Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([NH:5][CH3:6])=[O:4].Cl>CO.C(Cl)Cl>[OH:1][C@@H:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([NH:5][CH3:6])=[O:4]
Reactant: CNC(=O)C(=O)C(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)[C@@H](O)C(C)(C)C

Procedure:
The experiment was carried out in an analogous manner to Example 1. The asymmetric hydrogenation of 55.0 g (0.384 mol) of 2-keto-3,3,N-trimethyl-butyramide in 270 ml of methanol and 30 ml of methylene chloride in the presence of a catalyst prepared from 296 mg (0.384 mmol) of [Ru(OAc)2((S)-BIPHEMP)] and 31 ml of a 0.025 molar methanolic hydrochloric acid solution gave, after crystallization, 34.4 g (62%) of (S)-2-hydroxy-3,3,N-trimethyl-butyramide, m.p.=60-62° C., [α]=−59.9° (c=1, CHCl3), ee=99.2%.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[Cl:8][C:9]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Oc2ccccc2)cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.0 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(2,6-dichlorobenzamido)-4-phenoxybenzoate and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 70 mg of 2-(2,6-dichlorobenzamido)-4-phenoxybenzoic acid as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]([OH:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C.CCOC(C)=O>[Si:22]([O:12][CH:8]1[CH2:7][CH2:6][CH2:5][C:4]2[N:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]1=2)([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: OC1CCCc2nc(Cl)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CCCc2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
A solution of 2-chloro-5,6,7,8-tetrahydroquinolin-5-ol (500 mg, 2.72 mmol) in DMF (10 mL) was treated with imidazole (260 mg, 3.81 mmol). After complete dissolution TBDMS-Cl was added and the resulting mixture was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc (40 mL) and was washed with brine (5×). The organic layer was collected, dried with Na2SO4, filtered, and the solvent was evaporated at reduced pressure yielding the titled compound as an oil. Amount 760 mg. Yield 94%.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:13][C@H:14]1[C@@H:18]([C:19]([F:22])([F:21])[F:20])[CH2:17][C:16](=N)[NH:15]1)CC1OC=C(C(O)=O)N=1.Cl.C[OH:26]>>[O:26]=[C:16]1[NH:15][CH:14]([CH2:13][CH:3]=[O:2])[CH:18]([C:19]([F:22])([F:21])[F:20])[CH2:17]1
Reactant: CO
Reactant: N=C1C[C@H](C(F)(F)F)[C@H](CC(O)Cc2nc(C(=O)O)co2)N1
Agent: Cl
Product: O=CCC1NC(=O)CC1C(F)(F)F

Procedure:
Isomer B: (±) (cis) 2-[2-hydroxy-3-[5-imino-3-(trifluoromethyl)pyrrolidin-2-yl]propyl]oxazole-4-carboxylic acid, monohydrochloride ##STR229## 224 A) The product of Example 223 B in MeOH is treated with HCl (1N) to yield 5-oxo-3-(trifluoromethyl)pyrrolidine-2-acetaldehyde which is used directly in the next step.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]2[NH:16][C:15](=[O:17])[C:14]3([CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18]3)[N:13]([C:24]([O-:26])=[O:25])[CH2:12]2)[CH:8]=[CH:9][CH:10]=1>CO>[C:7]([O:25][C:24]([N:13]1[C:14]2([CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23]2)[C:15](=[O:17])[N:16]([CH2:10][C:5]([OH:4])=[O:1])[CH:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH2:12]1)=[O:26])([CH3:11])([CH3:8])[CH3:6]
Reactant: COc1cccc(C2CN(C(=O)[O-])C3(COCCOC3)C(=O)N2)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(C2CN(C(=O)OC(C)(C)C)C3(COCCOC3)C(=O)N2CC(=O)O)c1

