Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C.CN(C)C(=O)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O.CO>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[O:12][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1cc(Cl)c([N+](=O)[O-])cc1OC(=O)c1ccccc1
Yield: 93.4 %

Procedure:
377 g (2 moles) of 2-amino-4-chloro-5-nitrophenol and 280 ml (2 moles) of triethylamine were added to 1 liter of N,N-dimethylacetoamide, followed by dropping 281 g (2 moles) of benzoyl chloride at about 50° C. in about 30 minutes. After continuing the agitation for further 30 minutes, 1 liter of methanol and 1 liter of water were added to the reaction solution. The resulting crystals were filtered and washed with 1 liter of methanol, thereby obtaining 547 g (yield 94%) of captioned benzoate compound. m.p. 207°-210° C., IR spectrum νC=0, 1725 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[CH:19]([C:18]1[CH:21]=[CH:22][C:15]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:16][CH:17]=1)=[O:20]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1

Procedure:
1-(t-Butoxycarbonyl)piperazine (1.86 g, 10 mmol), p-fluorobenzaldehyde 27 (1.24 g, 10 mmol), and K2CO3 (1.74 g, 11 mmol) in dry pyridine (10 mL) are stirred at reflux under a nitrogen atmosphere for 24 h. Most of the solvent is removed under vacuum and the residue is partitioned between EtOAc (150 mL) and water (100 mL). The aqueous layer is washed with EtOAc (2×50 mL) and the combined organic layers are sequentially washed with 3% aq. citric acid (2×100 mL), water (100 mL), brine (100 mL), and dried (MgSO4). The solvent is removed under vacuum and the residue washed with hexanes and dried under vacuum. The product-can be used as such, or further purified by silica gel column chromatography (dichloromethane-MeOH gradient).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:16])[C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(O)(=O)C.S(=O)(=O)(O)O>O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:16])[C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(F)c2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2cc(F)c(F)c(F)c2c1=O
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 95.6 %

Procedure:
A mixture of 1.54 g of ethyl 1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 8 ml of glacial acetic acid, 6 ml of water and 1 ml of conc. sulfuric acid was stirred at 120° C. for 1.5 hours. After cooling, the crystals which precipitated were collected by filtration, and washed successively with water and ethanol to give 1.34 g of 1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as colorless needles. m.p. 295°-297° C. (decomp.)
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)(=O)=O)=CC=1.[CH2:18]([P:27]([O:32]CC)(=[O:31])[O:28]CC)[P:19]([O:24]CC)(=[O:23])[O:20]CC.C(P([O-])(=O)[O-])CP([O-])(=O)[O-]>>[N:12]1([CH2:11][CH:18]([P:27]([OH:32])(=[O:28])[OH:31])[P:19]([OH:24])(=[O:20])[OH:23])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Cc1ccc(S(=O)(=O)OCn2ccnc2)cc1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: O=P([O-])([O-])CCP(=O)([O-])[O-]
Product: O=P(O)(O)C(Cn1ccnc1)P(=O)(O)O

