Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].CS[C:4]1[N:5]2[CH:17]=[CH:16][N:15]=[C:6]2[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O)CCCC>>[ClH:1].[ClH:1].[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:4]2[N:5]3[CH:17]=[CH:16][N:15]=[C:6]3[S:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:23][CH2:22]1
Reactant: OCCN1CCNCC1
Reactant: CSC1=Nc2ccccc2Sc2nccn21
Agent: Cl
Solvent: CCCCCO
Product: OCCN1CCN(C2=Nc3ccccc3Sc3nccn32)CC1

Procedure:
A mixture of 5 g of 5-methylthio-imidazo[2,1-b][1,3,5]benzothiadiazepine hydrochloride, 2.86 g of N-β-hydroxyethylpiperazine, and 175 ml of amyl alcohol is refluxed under nitrogen for 48 hrs. with stirring. The solvent is removed under vacuum, the residue is triturated with methylene chloride, washed with 2 N sodium hydroxide solution, dried over MgSO4, and evaporated to dryness. The residue is dissolved in 5 ml of methanol and treated with 2 N ethereal hydrochloric acid solutions to give 5-(4-β-hydroxyethylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine dihydrochloride melting at 212°-214°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([C:8]2(C(O)=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1C1(C(=O)O)CCOCC1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Br)cnc1C1CCOCC1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A solution of 4-(5-bromo-3-methylpyridin-2-yl)tetrahydro-2H-pyran-4-carboxylic acid (420 mg) in dimethylsulfoxide (1 ml) was stirred at 150° C. for 1.5 hours. After completion of the reaction, the mixture was cooled to room temperature, water was added thereto, and extracted with chloroform. The organic layer was washed with water and saturated brine sequentially, then dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (316 mg) as a white solid. MS (ESI) m/z: 256, 258 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11](Br)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH2:20]([Mg]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOCC>C(OCC)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CCN1CCN(c2nc(Cc3ccccc3)cc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a mixture solution of 1-(4-ethylpiperazin-1-yl)-3-bromoisoquinoline (0.71 g) cooled to 0° C. and [1,3-bis(diphenylphosphino)propane]dichloronickel(II) (0.05 g) in diethyl ether (20 ml) was dropwise added 1M benzylmagnesium chloride/ether solution (4.5 ml) in nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with ether (30 ml), washed with water and brine, and then dried over magnesium sulfate. The solvent was removed, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/acetone system), to give the title compound (0.44 g; 59.5%) as a pale yellow oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.S(=O)=[O:16].C1(NC2C=CC=CC=2)C=CC=CC=1>CCOCC>[C:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:16])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: O=S=O
Agent: c1ccc(Nc2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Product: O=C(c1ccccc1)c1ccccc1
Yield: 95 %

Procedure:
Ten millimoles of diphenylmethane was heated at 400° C. for 1 hour with 1.35 ml of water saturated with sulfur dioxide in the microreactor described in Comparative Examples 1 to 10. After cooling, the product was entracted with ether. The ether layer was dried (Na2So4) and concentrated to yield 95% of benzophenone and 5% of diphenylamine. Colloidal sulfur was observed in the aqueous layer.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH:10]1([N:13]2[C:17]([C:18]3[CH:19]=[C:20]([CH:24]4[CH2:33][C:32]([CH3:35])([CH3:34])[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([C:36](O)=[O:37])[CH:30]=5)[NH:25]4)[CH:21]=[CH:22][CH:23]=3)=[N:16][N:15]=[N:14]2)[CH2:12][CH2:11]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH:10]1([N:13]2[C:17]([C:18]3[CH:19]=[C:20]([CH:24]4[CH2:33][C:32]([CH3:34])([CH3:35])[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([C:36]([NH:9][S:6]([CH:3]6[CH2:5][CH2:4]6)(=[O:8])=[O:7])=[O:37])[CH:30]=5)[NH:25]4)[CH:21]=[CH:22][CH:23]=3)=[N:16][N:15]=[N:14]2)[CH2:12][CH2:11]1
Reactant: CC1(C)CC(c2cccc(-c3nnnn3C3CC3)c2)Nc2ccc(C(=O)O)cc21
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(-c3nnnn3C3CC3)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (535 mg, 13.7 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (1.65 g, 13.8 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A41. A solution of 2-[3-(1-cyclopropyl-1H-tetrazol-5-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (544.6 mg, 1.4 mmol) and 1,1′-carbonyldiimidazole (442 mg, 2.76 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B41. Solution B41 was added to Solution A41 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {2-[3-(1-cyclopropyl-1H-tetrazol-5-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (206.6 mg, 30%) as a white solid: MS (ESI) M+1=493.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=2)[CH2:22][NH:21][C:20]1=[O:30]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[CH2:22][NH:21][C:20]2=[O:30])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)NCc2ccc(F)cc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NCc2ccc(F)cc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-6-fluoro-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 195-200° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1.[CH2:22]([NH:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)CO>O>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:5][C:6]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:29]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:30]=1
Reactant: NNCc1ccccc1
Reactant: N#Cc1c(-c2ccccc2)cc(N2CCOCC2)nc1Cl
Solvent: O
Solvent: OCCO
Product: Nc1nn(Cc2ccccc2)c2nc(N3CCOCC3)cc(-c3ccccc3)c12
Temperature: 130 °C

