Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([O:8][C:9]1[CH:10]=[C:11]([C:18](Cl)=[O:19])[CH:12]=[C:13]([CH:17]=1)[C:14](Cl)=[O:15])(=[O:7])[CH3:6].Cl.C(Cl)Cl.F[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:5]([O:8][C:9]1[CH:10]=[C:11]([C:18](=[O:19])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:12]=[C:13]([C:14](=[O:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:17]=2)[CH:17]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1cc(C(=O)Cl)cc(C(=O)Cl)c1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Oc1cc(C(=O)c2ccccc2)cc(C(=O)c2ccccc2)c1
Temperature: 17.5 °C
Reaction time: 12 h

Procedure:
Into a 250 mL three-necked, round-bottomed flask equipped with a magnetic stirrer, a nitrogen inlet, and a dropping funnel, aluminum chloride (10.85 g, 81.4 mmol) and fluorobenzene (80 mL) were introduced. The flask was then placed in an ice-water bath with its temperature maintained between 15-20° C. The solution of 5-acetyloxyisophthaloyl dichloride (8.5 g, 32.5 mmol) in fluorobenzene (20 mL) was then added dropwise for 20 min. The reaction mixture was then allowed to warm up to room temperature and stand with stirring at room temperature for 12 h. The resulting light brown solution was poured into ice-water (500 mL) containing hydrochloric acid (50 mL). Methylene chloride (50 mL) was then added to the mixture and the organic layer was separated with the aid of a separatory funnel. The solvent of the organic extract was then removed on a rotary evaporator. The resulting yellow jelly-like residue was further dried under the reduced pressure to give 11.8 g of 1-acetoxy-3,5-bis(benzoyl)benzene (95.5% crude yield). The 1-acetoxy-3,5-bis(benzoyl)benzene was then dissolved in ethanol (130 mL), followed by the addition of a solution of potassium hydroxide (10.0 g, 178 mmol) in water (20 mL). The resulting mixture was subsequently heated under the reflux for 1.5 h. After it was allowed to cool to near room temperature, the solution was poured into ice-water (500 mL) containing hydrochloric acid (50 mL). The precipitates were collected by suction filtration, air-dried overnight and finally recrystallized from toluene to afford 9.9 g (90% overall yield) of 3,5-Bis(4-fluorobenzoyl)phenol as white crystals, m.p. 133.5-134° C. Anal. Calcd. for C20H12F2O3: C, 71.01%; H, 3.58%; O, 14.19%. Found: C, 70.79%; H, 3.98%; O, 14.51%. FT-IR (KBr, cm−1): 1596, 1657, 3298. Mass spectrum (m/e): 338 (M+, 100% relative abundance). 1H-NMR (CDCl3, δ in ppm): 7.13-7.19 (d, 4H, Ar), 7.48-7.49 (d, 2H, Ar), 7.53-7.54 (d, 1H, Ar), 7.84-7.89 (dd, 4H, Ar). 13C-NMR (CDCl3, δ in ppm): 115.71, 120.52, 121.96, 132.73, 133.36, 138.83, 157.69, 167.34, 194.32.
Reaction SMILES: C(C1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=3[S:8](=[O:21])(=[O:20])[C:7]=2[CH:22]=1)#N.S(=O)(=O)(O)O.[C:28]([OH:31])(=[O:30])[CH3:29]>>[N+:17]([C:14]1[CH:15]=[CH:16][C:9]2[S:8](=[O:21])(=[O:20])[C:7]3[CH:22]=[C:29]([C:28]([OH:31])=[O:30])[CH:4]=[CH:5][C:6]=3[CH:12]=[CH:11][C:10]=2[CH:13]=1)([O-:19])=[O:18]
Reactant: CC(=O)O
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1C=C2
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1C=C2