Procedure:
Reaction of (imidazol-1-ylmethyl) p-toluenesulfonate with tetraethyl methanediphosphonate and hydrolysis of the primary ethanediphosphonate in accordance with Example 2 gives 2-(imidazol-1-yl)ethane-1,1-diphosphonic acid of m.p. 255° C. (dec.) and salts thereof, e.g. the disodium salt.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:18][CH:19]=[C:20]([C:22](=[O:35])[C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[N:21]=2)=[CH:13][CH:12]=1)C(=O)OC(C)(C)C.[ClH:36]>C(Cl)Cl.O1CCOCC1>[ClH:36].[CH3:1][NH:2][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[S:18][CH:19]=[C:20]([C:22]([C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)=[O:35])[N:21]=2)=[CH:15][CH:16]=1
Reactant: COc1cc(C(=O)c2csc(-c3ccc(CN(C)C(=O)OC(C)(C)C)cc3)n2)cc(OC)c1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNCc1ccc(-c2nc(C(=O)c3cc(OC)c(OC)c(OC)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
At 0° C., to a solution of 71a (60 mg) in 5 mL CH2Cl2 was added a solution of HCl in 1,4-dioxane (4 N, 2 mL) and stirred at RT for overnight. The precipitate (2s-HCl) was filtered and washed with diethyl ether. Yield: 81.3%. 1H NMR (500 MHz, CDCl3) δ 10.0 (s, 1H), 8.29 (s, 1H), 8.05 (d, 2H, J=6.0 Hz), 7.74 (s, 2H), 7.72 (d, 2H, J=6.0 Hz), 4.15 (s, 2H), 3.99 (s, 3H), 3.96 (s, 6H), 2.61 (s, 3H). MS (ESI) m/z 399.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH:9]([C:15]([CH3:17])=O)[C:10]([O:12]CC)=[O:11]>>[NH:1](/[C:15](/[CH3:17])=[C:9](/[CH3:8])\[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(C)C(C)=O
Product: C/C(Nc1ccccc1)=C(\C)C(=O)O

Procedure:
In the process of the invention, the 3-methyl substituted compound among the starting 2-formyl-3-substituted-4-(hydroxy or acyloxy) quinoline derivatives represented by the general formula (II) can be prepared by subjecting aniline to dehydration condensation with ethyl 2-methylacetoacetate to form a 3-anilino-2-methylcrotonic acid derivative, followed by intramolecular cyclization by heating to high temperature of, preferably, 200° to 250° C. to obtain 2, 3-dimethyl-4-quinoline. Moreover, this compound may further reacted with an anhydrous alkanoic acid such as, for example, acetic anhydride, to obtain 2, 3-dimethyl-4-acyloxyquinoline, e.g. 2, 3-dimethyl-4-acetoxyquinoline, followed by oxidation with selenium dioxide in an aqueous organic solvent to obtain the derivative.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:37])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[C:16]([Cl:37])=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)c(F)c2)c1OC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccc(F)c(F)c2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 124(b) from 4-acetoxy-7-cyano-1-(3,4-difluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NCS in MeCN. The title compound, ESI MS (m/z): 434 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].[C:14]12([NH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH:29]=O)[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:14]12([NH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][N:4]([CH2:1][CH2:2][CH3:3])[CH:5]3[CH2:13][CH2:12][C:8]4[N:9]=[CH:10][S:11][C:7]=4[CH2:6]3)[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: O=CCCCC(=O)NC12CC3CC(CC(C3)C1)C2
Reactant: CCCNC1CCc2ncsc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCN(CCCCC(=O)NC12CC3CC(CC(C3)C1)C2)C1CCc2ncsc2C1
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of 395 mg (2 mmol) propyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-amine and 748 mg (3 mmol) N-adamantyl-5-oxopentanamide in 1,2-dichloroethane (20 mL) is stirred for about 30 minutes. Then 0.75 g (3 mmol) of sodium triacetoxyborohydride is added and the mixture is stirred overnight. After hydrolysation with 30 mL of 1N aqueous NaOH solution the organic phase is separated, dried over sodium sulfate and concentrated in vacuum. The crude product obtained is purified via column chromatography on silica gel.
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([NH2:33])[CH:27]=4)[C:15](=[O:25])[N:16]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][N:10]=2)=CC=1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[NH2:33][C:28]1[CH:27]=[C:26]([C:14]2[C:15](=[O:25])[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=3)[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2ccc(F)c(N)c2)c(=O)n3-c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cc2c(cn1)cc(-c1ccc(F)c(N)c1)c(=O)n2-c1ccccc1
Yield: 46.2 %

