Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:30])[C:5]([C:3]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 38 %

Procedure:
A mixture of 1,3-dibenzyl-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (75 mg, 0.19 mmol), glycine (1.87 g, 24.9 mmol) and NaOMe solution (37.5 mL, 18.8 mmol, 0.5M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2 with 4M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was further purified by silica gel chromatography (20-100% EtOAc/hexanes+2% AcOH) to give 32 mg of the title compound as an off-white solid. MS: (+) m/z 444.11 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)[C:7]#N.C(O)=[O:17]>[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)[CH:7]=[O:17]
Reactant: N#Cc1cc(Cl)ccc1OCC(F)(F)F
Reactant: O=CO
Agent: [Ni]
Product: O=Cc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, in a round-bottom flask equipped with a refluxcondenser were placed 400 mg (1.7 mmol) of the above nitrile and 10 ml of formic acid. To the system were added ca. 500 mg of Raney nickel and the mixture was heated at reflux for 6 hours and stirred at room temperature overnight. The mixture was filtered through a pad of a diatomaceous earth,and the pad was rinsed with water and CHCl3. The layers were separatedand the aqueous phase was extracted with three portions of CHCl3. The combined organic fractions were dried and concentrated to obtain 270 mg ofthe title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][CH:19]([OH:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:26][CH:19]([CH3:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCC(C)O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(C)OC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 4-benzyloxybenzoic acid chloride (1.23 g) in methylene chloride (10 ml) was added slowly under ice cooling a solution of optically active 2-octanol (0.59 g), dimethylaminopyridine (0.55 g) and triethylamine (0.48 g) in methylene chloride (20 ml). The mixture was left to stand until it reached room temperature and was left to stand overnight in order to complete the reaction. The solution was poured in ice water and extracted with methylene chloride. The extracted layer was washed with dilute hydrochloric acid, water, 1N aqueous sodium carbonate solution and water, in this order, and dried over anhydrous magnesium sulfate. After the extract was distilled to remove the solvent until a crude product was obtained, the product was purified by toluene-silica gel column chromatography and further recrystallized from ethanol to obtain the titled compound (1.48 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[C:10]([N:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[CH3:17])[CH:11]=[CH:12]2)=[N:7]1.[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>C(O)(C)C.Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[C:10]([N:16]([CH3:17])[C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:28][C:29]4[CH:30]=[C:31]([S:35]([NH2:38])(=[O:36])=[O:37])[CH:32]=[CH:33][CH:34]=4)[N:19]=3)[CH:11]=[CH:12]2)=[N:7]1
Reactant: Cc1c2ccc(N(C)c3ccnc(Cl)n3)cc2nn1Cc1cccc(Cl)c1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: Cl
Solvent: CC(C)O
Product: Cc1c2ccc(N(C)c3ccnc(Nc4cccc(S(N)(=O)=O)c4)n3)cc2nn1Cc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 2-(3-chlorobenzyl)-N-(2-chloropyrimidin-4-yl)-N,3-dimethyl-2H-indazol-6-amine (40 mg, 0.1 mmol) and 3-aminobenzenesulfonamide (17.3 mg, 0.1 mmol) in isopropanol (2 ml) was added 2 drops of conc. HCl. The mixture was heated to reflux overnight. The mixture was cooled to rt. Precipitate was collected via filtration and washed with EtOH. HCl salt of 3-({4-[[2-(3-chlorobenzyl)-3-methyl-2H-indazol-6-yl](methyl)amino]-pyrimidin-2-yl}amino)benzenesulfonamide was isolated as off-white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) δ 9.52 (br s, 1H), 8.54 (br s, 1H), 7.85 (d, J=5.9 Hz, 1H), 7.77-7.79 (m, 2H), 7.49 (s, 1H), 7.30-7.36 (m, 5H), 7.22 (br, s, 2H), 7.14 (br s, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.80 (d, J=5.8 Hz, 1H), 5.64 (s, 2H), 3.48 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 534 (M+H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.F[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33]>C(#N)C>[F:31][C:29]1[CH:28]=[CH:27][C:26]([N+:32]([O-:34])=[O:33])=[C:25]([NH:2][C@@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)[CH:30]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](N)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(F)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride (0.1 g, 0.453 mmol) and DIPEA (0.237 mL, 1.359 mmol) in ACN (3 mL) was added 2,4-difluoro-1-nitrobenzene (0.072 g, 0.453 mmol). The reaction was stirred overnight at 80° C. The reaction mixture was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide cis-4-(5-fluoro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide as a yellow powder (0.123 g, 84% yield).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:33][CH2:32]1)(=[O:36])[CH3:35]
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f18) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:15]Br>ClCCl>[C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([Br:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: BrBr
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Yield: 32.4 %

