Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C[CH2:12][C:13]1[CH:18]=[C:17]([N:19]2[N:23]=[C:22]3[CH:24]=[CH:25][CH:26]=[C:27](Cl)[C:21]3=[N:20]2)[C:16]([OH:29])=[C:15]([C:30](C)(C)C)[CH:14]=1)CCCCCCC.[CH2:35](C(CCCC)COC(=O)CCC1C=C(N2N=C3C=CC(Cl)=CC3=N2)C(O)=C(C(C)(C)C)C=1)[CH3:36]>>[CH3:12][C:13]1[CH:18]=[C:17]([N:19]2[N:23]=[C:22]3[C:21]([CH:27]=[CH:26][CH:25]=[CH:24]3)=[N:20]2)[C:16]([OH:29])=[C:15]([CH2:30][CH:35]=[CH2:36])[CH:14]=1
Reactant: CCCCCCCCOC(=O)CCc1cc(-n2nc3cccc(Cl)c3n2)c(O)c(C(C)(C)C)c1
Reactant: CCCCC(CC)COC(=O)CCc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Product: C=CCc1cc(C)cc(-n2nc3ccccc3n2)c1O

Procedure:
Mixture of octyl-3-[3-tert-butyl-4-hydroxy-5-(chloro-2H-benzotriazole-2-yl)phenyl]propionate and 2-ethylhexyl-3-[3-tert-butyl-4-hydroxy-5-(5-chloro-2H-benzotriazole-2-yl)phenyl]propionate (TINUVIN109, product of Ciba Specialty Chemicals Inc.)
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]([NH:9]C(=O)OC(C)(C)C)[C:5]([CH3:8])=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:9][C:4]1[C:3]([CH3:17])=[C:2]([OH:1])[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: Cc1ccc(O)c(C)c1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(O)c(C)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of tert-butyl N-(3-hydroxy-2,6-dimethyl-phenyl)carbamate (657 mg, 2.8 mmol, 1.0 eq) in DCM (5 mL) was added TFA (5 mL) and the reaction stirred at room temperature overnight. The solvent was removed in vacuo. The residue was taken up in water and solution adjusted to pH 7 by addition of aqueous NaHCO3. The aqueous phase was extracted with EtOAc and the organic extract dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a yellow solid (370 mg, 97%) which was used without further purification.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(Cl)Cl>[C:24]([CH2:23][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1)([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Solvent: ClCCl
Product: CCOC(=O)CSc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
To 1.0 gm (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole in 50 ml methylene chloride at 0° was added a solution of 0.63 g (3.7 mmole, 0.43 ml) ethyl bromoacetate in 10 ml CH2Cl2 over a period of 10 minutes. The reaction was allowed to come to room temperature and was stirred for 30 minutes. The mixture was then diluted with methylene chloride and washed with 3N NaHCO3, saturated NaCl, treated with Na2SO4, stripped, then flash chromatographed on silica with methylene chloride containing 1% to 5% MeOH. The isolated material was recrystallized from ethyl acetate to give 0.35 g of the titled product. 27.2% yield, mp 102°-103° C. Analyzed for C21H21N3O2S, Calculated, C: 66.47, H:5.58, N: 11.07; Found, C: 66.39, H: 5.62, N: 10.97.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18](Br)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][C:25]([F:24])([F:37])[F:36])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(Br)c3c2CC1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4OC(F)(F)F)c3c2CC1
Yield: 29.4 %

