J=5.05 Hz, 3H), 3.05 (tdd, J=11.43, 3.79, 3.66 Hz, 1H), 6.65 (s, 2H), 7.09 (d, J=8.30 Hz, 1H), 7.20 (d, J=8.30 Hz, 1H), 8.42 (d, J=4.80 Hz, 1H). MS (ES+): m/z=247.87 (90) [M+1]. HPLC: tR=2.95 min (ZQ3, polar—5 min).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17]Br.N(OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:17][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: BrBr
Reactant: N#Cc1cnn(-c2ccc(Cl)cc2Cl)c1N
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cnn(-c2ccc(Cl)cc2Cl)c1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-amino-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carbonitrile and 3 ml of bromine in 50 ml of chloroform was added 1.7 g of isoamyl nitrite. The reaction mixture was stirred at room temperature for approximately 10 minutes and then refluxed for approximately one hour. The solution was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel employing toluene as the eluent. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford 0.8 g of 5-bromo-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carbonitrile after crystallization from 3A alcohol. mp=101°-102° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([CH:12]3[CH2:17][CH2:16][N:15]=[C:14]([CH3:18])[CH2:13]3)[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(F)(F)F.[CH3:23]COCC.[Li]C>C1COCC1>[CH3:18][C:14]1([CH3:23])[CH2:13][CH:12]([C:9]2[S:8][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=3[CH:10]=2)[CH2:17][CH2:16][NH:15]1
Reactant: COc1cccc2sc(C3CCN=C(C)C3)cc12
Reactant: CCOCC
Agent: FB(F)F
Agent: [Li]C
Solvent: C1CCOC1
Product: COc1cccc2sc(C3CCNC(C)(C)C3)cc12
Yield: 30.7 %

Procedure:
To a solution of the crude 4-(4-methoxybenzo[b]thiophen-2-yl)-2-methyl-3,4,5,6-tetrahydropyridine (2.19 g, 8.44 mmol) in THF (38 mL) cooled to −78° C. in a dry ice/acetone bath, was added dropwise BF3.Et2O (48%) (3.34 mL, 12.6 mmol) via a syringe. After stirring ten minutes, the solution was treated with 24.1 mL (33.77 mmol) of 1.4 M MeLi. The mixture was stirred for 16 h, then quenched with 100 mL of saturated aqueous NH4Cl and 50 mL of H2O. The mixture was then extracted with CH2Cl2 (3×100 mL). The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography [2.5 to 7% (2.0 M NH3 in MeOH)/CH2Cl2] to give the title compound as an orange oil (0.713 g, 30%). IR (KBr) 2936, 1571, 1471, 1259, 1049 cm1. Ion Spray MS 276.2 (M+H)+. [α]D=0 (c 0.578, MeOH). C16H21NOS.0.1H2O.0.1 CH2Cl2
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:30])[CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:7]=1.C([O-])(=O)C.[K+].[N:36]#[C:37]Br.Cl>O.CO>[NH2:36][C:37]1[O:30][CH:3]([CH2:4][NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[N:9]=[C:8]([N:17]3[CH2:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]3)[CH:7]=2)[CH2:2][N:1]=1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(O)CN)c2c1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3CN=C(N)O3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
A mixture of 1-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-2-ol (80 mg, 0.18 mmol, prepared in analogy to Example 9-7) and potassium acetate (89 mg, 0.91 mmol) in a mixture solution of methanol and water (7 ml, V/V=6/1) was added cyanogen bromide (89 mg, 0.84 mmol) at 0° C. After being stirred at room temperature for 3 hours, the mixture was stirred further with concentrated hydrochloric acid (3 mL) for 1 hour, and then concentrated in vacuo. The residue was dissolved in a saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with dichloromethane (15 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (10% methanol in dichloromethane) to afford 32 mg of the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.87 (m, J=4.6 Hz, 2 H), 7.72 (s, 1 H), 7.65-7.62 (t, J=3.7 Hz, 1 H), 7.49-7.45 (t, J=3.9 Hz, 1 H), 7.32 (d, J=2.1 Hz, 1 H), 7.23 (d, J=2.1 Hz, 1 H), 6.85 (t, J=2.6 Hz, 1 H), 6.46 (brs, 2 H), 6.10 (s, 1 H), 5.10 (s, 2 H), 4.82-4.77 (m, J=4.8 Hz, 1 H), 4.49 (brs, 2 H), 3.75 (m, 1 H), 3.63 (s, 2 H), 3.52 (m, 3 H), 2.35 (s, 3 H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>CCOC(C)=O.CO>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:27])[C:20]([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)=[CH:30][N:31]([CH3:33])[CH3:32])=[CH:17][CH:18]=1
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ncccc3n2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)C=C(C(=O)c1ccc(OCc2ccc3ncccc3n2)cc1)c1ccncc1
Yield: 99.7 %

