Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:22]1[O:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:22]1[O:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
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: C1COCCO1
Solvent: O
Product: COc1c(-c2ccc(C(=O)O)o2)cccc1[N+](=O)[O-]
Yield: 56.1 %

Procedure:
2-(2-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 6a (10 g, 35.85 mmol), 5-bromofuran-2-carboxylic acid (5.47 g, 28.66 mmol), tetrakis(triphenylphosphine)palladium (2.07 g, 1.79 mmol) and sodium carbonate (7.60 g, 71.66 mmol) were dissolved in the solvent mixture of 200 mL of 1,4-dioxane and 30 mL of water. The reaction mixture was heated to reflux for 2.5 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with 150 mL of water and adjusted to pH 3 with 1 N hydrochloric acid. Then the mixture was filtered and the filter cake was washed with 50 mL of the solvent mixture of n-hexane/ethyl acetate (V/V=1:1). The residue was dried to obtain the title compound 5-(2-methoxy-3-nitro-phenyl)furan-2-carboxylic acid 9a (4.23 g, yield 56.1%) as a grey solid.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[C:12]1(B(O)O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:2]2[CH:11]=[N:10][C:5]3[O:6][CH2:7][CH2:8][NH:9][C:4]=3[CH:3]=2)=[CH:14][N:13]=1
Reactant: Brc1cnc2c(c1)NCCO2
Reactant: OB(O)c1nccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(-c3cnc4c(c3)NCCO4)cncc2c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
Under nitrogen atmosphere, in a 10 ml flask, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (36.3 mg, 0.169 mmol), isoquinoline boronic acid (44 mg, 0.253 mmol), tetrakis triphenylphosphine palladium (19.5 mg, 0.017 mmol) and potassium carbonate (58.3 mg, 0.423 mmol) were dissolved in a solvent of tetrahydrofuran/water (6/1, 1.4 ml/0.3 ml). The reaction mixture was stirred for 30 minutes at 80° C. using microwave (40 W) device. After cooling to room temperature, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline solution. The combined organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain brown oil (22.6 mg, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[N:5]=[C:4]([CH2:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH:14]2[CH3:22])=[O:12])[N:3]=1.[I-].[K+].C[Si](C)(C)Cl>C(#N)C.O>[Cl:1][C:2]1[CH2:7][C:6](=[O:8])[N:5]=[C:4]([CH2:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH:14]2[CH3:22])=[O:12])[N:3]=1
Reactant: COc1cc(Cl)nc(CC(=O)N2c3ccccc3CC2C)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1Cc2ccccc2N1C(=O)CC1=NC(=O)CC(Cl)=N1
Temperature: 100 °C
Yield: 89 %

Procedure:
In a reactor suitable for microwave irradiation, 1.3 g of 2-(4-chloro-6-methoxypyrimidin-2-yl)-1-(2-methyl-2,3-dihydroindol-1-yl)ethanone are placed in 20 ml of acetonitrile, 2 g of potassium iodide and 1.7 ml of trimethylchlorosilane. The heterogeneous solution is stirred while microwave-heating at 100° C. for 90 minutes. The resulting product is taken up in 25 ml of water, extraction is carried out with ethyl acetate, washing is carried out with 25 ml of saturated NaCl solution, drying is carried out over MgSO4, filtration is carried out through a VF filter and the resulting product is concentrated under vacuum. The compound obtained is chromatographed on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and methanol (90/10, v/v). The fractions containing the expected compound are combined and evaporated. The compound obtained is triturated from a mixture of ethyl acetate and diisopropyl ether, filtered and dried at ambient temperature (20° C.). 6-Chloro-2-[2-(2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-5H-pyrimidin-4-one is isolated in the form of a beige solid (2.2 g), yield 89%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:39]=[CH:38][CH:37]=[C:36]([Cl:35])[C:41]=5[Cl:42])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(Cl)c5Cl)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2,3-dichlorophenylboronic acid. (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@H:22]2[C@H:26]([OH:27])[C@H:25]([OH:28])[C@@H:24]([CH2:29][O:30][CH3:31])[O:23]2)=[C:15]([NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:14]=1.C(N(CC)CC)C>O1CCCC1>[OH:27][C@@H:26]1[C@H:25]([OH:28])[C@@H:24]([CH2:29][O:30][CH3:31])[O:23][C@H:22]1[N:19]1[CH:18]=[N:17][C:16]2[C:20]1=[N:21][C:13]([CH2:12][NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[N:14][C:15]=2[NH:32][CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(CNS(=O)(=O)c4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Phenylsulfonylchloride (57 mg, 0.33 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-[2-(aminomethyl)-6-(phenethylamino)-9H-purin-9-yl]-5-(methoxymethyl)tetrahydro-3,4-furandiol (150 mg, 0.36 mmol) (preparation 48) and triethylamine (110 mg, 1.08 mmol) in tetrahydrofuran (24 ml). The reaction mixture was stirred for 30 min at room temperature and then the solvent was removed under reduced pressure. The residue was azeotroped with dichloromethane and then purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (95:5) to give the title compound (180 mg) as a foam. MS: 577 (MNa+).
Reaction SMILES: [C:1]([C:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][OH:12])=[O:10])#[N:2].C(N(CC)CC)C.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>O1CCCC1>[C:32]([O:12][NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([C:1]#[N:2])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:35])[CH2:33][CH3:34]
Reactant: CCC(=O)Cl
Reactant: N#CC(CCCCCC(=O)NO)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)ONC(=O)CCCCCC(C#N)(c1ccccc1)c1ccccc1
Yield: 89.5 %

