Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:17]=[CH:16][C:10]2[N:11]=[C:12]([S:14][CH3:15])[O:13][C:9]=2[CH:8]=1)(=O)=O.ClCC1C=CC2N=C(SC)OC=2C=1.[CH3:31][O:32][C:33]1[C:41]([O:42][CH3:43])=[CH:40][C:36]2[N:37]=[CH:38][NH:39][C:35]=2[CH:34]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:43][O:42][C:41]1[C:33]([O:32][CH3:31])=[CH:34][C:35]2[N:39]([CH2:6][C:7]3[CH:17]=[CH:16][C:10]4[N:11]=[C:12]([S:14][CH3:15])[O:13][C:9]=4[CH:8]=3)[CH:38]=[N:37][C:36]=2[CH:40]=1
Reactant: COc1cc2nc[nH]c2cc1OC
Reactant: CSc1nc2ccc(COS(C)(=O)=O)cc2o1
Agent: CSc1nc2ccc(CCl)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncn(Cc3ccc4nc(SC)oc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of a 9:1 mixture of (2-(methylthio)benzo[d]oxazol-6-yl)methyl methanesulfonate and 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (1.45 g) from Step 1 of this Example and 5,6-dimethoxybenzimidazole (945 mg, 5.31 mmol) in anhydrous DMF (10 mL) at rt was added solid K2CO3 (1.47 g, 10.62 mmol). The mixture was stirred at rt for 3 h. The mixture was partitioned between water and DCM. The organic layer was separated and washed with water. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM to 10% MeOH in DCM to afford 6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole (430 mg) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.66 (m, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.32 (dd, J=9.0, 3.0 Hz, 1H), 7.19 (s, 2H), 5.53 (s, 2H), 3.76 (s, 6H), 2.73 (s, 3H). LCMS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>O1CCOCC1.O>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([S:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=2)(=[O:24])=[O:23])[CH2:3]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O[C@H]1CCNC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2CC[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
The 3(S)-hydroxy-pyrrolidine (1.0 g, 11.5 mmol), triethylamine (2.32 g, 22.9 mmol, 2.0 equiv) in 1,4-dioxane (30 mL) and water (10 mL) is stirred at room temperature and then 4-methoxyphenylsulfonyl chloride (2.61 g, 12.6 mmol, 1.10 equiv) is added. The resulting solution is stirred at room temperature for 3 h. and then the solution is acidified to pH~1 with 1 N HCl. The solution is poured into water and then extracted with CH2Cl2. The organic extracts are dried (Na2SO4) and concentrated o an oil. The oil is purified by chromatography using 1/1 hexane/EtOAc as the eluent to afford 2.62 g (81%) of the desired product as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([C:7](OCC)=[O:8])[CH2:5][NH:4][C:3]1=[O:12].[NH3:13]>CO>[CH3:1][CH:2]1[CH:6]([C:7]([NH2:13])=[O:8])[CH2:5][NH:4][C:3]1=[O:12]
Reactant: CCOC(=O)C1CNC(=O)C1C
Reactant: N
Solvent: CO
Product: CC1C(=O)NCC1C(N)=O

Procedure:
A solution of ethyl 3-methyl-2-oxo-4-pyrrolidinecarboxylate [Chem. Pharm. Bull., 24, 1362 (1976)] (5 g) in methanol (100 ml) saturated with ammonia gas left at room temperature for 4 days. After the reaction mixture was concentrated and the residue was recrystallized from ethanol to give 3-methyl-2-oxo-4-pyrrolidinecarboxamide (3.4 g), mp 169°-171° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.Cl.[CH3:19][NH:20][CH3:21].C([O-])([O-])=O.[K+].[K+].[I-].[K+]>C(#N)C>[CH3:19][N:20]([CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:21]
Reactant: CNC
Reactant: ClCCCn1c2ccccc2c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CN(C)CCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 168 h