Procedure:
In a 5 mL round bottom flask equipped with a magnetic stirbar and a condenser with a calcium sulfate drying tube was stirred at reflux for 18 hours a mixture of Intermediate 4D, 1-(4-((1,5-naphthyridin-2-yl)methoxy)phenyl)-2-(pyridin-4-yl)ethanone (104 mg, 0.293 mmol) and N,N-dimethylformamide dimethyl acetal (1.0 mL, 7.53 mmol). The reaction mixture was checked by TLC (95:5 EtOAc/MeOH). The spot for starting material had been replaced by a lower Rf spot. Volatiles were removed under reduced pressure to give a brown oil, 1-(4-((1,5-naphthyridin-2-yl)methoxy)phenyl)-3-(dimethylamino)-2-(pyridin-4-yl)prop-2-en-1-one (120 mg, 0.292 mmol) that was dissolved in methanol (2.5 mL) and stirred at ambient temperature. Hydrazine monohydrate (0.02127 mL, 0.438 mmol) was added via syringe and the reaction mixture was stirred at reflux for 2 hours. Another 1.5 equivalents of hydrazine monohydrate was added and stirring at reflux was continued an additional 2 hours. Volatiles were removed under reduced pressure to give a tan solid that was rinsed with water 3 times then stirred with Et2O overnight. The Et2O was decanted away and the remaining solid was partitioned between CHCl3 and brine. The aqueous layer was extracted once more with CHCl3 and the combined organic layers were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a crude, bright yellow solid. This solid was purified by column chromatography on an Analogix IF-280 (Agilent SF15-24 g, 100% DCM to 98:2 DCM/2M NH3 in MeOH). Fractions #5-20 were combined and concentrated under reduced pressure to give a pale yellow solid. The solid was dissolved in warm CHCl3 and the resulting solution was filtered and concentrated under reduced pressure. The solid residue was rinsed with Et2O, then dissolved in a minimum of hot MeOH. The solution was placed in a 0° C. freezer to induce crystallization. Intermediate 4, 2-((4-(4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine was obtained by filtration as white crystals (16.5 mg, 14.9%). 1H NMR (300 MHz, methanol-d4) δ 8.98 (dd, J=4.2, 1.6 Hz, 1H), 8.48 (dd, J=8.6, 1.8 Hz, 2H), 8.36 (dd, J=4.7, 1.6 Hz, 2H), 8.02 (d, J=8.8 Hz, 1H), 7.97 (br s, 1H), 7.82 (dd, J=8.5, 4.3 Hz, 1H), 7.42-7.36 (m, 2H), 7.33 (d, J=5.9 Hz, 2H), 7.16 (d, J=7.3 Hz, 2H), 5.47 (s, 2H). MS (ESI) m/z=380 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([NH:22][C:8](=[O:9])[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])[CH2:19][CH2:20][CH3:21]
Reactant: CC(C(=O)Cl)(c1ccccc1)c1ccccc1
Reactant: CCCCN
Product: CCCCNC(=O)C(C)(c1ccccc1)c1ccccc1

Procedure:
The title compound, colorless oil, MS: m/e=282.2 (M+H+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl chloride and butylamine.
Reaction SMILES: Br.Br.[N:3]1([CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[N:3]1([CH2:8][C:9]2([C:29](=[O:30])[CH2:28][C:23]3[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=3)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Oc1ccc2c(c1)C(CN1CCCC1)NCC2
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Cl)c(Cl)c1)C1(CN2CCCC2)NCCc2ccc(O)cc21

