Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][CH2:22][C:23]#[CH:24].C(N(CC)CC)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:24]#[C:23][CH2:22][O:21][CH3:20])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Reactant: C#CCOC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC#Cc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 85 °C
Reaction time: 12 h
Yield: 79.4 %

Procedure:
To a solution of 1-benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 7, 6.5 g, 19.3 mmol) in N,N-dimethylformamide (30 mL) was added 3-methoxy-propyne (5 mL, 57.9 mmol), tetrakis(triphenylphosphine)palladium(0) (2.2 g, 1.93 mmol), copper (I) iodide (735 mg, 3.85 mmol) and triethylamine (8.1 mL, 57.9 mmol) at room temperature. The mixture was then heated at 85° C. and stirred for 12 h. The resulting mixture was cooled to room temperature, extracted with ethyl acetate (2×250 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 20% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine as a light yellow solid (5 g, 89.1%): LC/MS m/e calcd for C17H14N2O3S [M+H]+ 327.38, observed 327.0.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10](O)[CH3:11].O>CC(O)=O>[Br:1][CH:10]([C:4]1[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=1[Cl:2])[CH3:11]
Reactant: Br
Reactant: CC(O)c1ccc(Cl)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(Br)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
15 ml of a 33% solution of HBr in AcOH are cooled to 0° C., 2 ml of 2,4-dichloro-1-(1-hydroxyethyl)benzene are added dropwise and the reaction mixture is stirred for 30 minutes at 0° C. and then for 3 hours at RT. It is poured into iced water and extracted with AcOEt, the organic phase is washed with saturated aqueous NaHCO3 solution, with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 3.4 g of the expected product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH:5]([CH3:16])[CH2:4]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:16][CH:5]1[CH2:4][CH:3]([CH2:2][NH2:1])[CH2:8][CH2:7][NH:6]1
Reactant: CC1CC(CN)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CC(CN)CCN1

Procedure:
A mixture comprising tert-butyl 4-(aminomethyl)-2-methylpiperidine-1-carboxylate (2 g, 8.76 mmol) and trifluoroacetic acid (10 ml, 130 mmol) in DCM (29.2 ml) was stirred at room temperature for 1 hour. The resulting mixture was loaded on to an Isolute® SCX-2 10 g cartridge and washed with DCM. The product was eluted with 7M ammonia in MeOH and concentrated under reduced pressure. The crude material was suspended in EtOH and filtered. The filtrate was concentrated under pressure to afford the title compound which was used in the next step without further purification;
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:39]([NH2:45])[C:40]1[O:44][CH:43]=[CH:42][CH:41]=1>>[O:44]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:39][NH:45][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])=[CH:38][CH:37]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: NCc1ccco1
Product: O=C(NCc1ccco1)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 86.9 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30 mmol, 0.6M in DMF) were combined to give 53 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 610 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:10][CH:9]([O:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][NH:7]1)=[O:5].[C:22]([O:26][C:27]([NH:29][CH:30]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:2][O:3][C:4]([CH:6]1[CH2:10][CH:9]([O:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][N:7]1[C:31](=[O:32])[CH:30]([NH:29][C:27]([O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:28])[CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:5]
Reactant: COC(=O)C1CC(OS(=O)(=O)c2ccc(Br)cc2)CN1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CC(OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)C(NC(=O)OC(C)(C)C)C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.2 %

Procedure:
To a solution of 4-(4-bromo-benzenesulfonyloxy)-pyrrolidine-2-carboxylic acid methyl ester HCl salt (4 g, 10 mmol) in DCM (50 mL) was added tert-butoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (2.86 g, 11 mmol), HATU (5.7 g, 15 mmol) and DIPEA (7 mL, 40 mmol). The solution was stirred at room temperature for 16 h. The solution was diluted with DCM and washed twice with aq NH4Cl and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The desired product was purified by silica gel column chromatography from hexane/EtOAc to provide 4-(4-bromo-benzenesulfonyloxy)-1-[2-tert-butoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidine-2-carboxylic acid methyl ester (4.25 g 70% yield). LCMS found 606 ([M+H]+.
