Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([OH:35])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:38][CH2:39][CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:11]=[C:12]([O:35][CH2:38][CH2:39][CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])[CH:13]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCCCBr
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCC(=O)OC)cc(C(=O)OCc2ccccc2)c1
Yield: 92.5 %

Procedure:
A mixture of 10.0 g (0.02 mol) of 3-hydroxy-5-(octadecyloxy)benzoic acid phenylmethyl ester, 4.3 ml (0.03 mol) of methyl 5-bromovalerate, 5.6 (0.04 mol) of potassium carbonate and 3.0 g (0.02 mol) of sodium iodide in 300 ml of acetone and 75 ml of DMF was stirred at reflux under argon for 40 hours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure to a solid which was recrystallized from methylene chloride-methanol to give 11.3 g (92% yield, mp 40°-42°) of 3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]benzoic acid phenylmethyl ester. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].[H-].[Na+].C(Cl)(=O)C([Cl:16])=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:16])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cl)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-Bromonicotinic acid (1 g, 4.950 mmol) is placed in a 100 ml round bottomed flask and purged with Argon. Dry THF (20 ml) is added and the resulting solution is treated with NaH (60% dispersed in mineral oil) (0.202 g, 5.049 mmol) over a period of 5 minutes. The reaction mixture is stirred at room temperature for 10 minutes and then oxalyl chloride (0.453 ml, 5.198 mmol) is added slowly over 5 minutes followed by dry DMF (10 ul). The reaction mixture is stirred for a further 5 minutes, filtered through filter paper, concentrated in vacuo and dried under vacuum to afford the title compound.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[C@@H:6]([CH2:8][OH:9])[NH2:7])[CH3:3].N(C(OCC1C=CC=CC=1)=O)[C@H](C(O)=O)CC(=O)OCC1C=CC=CC=1.COC(=O)[C@H](CC1C=CC=CC=1)N[C:42](=[O:55])[C@:43]([NH2:54])([CH2:50][C:51](=[O:53])[OH:52])[NH:44][C:45](=[O:49])[CH:46]([CH3:48])[CH3:47]>>[CH2:2]([O:4][C:5](=[O:10])[C@@H:6]([CH2:8][OH:9])[NH:7][C:42](=[O:55])[C@:43]([NH2:54])([CH2:50][C:51](=[O:52])[OH:53])[NH:44][C:45](=[O:49])[CH:46]([CH3:48])[CH3:47])[CH3:3]
Reactant: CCOC(=O)[C@H](N)CO
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@](N)(CC(=O)O)NC(=O)C(C)C
Agent: Cl
Agent: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Product: CCOC(=O)[C@@H](CO)NC(=O)[C@](N)(CC(=O)O)NC(=O)C(C)C

Procedure:
This compound was prepared from 1.7 g D-serine ethyl ester hydrochloride, 3.6 g Z-Asp(OBzl) and 1.8 g N-t-butoxycarbonyl-α-aminoisobutyric acid N-hydroxysuccinimide ester in a manner similar to Example 20 (A), (C), (D) and (E). Yield: 1.2 g, m.p.: 175°-178° C.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:23]=1>>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3([CH2:18][NH:19][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:24]5[N:23]=[C:22]([C:21]([F:37])([F:36])[F:20])[O:26][N:25]=5)[CH:28]=4)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2csc(-c3ccccc3)n2)CCOCC1
Product: O=C(NCC1(c2csc(-c3ccccc3)n2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 45 %