Procedure:
Prepared as Ex. No. 5, from 3 g (7.61 mmoles) of 1-(pyrrolidin-1-yl)methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, 1.9 g (9.31 mmoles) of 3,4-dichlorophenylacetic acid, 2.3 ml (16.36 mmoles) of triethylamine and 3.2 g (15.61 mmoles) of dicyclohexylcarbodiimide in 110 ml of dry chloroform.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:13]=1[C:12]1[C@@H:11]([CH2:14][CH:15]([O:18][Si](C)(C)C)[C:16]#[N:17])[CH2:10][CH2:9][C:8]=1[S:7]2.Cl.C(=O)(O)[O-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:13]=1[C:12]1[C@@H:11]([CH2:14][CH:15]([OH:18])[C:16]#[N:17])[CH2:10][CH2:9][C:8]=1[S:7]2
Reactant: C[Si](C)(C)OC(C#N)C[C@H]1CCc2sc3ncnc(Cl)c3c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#CC(O)C[C@H]1CCc2sc3ncnc(Cl)c3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of 3-[(3R)-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]-2-[(trimethylsilyl)oxy]propanenitrile (240 mg, 0.68 mmol, 1.00 equiv) in methanol (5 mL) was added 1 mL of concentrated hydrochloric acid at 0° C. After stirring for 1 h at room temperature, the pH value of the solution was adjusted to 10 with saturated aqueous sodium bicarbonate, diluted with DCM, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 170 mg (89%) of 3-[(3R)-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]-2-hydroxypropanenitrile as a white solid. MS: m/z 280 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=O.C(O)(=O)C.C([NH2:18])(C)C>>[NH2:18][C@H:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(C)N
Reactant: CC(=O)c1cccc(O)c1
Solvent: CC(=O)O
Product: C[C@H](N)c1cccc(O)c1
Temperature: 37 °C

Procedure:
A total of 65 g of the 3-hydroxyacetophenone (compound (1)) substrate was charged to the stirred mixture as a powder. After addition of substrate was complete, the volume of the reaction was topped up to 1 L (if necessary) with the appropriate amount of 0.1 M TBA buffer, pH 7.5. The resulting slurry was stirred at 150 rpm at 37° C. (internal temperature). The temperature was monitored using an external temperature probe. The reaction was conducted under a constant nitrogen sweep of 5 L/min. Additional 5 M isopropylamine acetate (100 mL) was charged to the stirred mixture after 24 h and again after 48 h.
Reaction SMILES: Cl.[CH:2]([N:5]([CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:11][CH2:10]1)[CH2:6][CH2:7][CH3:8])([CH3:4])[CH3:3].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH:2]([N:5]([CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:11](=[O:33])[CH2:10]1)[CH2:6][CH2:7][CH3:8])([CH3:3])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCN(C(C)C)C1CSc2cccc(-c3ccccc3)c2C1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCN(C(C)C)C1Cc2c(-c3ccccc3)cccc2S(=O)C1

Procedure:
3-(N-Isopropyl-N-n-propylamino)-5-phenylthiochroman hydrochloride (310 mg, 0.86 mmol) was dissolved in 6 mL chloroform and to the cooled solution (ice-bath) was m-chloroperbenzoic acid (348 mg, 1.72 mmol) added in one portion.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21]>CN(C=O)C>[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21])=[CH:6][CH:7]=1)#[N:21]
Reactant: N#CCCCCCBr
Reactant: OCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCCCCOCCCc1ccc(OCCCCCC#N)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of 3-(4-hydroxyphenyl)-1-propanol (2.0 g, 13.1 mmole) in DMF (5 mL) was added to a solution of DMF (35 mL) containing NaH (1.31 g, 60% in mineral oil) at 0° C. under nitrogen atmosphere. The reaction mixture was slowly warmed to 80° C. After stirring for 1 h at 80° C., the reaction mixture was cooled to 0° C., and 6-bromohexanenitrile (5.78 g, 32.83 mmole) was added. The final mixture was re-heated to 80° C., and stirred for 24 h. The reaction mixture was quenched with saturated NaCl solution (200 mL), and the product was extracted with EtOAc (300 mL). The organic layer was washed with brine solution, dried with Na2SO4, and evaporated to dryness, yielding a pale yellow solid. Purification of the crude product by flash silica column chromatography: 4/1 to 1/1 hexane/EtOAc provided 6-{3-[4-(5-cyanopentyloxy)phenyl]propoxy}hexanenitrile in 30% yield (1.33 g). Rf=0.63 in 1/1 EtOAc/hexane. 1H-NMR (CDCl3, 299.96 MHz): δ (ppm) 7.09-7.07 (d, 2H), 6.81-6.78 (d, 2H), 3.96-3.92 (t, 2H), 3.42-3.37 (m, 4H), 2.64-2.58 (t, 2H), 2.39-2.32 (m, 4H), 1.87-1.52 (m, 14 H).
Reaction SMILES: [N+](C1C=CC(C(OO)=O)=CC=1)([O-])=[O:2].[CH3:14][S:15][C:16]1[S:17][CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[CH3:14][S:15]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])=[O:2]
Reactant: CSc1sccc1[N+](=O)[O-]
Reactant: O=C(OO)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CS(=O)c1sccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 2 h