Procedure:
A mixture consisting of 3.0 gm (0.01 mol) of 2-chloro-6-morpholino-4-phenyl-3-cyano-pyridine, 3.7 gm (0.03 mol) of benzyl-hydrazine and 30 ml of ethylene glycol was refluxed for 5 hours at about 130° C. The resulting solution was taken up in 100 ml of water, whereupon the reaction product separated out as a pasty precipitate which was collected and immediately recrystallized from methanol. 2.2 gm (57% of theory) of the compound named in the heading were obtained; after recrystallization from ethyl acetate it had a melting point of 147°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH:4]([C:9]1[CH:10]=[C:11]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[CH:12]=[C:13]([O:15]C2C=CC=C(C(F)(F)F)C=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:41][C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[C:46]([F:48])[CH:47]=1>>[CH3:1][O:2][C:3](=[O:40])[CH:4]([C:9]1[CH:10]=[C:11]([C:26]2[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:27]=2)[CH:12]=[C:13]([O:15][C:44]2[CH:43]=[C:42]([F:41])[CH:47]=[C:46]([F:48])[CH:45]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(Oc2cccc(C(F)(F)F)c2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cc(F)cc(F)c2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 15 %

Procedure:
The title compound was prepared in 15% yield from 2-[3′,5′-bis-trifluoromethyl-5-(3-trifluoromethyl-phenoxy)-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester (prepared in Example C) and 3,5-difluoro-phenylboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COc1cc(C)c([N+](=O)[O-])cc1C(=O)O
Temperature: 0 °C

Procedure:
A 2.00 g portion of 2-methoxy-4-methylbenzoic acid was dissolved in 10 ml of sulfuric acid. With stirring at 0° C., 0.88 ml of concentrated nitric acid was added thereto dropwise. After 4 hours of stirring at room temperature, and ice water was added. The thus formed crystals were collected by filtration, dried under a reduced pressure and then purified by column chromatography (chloroform:methanol=30:1) to give 1.32 g of 2-methoxy-4-methyl-5-nitrobenzoic acid as yellow crystals.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:16]1[C:17]2[NH:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[C:14]([C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][O:29][C:28]3=[O:32])[CH:21]=[N:20][CH:19]=2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(OCCN4CCOC4=O)c3)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OCCN1CCOc1cncc(-c2cnc3c(c2)CCCN3)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-{5-[2-(2-Oxo-oxazolidin-3-yl)-ethoxy]-pyridin-3-yl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (0.305 mmol) is dissolved in 2 mL of a 20% TFA solution in CH2Cl2 and the solution is shaken overnight at room temperature. The reaction is evaporated to dryness to give crude 3-{2-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yloxy]-ethyl}-oxazolidin-2-one and used as is in the next step.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=O)C.CO.[OH-].[Na+]>O1CCCC1>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:12]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[N:9]1[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]1
Reactant: CCOC(=O)N1CCN(C(c2ccc(Cl)cc2)c2ccccc2Cl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Clc1ccc(C(c2ccccc2Cl)N2CCNCC2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 62.3 %

Procedure:
To a stirred solution of 0.9 gram (0.002 mole) of N-(ethoxycarbonyl)-N′-[(2-chlorophenyl)(4-chlorophenyl)methyl]piperazine in 10 mL of tetrahydrofuran was added 10 mL of methanol and 10 mL of aqueous 50% sodium hydroxide. Upon completion of the addition the reaction mixture was warmed to 80° C., where it stirred for 24 hours. At the end of this time the reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in chloroform, and the solution was stirred for 40 minutes. The resulting precipitate was collected by filtration. The filtrate was concentrated under reduced pressure, yielding 0.6 gram of crude material. The crude material was purified by preparative thin layer chromatography (TLC). Elution was accomplished with 1:1 acetone: methanol. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.4 gram of N′-[(2-chlorophenyl)(4-chlorophenyl)-methyl]piperazine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([S:14]([C:13]2[C:7]3[O:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9][C:8]=3[CH:10]=[CH:11][C:12]=2[Cl:18])(=[O:16])=[O:15])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Yield: 73.3 %

