Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C[N:31]1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[NH4+].[OH-]>O.O1CCCC1>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22]([NH2:31])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CN1CCOCC1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(=O)O)ccc1F
Agent: COc1nc(Cl)nc(OC)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(N)=O)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
A 250 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid (2.58 g, 6.1 mmol), 4-methylmorpholine (2.0 mL, 18.3 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.28 g, 7.3 mmol) and tetrahydrofuran (30 mL). After stirring the mixture for 30 min at 25° C., NH4OH (15.0 mL) was added. The mixture was stirred for 30 min and diluted with water. The product precipitated from solution. The precipitated was filtered and washed with water and diethyl ether to give the title compound (2.55 g, 8%) as a white solid. 1H NMR (400 MHz, (CD3)2SO) δ 8.10 (m, 1H), 7.9 (dd, J=2.1 and 5.2 Hz, 1H), 7.65 (q, 6.7 and 8.5 Hz, 1H), 7.56 (t, J=9.1 Hz, 1H), 7.35 (td, J=2.4 and 8.2 Hz, 1H), 7.17 (td, J=2 and 6.6 Hz, 1H), 6.78 (s, 1H), 5.36 (s, 2H), 2 (s, 3H) ppm. ES-HRMS m/z 423. 0719 (M+H calcd for C20H15ClF3N2O3 requires 423.0718).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:42]=[CH:41][CH:40]=[CH:39][C:9]=1[CH2:10][N:11]1[C:15](=[O:16])[C:14]2([CH2:21][CH2:20][N:19](C(OCC3C=CC=CC=3)=O)[CH2:18][CH2:17]2)[N:13]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[F:38][C:35]1[CH:36]=[CH:37][C:32]([N:13]2[C:14]3([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[C:15](=[O:16])[N:11]([CH2:10][C:9]3[CH:39]=[CH:40][CH:41]=[CH:42][C:8]=3[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12]2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccc(F)cc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccc(F)cc2)C2(CCNCC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a solution of benzyl 3-(2-(tert-butoxycarbonyl)benzyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.5 g, 2.61 mmol) in methanol (25 mL), was added 10 wt % palladium on carbon (0.25 g). After stirring under hydrogen at room temperature and atmospheric pressure for 2 hours, the reaction mixture was filtered, washed with methanol, concentrated in vacuo to obtain tert-butyl 2-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (1.1 g, 96%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[C:4]([CH:3]=1)[CH:5]=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=S(=O)(O)O
Product: O=Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-4-fluorobenzaldehyde (5.00 g, 24.6 mmol) in sulfuric acid (25 mL) at 0 ° C. was added dropwise fuming nitric acid (3 mL) in sulfuric acid (30 mL), stirred at room temperature overnight, poured onto ice, the precipitate collected, washed with water, and dried. The crude product was purified by flash chromatography over silica gel eluting with ethylacetate/hexane (3:7) to provide 3.9 g of the title compound as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:33]1([C@H:39]([NH2:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:33]1([C@H:39]([NH:46][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:14]2[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:8][CH:7]=4)=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:16])[CH:27]=3)=[O:29])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3cccnc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: N[C@@H](c1ccccc1)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H](c1ccccc1)c1ccccn1)c1cnc2cc(NC(=O)c3cccnc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
7-{[2-(4-Trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-quinoline-3-carboxylic acid (30 mg, 0.069 mmol), [S]-C-phenyl-C-pyridin-2-yl-methylamine (15 mg, 0.082 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16 mg, 0.082 mmol), 1-hydroxybenzotriazole (10 mg, 0.075 mmol), and triethylamine (0.038 ml, 0.27 mmol) were combined in 1 ml of dichloromethane. After stirring overnight at room temperature, the mixture was diluted with 30 ml of dichloromethane and washed with 2×20 ml of water, the organic layer was dried (magnesium sulfate), filtered and concentrated under vacuum to provide 39 mg of a yellow solid. Purification by preparative thin-layer-chromatography on silica gel eluting with 4% methanol in dichloromethane. The product-containing band was collected and eluted with 5% methanol in ethyl acetate to afford 22 mg of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([OH:10])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].N1C2C(=CC=CC=2)C=CC=1>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:1]([OH:10])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC#CCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: CCCCCC/C=C\CO
Yield: 22.8 %

Procedure:
2-Nonyn- 1-ol (20 g, 0.4 mole) in 200 ml methyl alcohol is hydrogenated in a Parr bomb using a Lindlar catalyst (0.5 g Pd/BaSO4) and quinoline (0.5 g). The hydrogenation was monitored by gas liquid partition chromatography on diethylene glycol succinate. Hydrogenation is stopped when the concentration of the acetylenic alcohol equals that of the saturated alcohol. The hydrogenation mixture is filtered, diluted with water and extracted with ether. The ether extract is dried over anhydrous sodium sulfate, concentrated and distilled to yield 13 g of cis-2-nonen-1-ol, b.p. 60°-64°C/0.5 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:22])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:22])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(CCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.1 %

