Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH:11](O)[C:10]=2[CH:21]=1)(=[O:5])=[O:4].O1CCOCC1.[ClH:29]>CCOCC>[Cl:29][CH:11]1[C:10]2[CH:21]=[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:22])[CH3:1])[CH:7]=[CH:8][C:9]=2[CH:15]=[CH:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=2
Reactant: Cl
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)C(O)c1ccccc1C=C2
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(Cl)c1ccccc1C=C2
Reaction time: 5 h

Procedure:
A solution of 1.0 g. (0.00317 mole) of 3-dimethylsulfamoyl-5H-dibenzo[a,d]cyclohepten-5-ol in a mixture of 2 ml. of dry dioxane and 2 ml. of absolute ether is cooled in ice and saturated with dry hydrogen chloride. The mixture is allowed to stand at room temperature for 5 hours and then is refrigerated overnight. The white crystalline product is collected, washed with petroleum ether, and dried in a vacuum desiccator over calcium chloride. The yield of 5-chloro-3-dimethylsulfamoyl-5H-dibenzo[a,d]cycloheptene is 600 mg., m.p. 139.5°-143.5° C. Dilution of the mother liquor with petroleum ether gives a second crop which is recrystallized from a mixture of ether and a petroleum ether affording 250 mg., m.p. 138.5°-142.5° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[C:12]2[CH:17]=[C:16]([NH2:18])[C:15]([NH:19][CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:14][C:13]=2[N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:6][CH:5]=1.[Cl:34][C:35]1[C:48]([N:49]=[C:50]=S)=[C:47]([Cl:52])[CH:46]=[CH:45][C:36]=1[CH2:37][NH:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41].CC(C)N=C=NC(C)C>CC#N>[F:33][C:2]([F:1])([F:32])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:12]2[C:13]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:14][C:15]3[N:19]([CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])[C:50]([NH:49][C:48]4[C:47]([Cl:52])=[CH:46][CH:45]=[C:36]([CH2:37][NH:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C:35]=4[Cl:34])=[N:18][C:16]=3[CH:17]=2)=[O:31])=[CH:6][CH:5]=1
Reactant: CC(C)(O)CNc1cc(N2CCOCC2)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: CC(C)(O)Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c(N3CCOCC3)cc21

Procedure:
The title compound is prepared in analogy to 6c from N-(4-trifluoromethoxyphenyl)-2-(morpholinyl)-4-(2-hydroxy-2-methyl-propylamino)-5-amino-benzoic acid amide (94 mg, 0.20 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (64 mg, 0.20 mmol), DIC (31 μL, 0.20 mmol) and MeCN (5 mL).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18]C)=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[S:7][C:6]=2[C:16]=1[Cl:17].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[S:7][C:6]=2[C:16]=1[Cl:17]
Reactant: COc1cc2cc(C3CCCCC3)sc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1cc2cc(C3CCCCC3)sc2c(Cl)c1Cl
Reaction time: 5 h

Procedure:
A mixture of 5.0 of 6,7-dichloro-2-cyclohexyl-5-methoxybenzo[b]thiophene and 50 g of pyridine hydrochloride is stirred at 195° for 5 hrs. The cooled mixture is diluted with 250 ml of water and the resulting aqueous mixture is extracted with 3×250 ml ether. The organic layers are combined, washed with 150 ml of 2N hydrochloric acid, 2×100 ml of water, dried over anhydrous magnesium sulfate and filtered. The solvent is removed and the residue is chromatographed on a silical gel column using hexane and then 1:1 ether-hexane as eluting solvents. Evaporation of the eluents gives 3.2 g of 6,7-dichloro-2-cyclohexyl-5-hydroxybenzo[b]thiophene. Crystallization from pentane gives the analytical sample, mp 59°-60°.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([CH3:13])([CH3:12])[S:4]1)[OH:2].[CH3:14][N:15]=[C:16]=[O:17]>>[CH3:14][NH:15][C:16]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([CH3:12])([CH3:13])[S:4]1)=[O:17]
Reactant: CN=C=O
Reactant: CCCCC1=NC(=NO)SC1(C)C
Product: CCCCC1=NC(=NOC(=O)NC)SC1(C)C

Procedure:
2-oxo-4-butyl-5,5-dimethyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4-butyl-5,5-dimethyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 128°-130° C. The 2-oxo-4-butyl-5,5-dimethyl-3-thiazoline-oxime starting material melts at 117°-119° C.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[C:22]([F:25])([F:24])[F:23]>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=3[C:22]([F:23])([F:25])[F:24])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCN(CC2CCNCC2)C1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Product: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)c(C(F)(F)F)c1

