Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[N:19][C:20]([N:28]2[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)=[N:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:6][CH:5]=1.[Cl-].[NH4+].[CH2:37](O)C>>[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[N:19][C:20]([N:28]2[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]2)=[N:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12]2[C:17]([CH3:37])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:8][CH:9]=1
Reactant: Cc1ccccc1C(=NC(=Nc1ccccc1)N1CCC(=O)CC1)Nc1ccc(F)cc1
Reactant: CCO
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cccc(C)c1C(=NC(=Nc1ccccc1)N1CCC(O)CC1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
Sodium borohydride (0.006 g, 0.152 mmol) was added to a solution of the product from Example 8, free base, (0.067 g, 0.152 mmol) in ethanol (6 mL) and the mixture was stirred at room temperature for 2 hours. Saturated ammonium chloride was added and the mixture was extracted with methylene chloride (twice). The organic layer was dried (potassium carbonate), filtered, and concentrated. The residue was dissolved in dioxane and hydrogen chloride (g) was bubbled through. After removal of volatiles, the salt obtained was purified by silica gel flash chromatography to give the title compound (0.033 g, 45%), hydrochloride salt, as an off-white solid.
Reaction SMILES: [I-].[K+].[N+]([O-])(O)=O.O=O.[CH2:9]=[CH2:10].[C:11]([OH:14])(=[O:13])[CH3:12]>>[CH3:12][C:11]([O:14][CH2:9][CH2:10][O:14][C:11]([CH3:12])=[O:13])=[O:13]
Reactant: CC(=O)O
Reactant: C=C
Agent: O=O
Agent: [I-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Product: CC(=O)OCCOC(C)=O
Temperature: 65 °C

Procedure:
To a reactor similar to that described in Example 1 were added 3.3 g (20 millimoles) of potassium iodide, 1 ml (10 millimoles) of nitric acid, 0.5 g of activated carbon prepared from coconut shells (manufactured by Dai-ichi Carbon Industries Company) and 80 ml of acetic acid. The flask was set up in an oil bath maintained at 65° C. A gas mixture comprising by volume 8.5% of oxygen, 80% of nitrogen and 11.5% of ethylene was fed through the reaction mixture at a rate of 1.15 standard liters per hour with continuous stirring of the reaction mixture. At the conclusion of the one hour reaction period, the conversion of ethylene was 90%. The combined yields of EGDA and EGMA were 95% based on the reacted ethylene. Trace amounts of EDA and AcH were detected as by-products.
Reaction SMILES: [C:1]([NH:5][C:6](=[N:9][S:10](=[O:20])(=[O:19])[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:7][CH3:8])(OC)=[O:2].[H-].[Na+].O>C1COCC1>[CH2:12]([N:11]1[C:1](=[O:2])[NH:5][C:6]([O:7][CH3:8])=[N:9][S:10]1(=[O:20])=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)NC(=NS(=O)(=O)NCc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1=NS(=O)(=O)N(Cc2ccccc2)C(=O)N1

Procedure:
A solution of N-carbomethoxy-N'-benzylsulfamoyl-O-methylisourea (215 g) in anhydrous THF (200 ml) is added dropwise to a stirred suspension of sodium hydride (43 g of 60% dispersion) in anhydrous THF (900 ml) and refluxed for 2 hours under nitrogen. Water (800 ml) is added to the cooled reaction mixture and the aqueous mixture washed with ether. The pH of the aqueous layer is adjusted to about 3.2 and the resulting suspension extracted with methylene chloride. The methylene chloride extract is dried, filtered, and evaporated in vacuo. The residue is taken up in hot isopropyl alcohol, treated with charcoal, filtered hot, concentrated, cooled, the resulting precipitate filtered and dried in vacuo yielding the desired product, M.P.=141°-144° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]([N:26]2[CH2:30][CH2:29][N:28]([CH3:31])[C:27]2=[O:32])=O)[CH2:7]1)(=[O:4])=[O:3].CO>O1CCCC1.C(OCC)(=O)C>[CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([CH2:24][N:26]2[CH2:30][CH2:29][N:28]([CH3:31])[C:27]2=[O:32])[CH2:7]1)(=[O:4])=[O:3]
Reactant: CN1CCN(C(=O)[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCN(C[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48.6 %

