Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][C:6]1=[CH2:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.S(=O)(=O)(O)O>ClC1C=CC=CC=1Cl.O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:9](=[O:10])[CH2:8][C:6](=[CH2:7])[C:5]([OH:11])=[O:12])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: C=C1CC(=O)OC1=O
Reactant: Clc1ccc(-c2ccccc2)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: C=C(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 20 °C
Yield: 70 %

Procedure:
193.3 g (1.45 mol) of anhydrous aluminum chloride are introduced in 1100 g of o-dichlorobenzene and the mixture is brought to 45° C. with stirring. A solution of 80.9 g (0.72 mol) of itaconic anhydride and 132 g (0.7 mol) of 4-chlorobiphenyl in 700 g of o-dichlorobenzene at 50° C. is added dropwise in the course of three hours. The reaction mixture is stirred at 25° C. for four hours and then added to an ice-cold mixture of 1000 g of water and 25 g of sulfuric acid (96%). The aqueous phase is separated off. The organic phase is washed three times with a mixture of 1000 g of water and 15 g of sulfuric acid (96%) in each case. After washing three times, it is allowed to cool to approximately 20° C. and the colorless product is then filtered off with suction. This is then washed three times with 150 g of ethanol (96%) in each case. The product is dried at 60° C. and about 100 mbar until free of solvent and water. 148 g (0.49 mol) of 4-(4′-chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid (70%) are obtained as a colorless, finely crystalline powder. By working up the mother liquor, as described in Example 1, the yield is increased to 83%. (HPLC purity 99.6-99.8%)
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[NH:7][C:8]2=[O:13].Br[CH2:21][CH2:22][CH2:23][OH:24]>>[CH3:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH2:23][OH:24])[CH2:16][CH2:15]1)[NH:7][C:8]2=[O:13]
Reactant: OCCCBr
Reactant: Cc1cccc2c(=O)[nH]c(C3CCNCC3)cc12
Agent: Cl
Product: Cc1cccc2c(=O)[nH]c(C3CCN(CCCO)CC3)cc12
Yield: 20.5 %

Procedure:
By the reaction in the same manner as in Example 2a, using 5-methyl-3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (1 g) and 3-bromo-1-propanol (751 mg), 5-methyl-3-[1-(3-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-1-one (221 mg) was obtained.
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=1.CON(C)[C:17]([CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18]>C1COCC1>[CH3:12][N:11]1[C:7]([C:17]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])=[CH:8][N:9]=[C:10]1[CH3:13]
Reactant: CON(C)C(=O)C1CCOCC1
Reactant: Cc1ncc(Br)n1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncc(C(=O)C2CCOCC2)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of n-BuLi (4.0 mL, 10 mmol, 2.5 M solution in hexane) was slowly added to a solution of 5-bromo-1,2-dimethyl-1H-imidazole (1.77 g, 10.2 mmol) in THF (70 mL) at −78° C. After addition, stirring was continued for an additional 30 minutes and N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (1.76 g, 10.1 mmol, Intermediate 1: step a, Procedure A) dissolved in THF (25 mL) was slowly added. An additional 6 mL of THF was used to complete the quantitative addition. The mixture was stirred at −78° C. for 5 minutes then warmed to room temperature and stirred for 1 hour. The solution was quenched with water and layers were separated. The aqueous layer was extracted with DCM and the combined organic extracts washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified using flash column chromatography (0 to 6% MeOH/DCM) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CC1C2C(=CC=CC=2)C=CC=1.[C-:25]#[N:26].[Na+]>CN(C)C1C=CN=CC=1.[Cu]I.O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:25]#[N:26])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: [C-]#N
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Agent: [Cu]I
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: Cc1cccc2ccccc12
Solvent: O
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C