Procedure:
3-Benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (4.00 g, 10.8 mmol) was suspended in benzene (170 mL). 2-(Trifluoromethoxy)-phenylboronic acid (4.48 g, 21.7 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.433 g, 0.617 mmol) and 2M Na2CO3 (17.6 mL) were added to the reaction mixture. Ar was bubbled through the reaction mixture for 20 min. The reaction mixture was heated at reflux for 11 h. After cooling, the reaction mixture was concentrated. The residue was combined with EtOAc (250 mL) and H2O (400 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product (7.95 g) was recrystallized from CH3OH to yield 3-benzoyl-10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.43 g). The crude product from the mother liquors was chromatographed (SiO2 250 g, eluted with 2:1 toluene:EtOAc) to give 3-benzoyl-10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (5.21 g). The yield of the reaction was 87%. IR (diffuse reflectance) 3266, 3227, 3187, 1615, 1574, 1498, 1483, 1464, 1428, 1382, 1354, 1334, 1323, 1288, 1253, 1221, 1202, 1167, 926, 790, 767, 750, 732, 704, 626 cm−1; MS (ESI+) for C26H21F3N2O2 m/z 450.9 (M+H)+; Anal. Calcd for C26H21F3N2O2: C, 69.32; H, 4.70; N, 6.22; found: C, 69.25; H, 4.78; N, 6.25.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8]=O)=[N:6][CH:5]=[N:4]1)[CH3:2].Cl.[NH2:11][OH:12].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([N:3]1[C:7]([CH:8]=[N:11][OH:12])=[N:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncnc1C=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCn1ncnc1C=NO
Yield: 31.1 %

Procedure:
A mixture of crude 1-ethyl-1H-1,2,4-triazole-5-carbaldehyde (17.7 g), hydroxylamine hydrochloride (12.7 g, 0.182 mol), sodium bicarbonate (15.3 g, 0.182 mol) and ethanol (60 mL) was heated at reflux for 3 hours. After cooling, the reaction was filtered and the filtrate concentrated in vacuo. The resulting residue was crystallised from ethanol to give the title compound (6.17 g) 1H-NMR (d6-DMSO) δ 1.32 (3H, t, J=7 Hz), 4.41 (2H, q, J=7 Hz), 8.02 (1H, s), 8.25 (1H, s), 12.70 (1H, s)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:13]([Mg]Br)=[CH2:14].Cl>O1CCCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:7]([OH:8])[CH:13]=[CH2:14])[CH:9]=1
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(O)c1cc(O)ccc1[N+](=O)[O-]
Temperature: -78 °C
Yield: 73 %

Procedure:
5-Hydroxy-2-nitrobenzaldehyde (60 g) is dissolved in dry tetrahyrofuran (90 ml) and thereto is added dropwise vinylmagnesium bromide (2.3 equivalents) with stirring at -78° C. The temperature of the reaction mixture is raised gradually. After completion of the reaction, 1N HCl is added to the reaction mixture, and the mixture is extracted with ethyl acetate, and the organic layer is separated, washed with an aqueous saturated saline solution, dried over sodium sulfate, and then distilled off the solvent. The residue is purified with a silica gel column chromatography to give 1-(5'-hydroxy-2'-nitrophenyl)-2-propen-1-ol (5.09 g) as yellowish brown powders.
Reaction SMILES: [F:1][C:2]1[C:30]([F:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[NH:12][N:13]=3)[C:4]=2[CH:3]=1.[Na].[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41]Cl)[CH2:36][CH2:35]1>CN(C)C=O.C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:30]([F:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[N:12]([CH2:41][CH2:40][N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)[N:13]=3)[C:4]=2[CH:3]=1
Reactant: CN1CCN(CCCl)CC1
Reactant: CCCN(CCC)CC(=O)N1c2cc(F)c(F)cc2-n2c(n[nH]c2=O)-c2cccnc21
Agent: [Na]
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: CCCN(CCC)CC(=O)N1c2cc(F)c(F)cc2-n2c(nn(CCN3CCN(C)CC3)c2=O)-c2cccnc21
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 6,7-difluoro-2,9-dihydro-9-[ (dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one in dimethylforamide is added a solution of sodium hydrided in mineral oil. The mixture is allowed to react at about 95°C. for 40 minutes and after cooling [2-(4-methylpiperazino)-ethyl]chloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 6,7-difluoro-2.9-dihydro-2-[2-(4-methylpiperazino)ethyl]-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]-benzodiazepin-3-one.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:17]CCl.Cl>CSC>[ClH:17].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2
Reactant: ClCCl
Reactant: COc1ccc2c(c1)CCNC2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CSC
Product: Oc1ccc2c(c1)CCNC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In dimethyl sulfide (20 ml), 6-methoxy-1,2,3,4-tetrahydroisoquinoline (7.75 g) was dissolved. Under ice cooling, aluminum chloride (19.0 g) was added to the resulting solution, followed by stirring at room temperature for 3 hours. Dichloromethane and dilute hydrochloric acid were added to separate the water layer. The water layer was made basic by the addition of a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was dissolved in saturated solution of hydrochloride in ethanol (100 ml). To the residue obtained by distilling off the solvent under reduced pressure, ethyl acetate was added. The solid thus precipitated was collected by filtration, whereby the title compound (7.91 g, 90%) was obtained.
Reaction SMILES: [C:1]1([N:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[CH2:16][CH2:17][OH:18])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:32]([N:37]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:38](Cl)=[O:39])[CH2:33][CH2:34][CH2:35][CH3:36]>O1CCCC1>[C:19]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:38](=[O:39])[N:37]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:12][CH:11]2[CH2:16][CH2:17][OH:18])=[O:9])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCCCN(CCCCC)C(=O)Cl
Reactant: O=C(N(c1ccccc1)c1ccccc1)N1CCNCC1CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)C(CCO)C1
Temperature: 60 °C
Reaction time: 48 h
Yield: 64.2 %