Procedure:
To a solution of (2S,4R)-4-methanesulfonyloxy-2-(3-methyl-2-oxoimidazolidin-1-yl)carbonyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.70 g) in tetrahydrofuran (3.5 ml) was added 1.0M solution of borane-tetrahydrofuran complex in tetrahydrofuran (20.9 ml) and the mixture was stirred at ambient temperature for 1 hour and at 35°-40° C. for 2.5 hours. Methanol (20 ml) was added dropwise to the reaction mixture on ice-bath and the mixture was evaporated in vacuo. The resulting residue was dissolved in a mixture of methanol (20 ml) and 1.7M solution of hydrogen chloride in methanol (1 ml) and the mixture was allowed to stand overnight. The reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (60 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate and aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (30 g) eluting with a mixture of chloroform and methanol (9:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-2-(3-methyl-2-oxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.33 g).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][C:8]=2[CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C2CCCCC2)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)ccc1C1CCCCC1
Temperature: 50 °C

Procedure:
To a solution of crude 1-cyclohexyl-4-methoxy-2-methyl-benzene in dry DCM (10 mL) is added BBr3 at −78° C. Following this addition, the mixture is heated at 50° C. for 12 hours. The reaction mixture is cooled in an ice bath, and the reaction is quenched by the dropwise addition of water. The mixture is extracted with DCM. The combined organic phases are washed with 10% NaHCO3 (aq), brine, and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (10% EtOAc in hexanes) to give 4-cyclohexyl-3-methyl-phenol.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](Cl)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1)([O-:21])=[O:20].O>CN1C(=O)CCC1>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:31]2[CH2:30][CH2:29][CH:28]([C:25]3[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=3)[CH2:33][CH2:32]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Reactant: Clc1nnc(Cc2ccccc2)c2ccccc12
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(C2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cc1
Temperature: 150 °C
Yield: 81.6 %

Procedure:
To a solution of 1-benzyl-4-chloro-phthalazine (1.08 g, 4.04 mmol) in 8 mL NMP is added 4-(4-nitro-phenyl)piperidine (1 g, 4.85 mmol), TEA (1.68 mL, 12.12 mmol). The reaction mixture was heated to 150° C. for 45 min in a microwave reactor. Water was added to the reaction mixture to form a precipitate and the solid is collected by filtration and dried under vacuum. The resulting solid is purified by HPLC with acetonitril in water (from 20% to 100% with 3% 1-propanol) at 220 nm wavelength detection to provide the title compound (1.4 g, 78%).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=3)[C:19](=O)[C:18]3[C:17]([C:28](OCC)=[O:29])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)=[O:4].O.[NH2:35][NH2:36]>>[CH3:33][N:2]([CH3:1])[C:3](=[O:4])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:35][NH:36][C:28](=[O:29])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[CH:9][CH:10]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(C(=O)N(C)C)cc1)N2
Solvent: O
Product: CN(C)C(=O)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2nccn2C)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
Ethyl 2-(4-(dimethylcarbamoyl)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (500 mg, 1.12 mmol) and hydrazine monohydrate (8 mL) were added and the mixture was stirred under 40° C. for 3 h. Then the mixture was cooled to room temperature and filtered to give the title compound (90 mg, yield 19%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.86 (s, 3H), 2.96 (s, 3H), 3.42 (s, 3H), 4.66-4.69 (d, J=10.4 Hz, 1H), 4.96-4.99 (d, J=10.4 Hz, 1H), 6.73 (s, 1H), 6.89 (s, 1H), 7.16-7.19 (m, J=7.6 Hz, 1H), 7.29-7.45 (m, 6H), 7.56-7.60 (t, J=7.6 Hz, 1H), 12.18 (s, 1H); LC-MS (ESI) m/z: 415 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15]#[N:16])[NH:8][C:7]2=[O:17])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15]#[N:16])[NH:8][C:7]2=[O:17]
Reactant: N#CCCn1[nH]c(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: N#CCCn1[nH]c(=O)c2cc(N)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.2 %

