Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1(F)[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1(F)[F:21].FC1(F)C2C(=CC([C@H]3CC[C@H](CCC)CC3)=CC=2)C(F)=CC1F.[Cl-].[NH4+]>C1COCC1.[NH4+].[OH-].[Zn]>[F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][CH3:20])[CH2:16][CH2:17]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[F:21]
Reactant: CCC[C@H]1CC[C@H](c2ccc3c(c2)C=CC(F)(F)C3(F)F)CC1
Agent: CCC[C@H]1CC[C@H](c2ccc3c(c2)C(F)=CC(F)C3(F)F)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](c2ccc3c(F)c(F)ccc3c2)CC1

Procedure:
A mixture of 1,1,2,2-tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthalene and 1,1,2,4-tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthalene, 25.6 g (78.4 mmol) in THF was stirred at ambient temperature with zinc dust (25.0 g, 382 mmol) and a solution containing ammonium chloride dissolved in aqueous 30% NH4OH. The reaction was terminated after 48 h. The mixture was filtered, and the zinc was washed with hexanes. The filtrate was transferred to a separatory funnel, the phases were separated, and the solvent was evaporated from the organic phase. The weight of product recovered was 21.9 g. GC analysis of the product showed that it contained 0.2% 1,1,2,2-tetrafluoro-6-(trans-4-propylcyclohexyl)-1,2-dihydronaphthalene, 2.1% 1,2,4-trifluoro-6-(trans-4-propylcyclohexyl)naphthalene, and 93.1% 1,2-difluoro-6-(trans-4-propylcyclohexyl)naphthalene.
Reaction SMILES: [Al+3:1].[Cl-].[Cl-].[Cl-].[C:5]([OH:17])(=[O:16])[CH2:6][C:7]([CH2:12][C:13]([OH:15])=[O:14])([C:9]([OH:11])=[O:10])[OH:8]>>[Al:1].[C:5]([OH:17])(=[O:16])[CH2:6][C:7]([CH2:12][C:13]([OH:15])=[O:14])([C:9]([OH:11])=[O:10])[OH:8]
Reactant: [Al+3]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Product: [Al]

Procedure:
A 600 ml beaker was charged with 258 g of a commercially available 34 weight % AlCl3 solution and 107.65 g of a 50% citric acid solution to provide a mole ratio of aluminum to citric acid of 2:1. The resulting solution was stirred vigorously for 35 minutes after which period 25 ml of a 50% NaOH solution was added via burette over a period of 36 minutes.
Reaction SMILES: [CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1.[C:41]1([C:47]2[CH:52]=[CH:51][C:50](B3OC(C)(C)C(C)(C)O3)=[CH:49][N:48]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:50]3[CH:49]=[N:48][C:47]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:52][CH:51]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Temperature: 100 °C
Yield: 74.2 %