Procedure:
To a solution of 174 mg (0.53 mmol) of (RS)-1-(N,N-diphenylcarbamoyl)-2-(2-hydroxyethyl) piperazine in 10 mL of dry tetrahydrofuran was added 450ml (3.23 mmol) of triethylamine in one portion and 176 mg (0.80 mmol) of dipentylcarbamyl chloride (dissolved in 2 mL of dry tetrahydrofuran) and the mixture was stirred under nitrogen at 60° C. for two days. The solution was cooled and concentrated in vacuo. Flash chromatography on 25 g of silica gel using 75:25 v/v ethyl acetate/hexane as the eluant afforded 173 mg (64%) of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([S:11][CH2:12]C[Si](C)(C)C)=[C:6]([Cl:18])[C:5]=1[NH2:19].COC(=O)C1C=C(N)C([SH:31])=C(Cl)C=1N.C(=S)=S.[OH-].[Na+]>CCO>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH2:19])=[C:6]([Cl:18])[CH:7]2[S:11][C:12]([SH:31])=[N:10][CH:8]2[CH:9]=1)=[O:20]
Reactant: COC(=O)c1cc(N)c(SCC[Si](C)(C)C)c(Cl)c1N
Reactant: COC(=O)c1cc(N)c(S)c(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: S=C=S
Solvent: CCO
Product: COC(=O)C1=CC2N=C(S)SC2C(Cl)=C1N

Procedure:
This compound is synthesized as reported in U.S. Pat. No. 4,454,148. 2,5-Diamino-3-chloro-4-(2-trimethylsilanyl-ethylsulfanyl)-benzoic acid methyl ester (step d in example H17) is used as starting material and after thiol deprotection (step f in example H17), the crude 2,5-diamino-3-chloro-4-mercapto-benzoic acid methyl ester is cyclized with CS2, NaOH in EtOH at 70° C. The crude is directly used in the next step without further purification; LC/MS: 275/277 (M+1)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:17]>C(C(C)=O)C>[O:13]([CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(COc1ccccc1)c1ccc(Cl)cc1
Yield: 50.4 %

