Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[OH-].[K+].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>CS(C)=O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1c[nH]cn1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-n1ccnc1
Temperature: 0 °C
Yield: 64.2 %

Procedure:
A solution of 2-chloro-5-nitroanisole (1.0 g, 5.33 mmol), KOH (0.438 g, 7.81 mmol) and imidazole (1.45 g, 21.3 mmol) in DMSO (5 mL) was heated to 80° C. for three hours. The reaction mixture was poured into ice water. The precipitate was collected and washed with water to afford the title compound (0.75 g, 64%). 1H NMR (CDCl3): δ8.84 (1H, s), 8.07 (2H, m), 7.66 (1H, d), 7.55 (1H, s), 7.44 (1H, s), 4.09 (3H, s); LC-MS: m/z 220.07 (M+H)+
Reaction SMILES: O[C:2]1([C:14]([CH3:16])=[CH2:15])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[Al]>>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[C:14]([C:2]1[CH2:3][NH:4][CH2:5][CH:6]=1)([CH3:16])=[CH2:15]
Reactant: C=C(C)C1(O)CCN(C(=O)OC(C)(C)C)C1
Agent: [Al]
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)C1=CCNC1
Reaction time: 8 h

Procedure:
tert-Butyl 3-hydroxy-3-isopropenylpyrrolidine-1-carboxylate (1.51 g, 0.00664 mol) was dissolved in trifluoroacetic acid (10.0 mL, 0.130 mol) under N2 at rt. The reaction flask was wrapped with aluminum foil and the mixture was stirred overnight. The reaction mixture was then concentrated in vacuo and the residue was used directly in the next step without further purification.
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[OH:38])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.[Cl-].C[N+]1C=CN([C:48]([O:50][CH2:51][C:52]2[C:61]([N+:62]([O-:64])=[O:63])=[CH:60][C:57]([O:58][CH3:59])=[C:54]([O:55][CH3:56])[CH:53]=2)=[O:49])C=1>ClCCl.N1C=CC=CC=1>[N+:62]([C:61]1[C:52]([CH2:51][O:50][C:48]([O:38][C@@H:25]2[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26]2)=[O:49])=[CH:53][C:54]([O:55][CH3:56])=[C:57]([O:58][CH3:59])[CH:60]=1)([O-:64])=[O:63]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COc1cc(COC(=O)n2cc[n+](C)c2)c([N+](=O)[O-])cc1OC
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(COC(=O)O[C@H]2C[C@H](n3cc(C)c(=O)[nH]c3=O)O[C@@H]2CO)c([N+](=O)[O-])cc1OC
Temperature: 4 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of 1.97 g 5′-O-(4,4′-dimethoxytrityl)thymidine (3.62 mmol) in 18 ml absolute dichloromethane and 2 ml absolute pyridine is added in a nitrogen atomsphere and in the absence of light to an N-methyl-N3-[(6-nitroveratryl)oxycarbonyl]imidazoliumchloride acylation reaction (19) (produced from 7.25 mmol chloroformic acid-6-nitroveratryl ester). The reaction mixture is stirred in the dark at 4° C. overnight. The molecular sieve is separated and the organic phase is extracted twice against saturated NaHCO3 (100 ml). After drying via Na2SO4, 200 ml of a 10% trichloroacetic acid in dichloroethane are added to the organic phase and stirred at room temperature for 5 minutes. The deep-red solution is extracted twice with saturated NaHCO3 (200 ml), the organic phase is dried via Na2SO4 and evaporated. Purification via flash chromatography (66-80% ethyl acetate in toluene) yielded 1.153 g of the title compound (66% yield)
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]([NH:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[S:13])[CH2:6][CH2:5]1)(=O)C.[BrH:24].BrBr>O>[BrH:24].[BrH:24].[NH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]2[S:13][C:23]3[CH:22]=[C:18]4[O:19][CH2:20][O:21][C:17]4=[CH:16][C:15]=3[N:14]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCC(CNC(=S)Nc2ccc3c(c2)OCO3)CC1
Agent: Br
Agent: BrBr
Solvent: O
Product: c1c2c(cc3sc(NCC4CCNCC4)nc13)OCO2
Reaction time: 8 h
Yield: 58.4 %

