Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=1.Cl[C:32]([CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:33].Cl>C1COCC1>[OH:30]/[C:28](/[C:25]1[CH:26]=[CH:27][C:22]([S:21][CH3:20])=[CH:23][CH:24]=1)=[CH:29]\[C:32](=[O:33])[CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38]
Reactant: CSc1ccc(C(C)=O)cc1
Reactant: COC(=O)CCCC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)CCCC(=O)/C=C(\O)c1ccc(SC)cc1
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide mono(tetrahydrofuran) in cyclohexane (1.5 M; 28 mL, 42 mmol) was added to a solution of 1-(4-methylthiophenyl)ethan-1-one (5.16 g, 31 mmol) in THF (120 mL) and stirred for 30 minutes at −72° C. A solution of methyl 4-(chloroformyl)butyrate (1.78 g, 10.8 mmol) was added to the above solution and stirred for 30 minutes and then warmed slowly from the −72° C. to −45° C. To the reaction mixture was added 3N HCl (50 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and evaporated. Trituration of the residue with diethyl ether/hexane gave a mixture of the title compound and starting material (˜30% yield) as a solid (2.42 g). The crude material was used in the next step without purification. A small quantity of pure sample was obtained at the beginning of the trituation. Mp. 92–93° C. 1H NMR (CDCl3) δ 15.1 (br, 1H), 7.79 (d, J=8.6 Hz, 2H), 7.27 (d, J=8.6 Hz, 2H), 6.13 (s, 1H), 3.69 (s, 3H), 2.52 (s, 3H), 2.48 (t, J=7.4 Hz, 2H), 2.42 (t, J=7.4 Hz, 2H), 2.02 (m, 2H). 13C NMR (CDCl3) δ 194.8, 183.0, 173.4, 144.9, 131.0, 127.3, 125.2, 95.6, 51.5, 37.9, 33.1, 20.8, 14.8.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]2=[O:22])[CH2:2]1.[Cl:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:35]>>[ClH:23].[CH3:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([CH3:34])[C:28]=1[O:27][CH2:26][CH2:25][CH2:24][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]2=[O:22])[CH2:2]1
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCNC1)CC2
Reactant: Cc1cccc(C)c1OCCCCl
Product: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(CCCOc3c(C)cccc3C)C1)CC2
Product: Cl

Procedure:
Prepared from 2-[(piperidin-3-yl)-methyl]-6,7-dimethoxy- 1-oxo-1,2,3,4-tetrahydro-isoquinoline and 1-chloro-3-(2,6-dimethylphenoxy)-propane analogously to Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:33]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2CCc2ccccc2)cc1
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2CCc2ccccc2)cc1

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chlorophenyl)-4-(phenethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 372) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.075 g, 17%). semi-solid; 1H NMR (300 MHz, DMSO d6) δ 2.80 (m, 4H), 3.29–3.42 (3H, obstructed by H2O), 6.96 (m, 2H), 7.14–7.28 (m, 3H), 7.46–7.68 (m, 7H), 7.78 (m, 1H), 7.92 (m, 2H), 8.01 (s, 1H). MS (DCI/NH3) m/z 466 (M+H)+, 483 (M+NH4)+. Anal. calc. for C24H20ClN2O3S.0.25 H2O: C, 61.27; H, 4.39; N, 8.93. Found: 61.18; H, 4.68; N, 8.58.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([N:5]1[CH2:6][CH2:7][CH:2]([O:1][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:3][CH2:4]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(S(C)(=O)=O)CC1
Yield: 80.9 %

Procedure:
To a solution of 4-hydroxypiperidine (5.10 g, 50 moles) and triethylamine (20.9 ml, 150 moles) in methylene chloride (150 ml) was added methanesulfonyl chloride (8.54 ml, 110 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed in turn with an aqueous saturated sodium bicarbonate solution and saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was solidified with ethyl acetate-n-hexane to obtain 11.45 g of the desired product (88.3%, pale yellow solid).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:17]([C:27](=[O:45])[N:28]([CH2:30][C:31]3[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=3)[CH3:29])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:40][C:37]([F:38])([F:39])[C:35]1[CH:36]=[C:31]([CH:32]=[C:33]([C:41]([F:42])([F:43])[F:44])[CH:34]=1)[CH2:30][N:28]([CH3:29])[C:27]([C:17]1[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[CH:19][C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[N:15][CH:16]=1)=[O:45]
Reactant: Cc1ccccc1-c1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1cc(C2=CCNCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 62.2 %

