Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:20].B1([O-])OO1.O.O.O.O.[Na+]>CO>[N:1]1([CH2:7][CH2:8][S:9]([C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[O:20])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(SCCN2CCOCC2)cc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(S(=O)CCN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A cold (0° C.) solution of 1-[[(4-morpholinyl)ethyl]thio]-4-nitrobenzene in methanol is treated slowly with excess 30% sulfuric acid and then sodium perborate tetrahydrate (10 equivalents) is added. The mixture is stirred at 0° C. for 2 hrs and then at ambient temperature for 2 hrs. The methanol is removed in vacuo and the residue basified with 50% sodium hydroxide solution and filtered. The filter cake is washed with methylene chloride and the aqueous filtrate extracted with the methylene chloride washings. The combined extract is washed with water, dried, and concentrated to obtain the product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.I[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]([C:14]([OH:16])=[O:15])=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=C(O)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccc(-c2ccccc2C(=O)O)c1
Yield: 41.5 %

Procedure:
In an oven dried flask flushed with N2 was combined 2.7 g (20.0 mmol) of 3-methylbenzeneboronic acid, 3.64 g (15 mmol) of 2-iodobenzoic acid, 150 mL of DME, 26 mL of 10% Na2CO3 and 600 mg (0.5 mmol) of Pd(PPh3)4. The mixture was warmed to reflux for 24 h and partitioned between 100 mL of NaHCO3 and 100 mL of ether. The ether layer was extracted with 2×50 mL of NaHCO3 and the combined NaHCO3 fractions were washed with 2×50 mL of ether, acidified with 10% HCl and extracted with 3×75 mL of ether. The combined ether extracts were washed with 50 mL of H2O, 50 mL of brine, dried (MgSO4) and concentrated in vacuo. The oil was crystallized from ether/hexanes (1/1) at -20° C. as a white precipitate, which after filtration, provided 1.32 g (41% yield) of 3'-methyl-2-biphenylcarboxylic acid as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[S:30])=[CH:24][CH:23]=1)([O-:21])=[O:20]>CCOCC>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:1][C:29]([NH:28][C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][CH:26]=1)=[S:30]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Solvent: CCOCC
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccc([N+](=O)[O-])cc1
Yield: 81.8 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.976 g, 4.02 mmol) and 4-nitrophenyl isothiocyanate (0.723 g, 4.02 mmol) to afford the product (1.39 g) after trituration in ether; m.p. 183-184° C.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:13][C:14]([F:23])([F:22])/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[CH3:12][O:11][C:8]1[C:9]([CH3:10])=[C:2]2[C:3]([CH:4]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]([C:14]([F:13])([F:23])[F:22])[O:1]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(O)c1C
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)C1=Cc2ccc(OC)c(C)c2OC1C(F)(F)F
Temperature: 60 °C

Procedure:
A mixture of benzaldehyde from Step 1 (3.0 g, 18.07 mmole) and ethyl 4,4,4-trifluorocrotonate (4.5 g, 27.11 mmole) was dissolved in anhydrous DMF (20 mL), warmed to 60° C. and treated with anhydrous K2CO3 (4.99 g, 36.14 mmole). The solution was maintained at 90° C. for 24 hours. LCMS analysis indicated that the reaction was complete. After the reaction was cooled to room temperature, the solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford brown solid, that was dissolved in MeOH (40 mL) and was precipitated upon adding 13 mL water. The suspension was filtered and dried on vacuum yielding a light brown solid: (4.37 g, 76.6%): LCMS m/z339.10 (M+Na). 1H NMR (CDCl3/400 MHz) 7.68 (s, 1H), 7.03(d, 1H, J=8.7 Hz), 6.50 (d, 1H, J=8.7 Hz), 5.70 (q, 1H, J=6 Hz), 4.29 (q, 2H, J=7.2 Hz), 3.84 (s, 3H), 2.09(s, 3H), 1.33 (t, 3H, J=7.2 Hz).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])(=[S:56])C.C(N(C(C)C)CC)(C)C.N#N>O1CCOCC1>[SH:56][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11]
Reactant: CC([O-])=S
Reactant: O=C1CCc2c(Br)cccc21
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2c(S)cccc21
Temperature: 120 °C
Yield: 54 %