Procedure:
To 28.4 g (213 mmole) of anhydrous potassium carbonate suspended in 100 ml of methyl ethyl ketone was added 20 g (213 mmole) of phenol and 47 g (201 mmole) of 2-bromo-4'-chloroacetophenone. The reaction mixture was refluxed for 2.5 hours, cooled, concentrated in vacuo, partitioned between diethyl ether and water, washed with dilute aqueous sodium hydroxide, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to yield 25 g of 2-phenoxy-4'-chloroacetophenone, a white solid, mp 80°-83° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1.[H-].[Na+].CO>CN(C=O)C>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:17][CH:18]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(ccn2Cc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
To a solution of methyl 1H-indole-5-carboxylate (1.09 g, 6.2 mmol, 1 equiv) and 1-(bromomethyl)-4-bromobenzene (1.70 g, 6.82 mmol, 1.1 equiv) in anhydrous DMF (30 mL) under argon atmosphere was added sodium hydride (500 mg, 12.4 mmol, 2 equiv) in small portions. The mixture was stirred 2 h at room temperature. The reaction mixture was then neutralized by addition of methanol and concentrated in vacuo. The residue was dissolved in AcOEt, washed with brine and dried over MgSO4. The crude was purified by flash chromatography (Hexane/AcOEt 7.5/2.5) to afford the title compound as a white powder (1.09 g, 3.2 mmol, 52%). ESI-MS (m/z): 344/346 [M+H]+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)[CH:14]=O)([CH3:10])([CH3:9])[CH3:8].CC(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:7]([C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)[CH:14]=[CH2:1])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: C=Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
Dry tetrahydrofuran (80 ml) was added to a mixture of potassium t-butoxide (6.740 g, 60.06 mmoles) and methyltriphenylphosphonium bromide (24.276 g, 60.06 mmoles) and stirred at room temperature for 30 minutes. A solution of 3,5-di-t-butylbenzaldehyde (10.087 g, 46.20 mmoles) in dry tetrahydrofuran (30 ml) was then added and the reaction mixture was stirred at room temperature for 17 hours. Acetone (50 ml) was then added and then all of the solvent was removed under vacuum. Pet. ether (60-80, 150 ml) was then added to the residue and the mixture was stirred vigorously for 30 minutes. The solution was then filtered through silica, rinsing thoroughly with pet. ether (60-80) and the solvent removed under vacuum to give 3,5-di-t-butylstyrene (9.302 g, 93%).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][CH:11]([OH:18])[CH2:12][C:13]([CH3:17])([O:15][OH:16])[CH3:14]>C(N(CC)CC)C.CCOCC>[CH:1]1([NH:7][C:8](=[O:9])[O:18][CH:11]([CH3:10])[CH2:12][C:13]([CH3:17])([O:15][O:16][C:8](=[O:9])[NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)CC(C)(C)OO
Reactant: O=C=NC1CCCCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(CC(C)(C)OOC(=O)NC1CCCCC1)OC(=O)NC1CCCCC1
Reaction time: 48 h
Yield: 39 %