Procedure:
A 100-mL, three-necked flask equipped with a mechanical stirrer, thermometer and condenser was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (5.0 g, 0.020 mol, 99.1% purity) and 1-methylnaphthalene (20 g) while maintaining a flow of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature, and powdered sodium cyanide (powdered just prior to use) (1.25 g, 0.024 mol, assuming 95% purity), copper(I) iodide (0.57 g, 0.0030 mol) and 4-(dimethylamino)pyridine (2.10 g, 0.017 mol) were added. The mixture was heated at 160 to 165° C. for 4.25 h and then allowed to cool to 25° C. Water (20 mL) was added dropwise to the reaction mixture over 5 minutes while stirring. After stirring for an additional 30 minutes, the reaction mixture was filtered, and the solid collected was washed with water (3×10 mL) and xylenes (10 mL), and then dried to a constant weight in a vacuum-oven at 50° C. to give the title compound as a light brown solid (3.9 g).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.C([C:25]1C=C(C)C=[C:27](C(C)(C)C)[C:26]=1[OH:36])(C)(C)C.[OH:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43](=[O:46])[CH:44]=[CH2:45].C(OCC1OC1)C1OC1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(N(C)C)=O>[C:43]([O:42][CH2:41][CH2:40][CH2:39][CH2:38][O:37][CH2:25][CH:26]([OH:36])[CH2:27][O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:46])[CH:44]=[CH2:45]
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)OCCCCO
Agent: C(OCC1CO1)C1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: C=CC(=O)OCCCCOCC(O)COC(=O)c1ccccc1C(=O)c1ccccc1

Procedure:
A reaction mixture containing 2-benzoyl benzoic acid (40.0 g, 0.1722 mol), acetonitrile (300 mL), dimethylacetamide (10 mL), tetrabutylammonium bromide (5.6 g, 17.22 mmol) and 2,6-di-tert-butyl-4-methylphenol (0.3 g, 1.4 mmol) was heated to reflux. At this temperature 4-hydroxybutylacrylate glycidylether (28.0 g, 140 mmol) was added and the mixture was allowed to stir at reflux temperature for 16 hours.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH3:14])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1)[CH3:21].C(=O)([O-])[O-].[K+].[K+].Cl>CCOCC.C1COCC1>[ClH:1].[CH2:13]([O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]2[NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:20][CH3:21])=[N:24][CH:25]=1)[CH3:14]
Reactant: CCOC(=O)c1cnc2ccc(OCC)nc2c1Cl
Reactant: CCOc1ccc(N)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1cnc2ccc(OCC)nc2c1Nc1ccc(OCC)nc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 4-chloro-6-ethoxy-1,5-naphthyridine-3-carboxylate (2.1 g), 2-ethoxy-5-aminopyridine (1.08 g), anhydrous potassium carbonate (2.17 g) and THF (60 ml) was stirred at ambient temperature for 48 hours. The mixture was evaporated to dryness and water added to the residue. The mixture was extracted with dichloromethane to give an oily solid. This solid was dissolved in IMS (20 ml) and the solution saturated with hydrogen chloride gas while cooling in ice. Ether was added to induce precipitation. The mixture was filtered to give ethyl 6-ethoxy-4-(2-ethoxy-5-pyridylamino)-1,5-naphthyridine-3-carboxylate hydrochloride, m.p. 187°-189° C. Borderline active (1/1) at 30 mg/kg.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:29](=[O:30])[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:21]2[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]2[C:19]1=[O:37].[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:29](=[O:30])[C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:21]4[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]4[C:19]3=[O:37])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: Sc1cccc2nccn12
Reactant: O=c1c(-c2ccccc2)c2n(c(=O)n1CCCCCl)CCCS2(=O)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(-c2ccccc2)c2n(c(=O)n1CCCCSc1cccc3nccn13)CCCS2(=O)=O
Reaction time: 0.17 h