Procedure:
400 Mg. 3-cyano-8-nitrodibenzo[b,f]thiepin-5,5-dioxide is refluxed in 5 cc. acetic acid and 5 cc. 50% aqueous sulfuric acid for 24 hours. The mixture is cooled down, the crystallized material is filtered, washed with water, dried at 135° C. in vacuum to yield 345 mg. (81.2%) acid, m.p. 310°-312° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.C([Li])CCC.C([O-])(=O)CC([O-])=O.[F:22][C:23]1([F:29])[CH2:25][CH:24]1C(Cl)=O.[Mn]([O-])(=O)(=O)=O.[K+].C(=O)([O-])O.[Na+]>C1COCC1.[Cl-].[Na+].O>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([CH:24]1[CH2:25][C:23]1([F:29])[F:22])=[O:5])[CH3:9]
Reactant: O=C(Cl)C1CC1(F)F
Reactant: CCOC(=O)CC(=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=C([O-])CC(=O)[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)C1CC1(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To monoethyl malonate (2.164 g, 16.4 mmol) in a round bottom flask under inert argon atmosphere was added 60 ml of THF and the vessel was cooled to −78° C. To this was added n-butyllithium solution (20.48 ml of 1.6 M in hexane, 32.8 mmol) and the temperature was raised gradually until it reached 0° C. for 15 minutes. The lithiated malonate solution was then cooled to −78° C. again and the crude 2,2-difluoro-cyclopropanecarbonyl chloride dissolved in THF (10 mL) was added drop wise over 20 minutes and the reaction mixture was warmed to 0° C. at which time the reaction was complete as shown by TLC (potasiumpermanganate stain). The reaction mixture was then worked up with (2×20 ml) saturated sodium hydrogen carbonate solution and (1×20 ml) saturated brine solution. This was then extracted with (2×20 ml) ethyl acetate and the organic portion of the reaction mixture was then reduced in-vacuo and subsequently adsorbed onto silica and chromatographed (AcOEt 10:90 heptane). Combination of the desired fractions and evaporation afforded 3-(2,2-difluoro-cyclopropyl)-3-oxo-propionic acid ethyl ester (678 mg, 43% yield) as a colourless liquid. MS (ESI+): 193.3, 4 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:23])[C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[NH:10][C:11]3([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]3)[C:12]=2[OH:13])[CH:7]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].N1C=CC=CC=1.Cl>C(#N)C>[CH2:28]([O:27][C:25](=[O:26])[O:13][C:12]1[C:11]2([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[NH:10][C:9](=[O:21])[C:8]=1[C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([F:23])[C:5]=1[CH3:22])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: CON1CCC2(CC1)NC(=O)C(c1cc(Br)cc(F)c1C)=C2O
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC(=O)OC1=C(c2cc(Br)cc(F)c2C)C(=O)NC12CCN(OC)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(5-bromo-3-fluoro-2-methyl-phenyl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (350 mg) and ethyl chloroformate (77 μl) in acetonitrile (2 ml) was added pyridine (80 μA) and the reaction mixture stirred at room temperature for one hour. The mixture was poured on diluted HCl and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/cyclohexane 3:1). Yield: 310 mg of carbonic acid 3-(5-bromo-3-fluoro-2-methyl-phenyl)-8-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester ethyl ester (title compound E4) as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:2][CH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc2c(c1)ncn2-c1cccc(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)ncn2-c1cccc(CO)c1
Temperature: 0 °C