Procedure:
N-boc-4-piperidone (100 gm, 0.5 mole) obtained in step H1 was dissolved in 4.0 L of dichloromethane. Bromine (96.3 gm, 0.6 mole) in 100 ml of dichloromethane was added at room temperature under stirring and nitrogen bubbling. After completion of bromine addition, the reaction mixture was stirred further at room temperature for additional 30 minutes and then filtered. Filtrate was concentrated and crystallized by dichloromethane/petroleum ether to get the product N-boc-3-bromo-4-piperidone (45.0 gm).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1>C(N(CC)CC)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][C:14]1[CH:13]=[N:12][CH:11]=[C:10]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=1
Reactant: Cc1cncc(Br)c1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1cncc(C#Cc2ccccc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
Add phenylacetylene (0.460 mL, 4.2 mmol), copper (I) iodide (0.072 g, 0.38 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.133 g, 0.19 mmol) to a solution of 3-bromo-5-methylpyridine, (prepared essentially as described in PREPARATION 1), (0.654 g, 3.8 mmol) in degassed triethylamine (20 mL) and stir under nitrogen at 80° C. for 16 h. Cool the reaction mixture to room temperature, filter through diatomaceous earth, wash with ethyl acetate, and concentrate. Purify the residue by silica gel chromatography, eluting with 80:20 hexanes:ethyl acetate, to give the title compound as a brown oil (0.398 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]#[N:18])=[C:6]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[OH-:19].[Na+].OO.Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:17](=[O:19])[NH:18][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: N#Cc1ccc(Cl)cc1NC(=O)c1ccccc1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(-c2ccccc2)nc2cc(Cl)ccc12
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a suspension of N-(5-chloro-2-cyanophenyl)benzamide (150 mg, 0.58 mmol) in H2O (5 mL) was added in sequence NaOH (100 mg, 2.5 mmol) and H2O2 (30% in H2O, 0.25 mL, 2.2 mmol). The reaction was heated to 80° C. for 24 h then cooled to rt and stirred at rt for 1 d. Aq HCl (2 M, 6 mL) was added forming a thick precipitate that was collected by a filtration. The filter cake was washed with H2O several times affording the title compound as a creamy-white solid; MS (ES+): m/z 257.1 (100) [MH+]; HPLC: tR=3.34 min (OpenLynx, polar—5 min).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH2:19]([OH:23])[CH2:20][CH2:21][OH:22].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([O:22][CH2:21][CH2:20][CH2:19][OH:23])[CH:7]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reaction time: 18 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step ii), 3 g) and propane-1,3-diol (1.1 g) in THF (50 ml) was added NaH (390 mg) slowly and the reaction was then allowed to stir at mom temperature for 18 h. The reaction mixture was then partitioned between DCM (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow oil. Yield 2.95
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]2[C:19](=[O:36])[CH2:20][NH:21][C:22](=[O:35])[NH:23][C:24]2[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH:5]=[CH:6][CH:7]=1>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:9]2[C:19](=[O:36])[CH2:20][NH:21][C:22](=[O:35])[NH:23][C:24]2[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(c3ccccc3)CCC2c2cccc(O)c2)c1
Solvent: CO
Product: O=C(O)Cc1cccc(NC(=O)NCC(=O)N2C(c3ccccc3)CCC2c2cccc(O)c2)c1
Yield: 44.8 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 0.46 g of methyl (2RS,5SR)-3-{3-{2-[2-(3-hydroxyphenyl)-5-phenyl-1-pyrrolidinyl]-2-oxoethyl}ureido}phenylacetate in solution in 10 cm3 of methanol and 0.1 g of potassium hydroxide in solution in 2 cm3 of water, and after treatment and recrystallization in ethanol, 0.2 g of (2RS,5SR)-3-{3-{2-[2-(3-hydroxyphenyl)-5-phenyl-1-pyrrolidinyl]-2-oxoethyl}ureido}phenylacetic acid, melting at 166° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][NH:22][CH3:23]>O1CCCC1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:22]([CH3:23])[CH3:21])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CNC
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])cc1Cl
Solvent: C1CCOC1
Product: COc1cc(N(C)C)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-nitro-phenyl ester (1.0 g) in tetrahydrofuran (2.0 mL) is added dimethylamine (4.0 mL of a 40% aqueous solution) and the mixture is stirred at room temperature for approximately 15 hours. The solution is then concentrated under reduced pressure and the residue is dissolved in ethyl acetate and then washed with water. The aqueous layer is extracted once with ethyl acetate and the combined organic layers are washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is triturated with hexanes to provide the desired product as a colorless solid.
Reaction SMILES: [CH:1]([C:4]([CH3:22])([N:7]1[C:11](=[O:12])[CH:10]2[CH2:13][CH2:14][C:15]3[N:16]([CH3:20])[CH:17]=[CH:18][C:19]=3[CH:9]2[C:8]1=[O:21])[C:5]#[N:6])([CH3:3])[CH3:2]>ClC1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH:1]([C:4]([CH3:22])([N:7]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]3[N:16]([CH3:20])[CH:17]=[CH:18][C:19]=3[C:9]=2[C:8]1=[O:21])[C:5]#[N:6])([CH3:3])[CH3:2]
Reactant: CC(C)C(C)(C#N)N1C(=O)C2CCc3c(ccn3C)C2C1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: Clc1ccccc1
Product: CC(C)C(C)(C#N)N1C(=O)c2ccc3c(ccn3C)c2C1=O
Reaction time: 8 h
Yield: 11.2 %