Procedure:
To a suspension of 0.24 g (6.0 mmol) of 60% oily sodium hydride in 40 ml of N,N-dimethylformamide, 0.98 g (6.0 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 10 minutes. To this mixture, 2.87 g (5.97 mmol) of 7-(4-chlorobutyl)-1,1-dioxo-9-phenyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]-thiazine-6,8(7H)-dione and 0.90 g (6.0 mmol) of sodium iodide were added, followed by stirring at 80° C. for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate/ethanol=10/1) to yield 1.26 g (43.7%, white foamy substance) of the desired product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[F:16][C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:19][CH:18]=1>>[F:16][C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]4([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]4)=[CH:5][CH:4]=3)[CH2:25][CH2:24]2)[CH:20]=[CH:19][CH:18]=1
Reactant: Fc1cccc(N2CCNCC2)n1
Reactant: CC(=O)NC1(c2ccc(CCl)cc2)CC1
Product: CC(=O)NC1(c2ccc(CN3CCN(c4cccc(F)n4)CC3)cc2)CC1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)cyclopropyl)acetamide obtained in Example 71(1) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(6-fluoropyridin-2-yl)piperazine obtained in Example 85(2) instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=135-136° C.
Reaction SMILES: [OH-].[Na+:2].[Na+].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([O-:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1.Cl[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH3:27])[CH:18]=1.[I-].[Na+]>C(O)C>[Na+:2].[CH3:27][C:19]1[CH:18]=[C:17]([CH2:16][O:4][C:5]2[CH:10]=[CH:9][C:8]([S:11]([O-:14])(=[O:12])=[O:13])=[CH:7][CH:6]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: Cc1cc(CCl)c2ccccc2n1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(COc2ccc(S(=O)(=O)[O-])cc2)c2ccccc2n1
Temperature: 25 °C
Yield: 73 %

Procedure:
Sodium hydroxide 3.0 M (8.7 ml) was added to a suspension of 4-hydroxybezenesulfonic acid sodium salt (5.0 g, 22.0 mmol), 4-chloromethyl-2-methylquinoline (5.0 g, 26.0 mmol) and sodium iodide (0.4 g, 2.7 mmol) in ethanol (80 ml). The reaction was heated to reflux for 18 h, allowed to cool to room temperature to crystallize a white solid. The solids were filtered off, washed with ethanol, chloroform and dried in vacuo to give 4-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonic acid sodium salt (5.5 g, 73%) as a crystalline solid. MS found: (M−Na)−=328.
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5](=[O:20])[C:6]([C:18]#[N:19])=[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[O:16][CH3:17])[CH3:8]>C(OCC)C.[Cu]I>[CH3:3][O:4][C:5](=[O:20])[CH:6]([C:18]#[N:19])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[O:16][CH3:17])([CH3:1])[CH3:8]
Reactant: COC(=O)C(C#N)=C(C)c1ccc(F)cc1OC
Reactant: [Li]C
Agent: [Cu]I
Solvent: CCOCC
Product: COC(=O)C(C#N)C(C)(C)c1ccc(F)cc1OC
Temperature: -25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a chilled (0° C.) suspension of 4.3 g (22.58 mmol) of copper (I) iodide (purified by Soxhlet extraction with THF) in 100 mL of diethyl ether was added 26 mL (41.60 mmol) of a 1.6 M solution of methyl lithium in ether over a 15 minute period. After the addition, the mixture stirred for 10 min and was then cooled to −25° C. and a solution of 4.0 g (15.19 mmol) of 2cyano-3-(4-fluoro-2-methoxyphenyl)but-2-enoic acid methyl ester in 50 mL of diethyl ether was added over a 20 minute period. The mixture stirred at −25° C. for 30 minutes and was then allowed to warm to room temperature. The reaction was monitored by proton NMR. After 1.5 hours, an aliquot partitioned between EtOAc and 1 N aqueous HCl indicated starting material was gone and desired product was present. The reaction was cautiously poured into brine and then saturated aqueous ammonium chloride was added followed by 1 N aqueous HCl and EtOAc. The mixture was filtered through diatomaceous earth and the aqueous layer was separated and extracted with three 50 mL portions of EtOAc. The combined organic layers were washed with 30 mL of 1 N aqueous HCl, 30 mL of brine, and three 25 mL portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated to afford 4.2 g (99%) of 2-cyano-3-(4-fluoro-2-methoxyphenyl)-3-methylbutyric acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[O:24]1[C:28]([CH:29]=O)=[CH:27][CH:26]=[N:25]1>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:29]([C:28]3[O:24][N:25]=[CH:26][CH:27]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: O=Cc1ccno1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1cc(Br)cc(N)n1
Product: Nc1cc(Br)cc2nc(-c3ccno3)nn12

