Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([OH:22])=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]#[N:37]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:35][C:36]#[N:37])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21]
Reactant: N#CCBr
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2c(Cl)ccc(OCC#N)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-ol (0.80 g), N,N-dimethylformamide (10 mL), potassium carbonate (1.0 g) and bromoacetonitrile (0.25 mL) was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and this mixture was washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as a light brown solid, 0.90 g.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].CCN(CC)CC>C(Cl)Cl.O>[Si:11]([O:18][CH2:19][CH2:20][CH2:21][CH:22]=[O:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCC=O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To CH2Cl2 (150 mL) at −78° C. were added oxalyl chloride (6.83 g, 53.8 mmol) and dry DMSO (8.41 g, 108 mmol), dropwise. After 5 min, 4-(tert-butyldimethylsilyloxy)butan-1-ol (10 g, 48.9 mmol) in CH2Cl2 (5 mL) was added dropwise. The mixture was stirred for an additional 30 min at −78° C., and Et3N (24.8 g, 245 mmol) was added. The mixture was then allowed to warm to room temperature over 30 min. After stirring for 3 hrs, 100 mL of water was added. The phases were separated, and the aqueous phase was extracted three times with 100 mL of diethyl ether. The combined organic phases were washed successively with 50 mL of aqueous 1% HCl, 50 mL of water, 50 mL of aqueous 5% NaHCO3 and 50 mL of saturated aqueous NaCl. The organic layer was dried over MgSO4, and the solvent was removed under reduced pressure, to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O=[C:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]#[N:16].[Cl-].[Ca+2].[Cl-]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]#[N:16])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: N#CC1CCCC1=O
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2ccc(Cl)cc2)CCC1

Procedure:
4-Chloro-aniline (Aldrich Chemicals) (2.6 g, 20 mmol), cyanoketone (Example 11) (2.2 g, 20 mmol), calcium chloride (2.5 g, 23 mmol) and T.H.F. (30 ml) were heated under reflux for 19 hours. After being allowed to cool, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (160° C., 0.3 mm Hg) gave the product as white crystals.
Reaction SMILES: [H][H].[CH2:3]([N:5]1[CH2:15][CH:14]2[O:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([N+:17]([O-])=O)=[CH:10][CH:9]=3)[CH2:6]1)[CH3:4]>[Pd].C(O)C.C(Cl)Cl>[CH2:3]([N:5]1[CH2:15][CH:14]2[O:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([NH2:17])=[CH:10][CH:9]=3)[CH2:6]1)[CH3:4]
Reactant: CCN1CC2OC(C1)c1cc([N+](=O)[O-])ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CCN1CC2OC(C1)c1cc(N)ccc12
Reaction time: 18 h
Yield: 87.4 %

Procedure:
Hydrogen was bubbled through a mixture of 10-ethyl-4-nitro-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (115 mg, 0.56 mmol) and 10% palladium on carbon (53 mg, 0.050 mmol) in ethanol (3 mL) and CH2Cl2 (3 mL) for 5 min. The reaction was then stirred under a hydrogen atmosphere for 18 h. Filtration through Celite and concentration gave 10-Ethyl-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine as an off-white foam (100 mg, 100%). MS (m/e) 205 (M+1.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([NH:29]N)[CH:26]=[CH:27][CH:28]=1>>[C:14]1([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:29]([C:25]4[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:31])[F:32])[CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1cccc(C(F)(F)F)c1
Yield: 58 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 3-(trifluoromethyl)-phenylhydrazine according to the method described for Example 1 in 58% yield. MS: M=383.0 (M+H)+
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1O
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl salicylate (3.04 g, 20 mmol) in pyridine (25 mL) is added dropwise methanesulfonyl chloride (2.17 g, 19 mmol) and the mixture is stirred at RT for 18 h. The solvent is removed under reduced pressure and the residue partitioned between EtOAc and water. The organic phase is washed sequentially with 1N HCl, 2N Na2CO3, 1N HCl, water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue purified by column chromatography using a gradient of 0-100% EtOAc/hexane as eluent to give the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:19](O)=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:46][CH2:47][C:48]1[C:49](=[O:56])[NH:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54].O>ClCCl>[CH3:54][C:53]1[CH:52]=[C:51]([CH3:55])[NH:50][C:49](=[O:56])[C:48]=1[CH2:47][NH:46][C:19]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:2]=1[CH3:1])=[O:20]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1c(C(=O)O)c2ccncc2n1C(C)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)c3ccccc3)c3cnccc23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.3 %