Procedure:
A mixture of 2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoic acid, methyl ester (Example 94; 2.1 g, 6.6 mmol) and 1N sodium hydroxide solution was stirred for 4 h at room temperature. The solution was filtered through Celite and the filter cake was washed with water (5 mL). 1N hydrochloric acid solution (22 mL) was added to the stirred filtrate and the resulting mixture was stirred for 2 h and then filtered. The solid was washed with water, dried and crystallized from ether/hexane to afford 2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoic acid (1.59 g, 79% yield) as an off-white solid.
Reaction SMILES: ClC(Cl)C([O:5][N:6]=[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([OH:10])=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH:32][NH:33][CH2:34][CH2:35][CH2:36][P:37](=[O:40])([OH:39])[OH:38].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[Cl-].[Na+].N>C(Cl)Cl.O.CO>[OH:32][N:33]([CH2:34][CH2:35][CH2:36][P:37](=[O:38])([OH:40])[OH:39])[C:8](=[O:10])[C:7](=[N:6][OH:5])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)C(=NOC(=O)C(Cl)Cl)c1ccccc1
Reactant: O=P(O)(O)CCCNO
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=C(C(=NO)c1ccccc1)N(O)CCCP(=O)(O)O
Reaction time: 0.33 h
Yield: 43 %

Procedure:
To a suspension of 2-(2,2-dichloroacetoxyimino)-2-phenylacetic acid (3.06 g.) in methylene chloride (20 ml.) was added phosphorus pentoxide (2.28 g.) under ice-cooling, and the mixture was stirred for 20 minutes at the same temperature and then evaporated to dryness under reduced pressure to give a residue, which was dissolved in methylene chloride (10 ml.). This solution was added dropwise to a solution of 3-(N-hydroxyamino)propylphosphonic acid (1.55 g.) and N,O-bis(trimethylsilyl)acetamide (10 g.) in methylene chloride (30 ml.) at -30° to -40° C. in the course of 5 minutes, whereafter the mixture was stirred for half an hour at the same temperature and for additional an hour at 0° C. The reaction mixture was evaporated to dryness under reduced pressure to give an oily residue, which was dissolved in water (30 ml.), stirred for 20 minutes, saturated with sodium chloride, and extracted five times with ethyl acetate (each 20 ml.) and three times with n-butanol (each 30 ml.). These extracts were evaporated to dryness under reduced pressure to give an oily residue (4.5 g.), which was dissolved in water (40 ml.). This aqueous solution was passed through a column packed with activated charcoal (100 ml.), and elution was conducted with water and then 30% aqueous acetone. The fractions containing an object compound were collected and evaporated to dryness under reduced pressure to give an oil (1.4 g.), which was dissolved in methanol and adjusted to pH 7 with 28% aqueous ammonia. The precipitates were collected by filtration and dried to give monoammonium salt of 3-[N-hydroxy-N-(2-hydroxyimino-2-phenylacetyl)amino]-propylphosphonic acid (1.30 g.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:12](=[N:14][OH:15])[CH3:13])=[CH:10][N:11]=2)[CH:2]=1.C(=O)([O-])[O-].Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:12](=[N:14][O:15][C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH3:13])=[CH:10][N:11]=2)[CH:2]=1
Reactant: Clc1ncccn1
Reactant: CC(=NO)c1cnc(-c2cccnc2)s1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(=NOc1ncccn1)c1cnc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38 %

Procedure:
A suspension of 1-[2-(3-pyridyl)thiazol-5-yl]ethanone oxime (isomer A, 0.15 g, 0.657 mmol) in acetonitrile (5 ml) was stirred at ambient temperature and treated with carbonate (0.648 g, 1.97 mmol) and 2-chloropyrimidine (0.119 g, 0.985 mmol) and allowed to stir at ambient temperature. After 2 days (80% conversion), the reaction mixture was concentrated in vacuo and the residue was stirred with ethyl acetate, filtered and the ethyl acetate concentrated in vacuo. Purification by flash chromatography eluting with ethyl acetate gave 1-[2-(3-pyridyl)thiazol-5-yl]-N-pyrimidin-2-yloxy-ethanimine (0.074 g, 38%) as a single isomer as slightly yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[NH:29][C:11]3=[N:12][C:13]([N:16]4[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])[CH2:17]4)=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:30][S:31]([O-:33])=[O:32].[Na+].N1CCC[C@H]1C(O)=O.[OH-].[Na+]>CS(C)=O.[Cu](I)I>[CH3:30][S:31]([C:2]1[CH:3]=[C:4]([C:8]2[NH:29][C:11]3=[N:12][C:13]([N:16]4[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])[CH2:17]4)=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[N:6][CH:7]=1)(=[O:33])=[O:32]
Reactant: CS(=O)[O-]
Reactant: O=C(C1CCCN(c2ccc3nc(-c4cncc(Br)c4)[nH]c3n2)C1)N1CCCC1
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cncc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)c1
Temperature: 90 °C
Yield: 55 %