Procedure:
Activated manganese dioxide (27.0 g, 0.310 mol) is added to a solution of 3,3a,4,5,6,8b-hexahydro-α-isopropyl-α,6-dimethyl-1,3-dioxobenzo[1,2-b:3,4-c']dipyrrole-2(1H)-acetonitrile (51.3 g, 0.167 mol) in chlorobenzene. The reaction mixture is stirred overnight at reflux temperature, cooled and filtered twice through diatomaceous earth with methylene chloride. The filtrate is concentrated in vacuo to a black oil which is flash chromatographed twice with methylene chloride then hexanes:methylene chloride to afford a yellow solid (5.50 g, 11.6%). Recrystallization from hexanes:methylene chloride afforded the title product, mp 123°-128° C.
Reaction SMILES: [C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=2[O:24]CC2C=CC=CC=2)=[C:11]([F:32])[CH:10]=1)[CH2:5][CH2:6][CH2:7][NH2:8])(=[O:3])[CH3:2].O1CCCC1>CO>[C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=2[OH:24])=[C:11]([F:32])[CH:10]=1)[CH2:5][CH2:6][CH2:7][NH2:8])(=[O:3])[CH3:2]
Reactant: CCc1ccc(Oc2ccc(N(CCCN)C(C)=O)cc2F)c(OCc2ccccc2)c1
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(N(CCCN)C(C)=O)cc2F)c(O)c1
Yield: 90.2 %

Procedure:
According to the procedure of example 20 (b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for N-acetyl-N1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine (70 mg, 0.16 mmol) and tetrahydrofurane for methanol (15 mL), the title compound (50 mg, 91%) was obtained as a brown liquid, after purification on silica gel (dichloromethane/ethyl acetate: 5/5)
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1.CN(C)C=O>CCOCC>[C:10]([Si:14]([O:9][CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][C:2]#[CH:1])([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCC(O)CCCC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CCC(CCCC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture consisting of 5 parts of 1-octyn-4(RS)-ol, 6.6 parts of tertiary-butyldimethylsilyl chloride, 6.8 parts of imidazole and 10 parts by volume of dimethylformamide is stirred at room temperature for about 16 hours, then is poured into ether. The resulting organic solution is washed several times with water, then dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure to afford 1-octyn-4(RS)-ol tertiary-butyldimethylsilyl ether, which exhibits a nuclear magnetic resonance maximum at δ0.9.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH:9]([CH2:12][CH3:13])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>C(O)CCC.[OH-].[Na+]>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:14](=[O:16])[C:3]3=[CH:4][NH:5][C:6]4[CH2:7][CH2:8][CH:9]([CH2:12][CH3:13])[CH2:10][C:11]=4[C:2]3=[N:27]2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CC(CC)CC2
Reactant: NNc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CCC1CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.6 g of ethyl 4-chloro-6-ethyl-5,6,7,8-tetrahydroquinoline-3-carboxylate in 30 ml n-butanol is treated with 1.38 g of 4-chlorophenylhydrazine at room temperature under nitrogen. After stirring at room temperature overnight, the reaction mixture is heated at reflux for 41/2 hours. The reaction mixture is cooled to room temperature, the precipitate is filtered off, washed with hexane and air-dried to yield a yellow solid. The crude product is dissolved in 30 ml 1N NaOH and extracted with ether. The aqueous layer is then treated with 1.6 g of NH4Cl. The precipitate which forms is filtered off, washed with water, and dried in a vacuum oven at 120° overnight to yield 2,3,6,7,8,9-hexahydro-2-p-chlorophenyl-8-ethylpyrazolo[4,3-c]quinolin-3-(5H)-one, m.p. 318°-320°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:16]=2[O:17][CH2:18][CH2:19][OH:20])[C:11](O)=[O:12])[CH:5]=[CH:6][CH:7]=1.[CH3:28][O:29][C:30]1[CH:45]=[CH:44][C:33]([C:34]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])=[O:35])=[CH:32][CH:31]=1>>[OH:20][CH2:19][CH2:18][O:17][C:16]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:9][C:10]([C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][O:36][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:45][CH:44]=2)=[O:12])=[CH:14][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1
Reactant: COc1ccc(C(=O)OCCCCCCN)cc1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Product: COc1ccc(C(=O)OCCCCCCNC(=O)c2cc(-c3cccc(Cl)c3)c(OCCO)c(-c3cccc(Cl)c3)c2)cc1