Procedure:
9-(3-chloropropyl)carbazole (2.5 g, 10 mmol) was dissolved in acetonitrile (50 mL) in a pressure tube and dimethylamine hydrochloride (12.2 g, 150 mmol, followed by K2CO3 (20.8 g, 150 mmol) and potassium iodide (0.2 g, 1 mmol) were added and the mixture was stirred at room temperature for 7 days, then filtered and the filtrate concentrated in vacuo. The crude was purified by column chromatography (eluting with 5% methanol in dichloromethane) to afford 1.87 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[N:14]([CH:15]=1)[CH:13]=[CH:12][O:11]2.[C:16](OC(=O)C)(=[O:18])[CH3:17]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[N:14]([C:15]=1[C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][O:11]2
Reactant: Clc1ccccc1-c1cn2ccoc2n1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1c(-c2ccccc2Cl)nc2occn12
Temperature: 135 °C
Yield: 83 %

Procedure:
To a mixture of 6-(2-chlorophenyl)-imidazo[2,1-b]oxazole (1.0 g, 4.57 mmol) and acetic anhydride (23 ml) is added 3 drops of concentrated sulfuric acid. The reaction mixture is heated at 135° C. for 1 hour. The reaction mixture is then poured onto 50 ml of ice, and diluted with 100 ml of water and the resulting mixture is extracted three times with 75 ml each of ethyl acetate. The combined extracts are dried with magnesium sulfate, filtered and concentrated in vacuo, to give a brown oil. The product is purified by flash chromatography on silica gel (hexane/ethyl acetate 3:1), yielding 994 mg of an off-white solid (83%). M.p.=121-122° C.; 300 MHz 1H NMR (CDCl3) δ: 8.02 (d, J=1.6 Hz, 1H), 7.56-7.38 (m, 5H), 2.05 (s, 3H). LCMS: 261 [M+H]; calc. for C13H9ClN2O2: C, 59.84; H, 3.48; N, 10.74; found. C, 60.18; H, 3.16; N, 10.61.
Reaction SMILES: [C:1]1([C@@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[C:1]1([C:7]2[C:16]3[CH2:17][CH2:18][N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nc3ccccc3c21
Temperature: 120 °C
Reaction time: 4 h
Yield: 57.6 %

Procedure:
A mixture of tert-butyl (3aR*,4S*,9bR*)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (20.5 g, 58.6 mmol), manganese dioxide (50.9 g, 586 mmol) and toluene (400 ml) was stirred at 120° C. for 4 hrs. The reaction mixture was cooled to room temperature, insoluble materials were filtered off through celite, and the residue was washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was subjected to column chromatography using basic silica gel, and eluted with hexane-ethyl acetate (10:1-8:1, v/v). The concentrated object fraction was recrystallized from hexane-ethyl acetate to give the title compound (11.7 g, 58%) as colorless needle crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].Br[C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].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>C1(C)C(C)=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:12][C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C)cnc1N
Reactant: Brc1cncnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C)cnc1Nc1cncnc1
Temperature: 140 °C
Reaction time: 5 h