Procedure:
A mixture of 33.3 parts of N-[(1-acetyl-4-piperidinyl)methyl]-N'-(1,3-benzodioxol-5-yl)thiourea, 112.5 parts of a hydrobromic acid solution 48% in water and 75 parts of water was stirred till all solid entered the solution. Then there were added 16 parts of bromine and stirring was continued overnight at reflux. After cooling, the product was filtered off, washed with ethanol and dried, yielding 26.5 parts (58.4%) of N-(4-piperidinylmethyl)-1,3-dioxolo[4,5-f]benzothiazol-6-amine dihydrobromide; mp. >260° C. (intermediate 44).
Reaction SMILES: [CH2:1]([C:4]1[CH:16]=[C:15](Br)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=[CH2:3].[C:18]([C:20]1([OH:28])[CH:25]2[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]2)[CH2:21]1)#[CH:19].C(N(CC)CC)C.CN(C)C=O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.O>[CH2:1]([C:4]1[CH:16]=[C:15]([C:19]#[C:18][C:20]2([OH:28])[CH:25]3[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]3)[CH2:21]2)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(Br)ccc1OCC(=O)OCC
Reactant: C#CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCc1cc(C#CC2(O)CN3CCC2CC3)ccc1OCC(=O)OCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
A mixture of ethyl 2-allyl-4-bromophenoxyacetate (912 mg), 3-ethynyl-3-hydroxyquinuclidine (453 mg), bis (triphenylphosphine)-palladium (II) chloride (106 mg), copper (I) iodide (53 mg), triethylamine (3 ml) and dimethylformamide (6 ml) was stirred at 80° C. under an atmosphere of argon for 8 hours. The reaction mixture was cooled to ambient temperature and water (100 ml) was added. The mixture was extracted with ethyl acetate (3×50 ml). The ethyl acetate extracts were combined and filtered. The filtrate was washed with saturated brine solution (3×50 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography on Alumina (Fluka 507C) using ethyl acetate containing 2.5% methanol as eluent to give 3-[2-(3-allyl-4-ethoxycarbonylmethyloxyphenyl)ethynyl]quinuclidin-3-ol (220 mg) as a solid, mp 95.9° C.; microanalysis, found: C, 70.7; H, 7.30; N, 3.50%; C22H27NO4.0.25 H2O requires: C, 70.6; H, 7.35; H, 3.72%; NMR (CDCl3): 1.28 (3H, t), 1.34-1.47 (1H, m), 1.52-1.72 (1H, m), 1.90-2.25 (3H, m), 2.25-2.60 (1H, m), 2.62-2.92 (4H, m), 2.97-3.09 (IH, d), 3.25-3.35 (1H, d of d), 3.42 (2H, d), 4.26 (2H, q), 4.62 (2H, s), 5.02-5.15 (2H, m), 5.88-6.08 (1H, m), 6.60-6.68 (1H, m) and 7.17-7.27 (2H, m); m/z 370 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[Br:11][C:12]1[CH:13]=[C:14]([CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)O)[CH:15]=[CH:16][CH:17]=1.Cl>CCOCC.COCCOC.CCO.CCOCC.CO>[CH2:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([Br:11])[CH:13]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OC(c1ccccc1)c1cccc(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCO
Solvent: CO
Product: Brc1cccc(Cc2ccccc2)c1
Temperature: 0 °C
Yield: 71.1 %