Procedure:
2.5 ml (2.5 mmol) of a 1N aqueous sodium hydroxide solution were added to 0.38 g (0.82 mmol) tert-butyl (3-(3-methoxyphenyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecane-1-carboxylate in 5 ml MeOH. After 1 h MeOH was distilled off and the aqueous solution was acidified with 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The ethyl acetate phase was dried and evaporated down.
Reaction SMILES: [NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH:9]([S:17][C:18]3[NH:22][N:21]=[N:20][N:19]=3)[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[F:35][C:36]([F:45])([F:44])[CH2:37][S:38]([CH2:40][C:41](O)=[O:42])=[O:39]>CN(C)C=O>[F:35][C:36]([F:45])([F:44])[CH2:37][S:38]([CH2:40][C:41]([NH:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH:9]([S:17][C:18]3[NH:19][N:20]=[N:21][N:22]=3)[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][S:8][C@H:3]12)=[O:42])=[O:39]
Reactant: CS(=O)(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)CS(=O)CC(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CS(=O)CC(F)(F)F)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
A suspension of 4.35 g (0.01 mol) of 7β-amino-3-[1-(2methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 50 ml of dry dimethylformamide is treated with 2 ml of triethylamine and the mixture is stirred for 15 minutes at 25°. A slight excess of 0.01 mol of the activated ester of 2,2,2-trifluoroethylsulfinylacetic acid is added to the mixture and it is stirred an additional hour. The reaction mixture is evaporated to dryness and water and ethyl acetate are added to the residue. The layers are separated, the ethyl acetate layer is discarded, fresh ethyl acetate is added to the aqueous phase and it is acidified to pH 2.5 by addition of 6N hydrochloric acid. The mixture is filtered, the layers are separated and the aqueous phase is extracted with ethyl acetate. The combined extracts are washed with water, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([OH:16])[CH:7]=1)[CH3:2].F[C:19]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:20]=1[CH:21]=[O:22]>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:9]=[C:8]([O:16][C:19]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:20]=2[CH:21]=[O:22])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(O)cc(C(F)(F)F)c1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Product: CCOC(=O)Cc1cc(Oc2ccc([N+](=O)[O-])cc2C=O)cc(C(F)(F)F)c1

Procedure:
(3-Hydroxy-5-trifluoromethyl-phenyl)-acetic acid ethyl ester and 2-fluoro-5-nitrobenzaldehyde were reacted according to the procedure described in Example 21, Step 5, to give [3-(2-formyl-4-nitro-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15]1=[O:27]>N1C=CC=CC=1>[CH:1]([O:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15]1=[O:27])=[O:2]
Reactant: O=CO
Reactant: O=C(O)c1nc2ccccc2n(CCO)c1=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=COCCn1c(=O)c(C(=O)O)nc2ccccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Formic acid (3 ml., 98%) was added dropwise to acetic anhydride (6 ml) which was cooled below 5°. The mixture was heated at 50° for 15 minutes and cooled to below 5° and added slowly to a cold (5°-10°) solution of 3,4-dihydro-4(2-hydroxyethyl)-3-oxo-2-quinoxalinecarboxylic acid (3.2 g) in pyridine (40 ml). The solution was allowed to warm to room temperature, stirred for 6 hours and the pyridine was distilled off under reduced pressure. Hydrochloric acid (50 ml., 2N) was added to the residue and the solid was filtered off and dried, m.p. > 100°. Attempts to recrystallise this compound from dimethylformamide resulted in the loss of the formyl group.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:34][C:35]1[C:44]2[C:39](=[CH:40][C:41](O)=[C:42]([CH3:45])[CH:43]=2)[CH:38]=[CH:37][N:36]=1.CCOC(/N=N/C(OCC)=O)=O>CN(C=O)C.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][C:42]=2[CH3:45])[C:35]([NH2:34])=[N:36][CH:37]=[CH:38]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2c(N)nccc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2c(N)nccc2cc1OC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (231 mg, 1.15 mmol), triphenylphosphine (301 mg, 1.15 mmol), 1-amino-7-methylisoquinolin-6-ol (200 mg, 1.15 mmol) in DMF (5 ml) at 0° C., under argon, was added dropwise diethylazodicarboxylate (181 [μL, 1.15 mmol). The mixture was then warmed to ambient temperature and stirred for 24 h. Methanol was added and the mixture loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol. The crude product was isolated and further purified using prep-HPLC to give 3-(1-Amino-7-methylisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester. A mixture of the (3-(1-Amino-7-methylisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (10 ml) and trifluoroacetic acid (3 ml) was stirred at ambient temperature overnight. The mixture was concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol. The crude product was isolated and further purified using prep-HPLC to give 7-methyl-6-(piperidin-3-yloxy)isoquinolin-1-ylamine, El-MS: m/z=258.3 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:15]=[C:14]([C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:34])[CH:12]=2)[CH:7]=1)C.O.[OH-].[Li+]>O1CCCC1.O>[F:34][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([CH2:5][C:4]([OH:35])=[O:3])[CH:15]=[C:14]2[C:16](=[O:33])[C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:26]2[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]2)(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(S(=O)(=O)c2ccc(C(=O)c3cc(CC(=O)O)cc4ccc(F)cc34)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.5 %