Procedure:
A solution of 258 mg (0.407 mmol) 5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (Example 41) and 0.26 ml (3.2 mmol) trifluoroacetic acid in 2 ml dichloromethane was heated at reflux for 4 h. After cooling to room temperature the mixture was diluted with dichloromethane and washed with 1N aqueous sodium hydroxide solution. The aqueous layer was extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated. Column chromatography afforded 135 mg (62%) of the title compound as a light brown solid.
Reaction SMILES: [I:1][C:2]1[C:3]([S:11][C:12]2[N:20]=[C:19]3[C:15]([N:16]=[CH:17][NH:18]3)=[C:14](N)[N:13]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+].C[N:40](C=O)C>>[NH2:40][C:15]1[N:16]=[CH:17][N:18]=[C:19]2[C:14]=1[N:13]=[C:12]([S:11][C:3]1[C:2]([I:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=1)[N:20]2[CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28]
Reactant: CN(C)C=O
Reactant: CC(C)S(=O)(=O)NCCCBr
Reactant: Nc1nc(Sc2cc3c(cc2I)OCO3)nc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)S(=O)(=O)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of 8-((6-iodobenzo[d][1,3]dioxol-5-yl)thio-9H-purin-6-amine (118 mg, 0.28 mmol) in DMF (2 mL) was added N-(3-bromopropyl)propane-2-sulfonamide (350 mg, 1.4 mmol) and Cs2CO3 (188 mg, 0.56 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2Cl2:NH3-MeOH (7N), 20:1) to yield WS48 as a white solid (33 mg, 20%). 1H NMR (500 MHz, CDCl3/MeOH-d4): δ 8.20 (s, 1H), 7.41 (s, 1H), 7.09 (s, 1H), 6.08 (s, 2H), 4.35 (t, J=7.0 Hz, 2H), 3.10-3.22 (m, 3H), 2.07 (m, 2H), 1.37 (d, J=6.9 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4): δ 158.4, 156.1, 155.1, 153.9, 153.5, 151.8, 129.2, 123.5, 123.3, 117.9, 106.6, 98.3, 57.0, 44.8, 43.9, 34.3, 20.2; HRMS (ESI) m/z calcd. for C18H22IN6O4S2, 577.0189. found 577.0193.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([O:9][CH3:10])=[N:7][CH:8]=1)#[CH:2].ClCCl.I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]>C(N(CC)CC)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:10][O:9][C:6]1[C:5]([O:11][CH3:12])=[CH:4][C:3]([C:1]#[C:2][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:8][N:7]=1
Reactant: Cc1ccccc1I
Reactant: C#Cc1cnc(OC)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C#Cc2ccccc2C)cnc1OC
Reaction time: 16 h
Yield: 55.7 %

Procedure:
Bis(triphenylphosphine)palladium(II) dichloride (50 mg, 0.07 mmol), copper (I) iodide (25 mg, 0.13 mmol) and 5-ethynyl-2,3-dimethoxypyridine (Intermediate 32) (500 mg, 3.1 mmol) were suspended in degassed triethylamine (5 ml) and dichloromethane (5 ml) to give a brown suspension. To this was added 1-iodo-2-methylbenzene (670 mg, 3.1 mmol) by syringe and the reaction was allowed to stir for 16 hours before being diluted with ethyl acetate and washed with brine. The crude material was purified by column chromatography (SiO2; 0-10% ethyl acetate in petrol) to afford 2,3-dimethoxy-5-[(2-methylphenyl)ethynyl]pyridine (437 mg, 56% yield).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[OH:14])[N:6]2[N:5]=1)=O.[CH2:21]1[N:26]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:25][CH2:24][O:23][CH2:22]1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[N:26]1([C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([CH:13]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[OH:14])[N:6]4[N:5]=3)=[CH:31][CH:32]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CS(=O)c1ncc2ccc(C(O)c3ccccc3)n2n1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: OC(c1ccccc1)c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Yield: 4.7 %

Procedure:
(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl-methanol (86.0 mg, 0.299 mmol), 4-(4-morpholino)aniline (107 mg, 0.598 mmol) and N,N-Diisopropylethylamine (0.156 mL, 0.898 mmol) were suspended in 1-Methoxy-2-propanol (0.750 mL, 7.67 mmol) and the reaction was irradiated at 300 watts, 200° C. for 20 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced under nitrogen. The crude reaction mixture was purified via Gilson reverse phase chromatography to afford 5.69 mg of [2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl-methanol as a lyophilized powder. (M+H)=402.1. 1H NMR (400 MHz, DMSO, d6) δ 9.49 (s, 1H), 9.16 (s, 1H), 7.79 (d, 2H, J=7.12 Hz), 7.67 (m, 1H), 7.58 (m, 2H), 7.50 (d, 2H, J=7.89 Hz), 7.11 (m, 1H), 6.89 (m, 1H), 6.75 (d, 2H, J=8.44 Hz), 3.73 (m, 4H), 3.30 (m, 1H), 3.02 (m, 4H).
Reaction SMILES: NC1C=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[C:15]([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=S>O1CCOCC1>[NH+:17]1[CH:21]=[CH:20][NH:19][CH:18]=1.[N:22]1([C:15]2[NH:17][C:21]3[CH:20]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=3[S:11](=[O:13])(=[O:12])[N:14]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Product: c1c[nH+]c[nH]1
Yield: 68.3 %