Procedure:
This compound was synthesized from (4-(2-phenylthiazol-4-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (85 mg, yield 45%). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (t, J=6.2 Hz, 1H), 8.41 (m, 1H), 8.18 (d, J=7.8 Hz, 1H), 8.05 (d, J=7.6 Hz, 1H), 7.91-7.89 (m, 2H), 7.69-7.65 (t, J=7.8 Hz, 1H), 7.53 (s, 1H), 7.46-7.43 (dd, J=4.8 Hz, 1.9 Hz, 3H), 3.79-3.76 (m, 2H), 3.54-3.52 (d, J=6.2 Hz, 2H), 3.37 (m, 2H), 2.26-2.22 (d, J=13.8 Hz, 2H), 1.89-1.84 (m, 2H). MS (ESI) m/z: Calculated for C24H21F3N4O3S: 514.13. found: 515.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2.[H-].[Na+].CN([CH:17]=[O:18])C>C1COCC1>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[N:6][NH:7]2)=[CH:3][C:2]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Fc1cc2[nH]ncc2cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cc2cn[nH]c2cc1F
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-bromo-6-fluoro-1H-indazole (3 g, 13.95 mmol) in THF (10 mL) was added to a suspension of NaH (3.38 g, 141 mmol) in THF (100 mL) over 10 min at 0° C. The RM was cooled to −70° C. then the s-Buli solution (1.4 M, 19 mL) was added slowly over 20 min. It was stirred at this temperature for 45 min. A solution of DMF (6.18 mL, 80 mmol) in THF (10 mL) was added over 15 min at −70° C. and the RM was then warmed up to rt over 1 h 30. The reaction was quenched with 100 mL of 1 N HCl. The RM was extracted twice with EtOAc. Then the organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed. The residue was triturated for 1 h with Et2O. The precipitate formed was filtered off and identified as the desired aldehyde. The filtrate was left in the freezer over night and a second batch of the product was filtered off to afford the title compound as a light yellow solid (tR 0.7 min (conditions 2), MH+=165, 1H-NMR in DMSO-d6: 13.50 (s, 1H); 10.15 (s, 1H); 8.39 (d, 1H); 8.32 (s, 1H); 7.45 (d, 1H)).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1)=[C:2]=[S:3].[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[CH3:15][O:14][C:8]1[CH:7]=[C:6]2[C:11](=[C:10]([O:12][CH3:13])[CH:9]=1)[C:2](=[S:3])[NH:1][CH2:4][CH2:5]2
Reactant: COc1cc(CCN=C=S)cc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1)C(=S)NCC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.8 %

Procedure:
To a solution of 245 mg (1.10 mmol) of thioisocyanate 9 in 12 mL of methylene chloride was added 219 mg (1.65 mmol) of aluminum trichloride in one portion at 0° C. After stirring for 2.5 h at room temperature, the reaction mixture was quenched by dropwise addition of water. The layers were separated and the aqueous layer was extracted twice with 10-mL portions of methylene chloride. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed over silica gel (eluted with ethyl acetate) to afford 223 mg (91%) of 10 as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 6.44 (s, 1H), 6.30 (s, 1H), 3.92 (d, J=1.2 Hz, 3H), 3.85 (d, J=1.2 Hz, 3H), 3.40-3.32 (m, 2H), 2.93-2.83 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[CH3:28][CH:29]1[CH2:33][C:32]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=2[O:30]1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:3]1[N:4]([C:35]2[CH:36]=[CH:37][C:31]3[O:30][CH:29]([CH3:28])[CH2:33][C:32]=3[CH:34]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1Cc2cc(B(O)O)ccc2O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc3c(c2)CC(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 99.8 %