Procedure:
A mixture of 2-methyl-1-(1-phenylethyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (280 mg, 1.0 mmol) was added HATU (456 mg, 1.2 mmol), TEA (1 g, 10 mmol) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (182 mg, 1.2 mmol) in anhydrous dichloromethane (30 mL) was stirred at room temperature for 16 hours. To the reaction mixture was added water (10 mL), extracted with dichloromethane (30 mL×2). The organic layers were combined and concentrated to give a residue. The residue was recrystallized from MeCN to afford compound N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-phenylethyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxamide as an off-white solid (80 mg, 21.6%). LRMS (M+H+) m/z: calcd 414.21. found 414. 1H NMR (400 MHz, Methanol-d4) δ: 8.84 (s, 1H), 8.16 (d, J=7.6 Hz, 1H), 8.03 (d, J=6.8 Hz, 1H), 7.44-7.37 (m, 5H), 6.09 (s, 1H), 6.01-5.99 (m, 1H), 4.49 (s, 2H), 2.73 (s, 3H), 2.38 (s, 3H), 2.22 (s, 3H), 2.06 (d, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19](OC)=[C:18]([O:24][CH3:25])[CH:17]=3)[NH:12]2)=O)=[CH:4][C:3]=1[O:26][CH3:27].C1(C)C=CC=CC=1.C1C[O:38][CH2:37]C1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C@@H:11]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH2:17][C:18]([O:24][CH3:25])([O:38][CH3:37])[CH:19]=[CH:20][CH:21]=3)[NH:12]2)=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: COc1cc(NC(=O)[C@@H]2CC[C@H](c3ccc(OC)c(OC)c3)N2)ccc1Cl
Reactant: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(NC[C@@H]2CC[C@H](C3=CC=CC(OC)(OC)C3)N2)ccc1Cl
Temperature: 0 °C
Yield: 67 %

Procedure:
(2S,5R)5-(3,4-Dimethoxy-phenyl)-pyrrolidine-2-carboxylic acid (4-chloro-3-methoxy-phenyl)amide was dissolved in anhydrous THF and cooled to 0° C. in an ice bath. A 0.5M solution of alane complex in toluene (42.6 ml, 21.3 mmol, 3.0 equivalents) was added slowly and the reaction was allowed to stir and warm to room temperature overnight. The reaction was quenched upon addition of ethyl acetate:methanol (1:1, 5 ml). The resulting slurry was filtered through Celite and rinsed with ethyl acetate. The filtrate was concentrated in vacuo to afford (2S,R)(4-chloro-3-methoxy-phenyl)-[5-(3,3-dimethoxy-phenyl)-pyrrolidin-2-ylmethyl]-amine (1.80 g, 4.78 mmol, 67% yield). Analysis H1 NMR (400 MHz, CDCl3): 7.12 (1H, d), 6.98-6.90 (3H, m), 6.23 (1H, s), 6.19 (1H, d) 4.39-4.15 (2H, m), 3.76-3.53 (1H, m), 3.30-2.97 (2H, m), 2.34-1.55 (6H, m). MS (LC-MS): Calculated for C20H25ClN2O3 376.16, found 377.21 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].[C:15](Cl)(Cl)=[O:16]>C(Cl)Cl.ClC1C=CC(C)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:5]=[C:15]=[O:16])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccc(Cl)cc1
Product: O=C=Nc1ccc(N2CCOCC2)c(F)c1