Procedure:
To a stirred solution of {6-fluoro-4-[4-(4-methyl-piperazine-1-sulfonyl)-benzoyl]-naphthalen-2-yl}-acetic acid ethyl ester (0.05 g, 0.10 mmol) in tetrahydrofuran (6 mL) was added a solution of lithium hydroxide monohydrate (0.021 g, 0.50 mmol) in water (1.5 mL) and the reaction mixture was stirred for 48 hours at room temperature. The solvents were distilled off under reduced pressure, then the residue was diluted with water (4 mL) and washed with ethyl acetate (2×3 mL) to remove unwanted organic products. The aqueous layer was separated and acidified to pH ˜3-4 with a 1.0 N aqueous solution of hydrochloric acid. The resulting mixture was extracted with ethyl acetate (2×10 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 0.020 g (42%) of {6-fluoro-4-[4-(4-methyl-piperazine-1-sulfonyl)-benzoyl]-naphthalen-2-yl}-acetic acid as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09-8.19 (m, 2 H), 7.84-8.05 (m, 5 H), 7.71 (s, 1 H), 7.48-7.61 (m, 1 H), 3.81 (s, 2 H), 2.97 (br. s, 4 H), 2.38 (br. s, 4 H), 2.15 (s, 3 H). MS cald. for C24H23FN2O5S ([M+H]+) 471, obsd. 471.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[CH:5]=[C:4](Cl)[N:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CS(C)=O>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: C1CNCCN1
Reactant: Nc1nc(Cl)cc2nc(-c3ccco3)nn12
Solvent: CS(C)=O
Product: Nc1nc(N2CCNCC2)cc2nc(-c3ccco3)nn12
Temperature: 150 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
Into 180 mL of DMSO, 10.5 g (44.6 mmol) of Compound E and 19.2 g (223 mmol) of piperazine were dissolved, followed by stirring at 150° C. for about 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by silica gel column chromatography (23% aqueous ammonia/methanol/chloroform=1/10/90) and then recrystallized from ethyl acetate to obtain 9.91 g of Compound F as a white solid (yield: 78%).
Reaction SMILES: [H-].[Na+].[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)C=CC=CC=1.[C:30]1(=[O:42])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([CH:40]=O)=[N:32][NH:31]1>CCCCCC.CS(C)=O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12](/[CH:11]=[CH:40]\[C:33]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30](=[O:42])[NH:31][N:32]=2)[CH:13]=1
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1n[nH]c(=O)c2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: O=c1[nH]nc(/C=C\c2cccnc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Under N2 atmosphere, 723 mg NaH (60% in oil; 18.1 mmol) is washed twice with hexane, 21 ml DMSO is added, and the mixture heated for 20 min to 70° C. (gas evolution). After cooling to RT, the mixture is diluted with 15 ml DMSO, 6.71 g (17.2 mmol) triphenyl(pyridin-3-yl-methyl)phosphonium chloride (for preparation, see 1a) is added in portions, and the blackish-yellow solution is stirred for 10 min (Wittig reagent). A second flask is prepared with 3.0 g (17.2 mmol) phthalazin-1(2H)-one-4-carbaldehyde in 39 ml DMSO under an inert gas. The above Wittig reagent is added and a little DMSO is then rinsed in. After stirring for 75 min at RT, the mixture is poured onto water/EtOAc, the aqueous phase separated off and extracted again twice with EtOAc. The organic phases are washed with water and brine, combined and extracted twice with 1 N HCl and then discarded. The acidic aqueous phases are immediately adjusted to alkaline pH with sat. Na2CO3 solution and extracted three times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation. This yields the title compound as an E/Z mixture: TLC (EtOAc) Rf=0.18/0.22; HPLC5-40 tR=9.2/9.6; FAB-MS (M+H)+=250.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]#[N:22].Cl.[NH2:24][OH:25]>C(O)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21](=[N:24][OH:25])[NH2:22]
Reactant: N#CCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl)=NO
Reaction time: 11 h
Yield: 86 %

