Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[O:26])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([C:35]#[N:36])(C)C.Cl.C(OCC)(=O)C>C(#N)C.[I-].[Zn+2].[I-]>[OH:26][CH:25]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:14]1=[N:15][O:16][C:12]([C:9]3[C:8]([C:27]([F:28])([F:29])[F:30])=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:11][N:10]=3)=[C:13]1[CH2:24][CH2:23]2)[C:35]#[N:36]
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: C[Si](C)(C)C#N
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#CC(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 100 %

Procedure:
To 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 88A, 1 g, 2.4 mmol) in acetonitrile (75 mL) was added trimethylsilyl cyanide (0.49 mL, 3.7 mmol) and zinc iodide (0.79 g, 2.4 mmol). The reaction mixture was stirred for 70 min. at room temperature. After being cooled in ice-water bath, the mixture was acidified by addition of aqueous hydrochloric acid (1N, 4.4 mL, 4.4 mmol). Ethyl acetate (100 mL) was added and the layers were separated. The organic phase was washed with saturated sodium thiosulfate solution (5 mL×2). The organic phase was then dried, filtered, and concentrated to provide the product (±)-2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetonitrile (1.1 g, 2.4 mmol, 99% yield); LC/MS M+1=438.00; 1H NMR (400 MHz, CDCl3) δ ppm 8.09 (1H, d, J=7.92 Hz), 7.76 (2H, d, J=7.26 Hz), 7.50-7.68 (5H, m), 5.62 (1H, s), 3.11 (4H, s).
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.[CH2:6]([O:8][C:9](=[O:19])[CH2:10][CH:11]=[CH:12][CH2:13][C:14](OCC)=[O:15])[CH3:7]>>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[CH2:13][CH2:12][CH:11]2[CH2:10][C:9]([O:8][CH2:6][CH3:7])=[O:19])[CH2:3][CH2:2]1
Reactant: NCC1CC1
Reactant: CCOC(=O)CC=CCC(=O)OCC
Product: CCOC(=O)CC1CCC(=O)N1CC1CC1
Temperature: 165 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
78 g of cyclopropylmethylamine (1.1 mole) and 220 g of 3-hexenedioic acid diethyl ester are introduced into a liter autoclave. The mixture is heated to 165° C. and then kept at that temperature for 8 hours. After cooling, the product is distilled under vacuum, first eliminating the alcohol, then obtaining 155 g of a compound which distils at 157°-160° C. under 3 mm of Hg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[NH:5][CH:6]=[C:7]1[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]1=[O:16].[N:22]1([CH2:27][CH2:28][CH2:29]Cl)[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[N:22]1([CH2:27][CH2:28][CH2:29][O:1][C:2]2[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[NH:5][CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:14])([CH3:15])[O:9][C:8]2=[O:16])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1O
Reactant: ClCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OCCCN1CCCC1
Temperature: 80 °C
Yield: 37 %

Procedure:
A mixture of 5-((3-hydroxy-4-methoxyanilino)methylene)-2,2-dimethyl-1,3dioxane-4,6-dione (10 g, 34.1 mmol), (prepared as described for the starting material in Example 3), 3-(pyrrolidin-1-yl)propyl chloride (7.55 g, 51.1 mmol), (J. Am. Chem. Soc. 1955, 77, 2272), potassium carbonate (7.06 g, 51.1 mmol) and potassium iodide (600 mg, 3.41 mmol) in DMF (100 ml) was heated at 80° C. for 2 hours. The mixture was poured into water (800 ml) and the precipitate was collected by filtration. The solid was dissolved in methylene chloride and the organic solution was washed with brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was dissolved in ether and the insoluble materials were removed by filtration. The volatiles were removed by evaporation and the residue was precipitated by trituration with petroleum ether, collected by filtration and dried under vacuum to give 5-((3-(3-pyrrolidin-1-ylpropoxy)-4-methoxyanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (5.1 g, 37%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([CH3:31])=[C:22]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=4)[N:17]=3)[N:14]=2)=[C:5]([C:32]([F:35])([F:34])[F:33])[CH:4]=1)#[N:2].Cl.[NH2:37][OH:38].CCN(CC)CC>C(O)C>[OH:38][N:37]=[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([CH3:31])=[C:22]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=4)[N:17]=3)[N:14]=2)=[C:5]([C:32]([F:33])([F:35])[F:34])[CH:4]=1)[NH2:2]
Reactant: NO
Reactant: Cc1ccc(-c2cn3nc(-c4ccc(C#N)cc4C(F)(F)F)ccc3n2)cc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cn3nc(-c4ccc(C(N)=NO)cc4C(F)(F)F)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A 500-mL flask is charged with N-(5-(6-(4-cyano-2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)-2-methylphenyl)pivalamide (7.496 g, 0.0157 mol), hydroxylamine hydrochloride (6.55 g, 0.0942 mol), Et3N (15.32 mL, 0.1099 mol), ethanol (82.5 mL) and the resulting mixture is stirred for 2 hours at 80° C. The mixture is concentrated onto celite and purified by silica gel chromatography (eluted by 0 to 100% of 10:1 EtOAc:MeOH in CH2Cl2). The isolated solid material (over 20 g) contains triethylamine and hydroxylamine salts, and the salts stay even after attempted recrystallization with isopropanol. This solid product is then added to a stirred mixture of saturated aqueous NaHCO3 and EtOAc. Solid suspension is collected by filtration. The liquid portion is back extracted with EtOAc and the organic layers are combined, dried with Na2SO4, concentrated to afford additional solid product. The combined solid product is dried on a lyophilizer overnight, recrystallized from hot Isopropanol to afford the desired title product (6.56 g). LCMS (m/z)=511.6 [M+H]+, tR=2.49 min.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH3:19][O:20][C:21]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[S:31][C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:29][C:28]=12)=[O:22]>O1CCCC1>[CH3:19][O:20][C:21]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[S:31][C:30]([N:32]3[CH2:37][CH2:36][N:35]([C:7](=[O:9])[C:6]4[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=4[O:4][CH:1]([CH3:2])[CH3:3])[CH2:34][CH2:33]3)=[N:29][C:28]=12)=[O:22]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: COC(=O)c1cccc2sc(N3CCNCC3)nc12
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1cccc2sc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC(C)C)CC3)nc12