Procedure:
A suspension of 3-amino-6-methyl-pyrazine-2-carboxylic acid ethyl ester (500 mg, 2.8 mmol), 5-bromopyrimidine (614 mg, 3.9 mmol), water (104 μl, 5.8 mmol) and potassium carbonate (686 mg, 5.0 mmol) in xylene (7 ml) was vented with argon. Palladium(II) acetate (25 mg, 0.11 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 80 mg, 0.14 mmol) were consecutively added under inert gas atmosphere and the reaction mixture was heated to 140° C. and stirred for 5 h. After cooling-down to ambient temperature, the reaction mixture was diluted with water (5 ml) and extracted with methylenechloride. The organic layers were washed with water and brine, dried and concentrated in vacuo. The product was obtained after silica gel chromatography using a heptane/ethyl acetate gradient as light yellow solid (585 mg, 81.8%). MS: M=260.1 (M+H)+
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[C:14]([Br:15])=[CH:13][CH:12]=[C:11]([CH3:16])[N:10]=1>O1CCOCC1>[Br:15][C:14]1[C:9]([NH:8][C:5](=[O:7])[CH3:6])=[N:10][C:11]([CH3:16])=[CH:12][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(Br)c(N)n1
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(C)ccc1Br
Temperature: 50 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Acetic anhydride (21 mL, 223 mmol) was added to a solution of 2-amino-3-bromo-6-picoline (10 g, 53.46 mmol) in dioxan (50 mL) and the mixture was stirred at 50° C. for 18 hours. The solvent was then evaporated under reduced pressure and the residue was diluted with saturated sodium hydrogen carbonate solution (150 mL). The precipitate was filtered off, washed with water and re-dissolved in dichloromethane, and the filtrate was neutralised to pH7 with saturated sodium hydrogen carbonate solution and extracted with dichloromethane (3×100 mL). The organic solutions were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo to give a white solid. Purification of the solid by column chromatography on silica gel, eluting with ethyl acetate:heptane, 75:25, afforded the title compound as a white solid in 75% yield, 9.2 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C.[Cl-].[NH4+].OP(O)(O)=O>O1CCCC1.C1(C)C=CC=CC=1.CCCCCCC.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([B:26]([OH:31])[OH:27])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)c2)CC1
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(B(O)O)c2)CC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To the 4-tert-Butyloxycarbonyl-1-(3-bromophenyl)piperazine from Step 1 (118.30 g, 346.9 mmol) in tetrahydrofuran/toluene (1/1, 1.5 L) at −78° C. under nitrogen was added n-butyllithium (2.5M, 160 mL, 398.9 mmol) dropwise and the resulting reaction mixture was stirred at −78° C. for 20 minutes. Triisopropyl borate (96.4 mL, 416.3 mmol) was added dropwise and the reaction was warmed to 0° C. and stirred for 2 hours. Aqueous saturated ammonium chloride (400 mL), water (100 mL) and 1 equivalent of H3PO4 (20 mL) were added and the mixture was stirred for 15 minutes and then concentrated to a volume of approximately 200 mL (at which stage the mixture became bluish and a precipitate formed). The mixture was slowly diluted with heptane (800 mL) and the resulting suspension was stirred overnight. The suspension was filtered, the solid was washed with heptane and dried to afford the title boronic acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]1([N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[C:14]1([N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](=[O:22])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)N(c2ccccc2)c2ccccc2)n1

Procedure:
Following a procedure similar to that described in Preparation 13, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 7 g of diphenylcarbamoyl chloride, 30 ml of triethylamine and 20 ml of dimethylformamide. The resulting product was a brown oil having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:27])[C:5]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][C:15]([O:18]C)=[N:16][CH:17]=3)[C:9](=[O:20])[N:8]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:6]=2[N:7]=1.[Si](I)(C)(C)C.[NH4+].[OH-]>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:27])[C:5]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][C:15]([OH:18])=[N:14][CH:13]=3)[C:9](=[O:20])[N:8]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:6]=2[N:7]=1
Reactant: COc1ncc(-c2cc3c(C)nc(N)nc3n(C3CCOCC3)c2=O)cn1
Agent: C[Si](C)(C)I
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1nc(N)nc2c1cc(-c1cnc(O)nc1)c(=O)n2C1CCOCC1
Temperature: 82 °C
Yield: 29.4 %

Procedure:
A mixture of 2-amino-6-(2-methoxypyrimidin-5-yl)-4-methyl-8-(tetrahydro-2H-pyran-4-yl)pyrido-[2,3-d]pyrimidin-7(8H)-one (42.2 mg, 0.115 mmol), TMSI (0.10 mL, 0.70 mmol), and dry acetonitrile (2.3 mL) was heated at 82° C. for 1 h. After being cooled to room temperature, the mixture was treated with 20% NH4OH solution and concentrated. The mixture was purified by analytical group (HPLC) to give the title compound (12 mg, 30%).
Reaction SMILES: [C:1]1([C:7]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[N+:23]([O-])=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCOCC1>[C:1]1([C:7]2[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[NH2:23])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cccc2nc(-c3ccccc3)c(-c3ccccc3)nc12
Solvent: C1COCCO1
Product: Nc1cccc2nc(-c3ccccc3)c(-c3ccccc3)nc12
Reaction time: 30 h