Procedure:
To a hot solution of 2-amino-5-nitrobenzenesulfonamide (5 g) in dioxane (150 mL) was added thiocarbonyidiimidazole (14 g) and the reaction mixture was refluxed for 5 h. After cooling, the precipitate of the title compound was collected by filtration, washed with dioxane and dried to give the title compound (yield 5.7 g ); m.p. 246-248° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH:27]([N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1)([CH3:29])[CH3:28].C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[CH:27]([N:30]1[CH:34]=[C:33]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]4[CH:17]=[C:16]([N:18]5[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]5)[N:15]=[C:14]([NH2:25])[N:13]=4)[CH2:9]3)=[CH:4][CH:3]=2)[CH:32]=[N:31]1)([CH3:29])[CH3:28]
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
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: CO
Solvent: C1COCCO1
Solvent: O
Product: CC1Cc2ccc(-c3cnn(C(C)C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.2 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. It was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (4.4 mg). LCMS (M+H)+: m/z=447.4.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@:11]([OH:21])([C@H:18]([SH:20])[CH3:19])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1.[H][H].[CH3:24][S:25][CH2:26]Cl>CCCCCC.CN(C)C=O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@:11]([OH:21])([C@H:18]([S:20][CH2:24][S:25][CH3:26])[CH3:19])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: [H][H]
Reactant: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CSCS[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 86.8 %

Procedure:
31 mg (0.70 mmole) of sodium hydride (as a 55% w/w dispersion in mineral oil) were washed with anhydrous hexane and then suspended in 2 ml of dimethylformamide. 100 mg (0.35 mmole) of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol were then added at 0° C., with stirring, to the resulting suspension. After evolution of hydrogen gas had ceased, 67 mg (0.70 mmole) of methylthiomethyl chloride were added to the mixture. The resulting mixture was then stirred at the same temperature for 1 hour. At the end of this time, the reaction mixture was partitioned between ethyl acetate and an aqueous solution of sodium chloride. The organic layer was dried and concentrated by distilling off the solvent. The crude product thus obtained was purified by column chromatography through silica gel, using a 3:1 by volume mixture of ethyl acetate and hexane as the eluent, to afford 105 mg of the title compound as a solid. A pule specimen (78 mg), melting at 108°-109° C., was obtained by recrystallization of this solid from a mixture of ethyl acetate and hexane.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[C:9]([NH2:17])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)[CH:6]=1.C[Al](C)C.[CH3:22][C:23]([Si:26]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34]([C:38](OC)=[O:39])=[CH:33][CH:32]=[CH:31]2)([CH3:25])[CH3:24].[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH3:25][C:23]([Si:26]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34]([C:38]([NH:17][C:9]1[CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:12]=[C:7]([N:5]3[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]3)[CH:8]=1)=[O:39])=[CH:33][CH:32]=[CH:31]2)([CH3:22])[CH3:24]
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Reactant: COC(=O)c1cccc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc12
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cc1cn(-c2cc(NC(=O)c3cccc4cc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)ccc34)cc(C(F)(F)F)c2)cn1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
Under an argon atmosphere, a stirred solution of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzenamine (0.99 g, 4.1 mmol) in dry toluene (40 mL) is treated with a solution of AlMe3 (5 mL of 2 M in toluene; 10 mmol) at 40° C. After 45 min, a solution of 6[[(1,1-dimethylethyl)diphenylsilyl]oxy]-1-naphthalenecarboxylic acid, methyl ester (1.64 g, 3.72 mmol) in dry toluene (15 mL) is added and the stirred mixture is heated at 100° C. for 90 min. The cooled mixture is then added to a saturated aqueous solution of NH4Cl and stirred for 30 min. The organic phase is separated, washed with brine, dried (Na2SO4) and solvent is evaporated off under reduced pressure to give a residue, which is purified by column chromatography (SiO2; hexane/ethyl acetate 1:1) to afford the title compound as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl[CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[O:15].[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[S:26](Cl)(=[O:28])=[O:27]>>[NH2:16][C:14]([NH:13][CH2:12][CH2:11][S:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH:1][S:26]([C:18]1[O:17][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=1)(=[O:27])=[O:28])=[O:15]
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: NC(=O)NCCCl
Product: NC(=O)NCCSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1

