Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1)(=O)[CH3:2].[CH3:16][N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[NH:26][NH2:27]>CO.C(O)(=O)C>[CH3:16][N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[NH:26][N:27]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1)[CH3:2]
Reactant: CC(=O)c1cccc(-c2ccccc2)n1
Reactant: Cn1c(NN)nc2ccccc21
Solvent: CO
Solvent: CC(=O)O
Product: CC(=NNc1nc2ccccc2n1C)c1cccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-acetyl-6-phenylpyridine (0.50 g, 2.53 mmol) and 1-methyl-2-hydrazinobenzimidazole (0.41 g, 2.53 mmol) in 10 ml of methanol is stirred at room temperature for 12 hours after the addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored for 24 hours in a refrigerator at approximately 5° C. The precipitate is filtered, washed several times with water, and dried. The product is recrystallized from a mixture of methanol and water. Yield: 0.51 g (59% of theory).
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[C:9]([CH2:14]O)[N:8]=2)([CH3:3])[CH3:2].O=S(Cl)[Cl:18]>C(Cl)Cl>[ClH:18].[ClH:18].[Cl:18][CH2:14][C:9]1[N:8]=[C:7]2[S:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:13][C:12]2=[CH:11][CH:10]=1
Reactant: CC(C)Nc1nc2ccc(CO)nc2s1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)Nc1nc2ccc(CCl)nc2s1
Product: Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.9 %

Procedure:
To a solution of (2-(isopropylamino)thiazolo[5,4-b]pyridin-5-yl)methanol (0.71 g, 3.18 mmol, 1.0 eq.) in CH2Cl2 (11 mL) under nitrogen at 0° C. was added SOCl2 (1.0 mL, 13.7 mmol, 4.3 eq.). After 5 min., the cold bath was removed, and the reaction mixture was stirred to room temperature for 10 min. and then refluxed for 2.75 hr. After cooling to room temperature, the reaction mixture was concentrated in vacuo to give 5-(chloromethyl)-N-isopropylthiazolo[5,4-b]pyridin-2-amine dihydrochloride as a white solid (0.90 g, 90% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.CCN(CC)CC.CS(Cl)(=O)=O.[F:30][C:31]([F:40])([F:39])[C:32]1[C:33]([OH:38])=[N:34][CH:35]=[CH:36][CH:37]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:39])([F:40])[F:30])[C:33]2=[O:38])[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: Oc1ncccc1C(F)(F)F
Reactant: Cc1ccnc(CO)c1COC1CCCCO1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccnc(Cn2cccc(C(F)(F)F)c2=O)c1COC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
[4-Methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-methanol (138 mg. 0.58 mmol) was dissolved in DCM (5 mL) and cooled to 0° C. NEt3 (324 μL. 2.33 mmol) and methanesulfonyl chloride (90 μL. 1.16 mmol) were added and the reaction mixture was stirred for 1 h at 0° C. After removal of the solvents in vacuo the residue was dissolved in DMF (10 mL) and CsCO3 (570 mg. 1.75 mmol) and 3-trifluoromethyl-pyridin-2-ol (142 mg. 0.87 mmol) were added. After stirring for 2 h at RT the solvent was removed in vacuo and the residue was partioned between water (20 mL) and DCM (20 mL) extracted with DCM (3×20 mL) and the combined organic fractions were dried over Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EtOAc 2:1→1:1) to give the title compound. MS (m/z): 382.9 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:27])=[CH:8][N:7]=1)=[O:5].[CH3:32][S:33](Cl)(=[O:35])=[O:34].Cl.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>N1C=CC=CC=1.C1COCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:11]2[C:6]([C:4](=[O:5])[C:3]3[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=3[NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[N:7][CH:8]=[C:9]([Cl:27])[CH:10]=2)(=[O:15])=[O:14])=[CH:17][C:18]=1[C:23]([F:26])([F:25])[F:24]