Procedure:
Following the general procedure for the synthesis of sulfonylamides outlined in example 51, 2-tert-butyl-6-chlorbenzooxazole-7-sulfonyl chloride (5.0 g, 16.2 mmol), triethylamine (2.4 mL, 17.2 mmol), and piperazine-carboxylic acid tert-butyl ester (3.62 g, 19.4 mmol) were reacted in THF (50 mL) to afford the title compound (5.44 g, 67%). LCMS m/z 402(M−H)+ (desired -Boc).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:14](Cl)=[O:15].COC1C=C2C(C(=O)C=[CH:25][NH:26]2)=CC=1C(O)=O.CN.O>O1CCCC1>[CH3:25][NH:26][C:14]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[N:10]=[CH:9][CH:8]=[C:7]2[Cl:13])=[O:15]
Reactant: COc1cc2nccc(Cl)c2cc1C(=O)Cl
Reactant: COc1cc2[nH]ccc(=O)c2cc1C(=O)O
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1cc2c(Cl)ccnc2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
After dissolving 7-methoxy-4-chloro-quinoline-6-carbonyl chloride synthesized by the method of Production Example 152-2 from 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (947 mg) in tetrahydrofuran (70 ml), the solution was cooled to 0° C. A 40% aqueous methylamine solution (0.4 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Water was added, extraction was performed 3 times with ethyl acetate, and the organic layers were combined, washed with water and saturated brine, dried over sodium sulfate and then dried under reduced pressure to obtain the title compound (710 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][O:4][C:3]1=[O:7].[OH-:9].[K+:10]>C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.CCO.O>[OH:4][CH2:5][CH2:6][C:2]([CH3:8])([CH3:1])[C:3]([O-:9])=[O:7].[K+:10]
Reactant: [OH-]
Reactant: CC1(C)CCOC1=O
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(CCO)C(=O)[O-]
Temperature: 105 °C
Reaction time: 3.5 h
Yield: 71.1 %

Procedure:
A mixture of dihydro-3,3-dimethyl-2(3H)-furanone (10 mmol; 1.14 g), aqueous 1 M KOH solution (10 mmol) and one drop of phenolphthalein indicator (0.5% w/v in EtOH/water (1:1)) is stirred at 105° C. for 3.5 hours. The mixture is cooled to ambient temperature and concentration under reduced pressure. To the residue is added 10 mL of EtOH. To the solution is added 50 ml of Et2O, and the solid isolated by filtration and dried under 100 mbar at 50° C. to give potassium 4-hydroxy-2,2-dimethylbutyrate (1.21 g, 71%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[Cl-].[OH:16][NH3+:17]>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6]/[C:7](/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N:17]/[OH:16]
Reactant: [NH3+]O
Reactant: COCCCCC(=O)c1ccccc1
Agent: [Cl-]
Solvent: c1ccncc1
Product: COCCCC/C(=N/O)c1ccccc1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of the above ketone (8.8 g, 46 mmol), hydroxylammonium chloride (5.5 g, 78 mmol) and anhydrous pyridine (50 ml) was heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature and the solvent then evaporated in vacuo. To the residue was added 10% aqueous citric acid (100 ml) and the mixture was extracted with ethyl acetate (100 ml+50 ml). The combined organic phases were washed with 10% aqueous citric acid (25 ml), brine (25 ml) and dried (Na2SO4). The solvent was evaporated in vacuo and the residue purified by column chromatography on silica gel (250 g, n-heptane/ethyl acetate gradient 1/4 to 1/2 to give 7.25 g of Z-5-methoxy-1-phenyl-1-pentanone oxime as a colourless oil.
Reaction SMILES: [ClH:1].Cl.Cl.[N:4]1([C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[CH2:21][NH:20][CH2:19][CH2:18][NH:17]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[Cl:29][C:30]1[N:35]([CH3:36])[C:34](=[O:37])[CH:33]=[C:32]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][C:39]=2[F:44])[N:31]=1>O1CCCC1>[ClH:29].[ClH:1].[ClH:29].[F:44][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][C:38]=1[C:32]1[N:31]=[C:30]([N:20]2[CH2:19][CH2:18][NH:17][C@@H:16]([C:13]3[CH:12]=[CH:11][C:10]([N:4]4[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]4)=[CH:15][CH:14]=3)[CH2:21]2)[N:35]([CH3:36])[C:34](=[O:37])[CH:33]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Reactant: c1cc(N2CCCCC2)ccc1[C@H]1CNCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCN[C@@H](c3ccc(N4CCCCC4)cc3)C2)nc(-c2ccncc2F)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of (2S)-2-(4-piperidin-1-yl-phenyl)-piperazine trihydrochloride obtained in Reference Example 3 (199 mg, 0.561 mmol) and triethylamine (427 μl, 306 mmol) in tetrahydrofuran was refluxed for 15 minutes. After cooling to room temperature, 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (122 mg, 0.510 mmol) was added portionwise and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane and aqueous sodium bicarbonate, and the solution was passed through CHEM ELUT CE1010 (manufactured by VARIAN). The filtrate was concentrated, and the resulting residue was washed with diethyl ether. Hydrogen chloride in ethyl acetate (4N) was added to a solution of the resulting solids in ethyl acetate, and the precipitate was collected by the filtration and dried to furnish 6-(3-fluoro-pyridin-4-yl)-3-methyl-2-((3S)-3-(4-piperidin-1-yl-phenyl)-piperazin-1-yl)-3H-pyrimidin-4-one trihydrochloride (267 mg, 0.479 mmol, 94%) as pale yellow powder.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17])(=O)C.[OH-].[Na+].CO>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17]
Reactant: CCCS(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCS(=O)c1ccc(N)c([N+](=O)[O-])c1