Procedure:
To a suspension of 422 mg (11.12 mmol, 1.31 eq.) lithium aluminum hydride in 30 ml dry ether a solution of 1.38 g (10.35 mmol, 1.22 eq.) aluminum chloride in 18 ml dry ether was added cautiously under stirring. After the complete addition the resulting mixture was stirred for 30 min at r.t. before a solution of 2.24 g (8.52 mmol) (3-Bromo-phenyl)-phenyl-methanol (prepared above) in 19 ml dry ether was added dropwise. Then the mixture was refluxed for 12 h and after that cooled to 0° C. in an ice-bath. After adding cautiously 10 ml of a mixture of ether/methanol (1:1) 28 ml 1 N HCl-solution was added and the mixture was extracted with ether. The comb. org. fractions were washed with brine, dried over Na2SO4 and evaporated. Column chromatography (PE/CH2Cl2 (9+1)) yielded 1.50 g (6.06 mmol, 71.17%) 1-Benzyl-3-bromo-benzene (87) as a colorless liquid.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl.N1CCCNCC1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C1CNCCNC1
Reactant: ClCc1ccccc1
Agent: Cl
Solvent: CCO
Product: c1ccc(CN2CCCNCC2)cc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 101 mg of homopiperazine, 175 mg of homopiperazine dihydrochloride, 3 mL of ethanol was heated to 70° C. into a solution. 0.115 mL of benzyl chloride was added and the mixture was stirred at 70° C. for 3 hours. After cooling to room temperature, ethanol was removed under reduced pressure, and 20 mL of aqueous 2N sodium hydroxide solution was added to the solution, which was extracted with 20 mL×2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 1-benzyihomopiperazine.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.[OH-].[Na+].N>CN(C)C=O.[Cu](I)I.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[C:3](=[O:20])[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:7]=2)=[CH:24][CH:23]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Agent: I[Cu]I
Agent: N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Sc2ccc(Cl)cc2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
25 mg of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 20 ml of dimethylformamide. To the mixture were added 17 mg of 4-chlorothiophenol, 3 mg of sodium hydroxide and 2 mg of copper iodide, followed by stirring at 150° C. in nitrogen atmosphere overnight. After cooling to room temperature, the reaction mixture was poured into water. An aqueous ammonia was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 8 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[NH:9][N:8]=[CH:7][C:6]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:16]N1C(=O)CCC1=O>CO>[Br:16][C:7]1[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[NH:9][N:8]=1
Reactant: COCCc1[nH]ncc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: COCCc1[nH]nc(Br)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of 5-(2-methoxyethyl)-4-phenyl-1H-pyrazole (1.0 g, 4.94 mmol) in methanol (20 mL) was added N-bromosuccinimide (0.880 g, 4.94 mmol) in portions at room temperature. After stirred at room temperature for 16 h, the reaction was concentrated and extracted with EtOAc/H2O, purified by column chromatography to give the title compound as yellow oil (1.0 g). LCMS m/z=281.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.97 (t, J=6.63 Hz, 2H), 3.22 (s, 3H), 3.57 (t, J=7.07 Hz, 2H), 7.20-7.27 (m, 2H), 7.35-7.45 (m, 3H), 12.67 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([OH:9])=O.O1CCCC1.S(Cl)(Cl)=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:39]=[CH:40][C:41]=1[CH3:42])[O:23][C:24]1[CH:25]=[CH:26][C:27]2[N:28]([N:30]=[C:31]([NH:33][C:34]([CH:36]3[CH2:38][CH2:37]3)=[O:35])[N:32]=2)[CH:29]=1>CN(C)C=O.CN(C)C(=O)C>[CH:36]1([C:34]([NH:33][C:31]2[N:32]=[C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]4[CH:39]=[CH:40][C:41]([CH3:42])=[C:20]([NH:19][C:7]([C:3]5[N:4]=[CH:5][S:6][C:2]=5[CH3:1])=[O:9])[CH:21]=4)=[CH:29][N:28]3[N:30]=2)=[O:35])[CH2:37][CH2:38]1
Reactant: Cc1scnc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1NC(=O)c1ncsc1C
Yield: 78.2 %