Procedure:
A mixture of 3-Fluoro4-morpholinylaniline (PREPARATION 1, 12.01 g, 61.21 mmol) in methylene chloride (100 ml) is added to a mixture of phosgene (1.93 M in toluene, 63.4 ml, 122.4 mmol, 2.00 eq) in p-chlorotoluene (60 ml) over 15 min, a while maintaining the temperature from about −12 to 3°. The material is rinsed in with methylene chloride (30 ml). The mixture is then warmed to 130° under atmospheric pressure with concomitant distillation of methylene chloride, phosgene, toluene and hydrogen chloride gas into a caustic scrubber. The mixture is cooled to 25° and filtered. The precipitate is washed with methylene chloride (3×15 ml). The filtrate is concentrated under reduced pressure. Heptane (200 ml) is added to the concentrated filtrate and the resultant slurry cooled to −32°. The product is collected by filtration with reduced pressure, washed with heptane cooled to −30°, and dried in a nitrogen stream to give the title compound, HPLC (stationary phase is 4.6×250 mm zorbax RX C-8 column; mobile phase is acetonitrile (650 ml), triethylamine (1.85 ml) and acetic acid (1.30 ml) and water of sufficient amount to make 1,000 ml; flow rate=3.0 ml/min; UV detection at 254 nm) RT=1.08 min. Upon derivatizing as N-cabomethoxy-3-fluoro-4-morpholinylaniline by dissolving in methanol; NMR (CDCl3) 3.05, 3.86 and 6.78-6.89 δ; CMR (CDCl3) 50.90, 66.89, 113.11, 119.15, 120.83, 124.67, 127.65, 138.06 and 155.40 δ; MS (EI), m/z (relative intensity) 222 (37) and 164 (100).
Reaction SMILES: C1(CC([NH:10][C@@H:11]2[C:37](=[O:38])[N:13]3[C:14]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)=[O:26])=[C:15]([S:18]/[CH:19]=[CH:20]\[C:21]([O:23][CH3:24])=[O:22])[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl.O.CO>[NH2:10][C@@H:11]1[C:37](=[O:38])[N:13]2[C:14]([C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[O:26])=[C:15]([S:18]/[CH:19]=[CH:20]\[C:21]([O:23][CH3:24])=[O:22])[CH2:16][S:17][C@H:12]12
Reactant: COC(=O)/C=C\SC1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)/C=C\SC1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a cooled (0° C.) solution of 18.3 g (33.0 mM) of 4-methoxybenzyl 7β-phenylacetamido-3-[(Z)-2-methoxycarbonylvinylthio]-3-cephem-4-carboxylate in 200 ml of dry dichloromethane were added 7.82 g (99.0 mM) of pyridine and 13.7 g (65.8 mM) of phosphorus pentachloride, and the reaction temperature was raised to room temperature for a period of 30 minutes, and the mixture was stirred at the same temperature for 1 hour. To the cooled (-50° C.) reaction solution was added 100 ml of dry methanol, and the mixture was stirred at -20° C. for 1 hour. Upon continued cooling of the reaction mixture to -50° C., 100 ml of water was added, and the mixture was stirred under ice-cooling for 40 minutes. The mixture was made weakly basic by addition of a saturated aqueous sodium bicarbonate solution, and extracted with 300 ml of ethyl acetate, and the extract was washed with 200 ml of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated, and diethyl ether was added to the residue for powdering to give 10.6 g of 4-methoxybenzyl 7β-amino-3-[(Z)-2-methoxycarbonylvinylthio]-3-cephem-4-carboxylate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)([O-:22])=[O:21].O>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].CN1C(=O)N(C)CCC1>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]1[CH2:33][CH2:34][N:29]([C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=2)[CH2:30][CH2:31]1
Reactant: OCCCCCCCCCCCBr
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: O=[N+]([O-])c1ccc(N2CCN(CCCCCCCCCCCO)CC2)cc1
Temperature: 85 °C
Reaction time: 48 h
Yield: 51.9 %

Procedure:
10 g of 11-bromoundecan-1-ol, 4 g of dry potassium carbonate powder, 8.27 g of 4-nitrophenylpiperazine and 2 drops of the conventional and known phase transfer catalyst Aliquat® 336 in 50 ml of dimethylpropyleneurea were heated at 85° C. for 6 hours and then left to stand for 2 days. The reaction mixture was then poured into 500 ml of water. The precipitated crude product was filtered off under suction (first fraction). The water phase was extracted a further three times with 50 ml of toluene in each case and four times with 50 ml of ethyl acetate in each case. The combined extracts were evaporated down and the remaining crude product fraction (second fraction) was combined with the first fraction, after which the combined crude product fractions were recrystallized from a mixture of ethanol and water in a volume ratio of 2:1. The recrystallized product was dried under reduced pressure, after which 7.8 g of N-(11-hydroxyundecyl)-N'-(4-nitrophenyl)-piperazine resulted. The product had the following physical properties: melting point 118° C., IR spectrum (KBr pellet): bands at 3,550, 2,900, 2,850, 1,595, 1,575, 1,470, 1,333, 1,255, 1,250, 1,115, 820 and 750 cm-1 ; elemental analysis: calculated 66.8% C, 9.34% H, 11.13% N and 12.7% O; found: 66.8% C, 9.4% H, 11.1% N and 12.7% O.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[OH:10].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1>[CH3:11][S:12]([O:10][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: OC1Cc2ccccc2C1
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
2-Indanol (1.34 g) in pyridine (5 ml) was stirred with cooling to 0° C. Methylsulphonyl chloride (1.38 g) was added dropwise while maintaining the temperature at 0°. The mixture was then allowed to warm to room temperature and was stirred for 0.5 hour. The mixture was then poured on to ice and immediately a white precipitate formed; the mixture was allowed to stand overnight. The precipitate was then filtered off, washed with water and air-dried to give 2-methylsulphonyloxyindane (1.9 g), m.p. 75°-77° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[C:27]([F:30])([F:29])[F:28])[CH2:22]Br.O>COCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:22][C:21]2[CH:24]=[CH:25][C:26]([C:27]([F:28])([F:29])[F:30])=[C:19]([F:18])[CH:20]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: Fc1cc(CBr)ccc1C(F)(F)F
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)c(F)c1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (8.9 g, 42.3 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.69 g, 42.3 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-fluoro-4-(trifluoromethyl)benzyl bromide (9.0 g, 42.3 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 3 hrs. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1-toluene) and recrystallized from diisopropyl ether-hexane to give ethyl 3-(4-fluorophenyl)-2-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-oxopropionate (10.8 g, 66%).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Br:17]Br>C1COCC1>[Br:17][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9][CH:10]=1
Reactant: c1ccc(-n2ccnn2)cc1
Reactant: BrBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1cnnn1-c1ccccc1
Reaction time: 0.08 h