Procedure:
To a solution of R)-(1-(2-(5-bromopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (0.05 g, 0.1 mmol) in dimethylsulfoxide was added sodium methylsulfinate (NaSO2Me) (13 mg, 0.13 mmol), copper iodide, L-proline and sodium hydroxide. The reaction mixture was heated to 90° C. for 14 h. The reaction mixture was partitioned between water and ethyl acetate. The organics were concentrated under reduced pressure and the resulting crude was purified via preparative TLC to afford the title compound (25 mg, 45%). MS (ES+APCI) (M+H) 455.0; LCMS retention time: 3.859 min (Method I).
Reaction SMILES: [O:1]=[C:2]1[C:11]2=[N:12][N:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:14]([CH2:15][C:16](OCC)=[O:17])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:17][CH2:16][CH2:15][C:14]1[N:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=[C:11]2[C:10]=1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:3][C:2]2=[O:1]
Reactant: CCOC(=O)Cc1c2c(nn1-c1ccccc1)c(=O)[nH]c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2c2c(CCO)n(-c3ccccc3)nc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Ethyl (4-oxo-2-phenyl-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-1-yl)acetate (0.500 g, 1.44 mmol) was dissolved in 15 mL of tetrahydrofuran and cooled to 0° C. Lithium aluminum hydride (55 mg, 1.44) was added. The mixture was allowed to stir overnight, slowly warming to ambient temperature. An additional 55 mg of lithium aluminum hydride was added, and the mixture was stirred for 24 hours at ambient temperature. 0.15 mL of water, followed by 0.15 mL of 2 N aqueous sodium hydroxide and 0.45 mL of water was added. After stirring at ambient temperature for 1 hour, the mixture was dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and concentrated under reduced pressure. The residue was purified by automated flash chromatography eluting with a gradient of 0-50% CMA in chloroform. The residue was triturated with methanol, isolated by filtration and dried to provide 0.211 g of 1-(2-hydroxyethyl)-2-phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as a white solid, mp 310-312° C. MS (ESI) m/z 306 (M+H)+; Anal. calcd for C18H15N3O2: C, 70.81; H, 4.95; N, 13.76. Found: C, 70.52; H, 4.83; N, 13.66.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8])[CH3:2]>C(O)(=O)C.O=[Pt]=O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)=[O:8])[CH3:2]
Reactant: CCOC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1CCCNC1
Reaction time: 6 h
Yield: 80.8 %

Procedure:
A mixture of N-(3-pyridyl)-3(R)-(tert-butoxycarbonylamino)succinamic acid ethyl ester (0.62 g) and PtO2 (0.06 g) in acetic acid (12 ml) was hydrogenated. at atmospheric pressure for 6 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo. The residue was dissolved in water. The solution was adjusted to pH 10 with saturated aqueous potassium carbonate solution, and extracted with ethyl acetate. The extract was washed with water and brine, and dried over MgSO4, and evaporated in vacuo to give N-(3-piperidyl)-3(R)-(tert-butoxycarbonylamino)succinamic acid ethyl ester (0.51 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][O:23][CH3:24])=[C:6]([CH:20]=1)[CH:7]([C:10]1[C:15]([O:16][CH2:17][O:18][CH3:19])=[CH:14][CH:13]=[CH:12][N:11]=1)C#N.C(=O)([O-])[O-:26].[K+].[K+].CN(C=O)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][O:23][CH3:24])=[C:6]([CH:20]=1)[C:7]([C:10]1[C:15]([O:16][CH2:17][O:18][CH3:19])=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:26]
Reactant: COCOc1ccc(Br)cc1C(C#N)c1ncccc1OCOC
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)cc1C(=O)c1ncccc1OCOC
Temperature: 25 °C
Reaction time: 38 h
Yield: 87 %

Procedure:
A mixture of 2-(5-bromo-α-cyano-2-methoxymethoxybenzyl)-3-methoxymethoxypyridine (2.40 g), potassium carbonate (2.53 g), tetrabutylammonium hydrogensulfate (0.41 g) and DMF (24 ml) was stirred for 38 hours at room temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried (anhydrous sodium sulfate), and concentrated to leave an oily product. The oily product was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 2-(5-bromo-2-methoxymethoxybenzoyl)-3-methoxymethoxypyridine (2.03 g) as an oily product, whose spectrum data are shown below.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[Na+].[N+:16](CC)([O-])=O>C(O)(=O)C>[OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:16]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc(O)cc1O
Yield: 58.4 %