Procedure:
A mixture of 4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (3.0 g), (2-methyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (3.0 g), copper(II) acetate (3.1 g), pyridine (3.1 mL), triethylamine (3.4 mL), molecular sieves 4 A (6.0 g) and dichloromethane (60 mL) was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (4.1 g, 100%) as a pale-yellow liquid.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][N:5]=[C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]1=[N:15][OH:16].[CH2:17]1[O:19][CH2:18]1.C(O)(=O)C>O>[CH3:3][O:4][N:5]=[C:6]([C:7]1[O:19][CH2:18][CH2:17][O:16][N:15]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CON=C1C(=NO)Oc2ccccc21
Reactant: C1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CON=C(C1=NOCCO1)c1ccccc1O
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
At 20° C., 19.8 g (0.3 mol) of potassium hydroxide pellets are added to a suspension of 38.4 g (0.2 mol) of benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime in 400 ml of water and the mixture was stirred for 30 minutes, on which a solution forms. At 20° C., 17.6 g (0.4 mol) of ethylene oxide are introduced over a period of 75 minutes, and the mixture is stirred at 20° C. overnight, on which a precipitate forms. The mixture is then stirred at 60° C. for 11 hours, on which the precipitate redissolves. The solution is cooled and acidified to pH 5-6 with glacial acetic acid. The crystalline product is filtered off with suction, washed with 300 ml of water a little at a time and dried at 45° C. in a vacuum drying cabinet. 19.6 g (39.3% of theory) of (5,6-dihydro-[1,4,2]dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone O-methyl-oxime are obtained.
Reaction SMILES: [C:1]([C:6]1[N:10]2[CH:11]=[C:12]([CH3:26])[CH:13]=[C:14]([NH:15][CH2:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=3[CH3:25])[C:9]2=[N:8][C:7]=1[CH3:27])(OCC)=[O:2].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1>[CH3:27][C:7]1[N:8]=[C:9]2[C:14]([NH:15][CH2:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=3[CH3:25])=[CH:13][C:12]([CH3:26])=[CH:11][N:10]2[C:6]=1[CH2:1][OH:2]
Reactant: CCOC(=O)c1c(C)nc2c(NCc3c(C)cc(F)cc3C)cc(C)cn12
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(NCc2c(C)cc(F)cc2C)c2nc(C)c(CO)n2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.4 g (1.1 mmol) of 3-carboethoxy-2,6-dimethyl-8-(2,6-dimethyl-4-fluorobenzylamino)-imidazo[1,2-a]pyridine in 10 ml toluene was chilled with ice-water, (2.1 g, 6.6 mmol). Red-l 65% in toluene was added after 30 min. The solution was stirred for 2 h at room temperature. 10 ml of Rochelle-salt solution, (35 g sodium potassium tartrate tetrahydrate/250 ml water) was added dropwise, 10 ml toluene was added, the organic layer was separated, washed with water, dried over sodium sulfate and evaporated under reduced pressure.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C([O-])([O-])=O.[Na+].[Na+].[C:21]([NH:24][C:25]1[C:26](Cl)=[N:27][CH:28]=[CH:29][CH:30]=1)(=O)[CH3:22].[OH-].[Na+]>C1COCC1>[CH3:22][C:21]1[S:2][C:26]2[C:25]([N:24]=1)=[CH:30][CH:29]=[CH:28][N:27]=2
Reactant: CC(=O)Nc1cccnc1Cl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc2cccnc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosphorus pentasulfide (56.5 g) and Na2CO3 (13.7 g) were mixed together in 400 mL of THF for ~30 min. To this solution, a solution of the product of Step 1 (17.32 g) in 100 mL of THF was added and the mixture was stirred at room temperature overnight. 2M NaOH (500 mL) was added and the mixture was stirred at room temperature for 2 hr. The product was extracted in EtOAc, washed with brine, dried over Na2SO4, and purified by flash chromatography on silica with EtOAc: toluene 20:80; yield: 12.07 g, (83%).
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C([Li])CCC.[CH3:19][CH:20]1[CH2:25][C:24](=[O:26])[CH2:23][CH2:22][N:21]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C(OCC)(=O)C.O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:24]2([OH:26])[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH:20]([CH3:19])[CH2:25]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1CC(O)(c2ccc(F)cc2)CCN1C(=O)OC(C)(C)C
Yield: 100.7 %

Procedure:
To a tetrahydrofuran solution (10 mL) of 1-bromo-4-fluorobenzene (492 mg, 2.81 mmol), n-butyl lithium (1.62 M, hexane solution) (1.73 mL, 2.81 mmol) was added at −78° C. and the resultant mixture was stirred for 40 minutes. To the reaction solution, a tetrahydrofuran solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (500 mg, 2.34 mmol) was added and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product (729 mg) of the title compound.
Reaction SMILES: C(O)C.[OH-].[Na+].C([O:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]4[O:35][CH2:36][O:37][C:31]=4[CH:30]=3)[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:38])[CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])C>O>[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]4[O:35][CH2:36][O:37][C:31]=4[CH:30]=3)[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:38])[CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)([OH:10])=[O:8]
Reactant: CCOC(=O)C1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(Cl)ccc3n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(Cl)ccc3n2)CC1
Yield: 97.9 %

Procedure:
10 ml of ethanol, 5 ml of water and 820 mg of sodium hydroxide were added to 1 g of 2-(4-ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was refluxed for 20 minutes, concentrated under a reduced pressure and neutralized with 1N hydrochloric acid. The crystals thus precipitated were recovered by filtration to give 920 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]\[C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: COC(=O)/C=C\c1ccc(-c2nc(-c3ccc(OC(C)C)c(Cl)c3)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(/C=C\C(=O)O)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.4 %