Procedure:
To a solution of 3-(5-Nitro-3-oxo-2,3-dihydro-indazol-1-yl)-propionitrile (0.521 g) in MeOH (50 mL) was added Pd/C(10%) catalyst (0.13 g) and the reaction mixture was stirred for 20 hours at ambient temperature under a hydrogen atmosphere using a balloon. After this time the reaction mixture was filtered through Celite® which was washed with more EtOAc. The combined organic solution was evaporated in vacuo for afford the desired 3-(5-amino-3-oxo-2,3-dihydro-indazol-1-yl)-propionitrile (0.45 g) which was taken into the next reaction without further purification. MS (ESI+): 203.4 ([M+H]+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:34]=[N:33][CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=O.C(NC(C)C)(C)C.[C:42]1([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH2:55][N:56]2[CH:60]=[CH:59][C:58]([NH2:61])=[N:57]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C)C=O>[CH3:25][C:26]1[CH:34]=[N:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:61][C:58]1[CH:59]=[CH:60][N:56]([CH2:55][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[O:48][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:57]=1)=[O:30]
Reactant: Nc1ccn(Cc2ccccc2Oc2ccccc2)n1
Reactant: Cc1cnccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Cc1cnccc1C(=O)Nc1ccn(Cc2ccccc2Oc2ccccc2)n1
Reaction time: 0.17 h

Procedure:
A solution of HATU (38 mg, 0.1 mmol) in N,N-dimethylformamide (0.3 ml) was added to 3-methyl-isonicotinic acid (14 mg, 0.1 mmol, AstaTech Inc) followed by N,N-diisopropylamine (0.050 ml, 0.286 mmol) and left to stand for 10 minutes at ambient temperature. A solution of 1-{[2-(phenyloxy)phenyl]methyl}-1H-pyrazol-3-amine (for a preparation see Intermediate 38)(27 mg, 0.101 mmol) in N,N-dimethylformamide (0.1 ml) was then added and the solution left to stand at room temperature overnight. Purification by MDAP (Method D) gave the title compound (20.2 mg); LCMS: (System 1) MH+=385, tRET=0.93 min.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C:17](=[O:21])[NH:18]3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1.[Na+].[I-].Cl.[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH:3]2[CH2:8][CH2:7][CH:6]([CH2:9][O:10][C:11]3[CH:20]=[C:19]4[C:14]([CH2:15][CH2:16][C:17](=[O:21])[NH:18]4)=[CH:13][CH:12]=3)[CH2:5][CH2:4]2)[CH2:35][CH2:34]1
Reactant: O=C1CCc2ccc(OCC3CCC(CBr)CC3)cc2N1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: O=C1CCc2ccc(OCC3CCC(CN4CCN(c5cccc(Cl)c5Cl)CC4)CC3)cc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.7 %