Procedure:
To a pressure tube were charged tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (4.2 g, 5.97 mmol), 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2 g, 7.1 mmol), PdCl2(dppf).CH2Cl2 (240 mg, 0.33 mmol), DME (16 mL) and 2M Na2CO3 (8 mL). The mixture was briefly degassed with Argon and the tube was capped and heated at 100° C. for 15 hours. On cooling, H2O (20 mL) and EtOAc (40 mL) and aqueous layer was extracted with EtOAc (3×) and combined organic layers were washed with brine once and dried (MgSO4). After concentration in vacuo the residue was purified on silica gel. Elution with EtOAc/Hexanes (0-40%) gave tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (3.24 g, 74%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[CH3:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[CH3:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@@H]1CCNC1
Reactant: CC(F)(F)Oc1ccc(NC(=O)c2cnc(Cl)c(Br)c2)cc1
Product: CC(F)(F)Oc1ccc(NC(=O)c2cnc(N3CC[C@@H](O)C3)c(Br)c2)cc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(1,1-difluoroethoxy)phenyl)nicotinamide (Stage 215.2) and (R)-pyrrolidin-3-ol to afford a white solid. HPLC (Condition 4) tR=5.11 min, UPLC-MS (Condition 3) tR=1.02 min, m/z=440.3 [M−H]−.
Reaction SMILES: [BrH:1].[CH2:2]([NH:9][CH2:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.BrBr>C(O)(=O)C>[CH2:2]([NH:9][CH2:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:1])[CH:17]=2)[O:12]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Br
Reactant: c1ccc(CNC[C@H]2CCc3ccccc3O2)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)CC[C@H](CNCc1ccccc1)O2
Temperature: 16 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
In a 500-mL round bottom flask, N-benzyl[(2R)-3,4-dihydro-2H-chromen-2-yl]methanamine hydrobromide (33.4 g, 0.1 mole, 1.0 eq.) was suspended in 240 mL of acetic acid. The suspension was cooled to 16° C., then bromine (16 g, 0.1 mole, 1.0 eq.) was added over 20 minutes, maintaining the reaction temperature between 15-16° C. After 60 minutes, an HPLC analysis indicated the reaction was complete. The reaction mixture was then stirred for 30 minutes at room temperature, and the product was collected by filtration. The light gray moist product was suspended in dichloromethane (200 mL) and to this suspension was added 0.5M NaHCO3 (350 mL). Foaming ensued and the suspension became a bi-phasic solution. The aqueous phase was separated (14.5 L; pH=8) and the organic phase was washed with 50 mL water. The phases were separated and the organic phase concentrated in vacuo at 45° C. to yield 31.6 g of N-benzyl-N-{[(2R)-6-bromo-3,4-dihydro-2H-chromen-2-yl]methyl}amine. NMR (DMSO-d6) δ1.56 (m, 1H), 2.02 (m, 1H), 2.25 (bs, 1H), 2.73 (m, 4H), 3.75 (s, 2H), 4.05 (m, 1H), 6.70 (d, J=8.8 Hz, 1H), 7.25-7.40 (m, 7H); MS (El): m/z 232 (MH+), 234 (M+2).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].Br[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C.ClCCl>CCOCC>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]#[C:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:9])[CH:12]=1
Reactant: Brc1cccnc1
Reactant: C#CCCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: OCCCCCCC#Cc1cccnc1
Yield: 91 %