Procedure:
In the same manner as in Example 55 and using 5-methyl-1,3-thiazole-4-carboxylic acid (63.1 mg, 0.441 mmol), tetrahydrofuran (5 mL), thionyl chloride (77.0 μL, 0.888 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (129 mg, 0.399 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (140 mg, 78%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9](CC2C=CC(OC)=CC=2OC)[CH:10]=[O:11])[CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1>C(O)=O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][CH:10]=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(C=O)Cc2cccc(Br)n2)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=CO
Product: O=CNCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-((6-Bromopyridin-2-yl)methyl)-N-(2,4-dimethoxybenzyl)formamide obtained in Reference Example 20 (830 mg) and anisole (1.0 mL) were dissolved in formic acid (20 mL), and the solution was stirred at 100% for 8 hr. The mixture was allowed to be cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to azeotropy with toluene, to the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give the title compound (279 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]1([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=2[OH:38])[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:38][C:29]3[CH:30]=[C:31]([C:34]([F:35])([F:36])[F:37])[CH:32]=[CH:33][C:28]=3[CH:25]3[CH2:26][CH2:27]3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Oc1cc(C(F)(F)F)ccc1C1CC1
Product: CC(NC(=O)c1coc(Oc2cc(C(F)(F)F)ccc2C2CC2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 84.6 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with cyclopropyl-5-trifluoromethyl-phenol (53 mg, 0.26 mmol) to give the title compound (60 mg, 85%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)=[N:11][C:10]=1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C=C.C1([SiH3])C=CC=CC=1>ClCCl.C(O)(=O)C>[CH2:24]([C:10]1[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)[S:13][C:9]=1[C:5]1[NH:6][CH:7]=[CH:8][N:4]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)nc1Cc1ccccc1
Agent: [SiH3]c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2nc(Cc3ccccc3)c(-c3ncc[nH]3)s2)ccn1
Temperature: 40 °C
Reaction time: 3 h
Yield: 52.7 %

Procedure:
To a solution of N-{4-[5-(1-allyl-1H-imidazol-2-yl)-4-benzyl-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.210 g, 0.0505 mmol) in dichloromethane (0.38 mL) and acetic acid (0.13 mL) was added tetrakis (triphenylphosphine)palladium(0) (0.00292 g, 0.00253 mmol) followed by phenylsilane (0.0318 mL, 0.258 mmol). The solution was stirred at 40° C. for 3 hours. The solution was cooled to room temperature then concentrated in vacuo and diluted with ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted three more times with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (0.0100 g, 53%). LCMS: (FA) ES+ , 376. 1H NMR (400 MHz, d4-methanol) δ: 8.67-8.63 (m, 1H), 8.38-8.35 (m, 1H), 7.63-7.59 (m, 1H), 7.25-7.07 (m, 7H), 4.42 (s, 2H), 2.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:17].[K+].[K+].C(#N)C.O.C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:17])[C:6]=2[CH:12]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2O1
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)Oc2c(C(=O)O)cc(Cl)cc2C1=O

Procedure:
A solution of 5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (654) (2.39 g, 10.5 mmol), potassium persulfate (8.55 g, 31.6 mmol), cupric sulfate pentahydrate (2.62 g, 10.5 mmol) and acetonitrile/water (1:1) (90 mL) were heated at reflux for 1 hour. Ethyl acetate and water were added and the layers separated. The aqueous phase was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide 5-chloro-2,2-dimethyl-3-oxo-2,3-dihydrobenzofuran-7-carboxylic acid (655) as a yellow solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16](C(OC(C)(C)C)=O)[N:15]=[C:14]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:13]=1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[N:48]=[CH:47][C:46]([C:49](OC)=[O:50])=[CH:45][N:44]=2)[CH2:39][CH2:38]1>C1COCC1>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:14]2[CH:13]=[C:12]([NH:11][C:49]([C:46]3[CH:47]=[N:48][C:43]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)=[N:44][CH:45]=3)=[O:50])[NH:16][N:15]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2CCN(C)CC2)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN(C)CC4)nc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.6 %