Procedure:
Prepared from the product of Example 4 and 4-fluoro-3-trifluoromethyl-benzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Br)ccc1C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A 100 mL round-bottom flask was charged with 4-bromo-2-methoxybenzaldehyde (1.90 g, 8.84 mmol, 1.10 equiv), tert-butyl piperazine-1-carboxylate (1.50 g, 8.05 mmol, 1.00 equiv), and dichloromethane (30 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (5.10 g, 24.0 mmol, 3.00 equiv) was added. The resulting solution was stirred for overnight at room temperature and then diluted with water (30 mL). The resulting mixture was extracted with dichloromethane (2×20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 2.66 g (86% yield) of tert-butyl 4-[(4-bromo-2-methoxyphenyl)methyl]piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 385 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14][N:15]1[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]1=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=1.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14][N:15]1[C:16](=[O:25])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]1=[O:24])=[C:5]2[C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1
Reactant: COc1ccc(-c2c(CN3C(=O)c4ccccc4C3=O)n(C)c(=O)c3ccc(Cl)cc23)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2ccc(O)cc2)c2cc(Cl)ccc2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution of 2-{[6-chloro-4-(4-methoxyphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl}-1H-isoindole-1,3(2H)-dione (synthesized according to the method similar to that in Example 16(7)) (0.92 g, 2 mmol) in dichloromethane (10 ml) was added boron tribromide, (76 ml, 36 mmol) at 0° C. and the mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran-diisopropyl ether to give 2-{[6chloro-4-(4-hydroxyphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl}-1H-isoindole-1,3(2H)-dione (0.83 g, 94.3%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10](Cl)=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1.B1([C:25]2[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=2)OCCCO1>>[NH2:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: NC(=O)c1cnc(N)c2c1[nH]c1cc(Cl)ccc12
Product: NC(=O)c1cnc(N)c2c1[nH]c1cc(-c3cccnc3)ccc12

Procedure:
The title compound was prepared from 1-amino-7-chloro-5H-pyrido[4,3-b]indole-4-carboxamide (Example 27, step 5) and pyridine-3-boronic acid 1,3-propanediol cyclic ester using conditions described in example 2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15](Cl)=[O:16])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:18]1([NH2:27])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=[CH:19]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[N:18]1([NH:27][C:15]([C:11]2[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:16])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=[CH:19]1
Reactant: Nn1ccc2cccnc21
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid chloride (1 mmol) in EtOAc (10 mL) is added to a stirred solution of pyrrolo[2,3-b]pyridin-1-ylamine (1 mmol) and K2CO3 (1 mmol) in EtOAc (20 mL) and H2O (20 mL) at rt, then stirred at rt overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration. The solid is purified by silica gel chromatography eluting with 20-80% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid pyrrolo[2,3-b]pyridin-1-ylamide (162 mg, 47%) as a solid. MS: 348 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.78 (s, 3H), 6.59 (m, H) 7.09-7.58 (m, 4H), 7.96 (m, H), 8.22 (m, H), 8.31 (d, 2H), 9.14 (s, 2H). IC50=12 nM.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([Cl:9])[C:3]=1[Cl:10].[CH3:11][O-:12].[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([O:12][CH3:11])[CH:5]=[C:4]([Cl:9])[C:3]=1[Cl:10]
Reactant: Fc1cc(Cl)c(Cl)c(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(Cl)c(Br)c1

Procedure:
1-Bromo-2,3-dichloro-5-fluorobenzene (5.1453 g, 21.10 mmol) was dissolved in THF (25 mL) at room temperature and cooled to 0° C. Then, 5.1 g of sodium hydride (60%, 128 mmol) was added and 2.0 mL of methanol was added slowly. Additional THF (5 mL) was added. The mixture was stirred at room temperature for 10 minutes, then heated at 75° C. for four hours and cooled to room temperature. The mixture was poured into ice with some aq. sat. NH4Cl solution and extracted with EtOAc (3×100 mL). The organic solution was washed with brine, dried over Na2SO4, concentrated to dryness. The residue was purified with flash column chromatography on silica gel using hexane as solvent to afford the product (4.6727 g) as a white solid in 87% yield. 1H-NMR (CDCl3): δ 7.109 (d, J=3.0 Hz, 1H), 6.988 (d, J=3.0 Hz, 1H), 3.786 (s, 3H). The product was also synthesized from 1-bromo-2,3-dichloro-5-fluorobenzene and sodium methoxide in THF. The final product was purified by recrystallization from hexane.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)(O)[CH2:8][C:9]#[N:10])=[CH:3][CH:2]=1.CO>FC(F)(F)C(O)=O>[C:15]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:13][C:12]([C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:2][CH:3]=2)=[CH:8][C:9]#[N:10])=[CH:17][CH:16]=1
Reactant: N#CCC(O)(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N#CC=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 65 °C
Yield: 94.8 %