Procedure:
Following General Procedure A, B, the title compound was prepared from 2-Amino-4-chloro-benzenethiol, (2-chloro-ethyl)-urea and 1-benzofuran-2-sulfonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24].Cl>CN(C=O)C>[CH2:24]([O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: Cc1ccc(Oc2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Oc2ccc(C)cc2)cc1

Procedure:
A solution of 4-(4'-methylphenoxy)phenol (4.75 g, 23.30 mmol), potassium carbonate (4.17 g, 30.30 mmol) and allyl bromide (2.22 mL, 25.60 mmol) in DMF (50 mL) was stirred for 5 h at 60° C. After cooling, the reaction mixture was neutralized with 1 N HCl and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated to afford an oil which was chromatographed on silica gel (15% ethyl acetate/hexane) to afford 4-(4'-methylphenoxy)phenyl allyl ether.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:18])([CH3:17])[CH:6]1O)=[S:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:18])([CH3:17])[CH:6]=1)=[S:4]
Reactant: CNC(=S)C1c2cc(C#N)ccc2OC(C)(C)C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=S)C1=CC(C)(C)Oc2ccc(C#N)cc21

Procedure:
A mixture of 0.44 g of N-methyl-6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 0.07 g of p-toluenesulfonic acid monohydrate, and 30 ml of toluene was heated at reflux for 10 hours. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH2Cl2) to obtain 0.18 g of-N-methyl-6-cyano-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16].C(N(CC)CC)C.O>C(OC(O)C)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][CH:15]([OH:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: NCC(O)c1ccccc1
Agent: CCOC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: OC(CNc1ccnc2cc(Cl)ccc12)c1ccccc1

Procedure:
A solution of 4,7-dichloroquinoline (19.8 g), 2-amino-1-phenylethanol (13.7 g) and 20 ml of triethylamine (14.5 g) in 10 ml of ethoxyethanol was heated at 130° C. overnight. The mixture was poured into 600 ml of water and the solid product was collected by filtration, recrystallized from ethoxyethanol and washed with ethanol. The yield was 16 g, mp 221°-222° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2N=[N:11][CH:12]=[CH:13][C:8]=2[C:7]=1[OH:15])=[O:5])[CH3:2].[CH2:16](OC(=O)C1C=CN=CC=1Cl)C>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:9]2=[CH:16][N:11]=[CH:12][CH:13]=[C:8]2[C:7]=1[OH:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2nnccc2c1O
Reactant: CCOC(=O)c1ccncc1Cl
Product: CCOC(=O)c1oc2cnccc2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 3-chloroisonicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester;
Reaction SMILES: [CH3:1][S-:2].[Na+].[N+]([C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N+:10]([O-:13])=[CH:11][CH:12]=1)([O-])=O>CN(C)C=O>[CH3:1][S:2][C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N+:10]([O-:13])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(-c2ccccn2)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc[n+]([O-])c(-c2ccccn2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 21.6 %

Procedure:
Sodium thiomethoxide (1.06 g, 15.2 mmol) was added at 25° C. to 4-Nitro-[2,2′]bipyridinyl 1-oxide (3.0 g, 13.8 mmol) in dimethyl formamide (15 mL) and stirred for 2 hours at 50° C. The reaction mixture was added into ice (200 g) under vigorous stirring, the solid formed was filtered and washed with water (100 mL) and ether (100 mL), the filtrate was concentrated, diluted with water, extracted with dichloromethane (3×100 mL), dried with anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (0-100% Ethyl acetate in Hexane) to afford 4-methylsulfanyl-[2,2′]bipyridinyl 1-oxide as a white solid (650.0 mg, 22%).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[CH:6]([CH2:15][OH:16])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[CH:6]([CH2:15][O:16][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: OCC1c2ccccc2C=Cc2cc(Br)ccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2c3ccccc3C=Cc3cc(Br)ccc32)cc1
Yield: 88.9 %

Procedure:
To a solution of 2-bromo-5-hydroxymethyl-dibenzo [a,d]cycloheptene (6.1 g) in dry dichloromethane (60 ml) was added p-toluenesulphonyl chloride (4.9 g). pyridine (4 g) and 4-dimethylamino pyridine (100 mg). The reaction mixture was refluxed for 14 h, cooled, washed with water (2×50 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue. was purified by flash silica chromatography using 10% ethyl acetate in hexane as eluent to give the title compound as a colourless oil (8.2 g). δ (360 MHz, CDCl3) 2.46 (3H, s, CH3), 4.12 (1H, dd J=6.2 and 3.5 Hz, CH--CH2 --O), 4.24-4.32 (2H, m, CH--CH2 --O), 6.50 (1H, d, J=11.9 Hz, CHA =CHB), 6.73 (1H, d, J=11.9 Hz, CHA =CHB), 7.10-7.40 (11H, m, ArH).