Procedure:
1-(3-Carboxyphenyl)-5-methylbenzimidazole (2 g, 0.079 mM) was dissolved in dry tetrahydrofuran (100 ml) and cooled to 0° C. Lithium aluminium hydride (7.9 ml, 1.0 M solution) was added dropwise over 10 minutes. After complete addition the reaction was heated to reflux for 4 hours. The reaction was cooled and quenched by addition of water (2 ml) and 2N sodium hydroxide (4 ml). The reaction was diluted with ethyl acetate and filtered through hyflo, washing with ethyl acetate. Dried over magnesium sulphate and evaporated (1.2 g). MS M+ 239.
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24]([O:30]C)=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=5)[CH:20]=[C:19]([CH3:32])[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[Si](I)(C)(C)C.CO>CC#N>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24]([OH:30])=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=5)[CH:20]=[C:19]([CH3:32])[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ncc(C)cc1-c1cc(C)cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)n1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: CC#N
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(-c2cc(C)cnc2O)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
To a suspension of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (70 mg, 0.15 mmol) in CH3CN (3 mL) was added TMSI (44 uL, 0.30 mmol) dropwise at 20° C. The reaction was stirred at 50° C. for 30 min. MeOH (1.0 mL) was added and the solution was re-partitioned between EtOAc and H2O, washed with NaHSO3 (2×), brine, dried over MgSO4 and evaporated to dryness to yield a white solid. The crude material was further purified by column chromatography (0-10% MeOH-EtOAc) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-hydroxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (62 mg, 91%). H NMR (400 MHz, MeOD) 7.81 (s, 2H), 7.65 (s, 1H), 7.31 (d, J=1.5 Hz, 1H), 7.25 (dd, J=1.7, 8.3 Hz, 1H), 7.17-7.14 (m, 2H), 2.29 (s, 3H), 2.03 (s, 3H), 1.57 (dd, J=4.0, 7.0 Hz, 2H), 1.15 (dd, J=4.0, 7.0 Hz, 2H). Retention time: 1.42 min; ESI-MS m/z calc. 439.4. found 440.5 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:19]2[O:18][CH2:17][CH2:16][N:15]([CH3:20])[C:14](=[O:21])[C:13]=2[CH:12]=[CH:11][C:10]=1[O:22][C:23]1[CH:24]=[C:25]([CH:35]=[C:36]([O:38][C@@H:39]([CH3:42])[CH2:40][OH:41])[CH:37]=1)[C:26]([NH:28][C:29]1[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=1)=[O:27]>[Pd].C1COCC1.C(O)C>[OH:41][CH2:40][C@H:39]([CH3:42])[O:38][C:36]1[CH:35]=[C:25]([CH:24]=[C:23]([O:22][C:10]2[CH:11]=[CH:12][C:13]3[C:14](=[O:21])[N:15]([CH3:20])[CH2:16][CH2:17][O:18][C:19]=3[CH:9]=2)[CH:37]=1)[C:26]([NH:28][C:29]1[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=1)=[O:27]
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc3c(c2Cl)OCCN(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](CO)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.5 %

Procedure:
10% Palladium on carbon (30 mg) and triethylamine (2.0 mL) were added to a solution of 3-[(9-chloro-4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (160 mg; 0.32 mmol) in dry THF (4 mL) and dry ethanol (4 mL) under argon. The reaction was degassed and placed under a hydrogen balloon and stirred for 24 hours at RT. The mixture was filtered through diatomaceous earth and the filtrate was evaporated. Purification by column chromatography on silica, eluting with 0-5% methanol in DCM, yielded a colourless oil which solidified under vacuum to give the title compound as a white foam (62 mg, 33%). 1H NMR δ (CDCl3): 1.23 (d, 3H), 2.00 (dd, 1H), 3.14 (s, 3H), 3.51 (t, 2H), 3.64-3.71 (m, 2H), 3.73 (s, 3H), 4.34 (t, 2H), 4.46 (dq, 1H), 6.51 (d, 1H), 6.69 (d, 1H), 6.70-6.72 (m, 2H), 7.02 (t, 1H), 7.18 (t, 1H), 7.21 (d, 1H), 7.81 (d, 1H), 8.38 (s, 1H) m/z 467 (M+H)+ 465 (M−H)−
Reaction SMILES: [OH-].[K+].[CH3:3][S:4]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=1)(=[O:6])=[O:5].C(OCC)(=O)C>O>[CH3:3][S:4]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=1)(=[O:5])=[O:6]
Reactant: CCOC(=O)Cc1csc(NS(C)(=O)=O)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1nc(CC(=O)O)cs1
Yield: 73 %