Reaction SMILES: [CH:1]1([CH3:34])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([O:10][C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:26]=3[F:32])[C:14]2=[O:33])=[O:12])[CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].O>CN(C=O)C>[CH3:47][C:46]([O:45][C:43](=[O:44])[CH2:42][C:13]1([C:11]([O:10][CH:3]2[CH:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][CH:1]([CH3:34])[CH2:2]2)=[O:12])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:15]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:26]=2[F:32])[C:14]1=[O:33])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1CCC(C(C)C)C(OC(=O)C2C(=O)N(Cc3ccc(Br)cc3F)C(=O)c3ccccc32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCC(C(C)C)C(OC(=O)C2(CC(=O)OC(C)(C)C)C(=O)N(Cc3ccc(Br)cc3F)C(=O)c3ccccc32)C1
Temperature: 85 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
To a mixture of 2-[(4-bromo-2-fluorophenyl)methyl]-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinoline carboxylic acid menthyl ester (7.62 g, 14.37 mmol), K2CO3 (3.96 g, 28.74 mmol) in DMF (100 mL) was added tert-butyl bromoacetate (4.64 mL, 28.74 mmol). The mixture was stirred at 85° C. for 2 hours, poured into H2O (1000 mL) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexane/EtOAc:4/1) gave a clear oil (6.9 g, diastereomeric mixture). The two diastereomers were separated by preparative HPLC on prep. Pac silica column, (μ poraSi/125 Å, 15-20 μsilica) by elution with hexane/CH2Cl2 to give the less polar A-diastereomer as a white solid (2.4 g) and the more polar diastereomer B as a clear oil (2.2 g). The diastereomeric purity was determined by analytical HPLC, on Dynamax silica 25 cmx4.1 mm and was found to be greater than 99% for both diastereomers.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16](OC)(=[O:19])[C:17]#[CH:18]>CN(C)C=O>[CH3:14][C:12]1[NH:13][C:16](=[O:19])[CH:17]=[CH:18][C:11]=1[C:10](=[O:15])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: CC(N)=CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: C#CC(=O)OC
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)ccc1C(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
m.p. 282°-284° C., 5.0 g, was obtained following the procedure described in Example A-2 using 20 g of 3-(4-nitrophenyl)-1-methyl-3-oxo-1-propenamine, 9.5 ml of methyl propiolate and 100 ml of dimethylformamide.
Reaction SMILES: C[C:2]1([C:13]([O:15]C)=[O:14])C[N:6](C)C2C=CC=CC=2[O:3]1.[OH-].[K+].C([O:21][C:22]([CH:24]1[CH2:29][N:28]([CH3:30])[C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[O:25]1)=O)C.[CH:35]([N-:38][CH:39](C)C)([CH3:37])C.[Li+].IC>C(O)C.O1CCCC1>[C:13]([OH:15])(=[O:14])[C:2]([OH:21])=[O:3].[NH:38]1[CH2:35][CH2:37][N:6]=[C:39]1[C:24]1([CH3:22])[CH2:29][N:28]([CH3:30])[C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[O:25]1
Reactant: COC(=O)C1(C)CN(C)c2ccccc2O1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CN(C)c2ccccc2O1
Agent: [K+]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CI
Product: CN1CC(C)(C2=NCCN2)Oc2ccccc21
Product: O=C(O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,4-Dimethyl-2-methoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazine 20 ml of 5% KOH are added to 11.3 mmol (2.5 g) of 2-ethoxycarbonyl-4-methyl-3,4-dihydro-2H-1,4-benzoxazine (described in J. Heterocyclic Chem., 1985, 22, 177) in 10 ml of ethanol and 10 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 1 hour. The solvent is evaporated off, and the resulting residue is taken up in an ethyl acetate/water mixture, at acidic pH, and extracted. The organic phase is dried and concentrated. The residue is then dissolved in 90 ml of tetrahydrofuran and the temperature is reduced to -50° C. before the addition of 45.2 mmol (22.6 ml) of lithium diisopropylamide as a 2M solution in tetrahydrofuran. The reaction mixture is stirred for 2 hours at -50° C., and then 45.2 mmol (2.7 ml) of iodomethane are added and the temperature is brought back up to 25° C. in the course of 2 hours. After hydrolysis, the mixture is acidified to pH=4 and extracted with ethyl acetate. The organic phase is dried and concentrated. The residue is then dissolved in 150 ml of methanol in the presence of para-toluenesulphonic acid. The reaction mixture is heated at reflux for 18 hours. The solvent is evaporated off, and the mixture is taken up in an ethyl acetate/water mixture and extracted. The organic phase is dried, concentrated and purified by chromatography on silica gel using an ethyl acetate/petroleum ether mixture (3/7) as eluant to yield the expected compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH2:19]([O:23][C:24]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=1[C:26](O)=[O:27])[CH:20]([CH3:22])[CH3:21].C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:26]([C:25]3[CH:29]=[C:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=[CH:32][C:24]=3[O:23][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:27])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 (b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11](CC)[CH2:12][CH:13]([OH:16])[CH2:14][CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH2:20]1[CH2:24]OC(N2C(=O)NC(=O)C(F)=C2)[CH2:21]1.