Reactant: Nc1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide (24 mg, 0.048 mmol) in anhydrous pyridine (1 mL) was added methane sulfonyl chloride (9 mg, 0.075 mmol). The resulting mixture was stirred at room temperature for 2 h was poured into 1 M HCl and extracted with EtOAc. The extracts were concentrated under reduced pressure and the residues was purified by flash column chromatography to trissulfonamide Mass spectrum m/z: 515.0 (M+H). To this trisulfonamide (14 mg, 0.021 mmol) in THF was added TBAF (1 M in THF, 40 μL, 0.04 mmol) and the resulting mixture was stirred overnight. The reaction mixture was quenched with 1 M HCl and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (combi-flash) to provide 4-Chloro-N-[5-chloro-2-(2-methanesulfonylamino-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 9.60 (br, 2 H), 8.38 (d, J=2.0 Hz, 1 H), 8.16 (d, J=2.0 Hz, 1 H), 8.04 (d, J=2.0 Hz, 1 H), 7.87 (dd, J=8.4, 2.4 Hz, 1 H), 7.72-7.70 (m, 1 H), 7.62-7.57 (m, 1 H), 7.53 (d, J=8.4 Hz, 1 H), 7.29 (dd, J=8.0, 2.4 Hz, 1 H), 7.08-7.05 (m, 1 H), 3.07 (s, 3 H); Mass spectrum m/z: 515.0 (M+H).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[C:11](=[CH:17][C:18]([O:20][CH3:21])=[O:19])[CH2:10][CH2:9]2.Cl>C(OCC)C>[CH3:1][C:12]1[C:13]2[C:8](=[CH:7][C:6]([O:5][CH3:4])=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C[Mg]Br
Reactant: COC(=O)C=C1CCc2cc(OC)ccc2C1=O
Agent: Cl
Solvent: CCOCC
Product: COC(=O)Cc1ccc2cc(OC)ccc2c1C
Temperature: 180 °C
Reaction time: 1 h

Procedure:
To a mixture of 12 g. of methyl magnesium bromide and 200 ml. of diethyl ether, 25 g. of 6-methoxy-2-(methoxycarbonyl-methylene)-1-tetralone are added. The alkylating mixture is refluxed for one hour after it has been allowed to stand for one hour; the mixture is made acidic to litmus by the addition of 1N methanolic HCl, filtered, and evaporated. The residue, containing methyl 1-methyl-6-methoxy-3,4-dihydro-2-naphthylacetate, is added to 1 g. of 10% palladium-on-charcoal and the resulting mixture is heated to 180° C for 6 hours. The mixture is cooled, diluted with 200 ml. of chloroform, filtered, and evaporated to yield methyl 1-methyl-6-methoxy-2-naphthylacetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[N:24]=[C:25]=[S:26])[O:5][CH2:6][C:7]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12].I.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1.[OH-].[Na+].O1CCCC1>O>[N:28]1([C:25]([NH:24][C:23]2[CH:22]=[CH:21][C:4]([O:5][CH2:6][C:7]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:8]=3[O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:3][C:2]=2[F:1])=[S:26])[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1
Reactant: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(N=C=S)c(F)c1
Reactant: C1CCNNC1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(NC(=S)N2CCCCN2)c(F)c1
Yield: 81.2 %

Procedure:
By the method of Example 1, Step C, of U.S. Pat. No. 4,906,281, 1.50 g (0.004 mole) of methyl 2-[2-(3-fluoro-4-isothiocyanatophenoxymethyl)-5-methylphenoxy]propionate and 1.07 g (0.005 mole) of perhydropyridazine monohydroiodide (prepared by the method of Example 1, Step B, of U.S. Pat. No. 4,906,281) were reacted in the presence of 0.20 g (0.0050 mole of sodium hydroxide in 40 mL of water and 10 ML of tetrahydrofuran, yielding 1.50 g of methyl 2-[2-[4-(perhydropyridazin-1-ylthiocarbonylamino)-3-fluorophenoxymethyl]-5-methylphenoxy]propionate as a syrup. The NMR spectrum was consistent with proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:18]([O:20]CC)=[O:19])[CH:7]=[CH:6][C:5]2=1.[OH-].[Li+]>C1COCC1.CCO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:18]([OH:20])=[O:19])[CH:7]=[CH:6][C:5]2=1
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Br)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)O)ccc12
Yield: 284.9 %

Procedure:
A solution of ethyl 6-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (4.7 g, 8.85 mmol) and lithium hydroxide (0.848 g, 35 4 mmol) in THF/EtOH/H2O (3/1/1) (70 mL) was heated at 75° C. overnight. The reaction was concentrated and the resulting yellow solid was suspended in water. To above suspension, was added 1M HCl/conc. HCl until pH=2-3. The light yellow solid was collected by filtration and air-dried to furnish 8.4 g of 6-bromo-8-carbamoyl-9H-carbazole-2-carboxylic acid with ˜80% purity. This material was carried forward to the next step. MS (ESI) m/z−=331/363 [M−H]−, 1 Br isotope pattern. HPLC retention time 9.79 min. (Sunfire C18 3.5 μm, 4.6×150 mm column, 15 min gradient, 10-100% B, 1 mL/min. Solvent A: 5% CH3CN-95% H2O-0.1% TFA; Solvent B: 95% CH3CN-5% H2O-0.1% TFA). 1H NMR (DMSO-d6) δ ppm 13.0-12.65 (b, 1H), 11.80 (s, 1H), 8.65 (d, 1H, J=1.8), 8.39 (d, 1H, J=0.6), 8.30 (s, 1H), 8.29 (d, 1H, J=8.2), 8.20 (d, 1H, J=1.8), 7.79 (dd, 1H, J=1.5, 8.3), 7.66 (br. s., 1H).