Procedure:
4-Bromo-indanone (500 mg, 2.37 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (137 mg, 0.24 mmol), thioacetate (541 mg, 4.74 mmol) and diisopropylethylamine (1.64 mL, 5.69 mmol) are dissolved in 1,4-dioxane (2 mL). The mixture is degassed with N2 and tris(dibenzylideneacetone)palladium(0) (217 mg, 0.24 mmol) is added and heated under microwave irradiation at 120° C. for 2 hours. The solution is concentrated under vacuum. The crude product obtained is purified by flash chromatography (10-80% ethyl acetate in cyclohexane) to give the title compound (Yield: 210 mg). LC (METHOD 5): tR=0.89 min; Mass spectrum (ES−): m/z=163 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:22]2C(=O)C3=CC=CC=C3C2=O)=NN=[C:17]1[CH2:33][N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36].O.[NH2:43][NH2:44]>C(O)C>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[N:16]3[C:17]([CH2:33][N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])=[N:43][N:44]=[C:20]3[CH2:21][N:22]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1
Reactant: NN
Reactant: CC(C)N(Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl)C(C)C
Solvent: O
Solvent: CCO
Product: CC(C)N(Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2)C(C)C

Procedure:
In the manner given in Example 27, 2',5-dichloro-2-[3-[(diisopropylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-chloro-1-[(diisopropylamino)-methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=[O:26])=[CH:24][C:19]=2[O:18][CH2:17]1.C(OCC)=O>C1COCC1>[O:11]1[C:10]2[CH:14]=[CH:15][C:7]([CH:25]([C:23]3[CH:22]=[CH:21][C:20]4[O:16][CH2:17][O:18][C:19]=4[CH:24]=3)[OH:26])=[CH:8][C:9]=2[O:13][CH2:12]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Li]C(C)(C)C
Solvent: CCOC=O
Solvent: C1CCOC1
Product: OC(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of tert-butyllithium (1.8 mL, 3.1 mmol, 1.7M in pentane) at −78° C. was added dropwise a solution of 5-bromobenzo-1,3-dioxole (1.5 mmol) in THF (3 mL). After 30 min, benzo-1,3-dioxole-5-carbaldehyde (1.5 mmol) or ethyl formate (0.5 mmol) in THF (1 mL) was added. The mixture was stirred at −78° C. for 1 h and subsequently warmed to room temperature and stirred for an additional 4 h. The reaction was quenched by the addition of a saturated solution of NH4Cl and extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. Purification of the crude oil by flash chromatography (20% EtOAc/hexanes) provided the diphenyl methanol product.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][CH3:16])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].Br[CH:28]([CH2:33][CH2:34][CH2:35][Cl:36])[C:29]([O:31][CH3:32])=[O:30].O>CN(C=O)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([N:2]([CH3:1])[CH:28]([CH2:33][CH2:34][CH2:35][Cl:36])[C:29]([O:31][CH3:32])=[O:30])(=[O:5])=[O:4])=[CH:7][CH:8]=1)[C:14]#[C:15][CH3:16]
Reactant: COC(=O)C(Br)CCCCl
Reactant: CC#CCOc1ccc(S(=O)(=O)NC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(CCCCl)C(=O)OC)cc1
Reaction time: 0.25 h