Procedure:
The title compound, MS m/e (%): 280 (M+, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and isoxazole-5-carbaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+]([O-])=O)[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N+:7]=1[O-].[OH-].[Na+].C([Br:24])(=O)C>P(Br)(Br)Br>[Br:24][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[CH:5]=1
Reactant: CC(=O)Br
Reactant: Cc1cccc(-c2cc([N+](=O)[O-])cc(C)[n+]2[O-])n1
Agent: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(-c2cc(Br)cc(C)n2)n1
Temperature: 0 °C

Procedure:
6,6'-Dimethyl-4-nitro-2,2'-bipyridine-N-oxide (0.50 g, 2.0 mmoles) was dissolved in acetyl bromide (10.0 ml) and phosphorus tribromide (2.5 ml). After refluxing for 1.5 hours the mixture was poured into 100 g ice and the solution was neutralized with 30% sodium hydroxide solution. The mixture was extracted with chloroform, the chloroform phase was dried and evaporated. The product was purified by means of flash chromatography.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=[O:34])[C:23](=[C:35](SC)SC)[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-:41].[Na+].[O:43]1[CH2:47]CCC1>CO.Cl>[C:1]([O:5][C:6]([NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=[O:34])[CH:23]([C:35]([O:43][CH3:47])=[O:41])[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)=[O:40])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC(SC)=C1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Reactant: [OH-]
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Temperature: 50 °C

Procedure:
To a stirred solution of tert-butyl(1-(4-(6-(bis(methylthio)methylene)-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (140 mg, 0.24 mmol) in anhydrous tetrahydrofuran (2.8 mL) was added a solution of sodium hydroxide (96 mg, 2.4 mmol) in methanol (2.2 mL). The reaction mixture was heated to 50° C. under a nitrogen atmosphere for 2 hours. After allowing to cool to room temperature the mixture was diluted with 1M HCl solution (3 mL) and extracted into ethyl acetate (3×6 mL). The combined organic phases were washed with brine (3×6 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give the desired product as a brown solid (126 mg, quantitative yield). LCMS (Method A) RT=7.56 min, M+H+=527.14.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O.C(OCC)(=O)C.O>[C:10]([CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:11]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCC(C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
5 g of sodium hydride (as a 55% w/w dispersion in mineral oil) were added slowly to a solution of 11.7 g of phenylacetonitrile and 19.5 g of ethyl 4-bromobutyrate in 150 ml of dimethylformamide, and the reaction mixture was stirred for 4 hours at room temperature. It was then dissolved in ethyl acetate and water. The ethyl acetate layer was separated, washed with an aqueous solution of potassium bisulfate and then with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The oily residue was subjected to silica gel column chromatography using a 1:4 by volume mixture of ethyl acetate and cyclohexane as eluent, to give 13.5 g of the title compound as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[C:20]([CH3:31])=[N:21][C:22]([N:25]4[CH2:29][CH2:28][O:27][C:26]4=[O:30])=[CH:23][CH:24]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:32])[O:4][N:3]=1.[CH3:33][C:34](N=C(N(C)C)N(C)C)([CH3:36])[CH3:35].BrCC(C)C>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:19]3[C:20]([CH3:31])=[N:21][C:22]([N:25]4[CH2:29][CH2:28][O:27][C:26]4=[O:30])=[CH:23][CH:24]=3)[CH2:33][CH:34]([CH3:36])[CH3:35])(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[C:5]([CH3:32])[O:4][N:3]=1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: Cc1nc(N2CCOC2=O)ccc1NS(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Solvent: CC#N
Solvent: CC(C)CBr
Product: Cc1nc(N2CCOC2=O)ccc1N(CC(C)C)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 80 °C
Yield: 65 %