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH3:9][N:10]([CH3:37])[C:11]([C:13]1[N:14]=[CH:15][C:16]([O:19][C:20]2[CH:21]=[C:22]([CH:26]=[C:27]([O:29][C@H:30]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31]3=[O:36])[CH:28]=2)[C:23]([OH:25])=O)=[N:17][CH:18]=1)=[O:12].[CH3:38][C:39]1[N:40]=[C:41]([NH2:44])[S:42][CH:43]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:37][N:10]([CH3:9])[C:11]([C:13]1[CH:18]=[N:17][C:16]([O:19][C:20]2[CH:21]=[C:22]([C:23](=[O:25])[NH:44][C:41]3[S:42][CH:43]=[C:39]([CH3:38])[N:40]=3)[CH:26]=[C:27]([O:29][C@H:30]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31]3=[O:36])[CH:28]=2)=[CH:15][N:14]=1)=[O:12]
Reactant: Cc1csc(N)n1
Reactant: CN(C)C(=O)c1cnc(Oc2cc(O[C@H]3CCN(C)C3=O)cc(C(=O)O)c2)cn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1csc(NC(=O)c2cc(Oc3cnc(C(=O)N(C)C)cn3)cc(O[C@H]3CCN(C)C3=O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.14 mL, 1.1 mmol) was added to a solution of 3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoic acid (Intermediate 45) (358 mg, 0.9 mmol) in DCM (7 mL) and stirred at ambient temperature for 30 minutes. 4-Methyl-1,3-thiazol-2-amine (CAS no. 1603-91-4) (206 mg, 1.8 mmol) and pyridine (0.15 mL, 1.8 mmol) were added and the reaction stirred for 20 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), washed with water (2×10 mL) and brine (10 mL), dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica eluting with a gradient of 0 to 5% methanol in DCM to afford the product (200 mg, 45%). 1H NMR δ (300 MHz, CDCl3) 2.09-2.22 (m, 1H), 2.25 (s, 3H), 2.50-2.65 (m, 1H), 2.93 (s, 3H), 3.18 (d, 6H), 3.34-3.55 (m, 2H), 4.86 (t, 1H), 6.56 (s, 1H), 7.16 (s, 1H), 7.37 (s, 1H), 7.54 (s, 1H), 8.37 (s, 1H), 8.51 (s, 1H), 10.0-11.0 (br s, 1H); m/z 497 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18](OCC)=[O:19])=[C:5]2[OH:23].Cl.[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH2:29].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:29][CH2:28][C:27]([O:26][CH3:25])=[O:30])=[O:19])=[C:5]2[OH:23]
Reactant: COC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Temperature: 80 °C
Yield: 74.3 %

Procedure:
A mixture of ethyl 6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.810 g, 2.41 mmol), glycine methyl ester hydrochloride (0.39 g, 3.11 mmol, 1.3 eq.), 1,4-dioxane (7.0 mL) and DIPEA (1.3 mL, 7.46 mmol) was heated at 80° C. for 6 hours. The mixture was then cooled to room temperature and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with 2N HCl and brine. The solution was dried (MgSO4) and concentrated under reduced pressure to give a pale yellow solid. The product was recrystallized from EtOAc to give a colorless solid (0.68 g). MS m/e=380.0 (M+H)+.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]([C:7]1[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][CH2:25][NH:26][CH2:27][C@@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[OH:29])[CH:18]=2)=[CH:9][CH:10]=[C:11]([C:13]([O:15]C)=[O:14])[CH:12]=1)=[O:6].O.[OH-].[Li+]>CO.O>[OH-:4].[NH4+:23].[CH3:3][O:4][C:5]([C:7]1[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][CH2:25][NH:26][CH2:27][C@@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[OH:29])[CH:18]=2)=[CH:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[CH:12]=1)=[O:6]
Reactant: COC(=O)c1ccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(C(=O)O)ccc1-c1cccc(NCCNC[C@H](O)c2cccc(Cl)c2)c1
Product: [NH4+]
Yield: 20.4 %

Procedure:
The product was prepared from (R)-3′-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1′-biphenyl]-2,4-dicarboxylic acid dimethyl ester dihydrochloride (406 mg) and lithium hydroxide monohydrate (262 mg) in 3:1 methanol-water (20 mL). Silica gel chromatography eluting with 6:2:0.1 chloroform:methanol:ammonium hydroxide afforded the title compound (35 mg) as a white solid.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]3[C:33](=[CH:34][CH:35]=2)[O:32][C:19]2([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[CH2:18][C:17]3=[O:36])[CH:11]=[N:10]1>CCOCC>[ClH:1].[CH3:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]3[C:33](=[CH:34][CH:35]=2)[O:32][C:19]2([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[CH2:18][C:17]3=[O:36])[CH:11]=[N:10]1
