Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9]([Cl:17])=[CH:10][C:11]([Cl:16])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Cl:16][C:11]1[CH:10]=[C:9]([Cl:17])[C:8]2[C:13](=[C:14]([CH3:15])[N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)([C:3]#[N:4])[CH3:18])[N:7]=2)[CH:12]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: Cc1c2cc(Cl)cc(Cl)c2nn1CC(C)(N)C#N
Product: Cc1c2cc(Cl)cc(Cl)c2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(5,7-dichloro-3-methyl-2H-indazol-2-yl)propionitrile (40 mg, described in Example 103) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (64 mg, 92%). MS (ES): M/Z [M+H]=487. 1H NMR: (400 MHz, DMSO-d6): 1.83 (s, 3H), 2.73 (s, 3H), 5.00 (d, 1H), 5.06 (d, 1H), 7.45 (dd, J=1.6 Hz, 1H), 7.87 (d, J=8.2 Hz, 2H), 7.91 (dd, J=1.6 Hz, 1H), 8.00 (d, J=8.4 Hz, 2H) and 9.16 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCSc1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCSc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 117.97 g (0.53 mole) of 2-[(3,4-dichlorophenyl)thio]ethanol (prepared by reacting 3,4-dichlorothiophenol and 2-chloroethanol) and 53.5 g (0.53 mole) of triethylamine in 500 ml of benzene was added dropwise a benzene solution of 60.9 g (0.53 mole) of methanesulfonyl chloride over a one hour period with cooling in an ice bath. The reaction mixture was stirred at room temperature overnight and filtered. Solvent was removed from the filtrate in a rotary evaporator to give an oil which crystallized. A portion was recrystallized from isopropyl ether to give white crystalline solid, m.p. 53°-55° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])=[CH:22][CH:21]=1>C(#N)C>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])=[CH:24][CH:25]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Reactant: CC(C)(C#N)c1ccc(N)cc1
Solvent: CC#N
Product: CC(C)(C#N)c1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Yield: 88.2 %

Procedure:
A mixture of 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (40 mg, 0.14 mmol), 2-(4-aminophenyl)-2-methylpropanenitrile (100 mg, 0.63 mmol) (prepared according to the reference: Axton, C. A. et al, J. Chem. Soc. Perkin Trans. 1, 1992, 2203.), and acetonitrile (0.5 mL) was heated with microwave at 180° C. for 60 min. The solvent was removed in vacuo and the residue was purified by chromatography to give a light yellow solid (50 mg, 58%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[NH:5].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O>C(Cl)(Cl)Cl>[C:15]1([C:13]2[N:5]=[C:4]([C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[CH3:1])[NH:6][CH:12]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccccc1C(=N)N
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1-c1nc(-c2ccccc2)c[nH]1

Procedure:
To a solution of 6.1 g (0.0455 mole) of 2-methylbenzamidine in 25 ml of chloroform 3.6 g (0.018 mole) of α-bromoacetophenone were added and the resulting mixture was refluxed for four hours. After cooling and adding 50 ml of chloroform the reaction mixture was first washed with diluted ammonia and then with water and subsequently dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was chromatographed through silica gel by eluting with mixtures of CHCl3 /CH3COOC2H5 containing up to a maximum of 4% (in volume) of CH3COOC2H5. The fractions eluted with CH3Cl3 /CH3COOC2H5 =9/1 (v/v) were collected, the solvent was evaporated off and the residue was crystallized from diethylether/light petroleum. Yield 1.95 g (46.3%) of the title compound M.p. 145°-46° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CC1C=CC(S(O[CH2:16][CH2:17][C:18]#[C:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])(=O)=O)=CC=1>CN(C=O)C>[N:1]([CH2:16][CH2:17][C:18]#[C:19][Si:20]([CH2:25][CH3:26])([CH2:21][CH3:22])[CH2:23][CH3:24])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[Si](C#CCCOS(=O)(=O)c1ccc(C)cc1)(CC)CC
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[Si](C#CCCN=[N+]=[N-])(CC)CC
Temperature: 60 °C
Reaction time: 3 h
Yield: 103.6 %