Procedure:
To a solution of 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-[2-methyl-6-(2-oxo-1,3-oxazolidin-3-yl)-3-pyridinyl]benzenesulfonamide (137 mg, 0.299 mmol) and N″-(1,1-dimethylethyl)-N,N,N′,N′-tetramethylguanidine (51 mg, 0.299 mmol) in acetonitrile (2 mL) was added 1-bromo-2-methylpropane (0.065 mL, 0.598 mmol). The reaction vessel was heated at 80° C. for 8 hours. The reaction mixture was then separated between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulphate then concentrated in vacuo. The crude was purified by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane gradient) to give the title compound (100 mg) as a white foam. LCMS (2 min, formic) Rt 1.21 min, m/z (ES+) 515 (M+H).
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4]C.[C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])(=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:2](/[O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:6](=[O:8])[CH3:7])=[CH:3]\[CH3:4]
Reactant: CC(=O)Nc1ccccc1O
Reactant: CC=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C/C=C/Oc1ccccc1NC(C)=O

Procedure:
A heterogenic mixture of commercially available 1-chloro-2-butene (Aldrich, predominantly trans) (453 mg, 0.49 mL, 5.00 mmol), 2-acetamidophenol (756 mg, 5.00 mmol) and potassium carbonate (691 mg, 5.00 mmol) in aceton (10 ml) was heated to reflux over night. After evaporation of the solvent the residue was taken up by ethylacetate and water. Washing of the organic phase with water, 5-proz. sodium hyroxide and brine and evaporation of the solvent afforded the crude which was purified by flash chromatography on silica gel (heptane/EtOAc=3:2). Yield: 732 mg (71%) of a brownish yellow solid. Trans: cis=81:19 (ratio determined by 1H-NMR; 400 MHz, CDCl3):
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[H-].[Na+].Cl[CH2:11][O:12][CH3:13]>CN(C=O)C>[CH3:11][O:12][CH2:13][O:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: COCCl
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
Pyridin-3-ol (25 g, 260 mmol) was added to a stirring mixture of NaH (11 g of a 60 wt % dispersion with mineral oil, 260 mmol) and DMF (350 mL) at 0° C. After 30 min, the reaction mixture was allowed to warm to RT, stirred for 90 min, and then chloromethoxymethane (20 mL, 260 mmol) was added. After 18 h, the reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3, the layers were separated, the organic layer was washed with saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered, and the filtrate was concentrated. The residue was dissolved with CH2Cl2, the solution was filtered through a plug of silica gel (sequential elution; 9:1→1:1 hexane-ethyl acetate), and the second filtrate was concentrated to give 10 g (27%) of 3-(methoxymethoxy)pyridine as a clear yellow oil.
Reaction SMILES: [I-].[K+].CS(O[CH2:8][CH2:9][O:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[C:23]([F:35])[CH:22]=2)[NH:13][N:12]=1)(=O)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:35][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([O:10][CH2:9][CH2:8][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[C:19]=23)[CH:26]=[CH:25][C:24]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCOS(C)(=O)=O)c34)cc2F)cn1
Reactant: C1CCNC1
Agent: [I-]
Agent: [K+]
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCCC5)c34)cc2F)cn1
Yield: 54 %

Procedure:
The procedure described in Example 23 was repeated (except that potassium iodide was not used) using 2-{[4-({3-fluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate and pyrrolidine to give the title compound in 54% yield; NMR Spectrum: 1.67 (s, 4H), 2.45 (s, 3H), 2.54 (hidden by DMSO, 4H), 2.89 (t, 2H), 4.45 (t, 2H), 7.23 (m, 3H), 7.53 (dd, 1H), 8.01 (dd, 1H), 8.24 (d, 1H), 8.36 (s, 1H), 8.70 (br s, 1H); Mass Spectrum: 450 (MH+).