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 2-Piperazin-1-yl-benzothiazole-4-carboxylic acid methyl ester hydrochloride in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate), and the residue was then triturated in ether to yield the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]([O-:12])=[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:3]=1.[Br:25]N1C(=O)CCC1=O>CO.C(Cl)(Cl)Cl>[Br:25][C:3]1[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[N+:5]([O-:12])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: [O-][n+]1c(CCCCCCCCCCCO)cc(O)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CO
Product: [O-][n+]1c(CCCCCCCCCCCO)c(Br)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
In this example, 1 m mole of 4-hydroxy-2-(11-hydroxyundecyl) quinoline-N-oxide is dissolved in a liquid mixture of methanol-chloroform (5:1), and 1 m mole of N-bromosuccinimide is added thereto. The mixture is stirred at room temperature for one hour. After the reaction, the solvent is removed therefrom by distillation, and the residue is recrystallized from ethanol, whereby the captioned compound is obtained (yield: 70.5%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reaction time: 15 h

Procedure:
To a solution of 4-bromophenol (5.1 g; 29 mmol) and imidazole (2 g; 29 mmol) in CH2Cl2 (50 ml) at 0° C. is added t-butyldimethylsilyl chloride (4.4 g; 29 mmol) and the reaction is stirred for 15 hours. This is then diluted with CH2Cl2, washed with H2O, ammonium chloride solution, NaHCO3, dried (MgSO4) and concentrated in vacuo to yield 4-bromo-t-butyldimethylsilyloxybenzene as an oil which is used directly in Step B without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([S:32][CH2:33][CH2:34][CH2:35]Cl)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:16])[CH2:35][CH2:34][CH2:33][S:32][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(SCCCCl)cc1OC
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Solvent: c1ccncc1
Product: COc1ccc(SCCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5- tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-methylamine and 3-(3,4-dimethoxyphenylthio)-propylchloride with the addition of pyridine analogously to Example 3.
Reaction SMILES: CC(C)=O.C(=O)=O.[Br:8][C:9]1[N:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH3:17])[CH:10]=1.Cl[CH:19]([F:21])[F:20]>C(O)(C)C.[OH-].[Na+]>[Br:8][C:9]1[N:14]=[C:13]([CH3:15])[C:12]([O:16][CH:19]([F:21])[F:20])=[C:11]([CH3:17])[CH:10]=1
Reactant: FC(F)Cl
Reactant: Cc1cc(Br)nc(C)c1O
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: Cc1cc(Br)nc(C)c1OC(F)F
Temperature: 25 °C
Yield: 60 %