Procedure:
Sodium azide (1.80 g; 27.65 mmol) was added to a solution of 4-(triethylsilyl)but-3-ynyl 4-methylbenzenesulfonate (3.12 g; 9.22 mmol) in DMF (15 mL) and stirred at 60° C. for 3 hours. After cooling, the volatiles were removed under reduced pressure and the residue was partitioned between saturated ammonium chloride and ethyl acetate. The organic layer was dried and concentrated under reduced pressure to afford 2.0 g (quantitative yield) of (4-azidobut-1-ynyl)triethylsilane as a colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:13][CH3:12]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: O
Product: CNc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
2,4-Difluoro-1-nitrobenzene (25.0 g, 157 mmol) was stirred and thereto was added dropwise 40% aqueous methylamine solution (38.4 g) at 0° C. over not less than 15 min. After the completion of the dropwise addition, the mixture was continuously stirred at the same temperature for 1.5 hr. Water (500 mL) was added to the reaction mixture, and the resulting solid was collected by filtration to give the title compound (26.4 g, 99%) as yellow crystals.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17]N)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I.CS[C:22]1[NH:23][CH2:24][C:25](=[O:27])[N:26]=1.C(N(CC)CC)C>C(O)C>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][C:22]3[NH:23][CH2:24][C:25](=[O:27])[N:26]=3)[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CSC1=NC(=O)CN1
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Agent: I
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1CNC(CCCOc2cc(CN3CCCCC3)ccn2)=N1

Procedure:
3-(4-Piperidinomethylpyrid-2-yloxy)propylamine (2.57 g), 2-methylthio-imidazolin-4-one hydroiodide (2.60 g) and triethylamine (2.18 g) were refluxed in ethanol (20 ml) for 5 hours. The mixture was refluxed for a further hour in the presence of additional 2-methylthio-imidazolin-4-one hydroiodide (2.60 g) to ensure completion.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])[CH3:3].[OH-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:14][C:13]([C:7]1[CH:8]=[C:9]([S:11][CH3:12])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[O:17][CH3:20])([CH3:16])[CH3:15]
Reactant: CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(C)(C)C)cc(SC)cc1C(C)(C)C

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-(methylthio)phenol (1.16 g, 4.6 mmole) in dimethylformamide (15 ml) was added sodium hydroxide (0.37 g, 9.2 mmole). After the solution was warmed for one hour, methyl iodide (0.72 g, 5.1 mmole) was added, and the mixture was warmed for an additional three hours. The reaction mixture was poured into water (150 ml) and extracted with diethyl ether (180 ml in three positions). The ether extract was washed with saturated aqueous sodium carbonate, dried over sodium sulfate, filtered, and concentrated in vacuo to an oil. Upon standing the oil crystallized. Recrystallization from hexane gave the title compound, m.p. 50°-52°.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:11]([C:12]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[N:20]=2)[N:10]=[C:9]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[S:8]1)=[N+:2]=[N-:3].C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:11]([C:12]2[S:13][C:14]3[CH2:15][N:16]([CH3:37])[CH2:17][CH2:18][C:19]=3[N:20]=2)[N:10]=[C:9]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[S:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nc2c(s1)CNCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN=[N+]=[N-])c3ccccc3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (0.050 g, 0.100 mmol) in 1 mL DCE was added formaldehyde (0.033 g, 37 wt % in water, 0.401 mmol), followed by sodium triacetoxy borohydride (0.023 g, 0.110 mmol). The resulting suspension was stirred vigorously at room temperature overnight, then treated with saturated Na2CO3 solution (10 mL) and stirred for 10 minutes. The mixture was extracted with EtOAc (3×10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (0-3% MeOH/DCM) to afford the desired product as a yellow foam, 0.046 g, 89%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16]1.CO>C(O)(=O)C>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:24]([C:17]4[C:18]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[NH:15][CH:16]=4)=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)C(=O)Nc2cc3[nH]c(-c4c[nH]c5ccccc45)nc3cc21

Procedure:
3.1 g. 5,6-Diamino-3,3-dimethylindolin-2-one and 2.5 g. indole-3-aldehyde are stirred for 4 days at ambient temperature in 150 ml. methanol and 4 ml. glacial acetic acid. The solvent is then removed in a vacuum and the residue is purified by column chromatography on silica gel. The appropriate fractions are combined, the solvent is removed in a vacuum, the residue (3.7 g. of a yellow oil) is dissolved in methanol, dichloromethane added thereto until turbidity commences and then left to crystallise. There are obtained 3.1 g. of the title compound; m.p. 243°-245° C.
Reaction SMILES: [N:1]1[C:14]2[N:8]3[C:9](=[O:13])[NH:10][CH:11]=[CH:12][C:7]3=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C=O)C>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:10]2[CH:11]=[CH:12][C:7]3=[CH:6][C:5]4[CH:4]=[CH:3][CH:2]=[N:1][C:14]=4[N:8]3[C:9]2=[O:13])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1[nH]ccc2cc3cccnc3n12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc4cccnc4n3c2=O)cc1
Reaction time: 0.17 h
Yield: 39.3 %