Procedure:
A mixture of 2,4-dihydroxybenzaldehyde (5.0 g, 36.4 mmol), sodium acetate (5.94 g, 72.4 mmol), nitroethane (5.44 g, 72.4 mmol) and glacial acetic acid (10 ml) was refluxed for 6 hours. After cooling, the mixture was poured onto ice (100 g) and extracted with ethyl acetate (4×50 ml). The combined organic layers were washed with saturated NaHCO3 until the pH of the aqueous layer remained at 8, dried (Na2SO4) and the solvent removed in vacuo. Flash chromatography (SiO2, cyclohexane:ethyl acetate=1:1) afforded 2,4-dihydroxybenzonitrile (2.87 g, 59%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 6.33 (d, 1H, J=8.6 Hz), 6.43 (s, 1H), 7.37 (d, 1H, J=8.6 Hz), 10.35 (s, 1H), 10.78 (s, 1H). IB (KBr) 2200 cm−1.
Reaction SMILES: [Br:1][C:2]1[C:12]([OH:13])=[C:11]([Br:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].IC.[CH2:23](N(CC)C=O)[CH3:24]>CN(C=O)C>[Br:1][C:2]1[C:12]([O:13][CH2:23][CH3:24])=[C:11]([Br:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(Br)c(O)c1Br
Reactant: CCN(C=O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCC)c1Br
Temperature: 85 °C

Procedure:
Ethyl 2,4-dibromo-3-hydroxybenzoate (5.0 g) was added to a stirred suspension of potassium carbonate (106.4 g) in dry N,N-diethylformamide (DMF). A solution of iodomethane (25.7 g) in DMF was added over 18 minutes, and the resulting mixture was heated at 85° C. for 1.3 hours. The cooled mixture was poured onto water and extracted with ether. The extract was washed (brine solution), dried (anhydrous magnesium sulphate) and the solvent evaporated in vacuo to give ethyl 2,4-dibromo-3-ethoxybenzoate (52.08 g), NMR 1.4(t,3H), 1.5(t,3H), 4.1(q,2H), 4.4(q,2H), 7.35(d,1H), 7.55(d,1H).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[CH:17])[C:11]=1[F:18])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].[Cl-].[NH4+]>C1COCC1>[Si:5]([O:8][CH2:9][C:10]1[C:11]([F:18])=[C:12]([C:16]#[C:17][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH:13]=[CH:14][CH:15]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C#Cc1cccc(CO[Si](C)(C)C(C)(C)C)c1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCc1cccc(C#CC(=O)OCc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
tert-Butyl [(3-ethynyl-2-fluorobenzyl)oxy]dimethylsilane (1 g) was mixed with THF (20 ml), and a 1.65 M n-butyl lithium/hexane solution (2.5 ml) was added dropwise thereto at −78° C., followed by stirring at −78° C. for 30 minutes. Benzyl chloroformate (774 mg) was added dropwise thereto at the same temperature, followed by stirring overnight while raising the temperature to room temperature. A saturated aqueous ammonium chloride solution was added thereto at 0° C., followed by extraction with CHCl3. The organic layer was washed with water and saturated brine, and dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain benzyl 3-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]prop-2-ynoate (1.41 g).
Reaction SMILES: [OH-].[K+].O.C1OCCOCCOCCOCCOCCOC1.[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl.[CH2:31]([C:33]([CH3:35])=[O:34])[CH3:32]>C1(C)C=CC=CC=1>[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][CH:31]([CH3:32])[C:33](=[O:34])[CH3:35]
Reactant: Cc1ccccc1CCl
Reactant: CCC(C)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)C(C)Cc1ccccc1C
Temperature: 85 °C
Reaction time: 11 h
Yield: 23.1 %

Procedure:
56 g of KOH, 56 ml of water, 10 g of 18-crown-6 and 5 g of KI were warmed to 75° C. with 200 ml of toluene with exclusion of air. A mixture of 100 g of 2-methylbenzyl chloride and 100 g of methyl ethyl ketone was added dropwise over 30 minutes with vigorous stirring, and the mixture was stirred at 85° C. for 11 hours. The phases were then separated, and the organic layer was washed by shaking with water and distilled through a short packed column. After removing the solvent and the preliminary fraction, 29 g of 3-(2-methylbenzyl)-butanone were obtained at 54°-55° C./0.07 mbar. 25 g of this compound was stirred with 3 g of NaBH4 in 100 ml of ethanol, initially for 2 hours at 25° C., then for a further 2 hours at the reflux temperature. After the reducing agent and solvent had been removed, the reaction product was distilled through a short Vigreux column. 15.5 g of 3-methyl-4-(2-methylphenyl)-butan-2-ol were obtained from 64°-67° C./0.07 mbar.