Procedure:
1.04 g of 2,3-diphenyl-5-nitroquinoxaline was dissolved in 30 g of dioxane, then the reaction system was flushed with argon, and 0.5 g of Pd/C (anhydrous) was added to the reaction mixture. After the reaction system was again flushed with argon sufficiently, hydrogen was added thereto, and reaction was allowed at room temperature for 30 hr. After the reaction was over, filtration was conducted, the reaction solvent was removed, and the reaction product was separated and purified on a silica gel column (ethyl acetate:hexane=1:3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=1)[CH:8]=[C:7]2[C@@H:22]1[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]1[OH:24].[OH-].[Na+].Cl>C(O)C>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[C:7]([C@@H:22]3[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]3[OH:24])=[CH:8]2)=[CH:17][CH:16]=1)([OH:20])=[O:19]
Reactant: COC(=O)c1ccc(Cn2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(Cl)c32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Cn2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(Cl)c32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of 7-chloro-3-(β-D-glucopyranosyl)-1-[4-(methoxycarbonyl)benzyl]-1H-indole (71 mg) in ethanol (1 mL) was added 2 mol/L aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 2 mol/L hydrochloric acid (1 mL), and the solvent was removed under reduced pressure. The residue was purified by solid phase extraction on ODS (washing solvent: water, eluent: methanol) to give the title compound (68 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCOCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([Br:18])[N:3]=[C:2]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Reactant: NCCCN1CCOCC1
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)c2cc(Br)nc(NCCCN3CCOCC3)c2)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
0.162 g (0.00041 mol) of 4-(2,6-dibrompyridine-4-sulphonyl)-phenylamine was dissolved in 6 ml of dioxane and treated with 0.60 ml of 4-(3-aminopropyl)morpholine. The mixture was stirred at 60° C. for 24 hrs., the solvent was removed and the residue was chromatographed on silica gel with 3% methanol in dichloromethane. There was obtained 0.15 g (80%) of [4-(4-aminobenzenesulphonyl)-6-brompyridin-2-yl]-(3-morpholin-4-ylpropyl)amine as a white, amorphous solid. MS (ISP): me/e=457, 455 (C18H24BrN4O3S+).
Reaction SMILES: C(OC([CH:8]([NH:35][CH3:36])[CH2:9][O:10][C:11]1[CH:16]=[C:15]([C:17](C)(C)[O:18][SiH2]C(C)(C)C)[CH:14]=[C:13]([C:26](C)(C)[O:27][SiH2]C(C)(C)C)[CH:12]=1)=O)(C)(C)C.[ClH:37]>O1CCOCC1>[ClH:37].[OH:18][CH2:17][C:15]1[CH:16]=[C:11]([O:10][CH2:9][CH2:8][NH:35][CH3:36])[CH:12]=[C:13]([CH2:26][OH:27])[CH:14]=1
Reactant: CNC(COc1cc(C(C)(C)O[SiH2]C(C)(C)C)cc(C(C)(C)O[SiH2]C(C)(C)C)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCCOc1cc(CO)cc(CO)c1
Reaction time: 15 h

Procedure:
To a solution of 1-(2-(tert-butoxycarbonyl)-methylamino-ethoxy)-3,5-bis-(tert-butyl-dimethyl-silyloxy methyl)-benzene (590 mg) in dioxane (4 mL) was added a solution of hydrochloric acid 4N in dioxane (3.3 mL). After 15 h at rt, the resulting solid was filtered, washed with dioxane and dried in vacuo to give 3,5-bis-hydroxymethyl-(2-methylamino-ethoxy)-benzene hydrochloride (240 mg) as a white powder. LC/MS (Method A2): ES: m/z 212 (M+H)+; RT=0.14 min
Reaction SMILES: C([Si](C)(C)O[C:7]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH:8]=1)(C)(C)C.C1C[O:27]CC1>>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][C:9]1[C:8](=[O:27])[CH2:7][CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: Cc1ccccc1C=C1C=C(O[Si](C)(C)C(C)(C)C)CCCC1
Reactant: C1CCOC1
Product: Cc1ccccc1CC1=CCCCCC1=O
Reaction time: 0.5 h