Procedure:
To a cooled (0° C.) solution of 11a (500 mg, 2.7 mmol) in DMF (30 ml), NaH (130 mg, 3.2 mmol) was added. The mixture was stirred for 10 min. and a solution of p-toluensulphonyl chloride (570 mg, 3.0 mmol) in DMF (10 ml) was added. The mixture was stirred at room temperature for 1 h. and quenched with water (1 ml). The solvent was evaporated and the residue dissolved in AcOEt. The organic solution was washed with aq. Na2CO3, evaporated and purified by flash column chromatography. Elution with hexane/CH2Cl2 (1/1) gave 8,9-dihydro-8-(4methylphenylsulfonyl)pyrido[3′,2′:4,5]-pyrrolo[1,2-c]pyrimidin-9-one (360 mg, 40%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:12].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([OH:12])=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: O=Cc1c(Cl)ncnc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1c(Cl)ncnc1Cl
Temperature: 25 °C

Procedure:
A solution of 4,6-dichloro-5-pyrimidinecarbaldehyde (15.0 g, 84.8 mmol) in DMF (360 mL) was charged with potassium monopersulfate (38.9 g, 254 mmol) and stirred over night at rt. The reaction mixture was filtered through a pad of celite and partitioned between EtOAc and water and separated. The aqueous was extracted with EtOAc (3×) and the combined organic fractions were washed with water (2×), brine, and dried over sodium sulfate, filtered, and concentrated to afford the title compound. 1H NMR (DMSO-d6, 400 MHz): δ=9.02 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH2:11][N:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=3)[C:13]2=[O:26])=[CH:5][CH:4]=1.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10][CH2:11][N:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=3)[C:13]2=[O:26])=[CH:30][CH:29]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc2ccn(CCNc3ccc(OC)cc3)c(=O)c2c1
Product: COC(=O)c1ccc2ccn(CCN(Cc3ccc(Cl)cc3)c3ccc(OC)cc3)c(=O)c2c1

Procedure:
The title compound was prepared from methyl 2-{2-[(4-methoxyphenyl)amino]ethyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (60 mg, 0.17 mmol) and 4-chlorobenzaldehyde (34 mg, 0.24 mmol) following the procedure outlined in Example 54, step 3 (50 mg, 62%). LC-MS: (FA) ES+ 477.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:23])[N:19]([CH2:21][CH3:22])[CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:25])[CH:3]=1.[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>>[CH3:36][O:35][C:33]([C:32]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[C:9]([C:15]3[CH:16]=[CH:17][C:18](=[O:23])[N:19]([CH2:21][CH3:22])[CH:20]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:25])[CH:3]=2)=[CH:28][C:27]=1[F:26])=[O:34]
Reactant: CCn1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccc1=O
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Product: CCn1cc(C(O)(C(C)c2ccc(-c3ccc(C(=O)OC)c(F)c3)cc2Cl)C(F)(F)F)ccc1=O

Procedure:
In analogy to Example 150, step 2, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-ethyl-1H-pyridin-2-one (Example 183, step 2) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid to give the title compound as a colorless foam. MS (m/e)=512.3 [M+H+].
Reaction SMILES: [CH2:1]([CH:8]([CH2:11][OH:12])[CH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[O:10][CH2:9][CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:11][O:12]2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCC1COC(c2ccc(Br)cc2)OC1

Procedure:
Quantities: compound from Example 8 (44 g, 0.25 mol), 4-bromobenzaldehyde (42.8 g, 0.23 mol) and 4-toluenesulphonic acid (150 mg). The experimental procedure was as described in Example 11.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:32])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28](O)(=[O:30])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O=S(Cl)[Cl:35].CN(C=O)C>O=P(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:32])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([Cl:35])(=[O:30])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)Cl)cc1
Temperature: 75 °C