Procedure:
In a 100 ml 3 necked round bottom flask, 1-phenyl-1H-1,2,3-triazole (1.2 g) was taken in dry THF (25 ml) under nitrogen. n-Butyl lithium (3.36 ml) was added at −78° C. and stirred for 5 minutes, then bromine (3.76 ml) was added dropwise to the above reaction mixture. Reaction mixture was stirred at −78° C. for 1 hour. TLC was checked no starting material and the reaction mixture was quenched with saturated ammonium chloride (50 ml) and ethyl acetate was added. The organic layer was washed with sodium bisulphate, brine, dried and concentrated. The crude product was purified by column chromatography using pet ether & ethyl acetate as eluent to give 5-bromo-1-phenyl-1H-1,2,3-triazole as yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[H-].[Na+].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].Cl>CN(C)C=O>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])=[CH:4][CH:3]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: BrCc1ccc(I)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(I)cc1
Yield: 22.9 %

Procedure:
First, 0.55 g of 4-iodobenzyl bromide was dissolved in 10 ml of N,N-dimethylformamide, to which the suspension of 0.11 g of sodium hydride (60% in oil) and 0.30 g of (3,3,3-trifluoropropyl)malononitrile in 5 ml of N,N-dimethylformamide was added dropwise, while stirring under ice cooling. After stirring for 4 hours at 0° C., 10% hydrochloric acid was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was successively washed with water, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.16 g of 2-(4-iodobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (26)).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6].[Mn]([O-])(=O)(=O)=[O:16].[K+].Cl.C(Cl)Cl>CC(C)=O.O>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1)[C:5]([OH:16])=[O:6]
Reactant: O=Cc1cc(C(F)(F)F)cc(Cl)c1F
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a solution of 3-chloro-2-fluoro-5-trifluoromethyl-benzaldehyde (1.0 g, 4.41 mmol) in acetone (15 ml) and water (3 ml) was added potassium permanganate (0.837 g, 5.3 mmol, 1.2 equiv.) and the corresponding dark violet reaction mixture was stirred for 30 min to achieve full conversion. The solvents were removed under vacuum and the dark suspension was quenched upon addition of sodium sulfite solution (sat., 20 ml). The dark violet solid was filtered off and washed with water (10 ml). The turbid light brown mother liquor was treated with HCl (25%, 3 ml, 92.3 mmol, 20.9 equiv) adjusting the pH to 1 and CH2Cl2 (50 ml) was added. The phases were separated, the organic phase was washed with water (20 ml), whereas the aqueous phase was washed with CH2Cl2 (20 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent was exchanged under vacuum with methyl cyclohexane (35 ml). The turbid suspension was concentrated under vacuum, the white precipitate was filtered off and the crystals were dried under vacuum until weight constancy to yield the product as white crystals (1.02 g, 93.8% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[Br:10]C1C=C(C)C(C)=CC=1O>>[Br:10][C:6]1[CH:7]=[C:2]([F:1])[C:3]([CH3:9])=[CH:4][C:5]=1[OH:8]
Reactant: Cc1cc(O)ccc1F
Reactant: Cc1cc(O)c(Br)cc1C
Product: Cc1cc(O)c(Br)cc1F
Yield: 94 %

Procedure:
Prepared in 94% yield from 4-fluoro-3-methylphenol following the procedure for 2-bromo-4,5-dimethylphenol. 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J=8.5 Hz, 3H), 6.86 (d, J=7.0 Hz, 3H), 5.23 (s, 3H), 2.22 (d, J=1.8 Hz, 9H).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[O:15][CH3:16].[OH-].[Li+].Cl>O1CCCC1.O>[CH3:16][O:15][C:5]1[CH:6]=[C:7]([O:10][C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:9][C:4]=1[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1ccc(OC(F)(F)F)cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC(F)(F)F)ccc1C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
590 mg 2-Methoxy-4-trifluoromethoxy-benzoic acid methyl ester was dissolved in a mixture of 30 ml tetrahydrofuran and 10 ml water. 367 mg lithium hydroxide were added and the reaction mixture stirred at 60° C. for two hours. The cooled reaction mixture was acidified by dropwise addition of concentrated hydrochloric acid, then the mixture was extracted three times with portions of 80 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was removed in vacuo to obtain 518 mg 2-methoxy-4-trifluoromethoxy-benzoic acid.