Procedure:
To a hot solution of 1.0 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile in 75 ml of ethanol a solution of 0.42 g of hydroxylamine hydrochloride in 6.05 ml of 1 N sodium bicarbonate solution is added and heating is carried out at boiling for 11 hours under reflux. The solution is evaporated to dryness and recrystallised from methanol/water. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamidoxime is obtained with a yield of 86%; F 184°-186° (from toluene).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:11].[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH2:9][CH2:8][N:33]2[CH2:34][CH2:35][CH:30]([C:26]3[CH:25]=[C:24]([NH:23][C:21](=[O:22])[CH:20]([CH3:19])[CH3:36])[CH:29]=[CH:28][CH:27]=3)[CH2:31][CH2:32]2)=[CH:13][CH:14]=1
Reactant: O=C(CCCl)c1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(=O)c3ccc(Cl)cc3)CC2)c1

Procedure:
Procedure K (KI) and Scheme E (K2CO3) using 3-chloro-1-(4-chlorophenyl)-1-propanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 413.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[CH3:21])[CH:9]=[CH:10][C:11]=1[CH:12]=[O:13])[CH2:2][CH2:3][CH3:4].Br[CH2:23][C:24]1[N:28]([C:29]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:36])[N:27]=[CH:26][C:25]=1[CH:37]([CH3:39])[CH3:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:23][C:24]3[N:28]([C:29]4[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:36])[N:27]=[CH:26][C:25]=3[CH:37]([CH3:39])[CH3:38])=[CH:16][C:15]=2[CH3:21])[CH:9]=[CH:10][C:11]=1[CH:12]=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CBr
Reactant: CCCCOc1cc(-c2ccc(O)cc2C)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1cc(-c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)ccc1C=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
A solution of 3-butoxy-4′-hydroxy-2′-methyl-biphenyl-4-carbaldehyde (0.198 g, 0.696 mmol) and 5-bromomethyl-4-isopropyl-1-(2,6-dichloro-phenyl)-1H-pyrazole (0.242 g, 0.696 mmol) in DMF (2.0 mL) is treated with K2CO3 (0.192 g, 1.39 mmol). The mixture is stirred at 70° C. for 2 hours. The mixture is cooled to room temperature and quenched with water (10 mL). The mixture is extracted with ethyl acetate (20 mL×2), and the combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with 20% ethyl acetate in hexanes to give 3-butoxy-4′-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2′-methyl-biphenyl-4-carbaldehyde (0.125 g, 33%). ES/MS m/e 551.0; 553.0 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[C:22]([CH3:23])=[CH:21][C:11]3[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][O:14][C:10]=3[C:9]=2[CH3:24])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(S)C>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[C:22]([CH3:23])=[CH:21][C:11]3[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][O:14][C:10]=3[C:9]=2[CH3:24])=[CH:25][CH:26]=1
Reactant: CCOC(=O)Cc1coc2c(C)c(Oc3ccc(OC)cc3)c(C)cc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: CCOC(=O)Cc1coc2c(C)c(Oc3ccc(O)cc3)c(C)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
0.74 g (2.09 mmol) of ethyl 2-[6-(4-methoxyphenoxy)-5,7-dimethyl-1-benzofuran-3-yl]acetate, dissolved in 1 ml of dichloromethane, is [lacuna], at 0° C., to a solution of 0.84 g (6.26 mmol) of aluminum chloride and 0.65 g (10.44 mmol) of ethanethiol in 10 ml of dichloromethane. The reaction mixture is stirred overnight at room temperature, after which the solvent is removed in vacuo and the residue is subjected to chromatographic purification (cyclohexane/ethyl acetate=5.1). 0.52 g (73%) of ethyl 2-[6-(4-hydroxyphenoxy)-5,7-dimethyl-1-benzofuran-3-yl]acetate is obtained.
Reaction SMILES: C(O)C.C(=O)([O-])[O-].[K+].[K+].[Br:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1.Br[CH:19]([CH3:21])[CH3:20]>O>[Br:10][C:11]1[CH:12]=[C:13]([O:17][CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)Br
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cccc(Br)c1
Temperature: 78 °C
Yield: 89.8 %