Procedure:
To a solution of 7-cyano-7,7-diphenylheptanohydroxamic acid (4.0 g, 12.4 mmol) and triethylamine (2.5 g, 25 mmol) in tetrahydrofuran (80 ml) was added, while stirring under ice-cooling, propionyl chloride (1.15 g, 12.4 mmol). The mixture was stirred for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, which was washed with 0.5N HCl and a saturated aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate--hexane to give 4.2 g of the titled compound.
Reaction SMILES: S(=O)(=O)(O)O.[N+]([O-])(O)=O.FC1C=CC=CC=1.[Cl:17]Cl.[N+](C1C=CC=CC=1F)([O-])=O.[Cl:29][C:30]1[C:31]([F:39])=[C:32]([N+]([O-])=O)[CH:33]=[CH:34][CH:35]=1>>[CH:33]1[C:34]([Cl:17])=[CH:35][C:30]([Cl:29])=[C:31]([F:39])[CH:32]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1F
Reactant: ClCl
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1ccccc1F
Solvent: Fc1ccccc1
Solvent: O=[N+]([O-])O
Product: Fc1ccc(Cl)cc1Cl

Procedure:
Process for the preparation of 2,4-dichlorofluorobenzene in high yield and purity without intermediate separation of the isomers formed,(1) by nitrating 1 mol of fluorobenzene to give nitrofluorobenzene using a mixture comprising 35 to 65 parts by weight of 50 to 90% strength sulfuric acid and 35 to 65 parts by weight of a nitrating acid comprising 35 to 55 parts by weight of 95 to 98% strength sulfuric acid and 45 to 65 parts by weight of 96 to 98% strength nitric acid, with the proviso that 0.8 to 2.0 equivalents of the nitrating agent NO2+ are used per mol of fluorobenzene, at 20° to 90° C., (2) allowing 25 g to 150 g of chlorine, in the presence of a ring chlorinating catalyst, to act on each 100 g of the crude nitrofluorobenzene mixture obtained, at 20° to 100° C., and (3) allowing about 18 g to about 203 g of chlorine or equivalent amounts of a chlorine releasing agent to act on each 100 g of the crude chlorofluoronitrobenzene mixture obtained, after removal of the ring chlorinating catalyst, at 110° to 220° C., and isolating the 2,4-dichlorofluorobenzene.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][CH2:14][C:15]1[N:16]=[CH:17][N:18]2[CH:22]=[CH:21][S:20][C:19]=12>ClCCl>[CH3:8][S:9]([NH:13][CH2:14][C:15]1[N:16]=[CH:17][N:18]2[CH:22]=[CH:21][S:20][C:19]=12)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ncn2ccsc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ncn2ccsc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.18 ml) and 0.075 ml of methanesulfonyl chloride were added in that order under ice cooling to a solution of 134 mg of 7-aminomethylimidazo[5,1-b]thiazole in 2.5 ml of dry dichloromethane. In this state, the system was stirred for 2 hr while gradually raising the temperature to room temperature. The reaction solution was diluted with 20 ml of dichloromethane, followed by washing with saturated brine. The aqueous layer was extracted with 10 ml of dichloromethane. The organic layers were combined together, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by distillation. The oil thus obtained was purified using Sephadex LH-20 (dichloromethane:methanol=1:1) to give 130 mg of 7-(methanesulfonylaminomethyl)imidazo[5,1-b]thiazole as a light yellow solid.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH:8]2[CH:13]3[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:5][CH:4]=1.Br[C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1>>[N:10]12[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11]1)[CH:8]([O:7][C:6]1[CH:16]=[CH:17][C:3]([C:21]3[CH:29]=[C:28]4[C:24]([CH:25]=[CH:26][NH:27]4)=[CH:23][CH:22]=3)=[CH:4][CH:5]=1)[CH2:9]2
Reactant: C[Sn](C)(C)c1ccc(OC2CN3CCC2CC3)cc1
Reactant: Brc1ccc2cc[nH]c2c1
Product: c1cc2ccc(-c3ccc(OC4CN5CCC4CC5)cc3)cc2[nH]1