Procedure:
A mixture of intermediate 49 (70 mg, 0.2 mmol) and NaI (60 mg, 0.4 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 41 (81 mg, 0.3 mmol) and anhydrous K2CO3 (110 mg, 0.8 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred for 4 h. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=50:1) to give 7-((4-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)cyclohexyl)methoxy)-3,4-dihydroquinolin-2(1H)-one (compound 26) (63 mg, 63%). 1H NMR (300 MHz, CDCl3): δ 8.06 (s, 1H), 7.13-7.15 (m, 2H), 7.04 (d, J=8.4 Hz, 1H), 6.94-6.97 (m, 1H), 6.52 (dd, J=2.4 Hz, 8.4 Hz, 1H), 6.32 (d, J=2.1 Hz, 1H), 3.71-3.74 (m, 2H), 3.05-3.07 (m, 4H), 2.87-2.92 (m, 2H), 2.59-2.64 (m, 6H), 2.24 (d, J=6.9 Hz, 2H), 3.83 (d, J=9.9 Hz, 2H), 1.53-1.69 (m, 6H), 0.94-1.10 (m, 4H). HPLC: 99%, RT 2.652 min. MS (ESI) m/z 502.2 [M+H]+.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].O1C=CC=C(O)C1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[CH3:2][N:3]([C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CNO
Agent: Cl
Agent: OC1=CC=COC1
Solvent: O
Product: CN(O)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
The n-methyl hydroxylamine-HCl and m-pyrol were combined in a 250 milliliter (ml) round bottomed flask, cooled in an ice bath, and allowed to mix until most of the salt dissolved. The benzoyl chloride was slowly added over 15 minutes and allowed to stir for 1 hour. The water was then added and the product extracted three times with ethyl acetate. The ethyl acetate was evaporated from the product, and the product dissolved in 200 ml of 5% NaOH. The product was then extracted three times with 100 ml methylene chloride. The aqueous layer was acidified with H2S04 to a pH of 6 and then extracted three times with 100 ml of ethyl acetate. The organic layer was dried with MgS04 and silica gel, and evaporated to dryness yielding n-methylbenzohydroxamic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[C:4]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:15][C:14]([NH:13][C:4]1[CH:5]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:7]=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1)([CH3:17])[CH3:16]
Reactant: C1CNCCN1
Reactant: CC(C)(C)Nc1cc(NC(C)(C)C)nc(Cl)n1
Product: CC(C)(C)Nc1cc(NC(C)(C)C)nc(N2CCNCC2)n1
Yield: 76.5 %

Procedure:
By reacting 2-chloro-4,6-bis(1,1-dimethylethylamino) -pyrimidine with piperazine as described in Example 4, the title product is obtained in a yield of 76.5%, m.p.: 135°-138° C.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[CH3:11][O:12][C:13]1[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=1[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)=[O:16].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH3:11][O:12][C:13]1[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=1[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:7]2[CH2:8][CH2:9][C:10]3[O:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)=[O:22])=[CH:19][CH:18]=1)=[O:16]
Reactant: c1cc2c(o1)CCNC2
Reactant: COc1ccccc1C(=O)c1ccc(C(=O)O)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccccc1C(=O)c1ccc(C(=O)N2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.308 g (1.2 mmol) of 4-(2-methoxybenzoyl)benzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield the desired product.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[CH2:12][CH2:13][CH2:14][CH2:15][C:8]2=[N:7][C:6]=1[CH3:16].Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1.C[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)CC(=O)C>[ClH:2].[ClH:1].[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[C:26]2[CH2:27][CH2:28][N:29]([CH2:3][CH2:4][C:5]3[C:10](=[O:11])[N:9]4[CH2:12][CH2:13][CH2:14][CH2:15][C:8]4=[N:7][C:6]=3[CH3:16])[CH2:30][CH2:31]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)CC(C)C
Product: Cc1nc2n(c(=O)c1CCN1CCC(=C(c3ccccc3)c3ccc(F)cc3)CC1)CCCC2
Yield: 60 %

Procedure:
A mixture of 4.5 parts of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride, 4.6 parts of 4-[(4-fluorophenyl)phenylmethylene]piperidine hydrochloride, 2 parts of a sodium methoxide solution 30%, 8 parts of sodium carbonate, 0.2 parts of potassium iodide and 240 parts of 4-methyl-2-pentanone was stirred and refluxed for 22 hours. The reaction mixture was filtered hot and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (92:8 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in acetonitrile and 2-propanol. The salt was filtered off and dried, yielding 4.8 parts (60%) of 3-[2-[4-[(4-fluorophenyl)phenylmethylene]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one dihydrochloride; mp. 264.6° C. (compound 137).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10]C(=O)O[C:7](=[O:12])[C:6]=2[CH:13]=1.[CH3:14][N:15]1[C:19]([CH2:20][Li])=[N:18][N:17]=[N:16]1>>[NH2:10][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:13][C:6]=1[C:7](=[O:12])[CH2:20][C:19]1[N:15]([CH3:14])[N:16]=[N:17][N:18]=1
Reactant: [Li]Cc1nnnn1C
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Product: Cn1nnnc1CC(=O)c1cc(F)ccc1N