Procedure:
A mixture of 34.6 g of 7-octyn-1-ol 26.4 mL of 3-bromopyridine, 115 mL of triethylamine and 350 mL of dichloromethane was stirred and flushed with argon. To the mixture was added 3.85 g of bis triphenylphosphine palladium II chloride and 0.365 g of cuprous iodide and then the mixture was refluxed overnight. The cooled reaction mixture was diluted with ether and the solids were filtered, washed well with ether, and then discarded. The filtrates were extracted repeatedly with 1N hydrochloric acid and the combined aqueous layers were made strongly basic with excess sodium hydroxide. The mixture was extracted with dichloromethane, dried over sodium sulfate and evaporated to provide 51 g (91%) of crude 8-(3-pyridinyl)-7-octyn-1-ol. Catalytic hydrogenation in 1000 mL of ethanol using 5 g of 10% palladium on carbon provided, after distillation, 36 g (72%) of 3-pyridineoctanol, bp 145°-152° C. (0.3 mm). Analysis Calculated for C13H21NO: C, 75.32; H, 10.21; N, 6.76. Found: C, 75.13; H, 10.21; N, 6.66.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].F[C:22](F)(F)[C:23]([OH:25])=O.C(Cl)Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC.C(Cl)Cl.O>[NH2:14][C@@H:13]([C@H:23]([OH:25])[CH3:22])[C@@H:17]([OH:18])[C:16]#[C:15][C:3]1[C:2]([F:1])=[CH:10][CH:9]=[C:8]2[C:4]=1/[C:5](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19])/[C:6](=[O:11])[NH:7]2
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@H](O)[C@@H](N)[C@@H](C)O)c21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Using Method C above, 4R-(1S-hydroxy-prop-2-ynyl)-2,2,5R-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.2 g, 0.65 mmol) (Example 105A above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.1 g, 0.26 mmol) (Starting Material 6) using (Ph3P)4Pd (30 mg) (Aldrich) and Cul (6 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h. To the resulting compound in CH2Cl2 (10 mL) was added a 1:1 mixture of trifluoroacetic acid/CH2Cl2 (10 mL) and 5 drops of water at 0° C. and the mixture was stirred at 0° C. for 1.5 h. The mixture was then quenched with conc. NH4OH (10 mL) and diluted with EtOAc. The organic layer was washed with brine and dried with MgSO4. The product was purified via flash column chromatography (10% MeOH in CH2Cl2). (Yield 30 mg, 30%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:35]=[CH:34][C:20]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:33])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:19][CH:18]=1>CN(C)C=O>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:35]=[CH:34][C:20]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:33])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:19][CH:18]=1
Reactant: Oc1ccccn1
Reactant: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCOc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into 5 ml of dry dimethylformamide containing 150 mg of sodium hydride (60% suspension in mineral oil) was added 292 mg of 2-hydroxypyridine. After stirring the mixture at room temperature for 15 minutes, 1.2 g of ethyl 6-[p-(5-bromopentyloxy)phenoxy]-2,2-dimethylhexanoate was added thereto. The mixture was stirred at room temperature for 12 hours, and thereafter the solvent was removed from the reaction solution under reduced pressure. The remaining oily substance was dissolved in chloroform, washed with water, and then dried over anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure. The remaining oily substance was subjected to silica gel column chromatography and the product was eluted out using as an eluent chloroform-methanol (99:1). The solvent was distilled off from the eluate under reduced pressure to give the desired ethyl 6-[p-[5-(2-pyridyloxy)pentyloxy)phenoxy]-2,2-dimethylhexanoate as an oily substance (495 mg).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][SiH:10]([Cl:12])[Cl:11].[SiH4]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.COC.C=C.C(C1C(C)=CC=C(O)C=1C(C)(C)C)(C)(C)C>[C:3]1([CH2:2][CH2:1][Si:10]([Cl:12])([Cl:11])[Cl:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: C=Cc1ccccc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: C=C
Agent: COC
Product: Cl[Si](Cl)(Cl)CCc1ccccc1
Temperature: 90 °C
Yield: 94.2 %

Procedure:
About 468 grams (4.5 moles) of styrene and about 0.5 grams of di-t-butyl-p-cresol were charged to a one liter, three necked round bottom flask fitted with a magnetic stirrer, thermometer, dropping funnel and reflux condenser bearing a nitrogen by-pass on the vent. While stirring the flask contents were heated to 90° C, and a sufficient amount of about a 2% solution of chloroplatinic acid catalyst dissolved in dimethylether of ethylene glycok to give about 25 parts by weight of plantinum per million parts by weight of reactants was added. Then about 610 grams (4.5 moles) of trichlorosilane were slowly and continuously added via the dropping funnel over a one and one-half hour period while maintaining the reaction temperature at 90°-95° C. A vapor phase chromatogram on the reaction contents indicated there was an essentially complete conversion to product. The crude silane reaction product was then refined by a one plate distillation at 0.1 mm. pressure to yield about 1015 grams (4.24 moles) of phenylethyltrichlorosilane product ##STR22## (94.5% conversion) which had a boiling point of about 63°-64° C./0.1 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: NC(=O)c1c(Cl)cccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: O=C=NC(=O)c1c(Cl)cccc1Cl