Procedure:
The crude carbinol 3,3-bis[(1,1-biphenyl)-4-yl]-3-hydroxypropanenitrile (13.5 g; 0.036 mol) was dissolved in trifluoroacetic acid (30 mL) and the solution was heated at 65° C. for 10 min. After the solvent was removed in vacuo, the residue was triturated with water and the resulting solids were dissolved in dichloromethane. The dried (MgSO4) solution was evaporated to provide 12.2 g of 3,3-bis[(1,1'-biphenyl)-4-yl]-2-propenenitrile as an oil that was contaminated with a small amount of starting ketone.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.N1C=CC=CC=1.O.[NH2:23][NH2:24]>O>[Br:1][C:2]1[C:3]([NH:23][NH2:24])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: NN
Reactant: Clc1ccc(-c2ccnc(Cl)c2Br)cc1
Solvent: c1ccncc1
Solvent: O
Product: NNc1nccc(-c2ccc(Cl)cc2)c1Br
Temperature: 120 °C

Procedure:
A mixture of 3-bromo-2-chloro-4-(4-chlorophenyl)pyridine (10 g, 33 mmol), pyridine (50 mL) and hydrazine monohydrate (4.8 g, 96 mmol) was heated to 120° C. for 16 h. After cooling to room temperature, water (300 mL) was added, which caused solid desired product to precipitate. This was filtered, washed with water (2×50 mL), and dried to obtain the title compound as a pale yellow solid (6 g), which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:19][C:20]([CH3:22])=[O:21]>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:19][C:20](=[O:21])[CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 50 g (0.2 mol) of 4-benzyloxybenzaldehyde in 500 mL of acetone was diluted with 500 mL of water. To the cloudy emulsion which formed was added 20 mL of 1N sodium hydroxide and the mixture stirred at room temperature for 20 hours. The solids which precipitated were recovered by filtration. Recrystallization from methanol gave the above named product, as a tan flaky solid, in a yield of 51 g (87 percent of theoretical). The product melted at 102°-109° C.; 1H NMR (CDCl3) δ2.29 (s, 3H, CH3 --), 5.04 (s, 2H, --CH2 --), 6.48-7.52 (m, 11H, ArH's and --CH=CH--).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:12]2=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].[Li+].[OH-].O.Cl>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:12]2=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(F)cc3F)c(-c3ccc(F)cc3F)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCN1CCCc2nc(-c3ccc(F)cc3F)c(-c3ccc(F)cc3F)nc21
Reaction time: 72 h

Procedure:
Ethyl 7-(2,3-bis(2,4-difluorophenyl)-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) (480 mg, 0.931 mmol) in THF (2.5 ml) was treated with LiOH (178 mg, 7.45 mmol) followed by water (2.5 ml) and stirred vigorously for 3 days. The mixture was acidified to pH4/5 using 5M HCl and extracted with DCM. The combined organic extracts were dried (sodium sulphate), filtered and concentrated under reduced pressure. Purification was carried out on silica eluting with 20-25% TBME in DCM. The resulting product was further purified under the following conditions to afford the titled compound;
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH:26]([O:29][CH2:30]Cl)([CH3:28])[CH3:27]>C1COCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:30][O:29][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(C)OCCl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COC(C)C
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4.6 mL diisopropylamine in 40 mL of dry THF at −20° C. was added dropwise first 12.0 ml of 2.5 M butyllithium and then 8.1 ml of tributyltinhydride. After 10 min this solution was cooled to −78° C., and 3.25 g of chloromethyl isopropyl ether (Molina et al, 1982 Synthesis, 944) was added dropwise. After 10 min the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 1.5 h. The mixture was poured onto water and extracted with hexanes and the extracts were dried over sodium sulfate and evaporated. The crude product was distilled (0.2 mm, 110-130° C.) to afford 7.8 g of tributyl (isopropoxymethyl)tin as a colorless liquid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]2)=[CH:35][CH:34]=1.C[Si](Cl)(C)C>C(O)CCC.O1CCOCC1>[C:45]([N:42]1[CH2:41][CH2:40][N:39]([C:36]2[CH:37]=[CH:38][C:33]([NH:32][C:2]3[N:3]=[C:4]([NH:21][C:22]4[CH:23]=[C:24]([S:28]([NH2:31])(=[O:29])=[O:30])[CH:25]=[CH:26][CH:27]=4)[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=3)=[CH:34][CH:35]=2)[CH2:44][CH2:43]1)(=[O:47])[CH3:46]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(S(N)(=O)=O)c4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4cccc(S(N)(=O)=O)c4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 110 °C
Reaction time: 72 h
Yield: 28.8 %