Procedure:
There was added 0.95 g of p-nitroperbenzoic acid to a solution of 0.88 g of 2-methylthio-3-nitrothiophene in 15 ml of chloroform at a temperature from 0° to 10° C. After stirring for 2 hours at 5° C., a solution of 2 g of sodium bicarbonate in approximately 50 ml of water was added; the reaction mixture was then stirred for 15 minutes. The chloroform layer was separated, washed with water, and filtered. After distilling the solvent, the desired product was obtained in a yield of 0.95 g; melting-point 155° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Br[C:14]1C=C2C(CCCC2=O)=CC=1>>[Br:1][C:2]1[C:3]2[C:8](=[C:7]([O:12][CH3:14])[CH:6]=[CH:5][CH:4]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CCCc2ccc(Br)cc21
Reactant: O=C1CCCc2c(Br)cccc21
Product: COc1cccc2c(Br)cccc12

Procedure:
A third fraction of orange oil (9.06 g, 20.9%) was isolated. TLC showed it to be a nearly 1:1 ratio of 5-bromo-3,4-dihydro-1(2H)-naphthalenone, and 7-bromo-3,4-dihydro-1(2H)-naphthalenone.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C:5]([CH:18]([CH3:20])[CH3:19])=[CH:4][C:3]=1[O:21][CH3:22].[F-].[K+].[F:25][C:26](I)([F:28])[F:27].O>CN(C=O)C.[Cu]I>[CH:18]([C:5]1[CH:4]=[C:3]([O:21][CH3:22])[C:2]([C:26]([F:28])([F:27])[F:25])=[CH:7][C:6]=1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])([CH3:20])[CH3:19]
Reactant: FC(F)(F)I
Reactant: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1I
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1C(F)(F)F
Yield: 107.9 %

Procedure:
To a hot mixture of 1-Iodo4-isopropyl-2-methoxy-5-(toluene4-sulfonyl)-benzene (0.5 g, 1.12 mmol), CuI, KF in anhydrous DMF (10 ml) at 120° C. oil bath temperature, was added trifluoromethyl iodide (0.64 g, 4.48 mmol) in portions over 30 min. The reaction mixture was heated for 4 hrs and poured into H2O (100 ml). The insoluble solid, which was collected by filtration was triturated with methylene chloride, filtered and concentrated to give 1-Isopropyl-5-methoxy-2-(toluene4-sulfonyl)4-trifluoromethyl-benzene (0.45 g, 100%) as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1>O>[N:15]1[CH:16]=[CH:17][CH:18]=[N:19][C:14]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: c1cnc(N2CCNCC2)nc1
Reaction time: 1 h