Procedure:
95 g of 2,6-dichlorobenzamide are suspended in from 250 to 300 ml of dry methylene chloride. After the addition of 56 ml of oxalyl chloride the mixture is slowly heated to boiling point, at which temperature the starting material rapidly dissolves with a strong evolution of hydrochloric acid. After boiling for from 15-18 hours the mixture is concentrated by evaporation in a vacuum. The resulting 2,6-dichlorobenzoylisocyanide is used for the next reaction step without further purification.
Reaction SMILES: C[N+]1([O-])CCOCC1.[C:9]1([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C>[C:9]1([CH2:15][CH2:16][CH2:17][CH:18]=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCCCc1ccccc1
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
Tetrapropylammonium perruthenate(VII) (117 mg, 0.33 mmol, 0.1 equiv.) was added to a solution of 4 methylmorpholine N-oxide (580 mg, 5.00 mmol, 1.5 equiv.) and 4-phenyl-1-butanol (500 mg, 3.33 mmol, 1.0 equiv.) in acetonitrile (30 mL). The reaction mixture was stirred for 16 hours at room temperature then filtered through celite® then through a pad of silica (5 g) which was washed with acetonitrile (20 ml). The solvent was evaporated and the crude product purified by flash column chromatography (SiO2, ethyl acetate:heptane 5% to 50%) to afford crude 4-phenyl-1-butanal as a colourless oil, 62 mg (13% yield).
Reaction SMILES: [H-].[Na+].C1COCC1.[C:8]([O:12][C:13](=[O:21])/[CH:14]=[CH:15]/[C:16]1[CH:20]=[CH:19][NH:18][CH:17]=1)([CH3:11])([CH3:10])[CH3:9].[Br:22][C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>O>[C:8]([O:12][C:13](=[O:21])/[CH:14]=[CH:15]/[C:16]1[CH:20]=[CH:19][N:18]([S:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([Br:22])[CH:24]=2)(=[O:31])=[O:30])[CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A mixture of 0.77 g NaH (60%) with 65.0 ml THF is cooled to −30° C. Then 3.2 g 3.1 g (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester are added. During the addition there is liberated a gas. The solution is stirred at ambient temperature for 0.5 h. Finally 5.0 g 3-bromobenzenesulfonylchloride are added at −30° C. The suspension is stirred at ambient temperature for 24 h. The suspension is treated with water and the solution is extracted with ethyl acetate. The organic layer is dried over sodium sulfate and evaporated. The residue (oil) is crystallized from methanol. The crystals are dried in vacuo. By this method 5.7 g of colorless crystals are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10](Br)[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:18][N:19](C)C=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([C:18]#[N:19])[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc2c(Br)c(OC)ccc12
Solvent: c1ccncc1
Product: COC(=O)c1cccc2c(C#N)c(OC)ccc12
Temperature: 180 °C

Procedure:
A solution of bromine (26.6 g, 0.167 mole) in glacial acetic acid (25 ml) was added dropwise to a cooled suspension of 6-methoxy-1-naphthalenecarboxylic acid methyl ester (30 g, 0.13 9 moles) in glacial acetic acid (2.75 ml). The precipitate was collected, washed with water and crystallized from ethanol to give 33.3 g of 5-bromo-6-methoxy-1-naphthalenecarboxylic acid methyl ester; mp 119° C.; NMR (CDCl3) δ 3.97 (s, 3H), 4.03 (s, 3H), 7.35 (d, J=9.25 Hz, 1H), 7.4 (m, 1H), 8.05 (d, J=6.75 Hz, 1H), 8.45 (d, J=8.25 Hz, 1H), 8.9 (d, J=9.25, 1H). The latter ester (10.1 g, 34 mmoles) and Cu2 (CN)2.H2O (3.4 g, 17 mmoles) in distilled dimethylformamide (75 ml) containing 15 drops of pyridine was heated at 180° C. for 5 hr. The hot mixture was poured into a mixture of ice (50 g) and conc. NH4 0H (50 ml). The resulting precipitate was collected, washed with water, dried and recrystallized from chloroform-ethyl acetate to afford 5.6 g of 5-cyano-6-methoxy-1-naphthalenecarboxylic acid methyl ester: mp 210°-211° C., NMR (CDCl3)δ 3.95 (s, 3H), 4.15 (s, 3H). To a stirred solution of the latter ester (5.95 g, 24.66 mmoles) in 2-methoxyethanol (100 ml) at 20°-22° C., 4N aqueous NaOH solution (12.3 ml) was added. The reaction mixture was stirred at 20°-22° C. for 60 hr, diluted with water, cooled to 0° C. and rendered acidic with 1N aqueous HCl. The precipitate was collected and dried to yield 5.6 g of the title compound; mp>290° C.; NMR (DMSO-d6) δ 4.1 (s, 3H), 8.1 (m, 5H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][C:16]=1[C:21]([O:23]CC)=[O:22]>ClCCl>[C:1]([C:19]1[C:15]([CH3:14])=[C:16]([C:21]([OH:23])=[O:22])[NH:17][C:18]=1[CH3:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)O)c(C)c1C(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
To a mixture of benzoyl chloride (1 equiv.) and aluminum chloride (1 equiv.) in dichloromethane at 0° C. was added ethyl 3,5-dimethyl-2-pyrrolecarboxylate (1 equiv.). The mixture was stirred at 80° C. for 4 hr. The mixture was then extracted with ethyl acetate (EtOAc) and H2O. The combined organic extracts were washed with saturated sodium bicarbonate and brine, dried and concentrated to give (51%) of 4-benzoyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CCCCCC.[H-].[Na+].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18]>CN(C)C=O>[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:18]
Reactant: CCOC(CBr)OCC
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(F)cc1)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.8 %