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O3)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 N hydrogen chloride/dioxane solution was added to tert-butyl 6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (1.00 g), and stirred overnight at room temperature. Ether was added to the reaction liquid, the resulted precipitate was taken out through filtration, washed with ether, and dried under reduced pressure to obtain the intended compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:12]C[C:14]([NH:16]CO)=O.S(=O)(=O)(O)O>C(O)(=O)C.Cl.C(O)C.Cl>[ClH:12].[NH2:16][CH2:14][C:9]1[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: O=C(CCl)NCO
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(O)c(CN)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
A mixture of 4-(1,1-dimethylethyl)phenol (75 g., 0.50 mole), 2-chloro-N-(hydroxymethyl)acetamide (61 g., 0.50 mole) and 96% sulfuric acid (50 ml.) in acetic acid (500 ml.) is stirred at 20° C. for 4 hours and then poured into ice water (2 l.) providing a heterogenous mixture. After decanting the aqueous solution, the insoluble white gum is extracted with ether. The organic extract is washed with water and saturated brine and evaporated in vacuo leaving a residual oil. A solution of the latter in 12N hydrochloric acid-ethanol (1:1; 400 ml.) is heated at reflux for 4 hours, diluted with 12N hydrochloric acid (200 ml.) and slowly cooled to -20° C. The deposited white crystalline solid is collected to provide pure 2-aminomethyl-4-(1,1-dimethylethyl)phenol hydrochloride (55 g.), m.p. 227°-229° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[SH:11][CH2:12][CH:13]([OH:15])[CH3:14]>>[OH:15][CH:13]([CH3:14])[CH2:12][S:11][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C#N
Reactant: CC(O)CS
Product: Cc1cc(SCC(C)O)ccc1C#N

Procedure:
2 g of 4-bromo-2-methylbenzonitrile was reacted with 1-mercapto-2-propanol via Procedure Q to afford 4-(2-hydroxypropylthio)-2-methylbenzonitrile. 950 mg of 4-(2-hydroxypropylthio)-2-methylbenzonitrile was reacted via Procedure T to give 4-(2-hydroxypropylthio)-2-methylbenzoic acid. 1.0 g of 4-(2-hydroxypropylthio)-2-methylbenzoic acid was reacted via Procedure R to give 4-(2-hydroxypropylsulfonyl)-2-methylbenzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-hydroxypropylsulfonyl)-2-methylbenzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)-2-methylbenzamide. MS (Q1) 445.3 (M)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2.O.[CH3:24]CCCCC>C(Cl)Cl>[CH3:24][O:22][C:20]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:19]2[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc2cc(C(=O)O)ccc2[nH]1
Reactant: CCCCCC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]cc(C(=O)c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Alluminium trichloride (0.550 g, 2.50 mmol, 2.2 eq) was added to a solution of benzoyl chloride (0.319 g, 2.274 mol, 2 eq) in anhydrous DCM (5 ml). After stirring at room temperature under Ar for 30 min, methyl 5-carboxy indole (0.199 g, 1.157 mmol) was added. After stirring for 2 h at room temperature, the reaction mixture was poured into water (5 ml). The product was extracted with DCM (3×10 ml). The organic extracts were collected, dried over Na2SO4 and the solvent removed under reduced pressure to afford a brown solid. The pure compound rpm123 was obtained after trituration with hexane (10 ml) as a off-whte solid (0.205 g, 0.737 mmol, 64%), mp 271-273° C. 1H (400 MHz, DMSO-d6) δ 3.87 (3H, s), 7.52-7.61 (4H, m), 7.79-7.31 (2H, m), 7.87 (1H, dd, J 1.4, 8.6 Hz), 8.08 (1H, d, J 3.2 Hz), 8.9 (1H, d, J 1.2 Hz), 12.36 (1H, s). 13C NMR (100 MHz, DMSO-d6) δ 190.64, 167.70, 140.74, 140.16, 138.34, 132.07, 129.19, 129.14, 126.61, 124.77, 124.51, 123.93, 116.30, 113.13, 52.61.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH3:33][CH2:34][CH2:35][C:36](Cl)=[O:37]>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:36](=[O:37])[CH2:35][CH2:34][CH3:33])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCCC(=O)Cl