Procedure:
To a solution of potassium hydroxide (2.9 g.) in water (80 ml.) was added ethyl 2-methanesulfonamidothiazol-4-ylacetate (9.1 g.) under ice-cooling and stirring, and the mixture was stirred for 1 hour at room temperature. After the reaction, to the reaction mixture was added a mixture of water and ethyl acetate, and then the aqueous layer was separated. The remaining ethyl acetate layer was extracted twice with 10% hydroxide aqueous solution. The extracts were combined with the above obtained aqueous layer, and the mixture was acidified with hydrochloric acid under ice-cooling. The precipitated crystals were collected by filtration, washed with water and dried to give 2-methanesulfonamidothiazol-4-ylacetic acid (5.94 g.), mp 158°-160° C. (dec.).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14](S(CCC)(=O)=O)=[N:15][C:16]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CS(C)=O>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([C:1]#[N:2])=[N:15][C:16]=2[N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: [C-]#N
Reactant: CCCS(=O)(=O)c1nc(N2CCOCC2)c2ncn(-c3ccccc3Cl)c2n1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1nc(N2CCOCC2)c2ncn(-c3ccccc3Cl)c2n1
Temperature: 60 °C

Procedure:
Sodium cyanide (0.086 g) was added to a solution of the product from step (v) (0.74 g) in dimethylsulphoxide (10 ml) and heated at 60° C. for 36 h. The mixture was partitioned between ethyl acetate and brine, the organics washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 16% ethyl acetate in toluene. Yield 0.152 g
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)([CH3:22])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)=[O:8].[Br:29][C:30]([CH3:35])([CH3:34])[C:31](Br)=[O:32]>ClCCl>[Br:29][C:30]([CH3:35])([CH3:34])[C:31]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:12]2[CH:13]=[CH:14][C:9]([C:7](=[O:8])[C:6]([CH3:5])([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH3:22])=[CH:10][CH:11]=2)=[CH:17][CH:18]=1)=[O:32]
Reactant: CC(C)(C(=O)c1ccc(Oc2ccccc2)cc1)N1CCOCC1
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(Br)C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)N3CCOCC3)cc2)cc1
Yield: 100 %

Procedure:
21.59 (0.162 mol) of AlCl3 were added in portion to a solution of 12 g (0.0369 mol) of 2-methyl-2-morpholin-yl-1-(4-phenoxy-phenyl)-propan-1-one and 9.57 g of (0.0406 mol) of α-bromoisobutyrylbromide (97.5% w/w) in 240 ml of dichloromethane, between 0 and 5° C. under stirring. At the end of the addition the temperature was brought to 25° C. then after 2.5 h the reaction was quenched with 500 ml of water and ice. The organic phase was separated and washed with water and 5% NaOH, dried on sodium sulphate, filtered and evaporated obtaining 17.5 g of a reddish oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:13]=1[C:14](O)=O>>[CH3:10][O:11][C:12]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:13]=1[C:14]1[NH:9][C:5]2[C:6](=[N:7][C:2]([Cl:1])=[N:3][CH:4]=2)[N:8]=1
Reactant: Nc1cnc(Cl)nc1N
Reactant: COc1cc(OCc2ccccc2)ccc1C(=O)O
Product: COc1cc(OCc2ccccc2)ccc1-c1nc2nc(Cl)ncc2[nH]1

Procedure:
Prepared analogously to Example 5 from 2-chloro-4,5-diaminopyrimidine and 2-methoxy-4-benzyloxy benzoic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH:12](Cl)[F:13])=[CH:8][S:7][CH:6]=1)=[O:4].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH:12]([F:13])[C:11]([NH:10][C:9]2[C:5]([C:3]([OH:2])=[O:4])=[CH:6][S:7][CH:8]=2)=[O:15])=[CH:24][CH:25]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1cscc1NC(=O)C(F)Cl
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)c1ccc(OC(F)C(=O)Nc2cscc2C(=O)O)cc1