Procedure:
The product was prepared as a colorless, viscous oil (0.675 g, 71%) from 3,5-bis(3-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid (0.605 g, 1.5 mmol) and 4-methoxybenzoic acid, 6-aminohexyl ester (0.565 g, 2.25 mmol) using a procedure similar to step 3 of example 164; 1H NMR (400 MHz, DMSO-d6) 1.33-1.46 (m, 4H), 1.50-1.58 (m, 2H), 1.65-1.73 (m, 2H), 3.10-3.15 (m, 2H), 3.22-3.30 (m, 4H), 3.80 (s, 3H), 4.21 (t, J=6.6 Hz, 2H), 4.44 (t, J=6.6 Hz, 1H), 6.99-7.03 (m, 2H), 7.45-7.52 (m, 4H), 7.57-7.61 (m, 2H), 7.69 (s, 2H), 7.85-7.91 (m, 4H), 8.56 (t, J=5.5 Hz, 1H); IR (film) 3350, 2940, 1710, 1640, 1605, 1540, 1510, 1275 cm−1; mass spectrum[(+)ESI], m/z 636 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:34]=[CH:33][C:18]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:33][CH:34]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 59.3 %

Procedure:
A mixture of methyl 3-hydroxy-1-methyl-1H-pyrazol-4-ylacetate (245 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (452 mg), potassium carbonate (398 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 6 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 1-methyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-ylacetate (382 mg, yield 59%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: NCCN1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.C(N(CC)CC)C.[NH2:30][CH2:31][C@@H:32]([OH:34])[CH3:33]>C(O)C>[OH:34][C@@H:32]([CH3:33])[CH2:31][N:30]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1
Reactant: C[C@H](O)CN
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@H](O)Cn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C

Procedure:
A mixture of 5-benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate A, Step 3) (200 mg 0.59 mmol), triethylamine (82 μl, 0.59 mmol) and (S)-1-aminopropan-2-ol (44.6 mg 0.59 mmol) in ethanol (2 ml) was heated under microwave radiation for 1 hour. The reaction mixture was filtered and the residue rinsed with ethanol to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[OH-:14].[Na+]>CN1CCCC1=O>[Cl:1][C:2]1[C:10]([F:11])=[C:9]([Cl:12])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:14]
Reactant: O=C(O)c1cc(Cl)c(F)c(Cl)c1F
Reactant: [OH-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(O)c1cc(Cl)c(F)c(Cl)c1O
Temperature: 130 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
2.27 g (0.01 mole) of 3,5-dichloro-2,4-difluorobenzoic acid, 1.62 g (0.04 mole) of powdery 99% sodium hydroxide and 20 ml of 1-methyl-2-pyrrolidone were fed into a 100-ml four-necked flask provided with a thermometer, a stirrer and a reflux condenser. The mixture was stirred at 130° C. for 2 hours to give rise to a reaction. Then, the same post-treatment as in Example 2 was conducted to obtain 2.07 g of 3,5-dichloro-4-fluorosalicylic acid. The isolated yield was 91.4% relative to the 3,5-dichloro-2,4-difluorobenzoic acid used.