Procedure:
A solution of n-tetra-n-butylammonium fluoride (1M) in THF (1.35 mmol) is added using a syringe to a solution of the compound obtained in Step A (1.34 mmol) in 15 ml of anhydrous THF at 0° C., and the whole is stirred at that temperature for 1 hour 30 minutes. The reaction mixture is then concentrated to dryness and deposited directly over a column of silica gel (heptane/AcOEt 9/1) to yield the title product.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[Cl:12][CH:13]([Cl:18])[C:14]([CH2:16]Cl)=O>C(COC)OC>[Cl:12][CH:13]([Cl:18])[C:14]1[N:9]=[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N:7]2[CH:16]=1
Reactant: O=C(CCl)C(Cl)Cl
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: COCCOC
Product: FC(F)(F)c1ccc2nc(C(Cl)Cl)cn2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(Trifluoromethyl)pyridin-2-amine (12.9 g) was dissolved in dimethoxyethane (150 mL) was added 1,1,3-trichloroacetone (12.7 mL) at room temperature, and the mixture was stirred overnight. The precipitated solid was collected, and suspended in ethanol (50 mL), and the mixture was heated under reflux for 3 hr. After allowing to cool to room temperature, the solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate-tetrahydrofuran (1:1, volume ratio). The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give 2-(dichloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (10.3 g) as a white solid. The obtained solid was suspended in a mixed solvent of water (100 mL) and tetrahydrofuran (20 mL), and calcium carbonate (8.0 g) was added to the mixture at room temperature, and the mixture was stirred at 100° C. for 1 hr. The mixture was allowed to cool to room temperature, the insoluble material was filtered off, and the filtrate was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure to give a white solid. The residue was washed with diisopropyl ether to give the title object compound (7.3 g, 43%) as white crystals.
Reaction SMILES: Cl[C:2]([F:11])([F:10])[CH:3](Cl)[CH2:4][C:5]([F:8])([F:7])[F:6].C1S(=O)(=O)CCC1.[F-:19].[K+]>>[F:10][C:2]([F:11])([F:19])[CH:3]=[CH:4][C:5]([F:8])([F:7])[F:6]
Reactant: [F-]
Reactant: FC(F)(F)CC(Cl)C(F)(F)Cl
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: FC(F)(F)C=CC(F)(F)F
Yield: 89.5 %

Procedure:
960 g of 1,2-dichloro-1,1,4,4,4-pentafluorobutane were added dropwise to a mixture of 3 1 of distilled tetramethylene sulphone and 830 g of dried potassium fluoride at 190° C. and 1,1,1,4,4,4-hexafluorobut-2-ene was distilled off as it was formed. The product thus obtained was redistilled to give 650 g of 1,1,1,4,4,4-hexafluorobut-2-ene having a boiling point of 8° C at atmospheric pressure.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH:3]([CH:11](C(OCC)=O)[C:12]([O:14]CC)=[O:13])[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>O.C(O)C>[F:1][C:2]([F:22])([F:23])[CH:3]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C(C(=O)OCC)C(Nc1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC(Nc1ccccc1)C(F)(F)F
Yield: 13.4 %

Procedure:
A solution of compound 326 (2.16 g, 6.48 mmol) and sodium hydroxide (2.60 g, 64.8 mmol) in water (5.2 mL) and ethanol (26 mL) was stirred at room temperature for 24 h. The solvents were removed under reduced pressure leaving a white solid which was triturated in ether, isolated by filtration, rinsed with ether and dried under high vacuum. The white solid was dissolved in water (12 mL), and the solution was neutralized to pH 4 with a 3N HCl solution, extracted twice with EtOAc, the combined organic layers were dried over sodium sulfate and the solvent removed under reduced pressure. The solid was dissolved in dry toluene (20 mL), heated to reflux for 1 h with continuous stirring, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent EtOAc-hexane, gradient 0:100 to 40:60) to afford title compound 327 (204 mg, 0.87 mmol, 13% yield) as a beige solid. 1H NMR (400 MHz, CDCl3) δ ppm: 7.24-7.18 (m, 2H), 6.82 (tt, J=7.2, 1.0 Hz, 1H), 6.75-6.71 (m, 2H), 4.55-4.45 (m, 1H), 2.89 (dd, J=16.0, 4.4 Hz, 1H), 2.67 (dd, J=16.0, 8.8 Hz, 1H). LRMS (M−1) 231.9 (100%).