Procedure:
A suspension of Example A35 (2.5 g, 7 mmol) in 4-methoxybenzylmethylamine (5 mL) was heated at 160° C. for 3 h. The reaction mixture was cooled to RT and diluted with ether. The resultant white precipitate was collected by filtration and dried to obtained 7-((4-methoxybenzyl)(methyl)amino)3-(3-amino-4-fluorophenyl)-1-phenyl-1,6-naphthyridin-2(1H)-one (3 g, 77%), which was used in the next step without further purification. A suspension of 7-((4-methoxybenzyl)(methyl)amino)-3-(3-amino-4-fluorophenyl)-1-phenyl-1,6-naphthyridin-2(1H)-one (3.0 g, 6 mmol) in mixture of CF3CO2H and CH2Cl2 (3:7, 30 mL) was heated at reflux overnight. Then the solvent was removed under reduced pressure and the residue was recrystallized (EtOAc-petroleum ether) to give 3-(3-amino-4-fluorophenyl)-7-(methylamino)-1-phenyl-1,6-naphthyridin-2(1H)-one (1 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.43 (s, 1 H), 7.88 (s, 1 h), 7.60-7.50 (m, 3 H), 7.31-7.29 (m, 2 H), 7.10-6.75 (m, 4H), 5.26 (s, 1 H), 5.08 (s, 2 H), 2.63 (br s, 3 H); MS (ESI) m/z: 361.3 [M+H]+.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5](=[C:9]1[NH:14][CH2:13][CH2:12][CH2:11][S:10]1)[N+:6]([O-:8])=[O:7])[CH3:2].CC(C)=[O:17].I([O-])(=O)(=O)=O.[Na+].C(Cl)Cl>O>[CH2:1]([S:3]([CH2:4][C:5](=[C:9]1[NH:14][CH2:13][CH2:12][CH2:11][S:10]1)[N+:6]([O-:8])=[O:7])=[O:17])[CH3:2]
Reactant: CC(C)=O
Reactant: CCSCC(=C1NCCCS1)[N+](=O)[O-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CCS(=O)CC(=C1NCCCS1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2.34 g of 25 and 10 ml of acetone was added all at once to a solution of 2.25 g of sodium periodate in 15 ml of water. The resulting exothermic reaction was controlled between 25° and 35° by cooling. The mixture then was stirred at room temperature for 90 minutes, then was poured into a mixture of water and methylene chloride. The separated organic phase was washed with saturated sodium thiosulfate solution, and saturated sodium chloride. It then was dried (MgSO4) and the solvent evaporated under reduced pressure to give an oil, which was triturated with ether to give a yellow solid. This was chromatographed by a preparative thin layer chromatographic technique, on silica gel and using a mixture of methanol (2%) in methylene chloride as eluent, to give 26, as a yellow solid, m.p.: 102°-104°.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:7]=2[O:6][C:5](=O)[CH:4]=1)[CH3:2].[CH3:15][NH2:16]>>[CH3:15][N:16]1[C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[C:12]=2[C:3]([CH2:1][CH3:2])=[CH:4][C:5]1=[O:6]
Reactant: CN
Reactant: CCc1cc(=O)oc2c1C(=O)CCC2
Product: CCc1cc(=O)n(C)c2c1C(=O)CCC2

Procedure:
Prepared from 4-ethyl-5,6,7,8-tetrahydro-cumarin- 5-one and methanolic methylamine solution over 31 hours at ambient temperature.
Reaction SMILES: [Br-:1].O1CCO[CH:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N+:8]=1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Br-]>Br>[Br-:1].[CH:12]1[C:7]2[CH:3]=[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]3=[CH:13][N+:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(C[n+]2ccccc2C2OCCO2)cc1
Agent: Br
Agent: [Br-]
Product: c1ccc2c[n+]3ccccc3cc2c1
Yield: 87.6 %