Procedure:
The product of Example 2A (300 mg, 0.8 mmol) was coupled with 6-bromoindole (Aldrich, 196 mg, 1 mmol) according to the procedure in 2B. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) as a solid (30 mg, yield, 12%). 1H NMR (300 MHz, CD3OD) δ 1.45–1.58 (m, 1H), 1.64–1.90 (m, 2H), 2.01–2.15 (m, 1H), 2.17–2.24 (m, 1H), 2.75–3.04 (m, 5H), 3.30–3.42 (m, 1H), 4.53–4.61 (m, 1H), 6.43 (dd, J=3.1, 0.7 Hz, 1H), 6.97 (dt, J=8.8, 2.6 Hz, 2H), 7.21–7.27 (m, 2H), 7.52–7.60 (m, 4H) ppm. MS (DCl/NH3): m/z 319 (M+H)+.
Reaction SMILES: O=[CH:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH:12]1([C:18]2[C:19]3[CH:20]=[CH:21][C:22]([C:39]([O:41][CH3:42])=[O:40])=[CH:23][C:24]=3[N:25]3[C:32]=2[C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[O:29][CH2:28][C@H:27]([NH:37][CH3:38])[CH2:26]3)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(O)(=O)C.C([O-])(=O)C.[Na+]>CO.[Pd]>[C:7]([O:6][C:5]([NH:4][CH2:3][CH2:2][N:37]([CH3:38])[C@@H:27]1[CH2:26][N:25]2[C:24]3[CH:23]=[C:22]([C:39]([O:41][CH3:42])=[O:40])[CH:21]=[CH:20][C:19]=3[C:18]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:32]2[C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[O:29][CH2:28]1)=[O:11])([CH3:10])([CH3:9])[CH3:8]
Reactant: CN[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCNC(=O)OC(C)(C)C)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of tert-butyl (2-oxoethyl)carbamate (1 eq; 0.38 M) in dry MeOH was added a mixture of methyl (7R)-14-cyclohexyl-7-(methylamino)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate(0.14 M), acetic acid (2 eq) and sodium acetate (1 eq) in dry MeOH, and the mixture stirred at RT for 15 min. Then Pd/C (0.3 weight eq) was added as a slurry in MeOH under N2. The atmosphere in the reaction vessel was charged with H2, and the reaction stirred vigorously under a H2 atmosphere (balloon) at 60° C. overnight. The reaction was allowed to cool to RT, flushed with N2 and filtered through a plug of CELITE. The filtrate was concentrated in vacuo and the residue purified by FC (PE/EtOAc 2.5:1 to 1.5:1 gradient) to afford the title compound (82%). (ES+) m/z 562 (M+H)+; [α]D +67.1, c=0.67, CHC13
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13](O)[CH:14]=[CH2:15]>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:15][CH:14]=[CH2:13])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: C=CCO
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1ccc(O)c(OC)c1
Yield: 75 %

Procedure:
In a manner analogous to Example 1(a), 5 g (30 mmoles) of 4-hydroxy-3-methoxybenzoic acid treated at 100° C. for 4 hours with 50 ml of allyl alcohol and 820 μl of concentrated sulfuric acid, give 4.65 g (75% yield) of the expected ester in the form of a slightly yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:25][NH:26][CH3:27]>C1COCC1>[C:15]([C:7]1[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:26]([CH3:27])[CH3:25])([CH3:18])([CH3:17])[CH3:16]
Reactant: CNC
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CC(=O)Nc1cc([N+](=O)[O-])ccc1C(C)(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-Bromo-N-(2-tert-butyl-5-nitrophenyl)acetamide (80 g, 253, mmol) and potassium carbonate (70 g, 506 mmol) were combined in THF (1.75 L), and the mixture was cooled to 0° C. N,N-Dimethylamine (40 ml of a 2 M solution in THF, 800 mmol) was then added to the mixture through an addition funnel over a 30-min period. The mixture was then stirred at RT for 16 h. The mixture was then filtered and the filtrate was concentrated. The crude material was purified by silica chromatography using 50% EtOAc:hexanes as the eluent to give N-(2-tert-butyl-5-nitrophenyl)-2-(dimethylamino)acetamide as a brown solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7](Cl)=[O:8].[C:10]1([CH2:16][O:17][C:18]([C:20]2([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:10]1([CH2:16][O:17][C:18]([C:20]2([NH:26][C:7]([N:3]3[CH2:4][CH2:5][NH:6][C:2]3=[O:1])=[O:8])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[O:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: O=C(Cl)N1CCNC1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1NCCN1C(=O)NC1(C(=O)OCc2ccccc2)CCCCC1
Temperature: 60 °C
Reaction time: 96 h
Yield: 82.2 %