[CH3:34][CH2:35][C:36]1([OH:49])[N:41]=[C:40]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[Se:39][CH2:38][CH2:37]1>C(OCC)(=O)C>[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH:13]([OH:16])[CH2:14][CH2:15][CH2:21][CH2:20][CH3:24])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:34][CH2:35][C:36]1([OH:49])[N:41]=[C:40]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[Se:39][CH2:38][CH2:37]1
Reactant: CCC(O)CC(CC)COC(=O)c1ccccc1
Reactant: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Agent: CCC1(O)CC[Se]C(c2ccc(C)cc2)=N1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCC(O)CCCOC(=O)c1ccccc1
Reaction time: 123 h

Procedure:
A comparison thermal solvent dispersion 4-hydroxy-(2'-ethylhexyl) benzoate (TS-1), a liquid at room temperature, is prepared by similar means. An aqueous solution of 10% (w/w) aqueous DA-9 (6 g), 8.3% aqueous gelatin (about 54 g), and water (74.9 g) is combined with 15 g TS-1, stirred, passed through a colloid mill 5 times, chill set, and stored in the cold until it is used for melt preparation. This colloid milled dispersion is designated a TS-1 CM dispersion. A solid particle thermal solvent dispersion of 4-hydroxy-nonyl benzoate (TS-2; Pfaltz and Bauer; melting point 90°-93° C.) is prepared similarly. About 12 g of TS-2 was dissolved in 24 g of ethyl acetate and mixed with an aqueous gelatin solution comprising 4.8 g of 10% (w/w) aqueous DA-9, 43.3 g of 8.3% (w/w) aqueous gelatin, and 35.9 g of water to give a crude dispersion. This dispersion is passed through a colloid mill 5 times, chill set, noodled, washed to remove ethyl acetate, remelted, chill set, and stored in the cold until used for melt preparation. This colloid milled dispersion is designated TS-2 (CM). Another solid particle thermal solvent dispersion of TS-2 is prepared by roller milling methods. About 18 g of TS-2 is combined with 36 g of 10% aqueous DA-9 , 66 g of water, and about 100 mL of 1.8-2.1 mm-diameter zirconia milling media and placed in a sealed glass jar. This jar is placed on a roller mill for about 123 hours, and a fine particle sized aqueous dispersion is obtained. This dispersion is passed through a cloth filter. About 110 g of this filtrate is combined with about 55.3 g of 8.3% (w/w) aqueous gelatin and 1.9 g of water at about 40° C., stirred, chill set, and stored in the cold until it is used for melt preparation. This roller milled dispersion is designated TS-2 RM.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8](Cl)=[O:9])[CH2:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:18][C:19]=1[NH:20][CH:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][CH2:22]1)=[O:14].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>ClC(Cl)C>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:18][C:19]=1[N:20]([CH:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][CH2:22]1)[C:8]([C@@H:5]1[CH2:6][CH2:7][C:2]([CH3:1])=[CH:3][CH2:4]1)=[O:9])=[O:14]
Reactant: CC1=CC[C@H](C(=O)Cl)CC1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC2(CC1)OCCO2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC=C(C)CC1)C1CCC2(CC1)OCCO2
Temperature: 90 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
(R)-4-methylcyclohex-3-enecarbonyl chloride 504 (2.65 mmol), 5-(3,3-dimethyl-but-1-ynyl)-3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester 505 (250 mg, 0.66 mmol) and potassium phosphate tribasic (562 mg, 2.65 mmol) were suspended in dichloroethane (1.7 mL), sealed with a cap and heated to 90° C. After 16 hours, the reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Flash chromatography (10-40% EtOAc:Hexanes) afforded 220 mg (67% yield) of the desired 5-(3,3-dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-((1R)-4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester 506 as a beige foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(C)(C)[CH3:2].Br[C:16]1[N:17]=[C:18]([O:42][CH3:43])[C:19]([N:22](COCC[Si](C)(C)C)[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=2[Cl:33])(=[O:25])=[O:24])=[N:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[C:6]([O:5][CH2:1][CH3:2])(=[O:14])[CH3:7].[CH3:10][CH2:9][CH2:8][CH:7]([CH3:12])[CH3:6].[Cl:33][C:27]1[C:28]([Cl:32])=[CH:29][CH:30]=[CH:31][C:26]=1[S:23]([NH:22][C:19]1[N:20]=[CH:21][C:16]([O:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:5])=[O:14])=[CH:12][CH:11]=2)=[N:17][C:18]=1[O:42][CH3:43])(=[O:25])=[O:24]