Procedure:
A mixture of 1526.8 g (4.74 mol) of 2-(1,3-dioxolan-2-yl)-1-benzylpyridinium bromide in 9 L of 48% HBr solution was heated on a steam-bath until the bromide dissolved. The mixture was heated (heating mantle) in vacuo (aspirator) to remove HBr solution. The dry residue was suspended in 800 mL of HBr solution, cooled, and 4 L of THF was slowly added. The reaction mixture was filtered to afford 1080 g (87%) of benzo[b]quinolizinium bromide as a green solid. Benzo[b]quinolizinium bromide (586 g) was dissolved in 2.4 L of hot water and filtered to remove an insoluble dark material. The filtrate was cooled in ice-water for 4 h, filtered, and the residue was washed with water, dried in vacuo at room temperature for 9 days to afford 508.8 g (86.8%) of benzo[b]quinolizinium bromide (Formula II: R1 =R2 =R7 =H ;X- =Br-).
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][CH2:8][C@@H:9]([CH2:25][O:26][S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(C)(C)C.CC(C[AlH]CC(C)C)C.[BH4-].[Na+]>C(Cl)Cl>[OH:5][CH2:6][CH2:7][CH2:8][C@@H:9]([CH2:25][O:26][S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:28])=[O:29])[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:16])([CH3:17])[N:12]1[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CCC(=O)OC(C)(C)C)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H](CCCO)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-5-tert-butoxy-5-oxo-2-(tosyloxymethyl)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (317 mg, 0.58 mmol) in anhydrous DCM (8 mL) at −78° C. under N2 was added DiBAlH (1 M in hexane, 1.75 mL, 1.75 mmol) dropwise. After the addition, the reaction mixture was stirred for another 30 min. The reaction was quenched with MeOH (2 mL), followed by 50% Rochelle's salt aq solution and stirred 2 hr. The resulting solution was extracted with DCM (3×20 mL), the combined organic phases were concentrated and dissolved in THF/MeOH (10 mL, 4/1, v/v), and chilled to 0° C., NaBH4 (11 mg, 0.29 mmol) was added and stirred at this temperature for 30 min. The reaction was quenched by aqueous NH4Cl, then extracted with EtOAc (3×20 mL), the combined organic phases were washed with H2O, brine, and dried over Na2SO4, and filtered, and concentrated to give crude product (S)-tert-butyl 4-((R)-5-hydroxy-2-(tosyloxymethyl)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (255 mg, 92%). It was used without further purification.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([OH:25])[CH2:22][CH:23]=[CH2:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26](I)[CH3:27].[H-].[Na+]>C1COCC1>[C:14]([Si:1]([O:18][CH2:19][CH2:20][CH:21]([O:25][CH2:26][CH3:27])[CH2:22][CH:23]=[CH2:24])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:16])([CH3:17])[CH3:15]
Reactant: C=CCC(O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 1-(tert-butyl-diphenylsilanyloxy)-5-hexen-3-ol (Tetrahedron, 57, 4023-4034 (2001)) (5.0 g) and ethyl iodide (2.03 mL) in THF (10 mL) was added dropwise to a suspension of sodium hydride (60%, 1.85 g) in THF (40 mL) at 50° C. over 10 minutes. The reaction solution was stirred at 50° C. for one hour. Ethyl iodide (6.0 mL) was added to the solution at 50° C., and the mixture was stirred at 60° C. for 1.5 hours. The reaction solution was returned to room temperature and poured into ice water, followed by extraction with ethyl acetate. The extract was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain the title compound (4.1 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:25].[Li]CCCC.[CH:31]([CH:33]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]1)=[O:32]>C1COCC1>[C:40]([O:39][C:37]([N:35]1[CH2:36][CH:33]([CH:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)=[C:5]3[Cl:25])[OH:32])[CH2:34]1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -75 °C
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.0 g, 2.32 mmol, Intermediate 5: step d) was added THF (30 mL) at room temperature which resulted in a colorless homogeneous mixture. The solution was cooled to −75° C. and then n-BuLi (2.5 M in hexanes, 1.08 mL, 2.69 mmol) was added dropwise. After 2 minutes, tert-butyl 3-formylazetidine-1-carboxylate (545 mg, 2.94 mmol in 3 mL THF) was introduced. After 5 minutes, the reaction mixture was transferred to an ice-water bath and stirring was continued for 30 minutes. The reaction mixture was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (5×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was chromatographed on silica gel (20% EtOAc-hexanes increasing to 50% EtOAc) to provide the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])[CH2:9]2)=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([N:30]3[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]3)=[CH:7][CH:6]=2)[CH2:9][C:10]([C:20]([C:26]([F:27])([F:28])[F:29])([C:22]([F:25])([F:24])[F:23])[OH:21])=[N:11]1
Reactant: O=S1(=O)CCNCC1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2)C1)(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=S1(=O)CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 36 %