Procedure:
In analogy to Example 58, the title compound was prepared using 4-(2-chloro-2-fluoro-acetylamino)-thiophene-3-carboxylic acid methyl ester and 4-tert-butylphenol. MS (m/e): 350.3 (M−H).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]([O:6][C:7]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]2[C:8]=1[C:9]([CH3:31])=[C:10]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])[C:11]([O:18][CH:19]([F:21])[F:20])=[N:12]2)[CH3:5].CO.O.[OH-].[Li+]>C(O)(=O)C>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[CH2:22][C:10]1[C:11]([O:18][CH:19]([F:20])[F:21])=[N:12][C:13]2[C:8]([C:9]=1[CH3:31])=[C:7]([O:6][C@@H:4]([CH3:5])[C:3]([OH:32])=[O:2])[CH:16]=[CH:15][C:14]=2[F:17]
Reactant: COC(=O)[C@H](C)Oc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(Cl)cc3Cl)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Cc1c(Cc2ccc(Cl)cc2Cl)c(OC(F)F)nc2c(F)ccc(O[C@@H](C)C(=O)O)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-2-[3-(2,4-dichlorobenzyl)-2-difluoromethoxy 8-fluoro-4-methylquinolin-5-yloxy]propionic acid methyl ester (0.070 g), methanol (3.0 mL), water (0.1 mL) and 5.0 M aqueous lithium hydroxide solution (0.060 mL) was stirred at room temperature for 18 hours. The mixture was acidified by the addition of glacial acetic acid and concentrated under reduced pressure. The residue was triturated with water to afford title compound as a white solid, 0.067 g.
Reaction SMILES: CN(C)[CH2:3][CH2:4][OH:5].C([Li])CCC.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1.C(=O)C>CCCCCC.O>[CH3:18][C:14]1[C:13]([CH:4]([OH:5])[CH3:3])=[N:12][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccnc1
Reactant: CN(C)CCO
Agent: CC=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: Cc1cccnc1C(C)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve N,N-dimethylethanolamine (70.45 mmol) in hexane (90 mL) at 0° C., add 2.5M n-butyl lithium in hexane (140.9 mmol,) and stir for 30 min at this temperature. Add a solution of 3-picoline (35.23 mmol) in hexane (10 mL) and continue stirring at 0° C. for 1 h. Cool the resulting mixture to −78° C., add acetaldehyde (70.45 mmol) and continue stirring at −78° C. for 1 h. Dilute with water, warm to ambient temperature, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography eluting with hexane/EtOAc (85:15) to give the desired intermediate as a light yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OO)(=[O:18])C.O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]2[CH:12]([O:18]2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CC(COCc2ccccc2)CCC1
Reactant: CC(=O)OO
Solvent: ClCCl
Solvent: O
Product: c1ccc(COCC2CCC3OC3C2)cc1

Procedure:
A 500 mL round bottom flask equipped with a stirring bar was charged with 13.1g (0.065 mol) 3-benzoxymethylcyclohexene, and 100 mL of methylene chloride. Peracetic acid (15.5 g, 35 wt. % in acetic acid; 0.065 mol) in methylene chloride (80 mL) was added dropwise to the above mixture over 30 min. in an ice bath. After the above mixture was reacted at room temperature for 24 hrs, 250 mL of water was added to the above reaction mixture, the water layer was extracted with methylene chloride (2×150 mL), the organic layer was combined, and washed with saturated sodium carbonate solution (2×150 mL), then with water (2×150 mL) and dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:4][C:5](=O)[CH2:6][CH3:7])[CH3:3].C(OC(=O)CC)(=[O:18])CC.[Cl-].C([Mg]Cl)C(C1C=CC=CC=1)(C)C>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH:4]=[CH:5][CH2:6][CH3:7])[CH2:3][OH:18]
Reactant: CCC(=O)CC(C)(C)c1ccccc1
Reactant: CCC(=O)OC(=O)CC
Agent: CC(C)(C[Mg]Cl)c1ccccc1
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCC=CC(C)(CO)c1ccccc1