Procedure:
To a solution of (Z)-methyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)acrylate (30 mg, 0.075 mmol) in EtOH (2 mL) was added 2N aqueous NaOH (2 mL). The reaction was stirred at room temperature, under nitrogen, for 2 hours. Reaction was acidified via addition of 1N HCl, until a precipitate formed. Solid was collected by filtration, washed with 0.2N HCl, and dried in a vac oven to give (Z)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)acrylic acid (8.2 mg, 28.3%). LCMS (Table 1, Method c) Rt=2.64 min, m/z 385.12 (M+H)+. 1H NMR (400 MHz, DMSO) δ ppm 13.11-12.20 (m, 1H), 8.15 (d, 2H), 8.04 (d, 1H), 7.99 (dd, 1H), 7.78 (d, 2H), 7.37 (d, 1H), 7.03 (d, 1H), 6.12 (d, 1H), 4.81 (sept., 1H), 1.33 (d, 6H)
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[Br:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][NH:39][C:38](=[O:42])[CH:37]=2)=[N:32][CH:33]=1.Cl[CH2:44][C:45]([C:47]1[CH:56]=[C:55]2[C:50]([CH2:51][CH2:52][N:53]([C:57](=[O:62])[C:58]([F:61])([F:60])[F:59])[CH2:54]2)=[CH:49][CH:48]=1)=[O:46]>>[Br:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][N:39]([CH2:44][C:45](=[O:46])[C:47]3[CH:56]=[C:55]4[C:50]([CH2:51][CH2:52][N:53]([C:57](=[O:62])[C:58]([F:61])([F:59])[F:60])[CH2:54]4)=[CH:49][CH:48]=3)[C:38](=[O:42])[CH:37]=2)=[N:32][CH:33]=1
Reactant: O=c1cc(OCc2ccc(Br)cn2)cc[nH]1
Reactant: O=C(CCl)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Product: O=C(Cn1ccc(OCc2ccc(Br)cn2)cc1=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2