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCC(C)C
Product: COc1nc(Oc2ccc(C(=O)O)cc2)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 12 h

Procedure:
4-Hydroxybenzoic acid tert butyl ester (0.13 g), N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55 part a) (0.35 g) and caesium carbonate (0.42 g) in acetonitrile (10 mL) was heated at 50° C. After 12 h, the mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound protected with the SEM group and tert butyl group as an oil. The oil was dissolved in trifluoroacetic acid (2.0 mL) and stirred at room temperature for 3 h.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([OH:14])[C:10]=1[O:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[CH2:18](I)[CH3:19].[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([O:14][CH2:18][CH3:19])[C:10]=1[O:11][CH2:12][CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1c(O)cc(C(C)=O)cc1C(C)(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(C(C)=O)cc(C(C)(C)C)c1OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(3-tert-Butyl-4-ethoxy-5-hydroxyphenyl)ethanone (O3.010; 470 mg) and ethyl iodide (193 μl) were dissolved in DMF (6.2 ml), and sodium hydride (57 mg) was added. After stirring at RT for 0.5 h, the DMF was drawn off and the residue was taken up in EA, washed with water, dried and concentrated. The residue was purified using silica gel (40 g cartridge, n-heptane/EA gradient 0-30% within 60 min). 420 mg of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:35])=[C:30]([CH:33]=O)[NH:31][CH:32]=2)=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:30]2[NH:31][CH:32]=[C:28]([C:26]([N:21]4[CH2:20][C@H:19]([CH3:18])[NH:24][C@H:23]([CH3:25])[CH2:22]4)=[O:27])[C:29]=2[CH3:35])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(Br)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.8 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-bromo-phenyl)-3-[4-[(cis)3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (79 mg, 61%).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:9][N:8]=[C:7]([NH:19][CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])[N:6]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)Cl>[CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:18])=[O:33])[N:12]=3)=[CH:9][N:8]=[C:7]([NH:19][CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])[N:6]=2)[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2cnc(NCC(C)(C)O)nc2CC2CC2)n1
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2cnc(NCC(C)(C)O)nc2CC2CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a solution of 1-(4′-(Cyclopropylmethyl)-2-(methylthio)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol (90 mg, 0.261 mmol) in DCM (521 μl), mCPBA (70.6 mg, 0.287 mmol) was added in portions, and the reaction mixture was stirred at rt for 1 h. The crude product was purified by a Biotage silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product as a yellow solid (38 mg, 40% yield). MS (ES+): m/z=362.2 (100) [MH+]. HPLC: tR=0.90 min over 3 min. Purity: 100% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: CC([NH:5][S:6]([C:9]1[C:14]([S:15]([CH2:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7])(C)C.C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:31])C=1.O>FC(F)(F)C(O)=O>[CH2:17]([S:15]([C:14]1[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:16])=[O:31])[CH2:18][CH3:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCS(=O)c1cccnc1S(=O)(=O)NC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)c1cccnc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
To a stirred solution of 8.8 g (0.029 mol) of the product from Example 3 in. 400 mls methylene chloride cooled to -5e, under nitrogen, was added 6.6 g (0.038 mol) of 3-chloroperbenzoic acid and stirred at room temperature for 20 hours. The reaction mixture was poured into water and extracted with methylene chloride. The organic layers were combined and washed with saturated sodium bisulfite and brine, dried over magnesium sulfate, and evaporated to a solid mixture which was washed with hexanes to afford a white solid. The solid was dissolved and stirred in 150 mls trifluoroacetic acid for 72 hours. The solution was evaporated and triturated with ether to afford 5.3 g (46%) white solid: m.p. 153-157° ; NMR (CDCl3, 200 MHz) 1.06 (3H, t, J=7 Hz), 1.8 (2H, m), 3.7 (2H, m) 5.8 (NH2), 7.8 (1H, m), 8.6 (1H, m), 8.95 (1H, m); IR (nujol) 3390, 3180, 1360, 1310, 1175, 1150 cm-1.