Procedure:
In a similar manner to that described in Example 8(a), 6-fluoro-1H-3,1-benzoxazine-2,4-dione was reacted with (1-methyl-1H-tetrazol-5-yl)methyl lithium to give the novel compound 1-(2-amino-5-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone. This product was isolated as a gum which was used in the next stage without further purification.
Reaction SMILES: Cl[O-].[Na+].[OH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].[OH-].[Na+].[I-:16].[Na+]>CO>[OH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[I:16])[C:8]([OH:10])=[O:9]
Reactant: [I-]
Reactant: O=C(O)c1cccc(O)c1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(I)c(O)c1
Temperature: 0 °C
Reaction time: 72 h
Yield: 39.2 %

Procedure:
1319 g (1.52 mol) of commercial 9.6% sodium hypochlorite solution are added dropwise to a solution of 200 g (1.45 mol) of 3-hydroxybenzoic acid, 61 g (1.52 mol) of sodium hydroxide powder and 228 g (1.52 mol) of sodium iodide in 2 l of methanol cooled beforehand to 0° C. The reaction medium is stirred at room temperature for 72 hours. After evaporating off the methanol, the solution is cooled to 10° C. and acidified with aqueous hydrochloric acid solution to pH 2. The mixture is stirred for 2 hours and the product precipitates. The product is filtered off, washed thoroughly with water and dried under vacuum at 50° C. 150 g (39%) of 3-hydroxy-4-iodobenzoic acid are obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:22][CH2:23][CH3:24])=[C:4]([C:8]2[N:20]([CH3:21])[C:11]3=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([S:22]([CH2:23][CH3:24])=[O:33])=[C:4]([C:8]2[N:20]([CH3:21])[C:11]3=[N:12][CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCSc1c(Cl)cccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1c(Cl)cccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a mixture of 2-(3-chloro-2-ethylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.72 g) and chloroform (10 ml), 3-chloroperbenzoic acid (purity: 69-75%, 0.66 g) was added under ice-cooling, and then heated to room temperature, and stirred for 20 minutes. Into the reaction mixture, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were poured, and extracted with chloroform 2 times. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.67 g of 2-(3-chloro-2-ethylsulfinylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 89).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([OH:10])[C:6]([F:11])=[C:5]([F:12])[C:3]=1[OH:4].[C:13](O)(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>O1CCCC1>[C:13]([O:4][C:3]1[C:2]([F:1])=[C:8]([F:9])[C:7]([OH:10])=[C:6]([F:11])[C:5]=1[F:12])(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Oc1c(F)c(F)c(O)c(F)c1F
Reactant: CCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: C1CCOC1
Product: CCCCCCCCC(=O)Oc1c(F)c(F)c(O)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.2 %

Procedure:
2.0 g (11.0 mM) of 2,3,5,6-tetrafluorohydroquinone, 0.87 g (5.5 mM) of nonanoic acid, 1.13 g (5.5 mM) of dicyclohexylcarbodiimide and a catalytic amount of 4-pyrrolidinopyridine were added to 20 ml of tetrahydrofuran, followed by stirring for 3 hours at room temperature. After the reaction, the insoluble residue was filtered off, followed by distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: toluene) to obtain 0.57 g of an objective product (Yield: 32.2%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)[N:3]=[C:2]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Product: COc1cccc2c(-c3ccccc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and phenylboronic acid to give (5-Methoxy-1-phenyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 331(MH+).