Procedure:
A solution of 7.17 g (30 mmol) N-methyl-[4-(2-butynyloxy)-phenyl]sulfonamide] in 25 ml of DMF was cooled to 0° C. and 30 ml of 1M sodium hexamethyldisilazide (30 mmol) was slowly added and this mixture was stirred for 15 min and then added to a solution of 6.89 g (30 mmol) of methyl 2-bromo-5-chloropentanoate in 25 ml of DMF and was stirred at room temperature for 18 hours. The mixture was combined with water and the precipitate was collected and purified by chromatography on silica gel using hexane-ethyl acetate, 4:1 to give methyl 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-5-chloropentanoate Electrospray Mass Spec 410.2 (M+Na)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Sn](CCCC)(CCCC)CCCC.[CH2:20]([O:24][C:25]([N:27]([C:44]1[C:49]([O:50][CH3:51])=[N:48][C:47]([CH3:52])=[CH:46][N:45]=1)[S:28]([C:31]1[C:32]([C:37]2[CH:42]=[CH:41][C:40](I)=[CH:39][CH:38]=2)=[N:33][CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:26])[CH:21]([CH3:23])[CH3:22].O>C1(C)C(C)=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:20]([O:24][C:25]([N:27]([C:44]1[C:49]([O:50][CH3:51])=[N:48][C:47]([CH3:52])=[CH:46][N:45]=1)[S:28]([C:31]1[C:32]([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:39][CH:38]=2)=[N:33][CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:26])[CH:21]([CH3:23])[CH3:22]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(I)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(-c2ccccn2)cc1
Temperature: 125 °C
Yield: 31.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (45 mg) was added to a deoxygenated solution of (2-pyridyl)tributylstannane (294 mg) and N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-iodophenyl)pyridine-3-sulphonamide(465 mg) in xylene (15 ml). The mixture was stirred and heated under argon at 125° C. for 17 hours and then allowed to cool to ambient temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column, eluting with 0-65% ethyl acetate/hexane to give N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-(2-pyridyl)phenyl)pyridine-3-sulphonamide (135 mg) as a foam; 1H NMR (CDCl3): 0.7 (d, 6H), 1.7 (m, 1H), 2.5 (s, 3H), 3.8 (d, 2H), 4.0 (s, 3H), 7.5 (dd, 2H), 7.6-7.8 (m, 4H), 7.9 (s, 1H), 8.1 (dd, 2H), 8.7 (dd, 1H), 8.9 (dd, 1H), 9.0 (dd, 1H); mass spectrum (+ve ESP): 534 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[C@@:20]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:29])[CH2:19]2)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C@H:18]2[C@@:20]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH2:3][CH2:4][N:5]4[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)[C:21]3=[O:29])[CH2:19]2)=[CH:16][CH:17]=1
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: O=C1N(CCN2CCOCC2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to Example 70 starting from 4-(2-chloroethyl)morpholine hydrochloride (commercially available), (1S,2R) and (1R,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C22H23ClN2O2: 382, observed (M+H)+: 383.1 1H NMR (400 MHz, MeOD-d4) δppm 2.21-2.29 (m, 2 H) 3.30 (t, J=8.72 Hz, 1 H) 3.54-3.69 (m, 2 H) 3.97 (br. s., 8 H) 4.21-4.32 (m, 1 H) 4.36-4.48 (m, 1 H) 6.15 (d, J=7.33 Hz, 1 H) 6.83 (t, J=7.20 Hz, 1 H) 7.14-7.21 (m, 1 H) 7.22-7.30 (m, 3 H) 7.31-7.39 (m, 2 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[N:51][CH:52]=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:22]=[C:2]1[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([NH:53][C:54](=[O:60])[O:55][C:56]([CH3:58])([CH3:57])[CH3:59])=[N:51][CH:52]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CC(C)(C)OC(=O)Nc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cn1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and tert-butyl [5-(bromomethyl)pyridin-2-yl]carbamate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, tert-butyl {5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}carbamate was obtained (74%) as a colorless solid: mp 238-239° C.; 1H NMR (300 MHz, DMSO-d6) δ9.81 (s, 1H), 8.30-8.27 (m, 1H), 7.79-7.73 (m, 1H), 7.73-7.66 (m, 1H), 7.31-7.24 (m, 1H), 7.20-7.14 (m, 1H), 7.12-6.99 (m, 2H), 6.52 (s, 1H), 6.06 (s, 1H), 4.89 (ABq, J=22.9, 15.5 Hz, 2H), 4.74 (ABq, J=44.4, 9.3 Hz, 2H), 4.23-4.05 (m, 4H), 1.45 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ 176.7, 154.6, 152.6, 151.8, 146.9, 144.1, 141.8, 137.8, 137.2, 131.6, 128.7, 126.2, 123.6, 123.1, 121.1, 112.2, 110.8, 109.3, 98.8, 79.5, 79.3, 64.1, 63.5, 57.2, 27.9; MS (ES+) m/z 502.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH2:16]([O:18][CH2:19][CH2:20][NH2:21])[CH3:17].C(N(CC)CC)C>>[CH2:16]([O:18][CH2:19][CH2:20][NH:21][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])[CH3:17]
Reactant: CCOCCN
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: CCOCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 100.5 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.50 g, 5.16 mmol), 2-aminoethyl ethyl ether (0.46 g, 5.16mmol) and triethylamine (1.42 mL, 10.32 mmol) were reacted to form the desired product (1.78 g, 100%). LC-MS (m/z) 345.0 (M+).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[C:14]#[N:15])[C:4]=3[CH:3]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(Br)ccc21
Agent: OB(O)c1ccccc1
Product: COc1cccc(-c2ccc3c(c2)C(c2cccc(C#N)c2)=NCC(=O)N3C)c1
Yield: 58 %

Procedure:
Prepared from 3-(7-bromo-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 14 using the same method described for Example 1 and instead of using benzene boronic acid, we used 3-methoxyphenyl boronic acid. The title compound (110 mg) was obtained as a yellow solid, (yield=58%).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:21][C:22]([F:31])([F:30])[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([O:29][C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:30])([F:31])[F:21])=[CH:28][CH:27]=3)=[O:19])[CH2:16][CH2:17]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Cl)CC2)CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Oc3ccc(C(F)(F)F)cc3)CC2)CC1