Procedure:
A solution of 4-fluorophenol (28.1 g., 0.25 mole) in dry dimethylformamide (30 ml.) is added dropwise to a suspension of hexane (2 × 30 ml.)--prewashed sodium hydride (50% dispersion in mineral oil, 12.5 g., 0.26 mole) in dry dimethylformamide (120 ml.). After stirring at 25° C. for 10 minutes, the reaction mixture is treated with bromoacetaldehyde diethyl acetal (49.3 g., 0.25 mole) and heated at 100° C. for 4 hours. Upon cooling to 25° C., the reaction mixture is filtered to remove insoluble sodium bromide. The filtrate is evaporated in vacuo, leaving an oily residue which is triturated with acetone (100 ml.) at 25° C. and filtered to remove additional sodium bromide. Evaporation of the filtrate in vacuo provides a residual oil which is distilled to afford the title compound as a colorless oil (46.7 g., 82%), bp0.05 87° C.; pmr (CCl4) δ1.17 (6 H, t) 3.57 (2H, q), 3.61 (2H, q), 3.85 (2H, d), 4.68 (H, t) and 6.6-7.1 (4H, m).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])([O-:7])=[O:6]>>[CH:3]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N+:5]([O-:7])=[O:6])=[CH:2][CH3:1]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: C=CCBr
Product: CC=COc1ccccc1[N+](=O)[O-]

Procedure:
Allyl bromide was reacted with o-nitrophenol to yield 2-prop-1-en-oxynitrobenzene; which was reduced to the corresponding aniline; then reacted with N-hydromethyl-5-methyl-2-pyrrolidone to form the corresponding N-5-methyl-N-methylene-2-pyrrolidonyl derivative.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:6]([F:22])=[C:7]([O:14]CC2C=CC=CC=2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)(=O)[CH3:2]>C(O)C.C(O)(=O)C.[Pd]>[F:22][C:6]1[C:7]([OH:14])=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[C:1]([CH3:2])[NH:11]2
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc2c(F)c(O)ccc2[nH]1
Reaction time: 2 h

Procedure:
A solution of 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (300 mg, 0.99 mmol) in ethanol (10 ml) and acetic acid (1 ml) containing 10% palladium on charcoal (30 mg) was hydrogenated at 2 atmospheres pressure for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in ethyl acetate and the organic layer was washed with aqueous sodium hydrogen carbonate, brine and evaporated to give 4-fluoro-5-hydroxy-2-methylindole. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (3/7) to give 4-fluoro-5-hydroxy-2-methylindole (63 mg, 30%). Analytical data as above.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:9]([O:11]CC)=[O:10].[OH-].[K+]>CO>[CH3:1][C:2]1([CH3:14])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O

Procedure:
1.80 Parts of ethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-carboxylate prepared in the same manner as in Example 1 was agitated at 40° to 50° C. for 3 hours in the presence of 8.65 parts of a 10% solution of potassium hydroxide and methanol to effect hydrolysis of the ester and obtain 1.43 parts of 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-carboxylic acid, the data of the melting point and NMR spectrum of which were in agreement with the data described in Example 4.