Procedure:
1.5 G. of 1-acetamido-2-nitro-4-n-propylsulfinylbenzene is treated with 3 ml. of 5N sodium hydroxide solution and sufficient methanol to effect solution. After heating on a steam bath for 15 minutes, the mixture is diluted with water, cooled and filtered, yielding 1-amino-2-nitro-4-n-propylsulfinylbenzene.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]([CH2:27][CH:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:38][CH3:39])[CH2:29]1)=O.CCCCCC>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:25][CH2:27][CH:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:38][CH3:39])[CH2:29]1
Reactant: COc1cccc2c1CCC(CC=O)C2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1cccc2c1CCC(CC=C(Br)Br)C2
Reaction time: 0.17 h

Procedure:
To a solution of carbon tetrabromide (19.5 g) in methylene chloride (50 ml) was added triphenylphosphine (30.8 g) at 0° C., and the mixture was stirred for 10 min. To the mixture was added a solution of 2-formylmethyl-5-methoxy1,2,3,4-tetrahydronaphthalene (4.09 g; the compound prepared by method described in the specification of the Japanese Patent Application No. 3-130467) in methylene chloride (25 ml) at 0° C. The mixture was stirred for 30 min at 0° C. To the mixture was gradually added n-hexane, and filtrated to remove triphenylphosphineoxide. The filtrate was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=24:1) to give the title compound (6.42 g) having the following physical data.
Reaction SMILES: IC.[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[C:13](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([CH3:13])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
Iodomethane (12.2 mL, 195 mmol) was added to a solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (15.0 g, 97.7 mmol) and cesium carbonate (47.7 g, 146.5 mmol) in DMF (200 mL). The reaction mixture was stirred at room temperature 1 h, quenched with H2O (500 mL), and extracted with EtOAc (3×200 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash column chromatography (silica, 2:8→3:7 EtOAc:hexanes) provided the title compound as an off-white solid (15.4 g, 94%). MS: 168.5 (MH+); HPLC Rf: 3.45 min. (HPLC method 4); HPLC purity: 96%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][NH:39][C:40]([NH2:42])=[NH:41]>>[NH2:42][C:40]([N:39]([CH3:38])[C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:29]=[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:31]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1)=[NH:41]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CNC(=N)N
Product: CN(C(=N)N)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and N-methylguanidine according to conditions described in general procedure C. Mp: 155-157° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.19-3.33 (m, 7 H), 3.75-3.78 (m, 4 H), 6.50 (d, J=5.5 Hz, 1 H), 7.04 (d, J=12.0 Hz, 1 H), 7.27 (d, J=9.1Hz, 1 H), 7.34-7.68 (m, 7 H), 7.80 (d, J=8.8 Hz, 1 H), 7.99 (d, J=8.2 Hz, 1 H), 8.29 (d, J=5.5 Hz, 1 H), 10.47 (s, 1 H).