Procedure:
A process for preparing 2-methyl-2-phenyl-4-hexanone having the structure: ##STR47## comprising the step of intimately admixing propionic anhydride having the structure: ##STR48## with neophymagnesium chloride having the structure: ##STR49## in the presence of an inert solvent selected from the group consisting of diethylether, toluene and tetrahydrufuran, the reaction taking place in the presence of or in the absence of a cuprous chloride catalyst; the mole ratio of propionic anhydride:neophylmagnesium chloride being from 0.5:1 up to about 2:1; the temperature of reaction being from -10° C. up to 0° C.; the concentration of propionic anhydride in solvent being from about 1 up to about 5 moles of propionic anhydride per liter of solvent; the time of addition of one reactant to the other varying from 0.5 hours up to 4 hours and the time of aging of the reaction mass being from 0.5 up to 4 hours.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][N:14]=3)[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[N:22]1([C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([C:13]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][N:14]=4)[N:10]=[N:9]3)=[CH:4][CH:3]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: Clc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cn1
Reactant: C1COCCN1
Product: c1ccc2c(-c3cn(-c4ccc(N5CCOCC5)nc4)nn3)n[nH]c2c1
Temperature: 120 °C

Procedure:
A suspension of 3-[1-(6-chloropyridin-3-yl)-1H-1,2,3-triazol-4-yl]-1H-indazole (13 mg; 0.04 mmol; 1.0 eq.) in morpholine (0.5 mL) was heated in MW at 120° C. for 4.5 h. The precipitate obtained was filtered, washed with Et2O and dried under vacuum at 50° C. to afford the title compound as a beige solid. 1H NMR (DMSO-d6) δ: 13.33 (s, 1H), 9.18 (s, 1H), 8.74 (d, J=2.8 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H), 8.16 (dd, J=2.6, 9.1 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.43 (m, 1H), 7.23 (m, 1H), 7.07 (d, J=9.1 Hz, 1H), 3.72 (m, 4H), 3.55 (m, 4H). HPLC (Condition A): Rt 3.21 min (purity 97.3%). MS (ESI+): 348.3, MS (ESI−): 346.3.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:16]=[C:15]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)[CH:14]=[CH:13][C:12]=1[OH:22].[CH3:23][O:24][CH:25](Cl)Cl>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[C:15]([CH:17]2[O:18][CH2:19][CH2:20][O:21]2)[CH:14]=[CH:13][C:12]=1[O:22][CH2:23][O:24][CH3:25]
Reactant: COC(Cl)Cl
Reactant: Oc1ccc(C2OCCO2)cc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(C2OCCO2)cc1Br
Reaction time: 1 h
Yield: 93.4 %

Procedure:
(iPr)2NEt (6.0 mL, 35.0 mmol) was added dropwise to a stirred and cooled (0° C.) solution of alcohol 3a (4.0 g, 16.3 mmol) in CH2Cl2 (50 mL). After 15 min methoxymethylene chloride (MOMCl) (1.6 mL, 28 mmol) was added dropwise over a period of 5 min, and stirring was continued for 1 h. The cold bath was removed, and stirring was continued for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated. The residue was purified by flash chromatography using hexanes-ethyl acetate mixture (5:1) as eluent to give compound 4a (4.4 g, 94%) as a colorless liquid. Rf=0.48 (25% EtOAc-hexanes); IR (neat) 2956, 2889, 1606, 1497, 1246, 1100, 1043 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.64 (d, J=1.8 Hz, 1H), 7.31 (dd, J=8.7, 2.1 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 5.70 (s, 1H), 5.21 (s, 2H), 4.02 (m, 4H), 3.46 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 154.2, 132.8, 131.4, 126.7, 115.5, 112.6, 102.5, 94.8, 65.1, 56.2; EIMS (m/z, rel intensity) 290 (M++2, 54), 288 (M+, 58), 259 (23), 257 (23), 209 (56), 73 (100).