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
1,8-Diazabicyclo[5,4,0]-undec-7-ene (0.8 g, 5.3 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) in acetonitrile (100 mL). The mixture was stirred for 30 minutes. n-Butyryl chloride (0.3 g, 3.2 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with CH2Cl2 (60 mL) and 2NHCl (30 mL). Solid was collected and slurried with ethanol (20 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-butyramide (0.5 g, 67%) as a white solid: mp 244-246° C.; 1H NMR (DMSO-d6) δ 0.85 (t, J=7.4 Hz, 3H, CH3), 1.40-1.60 (m, 2H), 1.99-2.14 (m, 3H), 2.34-2.65 (m, 2H), 2.86-2.98 (m, 1H), 4.32-4.53 (m, 4H), 5.11-5.18 (dd, J=4.9 and 13.2 Hz, 1H, CH), 7.48-7.64 (m, 3H, Ar), 8.13 (t, J=5.1 Hz, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.67; 18.65, 22.61, 31.19, 37.16, 38.93, 46.15, 51.54, 121.62, 128.29, 130.60, 131.63, 134.82, 140.08, 168.08, 171.02, 172.01, 172.88; Anal. calcd. for C18H21N3O4: C, 62.96; H, 6.16; N, 12.24. Found: C, 63.08; H, 6.06; N, 12.08.
Reaction SMILES: O.[SH2:2].[Na].S.[CH2:5]([O:9][CH2:10][CH:11]([CH2:16][CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]1[O:8]C1.[CH3:18]O>>[CH2:16]([CH:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][O:9][CH:5]([CH2:6][OH:8])[CH2:18][SH:2])[CH3:17]
Reactant: S
Reactant: CO
Reactant: CCCCC(CC)COCC1CO1
Agent: [Na]
Solvent: O
Product: CCCCC(CC)COC(CO)CS

Procedure:
5 g of solid sodium hydrogen sulfide monohydrate are saturated with hydrogen sulfide at room temperature in 250 ml of methanol. Then 186 g (1 mole) of 2-ethylhexyl glycidyl ether are added dropwise at room temperature and with efficient stirring in the course of 2 hours, while simultaneously introducing hydrogen sulfide gas. The flow of hydrogen sulfide gas is constantly introduced in an amount just sufficient for the reaction solution to take up. The temperature should not exceed 30°-40° C. in order effectively to prevent the formation of corresponding thioethers. When the reaction of the epoxide is complete, the catalyst is destroyed with a small amount of dilute sulfuric acid and the reaction mixture is extracted with ether. The ethereal extract is washed neutral with water, dried over magnesium sulfate and the solvent is removed. Distillation of the residue at 75° C./10-3 torr yields the pure monothioglycerol 2-ethylhexyl ether with a SH content of 14.8%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]([CH3:15])=[CH:13][C:8]([NH:9][C:10](=[O:12])[CH3:11])=[C:7]([CH3:16])[CH:6]=1)=[O:4].[BH4-].[Na+].C(O)(=O)C.O>C(O)C>[CH3:16][C:7]1[CH:6]=[C:5]([CH:3]2[CH2:2][O:4]2)[C:14]([CH3:15])=[CH:13][C:8]=1[NH:9][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)Nc1cc(C)c(C(=O)CBr)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)Nc1cc(C)c(C2CO2)cc1C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a stirred solution of 4′-(2-bromoacetyl)-2′,5′-dimethylacetanilide (4.57 g) in ethanol (80 ml) was added sodium borohydride (608 mg) under ice-cooling, and the mixture was stirred for 1 hour. Acetic acid (3.7 ml) and water (200 ml) were added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in tetrahydrofuran (80 ml), and 5N aqueous sodium hydroxide solution (6.4 ml) was added to the solution under ice-cooling with stirring. The mixture was stirred for 30 minutes at room temperature, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. To the residue was added diethyl ether, and collection of the insoluble material by filtration gave 2′,5′-dimethyl-4′-oxiranylacetanilide (1.72 g).