Procedure:
A mixture of 18.7 g. (0.15 mole) of cyclohexyl isocyanate, 6.7 g. (0.05 mole) of 1,3-dimethyl-3-hydroperoxybutyl alcohol and 3 drops of triethylamine was stirred for 5 days at ambient temperature. The reaction vessel was protected with a calcium chloride tube to keep out moisture. Within 2 days, a solid began to appear, and after the 5 day stirring period the reaction mixture was stripped in vacuo. The residue was slurried in 100 ml of ether and filtered. The filter cake was washed with an additional 30 ml of ether and air dried. A total of 7.5 grams of a colorless solid was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])[N:14]=[CH:13][C:12]=3[N:25]=2)[CH:5]=[CH:6][C:7]=1[OH:8].CC1C=CC(S(O[CH2:37][CH2:38][CH:39]([OH:41])[CH3:40])(=O)=O)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])[N:14]=[CH:13][C:12]=3[N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:37][CH2:38][CH:39]([OH:41])[CH3:40]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)c(F)c3)nc2cn1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCCC(C)O)c(F)c3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and 3-hydroxybutyl 4-methylbenzenesulfonate, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccno3)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(4-fluorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][C:2]([CH:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[CH:7][N:8]=1)[CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[NH:29]1[CH2:30][CH2:31][CH:26]([C:2]([C:4]2[S:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]4[N:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][N:17]=4)[CH:10]=3)=[CH:7][N:8]=2)([OH:1])[CH3:3])[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O)(c1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1)C1CCNCC1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
To a stirred solution of the product of Step 4 (18.2 mg, 0.033 mmol) in dichloromethane (1 mL) was added TFA (1.00 mL, 12.98 mmol) and the mixture was stirred at room temperature. The solvent was removed by evaporation and stripped with ethyl acetate. The residue was concentrated and dried under high-vacuum to afford 1-(piperidin-4-yl)-1-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethanol (Example 15(2), 12.5 mg, 0.018 mmol) as a TFA salt. APCI: [M+H]+ m/z 450.1. 1H NMR (500 MHz, DMSO-d6): δ 10.34 (1H, s), 8.86 (1H, d, J=4.89 Hz), 8.43 (2H, broad s), 8.14 (1H, s), 8.01 (1H, s), 7.67 (1H, d, J=8.10 Hz), 7.39 (1H, t, 7.88 Hz), 7.34-7.29 (2H, m), 3.18-3.02 (2H, m), 2.61-2.54 (2H, m), 1.92-1.77 (2H, m), 1.51 (3H, s), 1.55-1.41 (1H, m), 1.38-1.22 (1H, m). rhSYK activity=+++
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[NH:6].[O-]CC.[Na+].C[O:19][C:20](=O)[CH2:21][C:22](=O)[C:23]([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:23]([C:22]1[N:7]=[C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:12])([F:13])[F:1])[NH:6][C:20](=[O:19])[CH:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)CC(=O)C(C)(C)C
Reactant: N=C(N)c1ccccc1C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc(=O)[nH]c(-c2ccccc2C(F)(F)F)n1
Yield: 32.4 %

Procedure:
A mixture of 2-trifluoromethylbenzamidine (1.12 g, 5 mmol), sodium ethoxide (1.02 g, 15 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid methyl ester (0.80 mL, 5 mmol) in ethanol (50 mL) and was heated at reflux for 16 hours. The reaction was cooled, concentrated, diluted with water and acidified with 2 N hydrochloric acid. This solution was extracted with ethyl acetate, dried over sodium sulfate and concentrated. Purification by flash chromatography [SiO2, methanol:dichloromethane (2:98)] provided the title compound (0.48 g, 32% yield) as a yellow solid; 1H-NMR (500 MHz, DMSO-d6) δ 12.8 (br s, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.78 (m, 2H), 7.71 (d, J=7.4 Hz, 1H), 6.24 (s, 1H), 1.20 (s, 9H) ppm; LC-MS 297.03 (M+H); Rt (Method A) 3.30 minutes.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Br:29].[Cl-].[NH4+]>C1COCC1>[Br:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)C
Reactant: BrCCCCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CCCCCCCBr
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (5.82 mL) in THF (30 mL) was added n-butyllithium (2.5M in hexanes, 16.4 mL) at 0° C. and the mixture was stirred for 30 min at this temperature before being cooled to −78° C. Ethyl isobutyrate (5 mL) was added dropwise and the resultant mixture was stirred at −78° C. for 1 h before addition of 1,7-dibromoheptane (6.4 mL). The reaction mixture was stirred at −78° C. for 1 h then at RT for 2 h before being poured into saturated ammonium chloride solution. The solution was extracted with ethyl acetate (×2) then the combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% ethyl acetate in cyclohexane to give the subtitled compound as a colourless liquid. Yield 1.27 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(OCC)(=O)C>[CH3:24][O:23][C:13]1[CH:12]=[C:11]([NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:3]=2)[CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: C1CCNCC1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Solvent: CCOC(C)=O
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(N2CCCCC2)n1
Yield: 22 %

Procedure:
This compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and piperidine in analogy to example 1c. Chromatography on Si—NH2 gel (Isolute) using ethyl acetate as an eluent gave the title compound as a colorless solid in 22% yield.