Procedure:
A solution of NaHMDS (2.100 ml, 2.10 mmol) in THF (1.0M) was added to a stirred solution of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (0.486 g, 1.4 mmol) and methyl 2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylate (0.397 g, 1.68 mmol) in THF (7.00 ml, cooled to −20° C.), over a period of 5 mins under nitrogen. The resulting solution was stirred at room temperature for 18 h. The mixture was heated to reflux for 90 min, then cooled to room temperature. More NaHMDS (2.100 ml, 2.10 mmol) was added and the mixture stirred for 70 mins. The mixture was allowed to stand for 96 h and then partitioned between ethyl acetate and 2.0M aqueous hydrochloric acid. The aqueous layer was separated and basified with 50% aqueous sodium hydroxide solution and then extracted with ethyl acetate (75 mL). The organic layer was washed with saturated brine (50 mL) and then dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (4.00 mg, 0.633%) as a white solid; 1H NMR (500.13 MHz, DMSO-d6, CD3CO2D) δ 2.34 (3H, s), 2.53 (4H, t), 2.90 (4H, t), 3.74 (6H, s), 3.89 (4H, t), 6.33 (1H, t), 6.35 (1H, s), 6.42 (2H, d), 8.89 (2H, s)
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:8][C:7]([N:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22])=[N:6][C:5]=2[S:4][C:3]=1[CH3:26].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[OH:22][CH2:21][CH2:20][N:19]([C:7]1[N:8]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:10]2[C:2]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:3]([CH3:26])[S:4][C:5]=2[N:6]=1)[CH2:23][CH2:24][OH:25]
Reactant: Cc1sc2nc(N(CCO)CCO)nc(NCc3ccccn3)c2c1Br
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cc1sc2nc(N(CCO)CCO)nc(NCc3ccccn3)c2c1-c1ccccc1
Reaction time: 1 h
Yield: 22 %

Procedure:
In a 10 ml glass tube were placed 2-[{5-bromo-6-methyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2-yl}-(2-hydroxyethyl)amino]ethanol (32 mg, 0.073 mmol), phenylboronic acid (20 mg, 0.166 mmol), sodium carbonate (26 mg, 0.249 mmol), triphenylphosphine (7 mg, 0.025 mmol), palladium(II)acetate (2 mg, 0.008 mmol), dimethoxyethane (0.75 ml) and water (0.25 ml). The tube was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200 W was used, the temperature being ramped from room temperature to 150° C. Once 150° C. was reached, the reaction mixture was held at this temperature for 1 hour. The resultant mixture was diluted with water (50 ml), extracted into dichloromethane (3×50 ml) and the combined organic extracts were dried (MgSO4). The solvent was removed in vacuo to give the crude product which was purified by flash chromatography (silica) eluting with ethyl acetate followed by 5% methanol in ethyl acetate to give 2-((2-hydroxyethyl)-{6-methyl-5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2-yl}amino)ethanol as a brown gum (7 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([CH2:40][CH2:41][OH:42])[CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:39][CH2:38][CH2:37][CH:36]([CH2:40][CH2:41][OH:42])[CH2:35]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CCCC(CCO)C1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCCC(CCO)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and racemic-2-(1-((2-bromophenyl)sulfonyl)piperidin-3-yl)ethanol. MS (ESI): mass calcd. for C23H25FN4O3S, 456.16; m/z found, 457.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.36-8.31 (m, 2H), 8.10-8.05 (m, 1H), 8.01-7.95 (m, 1H), 7.73-7.67 (m, 1H), 7.64-7.58 (m, 1H), 7.44-7.40 (m, 1H), 7.36-7.29 (m, 2H), 3.52-3.40 (m, 2H), 3.26-3.16 (m, 2H), 2.48-2.36 (m, 1H), 2.14-2.08 (m, 1H), 1.77-1.67 (m, 1H), 1.62-1.53 (m, 1H), 1.49-1.37 (m, 1H), 1.36-1.25 (m, 3H), 1.02-0.89 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:11]([NH:12][S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccc2cccnc2c1N
Agent: CN(C)c1ccncc1
Product: Cc1ccc2cccnc2c1NS(=O)(=O)c1ccccc1
Yield: 66.5 %

Procedure:
In the similar fashion using route 14 general procedure 27, 7-methyl-8-aminoquinoline (200 mg, 1.26 mmol), benzenesulfonyl chloride (260 mg, 1.5 mmol) and DMAP (cat.) gave the title compound (250 mg, 67%) after purification by column chromatography with DCM as the eluent.