Procedure:
The following reagents were combined sequentially: anhydrous ethanol (880 ml), potassium carbonate (448.0 g), 3-bromophenol (386.7 g), 2-bromopropane (400.0 g) and finally water (88 ml). The mixture was heated at reflux (78° C.) for 16 hours. Water (880 ml) was added to the reaction mixture and 900 ml of solvent was removed by distillation at atmospheric pressure during a 4 hour period. Heptane (880 ml) was added to the reaction mixture and later separated. The aqueous layer was extracted with heptane (80 ml) and the combined organic fractions were washed sequentially with 1N HCl (300 ml), water (300 ml), 1N NaOH (300 ml) and water (300 ml). Removal of the solvent by rotary evaporation (50° C., 5 mmHg) afforded 453.6 g (97%) of crude product. This was distilled through a short path distillation column (81°-85° C., 2 mmHg) to provide 431.5 g of the product as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:37][CH:38](I)[CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH:45](I)I>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][I:37])=[CH:16][CH:17]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[OH:22])[C:9]2=[O:30])=[CH:6][CH:7]=1
Reactant: IC(I)COCCOCC(I)I
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCOCCOCCI)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4 hydroxyphenyl)azetidin-2-one are dissolved in 10 ml of absolute dimethylformamide. 120 mg of powdered potassium carbonate and 0.4 ml of 1,2-bis(diiodoethoxy)ethane are then added. The reaction solution is stirred at room temperature overnight. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified using an SiO2 cartridge (n-heptane; n-heptane/ethylacetate 4:1). The product is obtained as an oil. C30H32F2INO5 (651) MS (ESI): M+-18
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][CH2:16][CH2:15]3)[N:3]=1.[H-].[Na+].[CH:23]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24]1.O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:4]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][CH2:16][CH2:15]3)[N:3]=1
Reactant: BrC1CCCC1
Reactant: Clc1nc(Nc2ccc3c(c2)CCC3)c2nc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nc(Nc2ccc3c(c2)CCC3)c2ncn(C3CCCC3)c2n1
Reaction time: 1 h
Yield: 69.5 %

Procedure:
(2-Chloro-9H-purin-6-yl)-indan-5-yl-amine (857 mg, 3 mmol) was dissolved in dry DMF (10 mL). NaH (94 mg, 3.9 mmol) was added in portions and the resulting mixture was stirred for 1 h. Cyclopentyl bromide (760 mg, 5.1 mmol) was then added and the reaction was stirred overnight at 80° C. under N2. After cooling, H2O (50 mL) was added and the mixture was extracted with CH2Cl2 (3×25 mL). The combined extracts were washed with brine (2×25 mL), dried over MgSO4, and evaporated. The residue was purified by flash chromatography (95:5 CH2Cl2/Et2O) to afford the title compound as a white powder (738 mg, 69.5%). TLC (95:5 CH2Cl2/Et2O): RF=0.38.