Procedure:
4-(5-Bromo-pyridin-2-ylmethoxy)-1-{2-oxo-2-[2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-ethyl}-1H-pyridin-2-one is prepared following preparation 15b (in acetonitrile as solvent) from 3.50 g (12.5 mmol) 4-(5-bromo-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 22.2) and 3.81 g (12.5 mmol) 1-[7-(2-chloro-acetyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone.
Reaction SMILES: [CH:1]1([C:7]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[CH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N)(=[O:19])C.[OH-].[K+]>C(O)(=O)C.C(OC(=O)C)(=O)C.C(Cl)Cl.CO>[CH:10]1([C:7]([OH:16])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8](=[O:19])[CH3:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC(N)=O
Reactant: C#CC(O)(c1ccccc1)C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)C(O)(c1ccccc1)C1CCCCC1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a solution of 204.8 g (0.95 mole) of 1-cyclohexyl-1-hydroxy-1-phenyl-2-propyne in 1500 mL of acetic acid and 150 mL of acetic anhydride was added 305 g (0.95 mole) of mercuric acetate. The reaction mixture was stirred overnight and then poured into a 3-L round bottomed flask equipped with an overhead stirrer and diluted with 1500 mL of methylene chloride. To this was added 86 g (1.18 mole) of acetamide and 1 L of celite. After being stirred overnight, the mixture was filtered through a large pad of celite. The filtrate washed three times with water twice with a 5% aqueous solution of sodium hydroxide, and once with brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was dissolved in a solution of 76 g (1.14 mole) of potassium hydroxide in 1250 mL of methanol and heated to reflux for 4 hours; the solution was cooled and then poured onto ice. The mixture was extracted four times with methylene chloride. The organic layers were combined, washed four times with water, once with brine, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. Distillation of the residue bulb-to-bulb, bath temperature 100° C. at 0.1 mm Hg, gave 189 g of 1-cyclohexyl-1-hydroxy-1-phenyl-2-propanone, NMR (CDCl3) 1.1-1.4 (m, 6 H), 1.5-1.9 (m, 4 H), 2.1 (s, 3 H), 2.4 (m, 1 H), 4.5 (s, 1 H), 7.2-7.6 (m, 5 H); IR (neat film) 3450, 2925, 2850, 1710, 1490, 1447, 1360 cm-1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:22]([CH:26]=1)[C:23](O)=[O:24]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:16][CH:15]3[CH2:14][N:13]([C:23]([C:22]4[CH:26]=[C:18]([F:17])[CH:19]=[CH:20][C:21]=4[C:27]4[N:28]=[CH:29][CH:30]=[CH:31][N:32]=4)=[O:24])[CH2:12][CH:11]3[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: Cc1cnc(C)c(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Product: Cc1cnc(C)c(N2CC3CN(C(=O)c4cc(F)ccc4-c4ncccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 34 and Intermediate 13. MS MS (ESI): mass calculated for C23H23FN6O, 418.47; m/z found 419.2 [M+H]+.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.[CH3:9][N:10]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[C:11]1[CH2:25][OH:26]>O=[Mn]=O>[CH3:9][N:10]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[C:11]1[CH:25]=[O:26]
Reactant: Cc1cn(C)c(CO)c1-c1ccccc1[N+](=O)[O-]
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cn(C)c(C=O)c1-c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
100 mg of MnO2, prepared according to Attenburrow's method, are suspended in a carbon tetrachloride/methylene chloride (4:1) mixture containing 500 mg of alcohol (12). The reaction medium is stirred at room temperature for 11/2 hours. The oxidizing agent is then filtered on celite. 230 mg of compound (13) are obtained (Yld:46%). This compound is purified by chromatography on a silica column (eluent:ethyl acetate/hexane, 1:1). It has the appearance of a yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][CH:26]=1)[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:20]([O:22]C)=[O:21])[CH:13]=[C:14]([CH:19]=1)[C:15]([O:17]C)=[O:16])=[O:4].[OH-].[K+]>CCO>[C:3]([C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][CH:26]=1)[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:20]([OH:22])=[O:21])[CH:13]=[C:14]([CH:19]=1)[C:15]([OH:17])=[O:16])([OH:4])=[O:2]
Reactant: COC(=O)c1cccc(COc2cc(C(=O)OC)cc(C(=O)OC)c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(COc2cc(C(=O)O)cc(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of dimethyl 5-[3-(methoxycarbonyl)benzyloxy]isophthalate (6.36 g, 16.5 mmol) in the mixture of KOH (15% aq., 45 mL) and EtOH (100 mL) was refluxed for 0.5 h, then cooled to room temperature and stirred overnight. The formed solution was extracted with dichloromethane (50 mL). The aqueous layer was separated, acidified with HCl conc. (to pH 2), and bulky precipitate formed was filtered and air-dried. White microcrystals; yield 4.71 g (97%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([OH:11])=[C:7]([CH:10]=1)C#N)=[O:2].[OH:15][C:16]1C=CC(C=O)=C[C:17]=1[O:24]CCO>>[OH:11][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([CH:1]=[O:2])=[CH:10][C:7]=1[O:15][CH2:16][CH2:17][OH:24]
Reactant: O=Cc1ccc(O)c(OCCO)c1
Reactant: N#Cc1cc(C=O)cc([N+](=O)[O-])c1O
Product: O=Cc1cc(OCCO)c(O)c([N+](=O)[O-])c1

Procedure:
Followed procedure described for Intermediate 61, starting from the 4-hydroxy-3-(2-hydroxyethoxy)benzaldehyde to give desired product, Intermediate 71.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].[N:17]([O-])=O.[Na+].Cl[Sn]Cl.O>Cl>[Cl:16][C:15]1[CH:14]=[CH:13][C:4]([CH2:5][NH:6][C:7](=[O:12])[C:8]([F:9])([F:10])[F:11])=[CH:3][C:2]=1[NH:1][NH2:17]
Reactant: O=N[O-]
Reactant: Nc1cc(CNC(=O)C(F)(F)F)ccc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(CNC(=O)C(F)(F)F)ccc1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 15385.3 %

Procedure:
To a cold solution of N-(3-amino-4-chlorobenzyl)-2,2,2-trifluoroacetamide (0.500 g, 0.017 mmol) in 6N HCl (50.0 mL), aqueous solution of NaNO2 (1.29 g, 0.018 mmol) was added at 0° C. and the reaction mass was stirred at 0-5° C. for 30 min. The reaction mass was added to a solution of SnCl2.H2O (22.18 g, 0.98 mmol) in 6N HCl at 0-5° C. and further continued stirring for 5-6 h at same temperature. The reaction mass was cooled, basified and extracted with DCM. The organic layer was separated, dried and concentrated to afford 0.700 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 4.22 (br s, 2H), 4.29 (d, J=6.0 Hz, 2H), 6.42-6.67 (m, 2H), 7.14-7.16 (m, 2H), 9.98 (br s, 1H).