Procedure:
A solution of 29.3 g of trans-4-(trans-4-n-pentylcyclohexyl)-cyclohexanecarbonyl chloride in 120 ml of toluene is added dropwise in the course of 2 hours with stirring to a boiling solution of 16.2 g of p-trifluoromethylphenol and 10 ml of pyridine in 120 ml of toluene. The reaction mixture is refluxed for a further 3 hours and then evaporated. The residue is worked up as conventional. p-Trifluoromethylphenyl trans-4-(trans-4-n-pentylcyclohexyl)-cyclohexanecarboxylate is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C(C)(C)C)cc1
Yield: 94.5 %

Procedure:
To 15.0 g of 4-tert-butylphenol dissolved in 100 ml of acetone were added 37.5 ml of methyl iodide and 83.0 g of potassium carbonate and heated at reflux for 20 hours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure. Diethyl ether was added to the residue to remove the insoluble matters by the filtration and the filtrate was concentrated at reduced pressure. The residue was purified by vacuum distillation to give 15.5 g of the title compound having the following physical properties.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:17])[C:10]3[CH:16]=[CH:15][S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].C(Cl)(Cl)Cl.C1C(=O)N([Br:29])C(=O)C1>CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:17])[C:10]3[CH:16]=[C:15]([Br:29])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CC2c3sccc3C(C)C2C1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)N1CC2c3sc(Br)cc3C(C)C2C1

Procedure:
A solution of the product from step i) (204 mg, 0.81 mmol) in AcOH (2 ml) and CHCl3 (2 ml) was treated with NBS (152 mg, 0.85 mmol) at 22° C. for 30 minutes. Next, the reaction was carefully quenched with sat. NaHCO3 (10 ml), extracted with EtOAc (2×75 ml) and the combined organic layers were dried (MgSO4). The crude product was filtered through a plug of silica gel using hexanes:EtOAc (50:50) to give the subtitle compound. MS calculated for C13H16BrNO2S+H 330, observed 332.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.[Na].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1[nH]c2c(Cl)nncc2c1C
Reactant: OCc1ccccc1
Agent: [Na]
Product: Cc1[nH]c2c(OCc3ccccc3)nncc2c1C
Temperature: 0 °C
Reaction time: 30 h

Procedure:
1.35 g (0.0074 mole) of 7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine was added to a solution, obtained by adding 0.26 g (0.011 mole) of sodium to 25 ml of benzyl alcohol at room temperature, and the resulting mixture was heated at 115° C. and, in the course of the heating, 10 ml of benzyl alcohol were additionally added thereto. The heating was continued for 30 hours with stirring. After completion of the reaction, the reaction mixture was poured into ice-water and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure and benzyl alcohol was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel using a 20:1 mixture of chloroform and methanol as an eluent to give 1.15 g of 7-benzyloxy-2,3-dimethylpyrrolo[2,3-d]pyridazine as a pale yellow powder.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([C:11]2[S:15][C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[CH:22]([CH3:24])[CH3:23].Cl>C(Cl)Cl>[CH3:23][CH:22]([C:18]1[S:17][C:16]([C:14]2[S:15][C:11]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:12][CH:13]=2)=[CH:20][CH:19]=1)[CH3:24]
Reactant: CC(C)Cl
Reactant: c1ccc(-c2ccc(-c3cccs3)s2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)c1ccc(-c2ccc(-c3ccccc3)s2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A stirred suspension of 0.55 gram (0.0041 mole) of aluminum chloride in 40 ml of methylene chloride was cooled to 0° C., and a solution of 1.0 gram (0.0041 mole) of 5-phenyl[2,2'-bithienyl], 0.9 gram (0.005 mole) of 2-chloropropane in 40 ml of methylene chloride was added dropwise. Upon completion of addition the reaction mixture stirred at 0° C. for 30 minutes, then was allowed to warm to ambient temperature where it stirred for 16 hours. The reaction mixture was poured into a mixture of ice and aqueous 10% hydrochloric acid. The layers were separated and the aqueous phase was extracted with three 25 ml portions of diethyl ether. The organic layers were combined and the combination washed in succession with a solution of aqueous 5% sodium bicarbonate, water, and an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished with 100% hexane. The appropriate fractions were combined and concentrated under reduced pressure to yield 0.7 gram of 5'-(1-methylethyl)-5-phenyl[2,2'-bithienyl]; m.p. 104°-106° C.