Procedure:
1.38 g (9.3 mmol) of 2-oxo-1-imidazolidinecarbonyl chloride was added to a solution of 2.17 g (9.3 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 1.04 g (10 mmol) of triethylamine in 100 ml of chloroform, and the mixture was stirred at 60° C. for 4 days. The reaction solution was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and the mixture was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained crystal was washed with diethyl ether to obtain 2.64 g (82%) of the title compound.
Reaction SMILES: [Cu][C:2]#[N:3].[ClH:4].[CH3:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O>CCOCC>[ClH:4].[C:2]([C:8]1[CH:7]=[C:8]2[C:7](=[CH:10][CH:9]=1)[CH2:5][NH:6][CH2:10][CH2:9]2)#[N:3]
Reactant: N#C[Cu]
Reactant: CN1CCCC1=O
Agent: Cl
Solvent: CCOCC
Product: N#Cc1ccc2c(c1)CCNC2
Yield: 85 %

Procedure:
As an alternative procedure to that contained within Description 1, a solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (6.0 g, 24 mmol) and triethylamine (7.4 ml, 5.36 g, 53 mmol) in dichloromethane (100 ml) was treated with trifluoroacetic anhydride (3.7 ml, 5.54 g, 26.4 mmol) with ice cooling. Mixture was stirred at 20° C. for 1.5 h. then partitioned between saturated aqueous NaHCO3 (250 ml) and dichloromethane (3×50 ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a solid (8.3 g). A mixture of the latter with copper (I) cyanide (5.1 g, 56.6 mmol) in 1-methyl-2-pyrrolidinone (100 ml) was heated at reflux under argon for 4 h, then cooled and partitioned between water (300 ml), 0.880 aqueous ammonia (100 ml) and dichloromethane (5×200 ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. The latter was dissolved in ether and treated with ethereal HCl to give the title compound (4.47 g, 85%) as a colourless solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([S:23][CH3:24])=[N:16][C:17]([CH3:22])=[CH:18][C:19]=2[S:20][CH3:21])=[O:12])[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:32][S:33]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([S:23][CH3:24])=[N:16][C:17]([CH3:22])=[CH:18][C:19]=2[S:20][CH3:21])=[O:12])[CH2:6][CH2:5]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCOS(C)(=O)=O)CC1
Reaction time: 0.75 h

Procedure:
To a solution of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (93 mg, 0.251 mmol) in THF (2 ml) were added triethylamine (51 mg, 0.502 mmol) and 4-(dimethylamino)pyridine (3 mg, 0.025 mmol), and then dropped methanesulfonyl chloride (43 mg, 0.377 mmol) with ice-cooling. The mixture was stirred for 45 minutes. The reaction solution was concentrated in vacuo to provide crude 2-[4-(2-methanesulfonyloxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[OH:27].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[O:27][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 200 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
A mixture of 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine (7) (1.0 g, 4 mmol), 2-fluoro-4-nitrophenol (0.942 g, 6 mmol) and K2CO3 (1.1 g, 8 mmol) in Ph2O (20 mL) was stirred at 200° C. for 24 h. The cooled reaction mixture was diluted with DCM (200 mL) and extracted with 1M HCl (200 mL). The aqueous phase was filtered through paper filter, basified (pH˜10) with conc. NH4OH to produce a cloudy mixture that was extracted with DCM. The organic phase was dried over anhydrous Na2SO4 and concentrated under pressure to give title compound 8 as an orange solid (0.667 g, 45% yield). MS (m/z): 371.0 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:8][N:7]([CH3:9])[C:6](=O)[N:5]1[CH3:11].P(Cl)(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(Cl)(Cl)Cl>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:8][N:7]([CH3:9])[C:6](=[N:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]1[CH3:11]
Reactant: CN1CC(CCCl)N(C)C1=O
Reactant: Nc1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN1CC(CCCl)N(C)C1=Nc1ccccc1
Reaction time: 2 h
Yield: 50 %

Procedure:
To 8.0 g (0.045 mole) of 4-(2-chloroethyl)-1,3-dimethyl-2-oxo-imidazolidine was added 50 ml of phosphorus oxychloride, and the solution was refluxed for 18 hours, and concentrated in vacuo. The residue was dissolved in 25 ml of methylene chloride and added dropwise to 4.2 g (0.045 mole) of aniline stirring at room temperature. Stirring was continued for two hours. The solution was diluted with chloroform and washed with dilute sodium hydroxide solution. The chloroform was dried, filtered and concentrated in vacuo. The residue was dissolved in isopropyl alcohol and treated with 5.2 g (0.045 mole) fumaric acid, and the resulting fumarate was recrystallized from isopropyl alcohol and weighed 9.0 g (50% yield); m.p. 109°-112° C.