Procedure:
5-(4-Bromo-phenyl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (100.0 mg, 0.20 mmol) prepared in Step 4 of Preparation 17, thiomorpholine-1,1-dioxide (32.0 mg, 0.24 mmol), Pd2(dba)3 (9.0 mg, cat.), BINAP (12.0 mg, cat.) and sodium t-butoxide (29.0 mg, 0.30 mmol) were added to toluene (20.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 40.0 mg of the titled compound as a white liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:18])[C:10]([C:13]([CH3:17])([CH3:16])[CH:14]=O)=[N:11][N:12]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:18])[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:11][N:12]=1
Reactant: Nc1ccccc1
Reactant: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)CNc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-[5-(2-Chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]-2-methylpropanal (200 mg) was dissolved in 1,2-dichloroethane (4 ml) and then aniline (73 μl) and sodium triacetoxyborohydride (225 mg) were added thereto, followed by stirring at room temperature for 3 days. The reaction solution was diluted with a saturated aqueous sodium bicarbonate solution (30 ml), followed by extraction with chloroform (10 ml×3). The organic layer was dried and then concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (methanol:chloroform=2:98). The resulting solid washed with diethyl ether to obtain 98 mg of N-{2-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]-2-methylpropyl}aniline (white solid).
Reaction SMILES: BrC1C=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=CC=1.COC1C=CC(CN2CC(C)(C)NC2=O)=CC=1.[CH3:41][C:42]1[C:43]([N:49]2[CH2:54][CH2:53][N:52]([C:55]([C:57]3[CH:62]=[CH:61][C:60]([N:63]4[C:67]([CH3:69])([CH3:68])[CH2:66][N:65](CC5C=CC(OC)=CC=5)[C:64]4=[O:79])=[CH:59][CH:58]=3)=[O:56])[CH2:51][CH2:50]2)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1>>[CH3:41][C:42]1[C:43]([N:49]2[CH2:50][CH2:51][N:52]([C:55]([C:57]3[CH:58]=[CH:59][C:60]([N:63]4[C:67]([CH3:68])([CH3:69])[CH2:66][NH:65][C:64]4=[O:79])=[CH:61][CH:62]=3)=[O:56])[CH2:53][CH2:54]2)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1
Reactant: COc1ccc(CN2CC(C)(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cc3)C2=O)cc1
Agent: COc1ccc(CN2CC(C)(C)NC2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NCC4(C)C)cc3)CC2)c(C)c1

Procedure:
Using (4-bromophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165 and 1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one (112 mg) described in Preparation Example 54 and by the reaction and treatment in the same manner as in Example 426, the title compound (57 mg) was obtained via 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6].[NH3:16]>>[NH2:16][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1Cl
Reactant: N
Product: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1N
Temperature: 180 °C

Procedure:
A mixture of 79.0 g (grams) (320 mmol (millimole)) of 3-chloro-2-methyl-4-methylsulfonylbenzoic acid, 1.0 g (12.6 mmol) of cupric oxide, and 500 mL (milliliter) of concentrated aqueous ammonia was heated at 180° C. for 17 hours in a stirred Parr reactor. The resulting dark mixture was concentrated by evaporation under reduced pressure. The residue was acidified with 2N aqueous hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The extract was filtered and concentrated by evaporation under reduced pressure. The solid residue was mixed with hexane, recovered by filtration, and dried to obtain 50.0 g (68 percent of theory) of the title acid compound as a light tan powder melting at 197-198° C.