Procedure:
A mixture of 2-chloro-N-(3-aminosulfonyl-phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.210 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (92 mg, 0.42 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (2 mL) and dioxane (2 mL) was heated at 110° C. for 72 h. More 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (92 mg, 0.42 mmol) was added. The mixture was stirred at 110° C. for another 72 h. It was then purified by HPLC to give 3-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide (40 mg)
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:24])[CH:10]=[C:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.CO.[Li+].[OH-].Cl>O>[CH:13]1[C:12]2[C:11](=[CH:10][C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2])=[O:24])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.8 %

Procedure:
5-(2-(9H-fluoren-9-ylidene)acetamido)pentanoic acid methyl ester (335 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture was neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (279 mg, 87% yield) as a white solid. LC-MS (m/z) 322 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].C[N+]1C=CN([C:26]([N:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=3)[CH2:31][CH2:30][CH2:29]2)=[O:27])C=1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:26]([N:28]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([C:38]([F:40])([F:39])[F:41])[CH:36]=4)[CH2:31][CH2:30][CH2:29]3)=[O:27])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccc(C(F)(F)F)cc32)c1
Agent: [I-]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCCc2ccc(C(F)(F)F)cc21

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was subjected to preparative HPLC (66%). HPLC-MS m/z: 483.1 (M+1), Rt: 5.87 min.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16]#[N:17])=[N:13][N:12]=2)[CH2:7][CH2:6]1.Cl.[NH2:24][OH:25]>>[Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[S:15][C:14]([C:16](=[N:24][OH:25])[NH2:17])=[N:13][N:12]=2)[CH2:9][CH2:10]1
Reactant: NO
Reactant: N#Cc1nnc(N2CCC(Oc3cc(F)ccc3Br)CC2)s1
Agent: Cl
Product: NC(=NO)c1nnc(N2CCC(Oc3cc(F)ccc3Br)CC2)s1

Procedure:
The title compound was prepared in a similar manner as described for Example 7, step 2 from 5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,3,4-thiadiazole-2-carbonitrile and hydroxylamine hydrochloride.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:14]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>C1(C)C(C)=CC=CC=1>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][Br:1])=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[O:23])=[CH:25][CH:26]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: NS(=O)(=O)c1ccc(CCBr)cc1
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1ccc(C(=O)NS(=O)(=O)c2ccc(CCBr)cc2)cc1

Procedure:
A mixture of 26.41 g (0.10 mol) of 4-(2-bromoethyl)benzenesulfonamide, 19.67 g (0.10 mol) of 4-t-butylbenzoyl chloride and 160 ml of xylene was heated at reflux for 20 hrs. The hot solution was cooled and the solid which crystallized was collected, recrystallized from isopropanol collected, washed with ligroine and dried.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][C:10]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH:22]([CH2:27][CH2:28][CH3:29])[CH2:21][C:20]=3[NH:19][C:18]([CH3:30])=[C:17]2[C:31]#[N:32])=[CH:9][C:8]=1[Br:33].C(N(CC)CC)C.[C:41](Cl)(=[O:45])[CH:42]([CH3:44])[CH3:43]>ClCCl>[Br:33][C:8]1[CH:9]=[C:10]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH:22]([CH2:27][CH2:28][CH3:29])[CH2:21][C:20]=3[NH:19][C:18]([CH3:30])=[C:17]2[C:31]#[N:32])[CH:11]=[C:12]([O:13][CH2:14][CH3:15])[C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:41](=[O:45])[CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)C(=O)Cl
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCCCCN)c(OCC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCCCCNC(=O)C(C)C)c(OCC)c1
Reaction time: 17 h

Procedure:
A mixture of the product of step b (117 mg), triethylamine (81 μl) and isobutyrylchloride (24 μl) in dichloromethane (3 ml) was stirred for 17 h. The mixture was diluted with dichloromethane and washed with 0.5N aqueous HCl. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/EtOAc (from 1/0 to 0/1) as eluent. Yield: 69 mg. MS-ESI: [M+H]+=610.4/612.4; HPLC: Rt=19.45 min. (method 1). Diast. ratio: 5:1