Procedure:
5′-[(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2′-methylbiphenyl-4-sulfonic acid (1.9 g, 4.3 mmol) was dissolved in POCl3 (30 mL) followed by the addition of SOCl2 (3 mL) and DMF (100 μl). The reaction mixture was heated at 70-80° C. for 15 min. The reagents were evaporated and re-evaporated with chloroform-toluene. The residual brown oil was diluted with chloroform (22 mL) and immediately used for sulfonylation. ESI-MS m/z calc. 469.0, found 470.1 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].[CH3:21][Si:22](Cl)([CH2:24][CH2:25][Si:26](Cl)([CH3:28])[CH3:27])[CH3:23]>O1CCCC1>[F:13][C:14]1[CH:15]=[C:16]([N:17]2[Si:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][Si:22]2([CH3:23])[CH3:21])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(F)c1
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of freshly distilled diisopropylamine (22.9 mL) in dry tetrahydrofuran (175 mL) at −78° C. under N2 is treated with n-butyllithium (1.6M in hexanes, 109 mL) dropwise over 15 minutes, and the resulting mixture is stirred at −78° C. for 45 minutes and is then added over ten minutes via cannula to a solution of 3-fluoroaniline (8.00 mL) in dry tetrahydrofuran (166 mL) at −78° C. under N2. The resulting reaction mixture is stirred at −78° C. for 50 minutes and is then treated with a solution of 1,1,4,4-tetramethyl-1,4-dichlorodisilethylene (18.3 g) in dry tetrahydrofuran (85 mL). The mixture is allowed to slowly warm to ambient temperature over four hours with stirring and is then washed with water (2×200 mL) and saline (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, NMR (CDCl3, 400 MHz) 7.12, 6.65, 6.58, 0.86, 0.24δ.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]1[C:27]([N:28]=[C:29]=[S:30])=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:29]2[S:30][C:18]3[C:27]([N:28]=2)=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=3)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)c(N=C=S)c1
Reactant: Nc1ncc(Br)cc1OCc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2sc(Nc3ncc(Br)cc3OCc3ccccc3)nc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
3-(Benzyloxy)-5-bromopyridin-2-amine (1.50 g, 5.37 mmol) was added to a mixture of methyl 6-chloro-5-isothiocyanatonicotinate (1.23 g, 5.37 mmol) in DMF (4 mL). The reaction mixture was stirred at 80° C. for an hour, then at 110° C. for 2 hours. The reaction mixture was cooled, partitioned between dichloromethane (200 mL) and water (200 mL) and 2N NaOH (15 mL). The organic layer was washed with water and brine, dried, and concentrated. The residue was dissolved in warm dichloromethane (70 mL), and to this was added warm hexanes (40° C.) (250 mL). The solution was cooled to ambient temperature and the resulting solids were collected by filtration to afford methyl 2-(3-(benzyloxy)-5-bromopyridin-2-ylamino)thiazolo[5,4-b]pyridine-6-carboxylate (1.77 g, 69.9% yield) as a white powder. 1H NMR (CDCl3) δ 3.98 (s, 3H), 5.15 (s, 2H), 7.35 (s, 1H), 7.46 (m, 5H), 8.10 (s, 1H), 8.42 (s, 1H), 8.76 (bs, 1H), 9.02 (s, 1H).
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]([O:11][NH2:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:13]=O>O.C1(C)C=CC=CC=1>[CH2:4]([O:11][N:12]=[CH2:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=O
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A NaOH (1.25 g, 31.32 mmol) solution in water (6 mL) was added to the mixture of O-benzyl-hydroxylamine hydrochloride (5.00 g, 31.32 mmol) and formaldehyde (˜37 wt. % in H2O) (2.3 mL, 31.32 mmol) in toluene (40 mL). The reaction mixture was stirred at room temperature for 1 h. After this time, the organic phase was separated and the water phase was extracted with dichloromethane (3×30 mL). The combined organic phases were dried over Na2SO4, and concentrated in vacuo to yield formaldehyde O-benzyl-oxime (LI, 4.15 g, 98%). 400 MHz 1H NMR (CDCl3, ppm) 7.40-7.29 (5H, m), 7.09 (1H, d, J=8.2 Hz), 6.47 (1H, d, J=8.2 Hz), 5.14 (2H, s).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(#N)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCNCC4)n3)cc2)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCN(S(C)(=O)=O)CC4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
To a solution of 2-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(piperidin-4-ylmethylamino)pyrimidine-5-carboxamide (22 mg, 0.049 mmol) and triethylamine (0.040 mL, 0.29 mmol) in acetonitrile (2 mL) at room temperature, methanesulfonyl chloride (0.020 mL, 0.26 mmol) was added. The solution was stirred at room temperature for 1 h. The mixture was then purified by HPLC to give the titled compound (14 mg). MS 531.36 (M+H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:23])=[C:18]([CH:22]=1)[C:19](O)=[O:20].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:23])=[C:18]([CH:22]=1)[C:19]([N:3]([O:4][CH3:5])[CH3:2])=[O:20]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Br)ccc1Cl
Reaction time: 0.17 h
Yield: 76.9 %

Procedure:
N-methyl-N-methoxylamine hydrochloride (3.41 g, 35 mmol) was dissolved in 140 mL methylene chloride. Triethylamine (14.6 mL, 105 mmol) was added and the reaction mixture was stirred for 10 minutes. Then the reaction mixture was stirred for 16 hours after 5-bromo-2-chloro-benzoic acid 6a (8.24 g, 35 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (10.69 g, 42 mmol) were added in turn. Thereafter, the reaction mixture was extracted with ethyl acetate (80 mL×3) after 120 mL water were added. The organic extract was washed with saturated sodium chloride solution (60 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound 5-bromo-2-chloro-N-methoxy-N-methyl-benzamide 6b (7.50 g, pale yellow solid), yield: 76.9%. MS m/z (ESI): 280.0 [M+1]; 1H NMR (400 MHz, CDCl3): δ 7.46-7.44 (m, 2H), 7.29-7.26 (m, 1H), 3.49 (s, 3H), 3.37 (s, 3H).