Procedure:
To a stirred, warm (approximately 50°) solution of anhydrous piperazine (100 g, 1.16 mole) and sodium carbonate (58 g, 0.47 mole) in 465 mL water was added 2-chloropyrimidine (53 g, 0.46 mole) in portions over about 1 hour. External cooling was required to maintain the temperature in the 50°-65° range. After the addition, the stirred reaction mixture was kept in the temperature range of 50°-65° for one hour and then allowed to slowly cool to 35° over a 2 hour period. The mixture was filtered, removing 1,4-dipyrimidinylpiperazine, and the filtrate was extracted with 350 mL portions of chloroform. The chloroform extracts were dried (MgSO4) and concentrated to 62 g (82%) of an oily solid which can be purified by distillation (b.p. 118°-120°/2 Torr.) or converted to a salt form.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[N+]=[N-])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:14][N:15]1[CH:20]=[CH:19][CH2:18][CH:17]=[CH:16]1>CCOCC>[CH3:14][N:15]1[CH:16]=[CH:17][CH2:18][CH:19]2[CH:20]1[N:11]2[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(N)cc1
Reactant: CN1C=CCC=C1
Solvent: CCOCC
Product: CN1C=CCC2C1N2S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A solution of 4-aminobenzenesulfonyl azide (0.63 g, 3.2 mmol) in 75 ml ether was added slowly to a solution of 1-methyl-1,4-dihydropyridine (0.30 g, 3.2 mmol) in 75 ml ether with stirring at 25° C. Evolution of nitrogen gas was immediate. The reaction was allowed to proceed for 2 hours and the solvent was removed in vacuo to give 2-methyl-7-[(4-aminophenyl)sulfonyl]-2,7-diazabicyclo[4.1.0]hept-3-ene (0.82 g, 97%) with mp 188-190° . Hydrogenation of 2-methyl-7-[(4-aminophenyl) sulfonyl]-2,7-diazbicyclo[4.1.0]hept-3-ene (33 mg, 0.117 mmol) in 15 ml ethanol was effected using 10% palladium on charcoal (15 mg) and hydrogen gas at 30 psi for 4 hours. Removal of the catalyst by filtration and evaporation of the solvent in vacuo gave 1-methylpiperidylidene-2-(4-aminophenyl)sulfonamide (31 mg, 93%) with mp 186-188° ; IR (KBr) 3480 and 3380 cm-1 (NH2) and 1590 cm-1 (C=N).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH:6]1([C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7]1>ClCCl>[Cl:4][CH:10]([C:9]([CH:6]1[CH2:8][CH2:7]1)=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)C1CC1
Solvent: ClCCl
Product: CCOC(=O)C(Cl)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.1 ml of sulphuryl chloride (38.2 mmol, 1.05 equivalents) were initially charged in 21 ml of dichloromethane, and 5.68 g of ethyl 3-cyclopropyl-3-oxopropanoate (36.4 mmol) were added dropwise on a water bath. The reaction mixture was stirred at RT for 2 h and then washed with water, 5% strength aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The crude product (6.8 g) was used without further purification for the next reaction.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([C:38]3[CH:37]=[C:36]4[C:31]([N:32]=[CH:33][CH:34]=[N:35]4)=[CH:30][C:29]=3[O:28][CH2:27]2)[C:19]1=[O:39]>>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([C:38]3[CH:37]=[C:36]4[C:31]([N:32]=[CH:33][CH:34]=[N:35]4)=[CH:30][C:29]=3[O:28][CH2:27]2)[C:19]1=[O:39]
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2ccccc2C12COc1cc3nccnc3cc12
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3nccnc3cc12

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 7H-spiro[furo[2,3-g]quinoxaline-8,3′-indolin]-2′-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(pyridin-2-ylmethyl)spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one was obtained (93%) as a pale orange solid: mp 232-233° C.; 1H NMR (300 MHz, CDCl3) δ8.64 (m, 1H), 8.59 (d, J=1.5 Hz, 1H), 8.44 (d, J=1.5 Hz, 1H), 8.05 (d, J=9.3 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.77-7.67 (m, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.28-7.17 (m, 2H), 7.10 (d, J=7.2 Hz, 1H), 6.96 (t, J=7.5 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 5.56 (d, J=16.5 Hz, 1H), 5.25 (d, J=9.0 Hz, 1H), 4.97 (d, J=9.0 Hz, 1H), 4.91 (d, J=16.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ177.2, 162.5, 155.9, 149.4, 144.9, 142.3, 142.1, 139.8, 139.8, 136.9, 132.6, 132.4, 128.8, 123.3, 123.2, 122.6, 121.9, 121.4, 116.6, 109.6, 82.6, 57.7, 46.5; MS (ES+) m/z 381.2 (M+1).