Procedure:
A three-necked round bottom flask (500 mL) equipped with dry ice condenser (−78° C., acetone/dry ice) was charged with a solution of 6-bromo-2,4-dimethyl-3-hydroxypyridine (7.2 g, 35.6 mmol) in i-propanol (100 mL) and aqueous sodium hydroxide solution (20%, 100 mL) was added. The reaction mixture was stirred vigorously at 40° C. for 5 hours while chlorodifluoromethane was bubbled continuously into the solution at a moderate rate. The reaction mixture was then cooled to room temperature and extracted with Et2O (3×100 mL). The combined extracts were washed with water (2×50 mL), dried over magnesium sulfate and concentrated in vacuo. Purification of the crude mixture by flash column chromatography using 5% ethyl acetate in hexane afforded the title compound (5.4 g, 60%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[CH3:28][C:29]1([CH3:44])[N:34]([CH3:35])[CH2:33][CH2:32][N:31]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)[CH2:30]1.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl.CO>[CH3:28][C:29]1([CH3:44])[N:34]([CH3:35])[CH2:33][CH2:32][N:31]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:5])=[N:41][CH:42]=2)[CH2:30]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)C(C)(C)C4)cn3)c3nccnc23)c1F
Reaction time: 0.25 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 5-(3,3,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 107.1), stirring the reaction mixture for 15 min at reflux, pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 563.1 [M+H]+; tR=3.72 min (System 1); TLC: Rf=0.33 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: C[O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12](=O)[CH2:13][C:14](=O)[CH3:15])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:18][NH:19][NH2:20].O>CO>[OH:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[CH:13]=[C:14]([CH3:15])[N:19]([CH3:18])[N:20]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CNN
Reactant: COc1cccc2oc(C(=O)CC(C)=O)cc12
Solvent: CO
Solvent: O
Product: Cc1cc(-c2cc3c(O)cccc3o2)nn1C
Temperature: -40 °C
Yield: 86.5 %

Procedure:
1-(4-Methoxybenzo(b)furan-2-yl)butan-1,3-dione (1.0 g) was dissolved in methanol (30 ml) and methylhydrazine (0.3 g) was added thereto. The mixture was refluxed under heating for 20 min. The reaction solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/acetone). To the obtained oil was added methylene chloride (30 ml), and the mixture was cooled to −40° C., and boron tribromide (1 ml) was added dropwise. After the completion of the reaction, the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and after filtration, the solvent was evaporated under reduced pressure to give 3-(4-hydroxybenzo(b)furan-2-yl)-1,5-dimethylpyrazole (0.85 g) as a brown oil. Using this and (S)-glycidyl nosylate (0.75 g) and in the same manner as in Starting Material Synthesis Example 1, the title compound (0.53 g) was obtained as a brown oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22].Cl.C(N(CC)CC)C>C(#N)C>[CH3:11][O:10][C:8]([C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:26]1[CH2:27][CH2:28][N:23]([C:21](=[O:22])[C:20]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:18]([O:17][CH3:16])[CH:19]=2)[CH2:24][CH2:25]1)=[O:9]
Reactant: COC(=O)c1ccccc1NC(=O)CCl
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccccc1NC(=O)CN1CCN(C(=O)c2ccc(OC)c(OC)c2)CC1

Procedure:
10.06 Grams of methyl o-(α-chloroacetylamino)benzoate, 15.2 g of N-(3,4-dimethoxybenzoyl)piperzine.monohydrochloride and 16 g of triethylamine were suspended in 55 ml of acetonitrile, and the mixture was reacted at 49°-50° C. for 4 hours. After completion of the reaction, the reaction mixture was ice-cooled, and the crystals formed were collected by filtration. Recrystallized from ethanol to obtain 14.68 g of o-methoxycarbonyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide in the form of colorless needle-like crystals. Melting point: 167.5°-169.0° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O1CCCC1>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
Triethylamine (0.94 mL, 6.71 mmol) was added to a stirred reaction mixture of N-tert-butoxycarbonyl piperazine (0.50 g, 2.68 mmol) in tetrahydrofuran (6 mL) at 0° C., then the reaction mixture was stirred at room temperature for 15 minutes. A solution of 4-bromo-benzenesulfonyl chloride (0.686 g, 2.68 mmol) in tetrahydrofuran (4 mL) was added to the reaction mixture and stirring continued for another 2 hours. Tetrahydrofuran was evaporated off under reduced pressure, then the reaction mixture was diluted with ethyl acetate (20 mL). The inorganic materials were filtered off through a celite bed. The filtrate was washed with 2 N aqueous HCl (5 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to yield 1.00 g (92%) of 4-(4-bromo-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester as a white solid, which was used in the next step without further purification. MS cald. for C15H21BrN2O4S [(M+NH4)+] 422, obsd. 422.1.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C-:25]#[N:26].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7]([C:25]#[N:26])=[O:8])=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: Cc1ccc(C(=O)C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
p-Toluoyl cyanide was prepared according to the general procedure reported by Olah et al. [supra]. Under dry conditions, 1.35 mL of p-toluoyl chloride (98%, Aldrich) (10.2 mmol), 26 mL of methylene chloride, freshly distilled from phosphorus pentoxide under nitrogen, and 1.53 mL of trimethylsily cyanide (11.5 mmol) were added to a 100-mL round bottom flask. To this solution 0.25 mL of tin (IV) chloride (2.1 mmol) was added. This mixture was stirred for 2 hr at room temperature. During the 2 hr, the color of the solution changed from pale yellow to dark brown. After 2 hr the reaction mixture was quenched with 75 mL of ice-cold water and then extracted with two 75-mL portions of methylene chloride. The methylene chloride extracts were combined, washed with two 75-mL portions of ice-cold water, dried with MgSO4, and filtered. The methylene chloride was removed by rotary evaporation to yield a dark brown oil which solidified on standing. This crude product was dissolved in hexanes and filtered. The solvent was removed by rotary evaporation to yield 1.266 g (86%) of p-toluoyl cyanide as a yellow solid: IR (CCl4) (partial) 2220, 1685, 1607 cm-1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:6])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26]>ClCCl>[N+:25]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:15]=1[NH:1][CH2:2][C:3]1([OH:6])[CH2:5][CH2:4]1)=[CH:23][CH:22]=[CH:21][CH:20]=2)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCC1(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CC1
Temperature: 25 °C

Procedure:
To a 0° C. mixture of 1-(aminomethyl)cyclopropanol (approximately 36.7 mmol, prepared as described by Lysenko, I. L. and Kulinkovich, O. G. Russ. i J. Org Chem. 2001, 17, 1238-1243) and triethylamine (6.30 mL, 45.4 mmol) in dichloromethane (120 mL) was added a solution of 4-chloro-3-nitroquinoline (7.28 g, 34.9 mmol) in dichloromethane (30 mL). The suspension was stirred at room temperature over the weekend. The dichloromethane was removed under reduced pressure and the residue was suspended in water (150 mL) and stirred at room temperature for 3 hours. A solid was isolated by filtration and dried in a vacuum oven to afford 8.99 g of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclopropanol as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][N:21]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:20][CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(NC4CCNCC4)ncnc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-(piperidin-4-yl)-9H-purin-6-amine (18.4 mg, 0.042 mmol, 1 eq.) in 2 mL of THF was added methanesulfonyl chloride (0.005 mL, 0.063 mmol, 1.5 eq.) and triethylamine (0.02 mL, 0.126 mmol, 3 eq.). The mixture was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 20 mg (91%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-(1-methanesulfonylpiperidin-4-yl)-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.58-1.76 (m, 2 H) 2.21 (d, J=10.64 Hz, 2 H) 2.76 (s, 3 H) 2.90 (t, J=10.93 Hz, 2 H) 3.77 (d, J=12.15 Hz, 2 H) 4.33 (br. s., 1 H) 5.84 (br. s., 1 H) 7.04-7.51 (m, 8 H) 8.36 (s, 1 H), [M−H]− 515.7.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[CH2:44][O:45][CH3:46]>C1COCC1>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:44][O:45][CH3:46])[N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCn1cc2cc(C)c(NC(=O)c3cc(OC)nn3-c3ncccc3Cl)c(C(=O)NC(C)C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropylamide (500 mg, 1.07 mmol) and diisopropylethylamine (225 μL, 1.2 mmol) in THF (10 mL) was treated dropwise with chloro-methoxy-methane (90 μL, 1.2 mmol). The resulting reaction mixture was stirred for 2 hours at ambient temperature. The reaction mixture was concentrated in vacuo. Purification of the residue by flash-chromatography (SiO2, CH2Cl2/acetone 7:3) afforded the title compound as a colorless crystalline solid. M.p. 148° C., LC/MS:512/514 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.Cl.[CH3:14][O:15][C:16]([C:18]1([NH2:27])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17]>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:14][O:15][C:16]([C:18]1([NH:27][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([Br:1])[CH:3]=2)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(Br)c2)Cc2ccccc2C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
3-Bromo-4-methoxybenzoic acid (22.8 g, 98.8 mmol) was dissolved in thionyl chloride (42 ml) and stirred at 60° C. for 30 min. The volatiles were evaporated in vacuo and the residue was stripped with dioxane. The obtained acid chloride was dissolved in DCM (50 ml). 2-Amino-indane-2-carboxylic acid methyl ester hydrochloride (15.0 g, 65.9 mmol) was suspended in DCM (100 ml), EDIA (10.2 g, 79.1 mmol) was added, the mixture was cooled in an ice bath, and the solution of the acid chloride was slowly added. The mixture was stirred overnight at room temperature and evaporated to dryness. The residue was purified by silica gel chromatography (DCM/methanol gradient) and subsequent crystallization from EA to give 21.8 g of the title compound.