Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([O:43][CH3:44])(=[O:42])[C:35]1[C:36](=[CH:38][CH:39]=[CH:40][CH:41]=1)[OH:37].O[CH2:46][CH2:47][N:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>C1COCC1>[CH3:44][O:43][C:34](=[O:42])[C:35]1[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=1[O:37][CH2:46][CH2:47][N:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: COC(=O)c1ccccc1O
Reactant: OCCN1CCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.6 %

Procedure:
To a mixture of triphenylphosphine (0.79 g, 3.0 mmol) in THF (15 ml) was successively added diisopropylazodicarboxylate (0.61 g, 3.0 mmol) followed by methyl salicylate (0.46 g, 3.0 mmol) and the resultant mixture stirred at ambient temperature for 1 h. 1-(2-Hydroxyethyl)-pyrrolidine (0.35 g, 3.0 mmol) was then added drop-wise and the reaction mixture left stirring at ambient temperature for a further 5 h. The reaction mixture was reduced in vacuo and purified by flash column chromatography [SiO2, EtOAc/MeOH (3:1, 1:1)] to give 2-(2-pyrrolidin-1-yl-ethoxy)-benzoic acid methyl ester as a clear yellow oil (446 mg, 60%). (LC/MS: Rt 1.58, [M+H]+ 250.05).
Reaction SMILES: [PH3]=O.[CH3:3][P:4]([CH3:8])[O:5]CC.[CH:9](=O)[CH3:10].[NH2:12][C:13]([NH2:15])=[O:14].B(F)(F)F.CCOCC>>[CH3:3][P:4](=[O:5])([CH3:8])[CH:9]([NH:12][C:13]([NH2:15])=[O:14])[CH3:10]
Reactant: CCOP(C)C
Reactant: CC=O
Reactant: NC(N)=O
Agent: FB(F)F
Agent: O=[PH3]
Solvent: CCOCC
Product: CC(NC(N)=O)P(C)(C)=O

Procedure:
This example shows the preparation of a phosphine oxide, that is a compound containing three P--C bonds. Warming (50°-100° C) of a mixture of ethyl dimethylphosphinite, acetaldehyde and urea in the presence of a catalytic amount of boron trifluoride etherate gives dimethyl (1-ureidoethyl)phosphine oxide, a product that cannot be hydrolyzed to an acid of phosphorus.
Reaction SMILES: [C:1]1([N:7]2[C:15]([NH2:16])=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:17]1([NH:16][C:15]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]3[C:14]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCCC1
Reactant: Nc1c2ccccc2nn1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Yield: 17.5 %

Procedure:
To a solution of 2-phenyl-2H-indazol-3-amine (800 mg, 4 mmol; Shirtcliff, Laura D.; Rivers, Jazmin; Haley, Michael M, Journal of Organic Chemistry (2006), 71(17), 6619-6622) in CH2Cl2 (43 ml) was added cyclohexanone (1.97 ml, 19 mmol; [108-94-1]), acetic acid (0.22 ml, 4 mmol) and sodium triacetoxyborohydride (2.43 g, 11 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was heated under reflux conditions for 12 h, poured onto ice water/aqueous NaHCO3 solution 1/1 and extracted two times with CH2Cl2. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure, the resulting brown oil was dissolved in MeOH (20 ml) and heated under reflux conditions for 30 min. Removal of the solvent under reduced pressure left a brown oil which was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (206 mg, 0.7 mmol; 18%) as yellow oil. MS: m/e=292.4 [M+H+].
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[C:7]([O:15][CH3:16])[CH:8]=[CH:9][C:10]=2[O:13][CH3:14])[CH2:5][C@H:4]1[OH:17].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>O.C1C=CC=CC=1>[C:18]([NH:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[C:7]([O:15][CH3:16])[CH:8]=[CH:9][C:10]=2[O:13][CH3:14])[CH2:5][C@H:4]1[OH:17])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(OC)c2c1C[C@@H](N)[C@H](O)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(OC)c2c1C[C@@H](O)[C@H](NC(=O)c1ccccc1)C2
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A solution of 74.8 g of trans-3-amino-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthalenol, hydrochloride in 2 liters of water is cooled in an ice bath and a solution of 40 g of benzoyl chloride in 300 ml of benzene is added. While stirring vigorously a solution of 23 g of sodium hydroxide in 100 ml of water is added dropwise at 0°-5° C over a period of 30 minutes. Semi-solid material begins adhering to the sides of the flask almost immediately. The mixture is stirred at 0°-5° C for an additional 2 hours. The solid is removed by filtration, washed with a small amount of water, then washed with chloroform and dried in vacuo over phosphorous pentoxide to give 78.5 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:47]=[CH:46][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([O:34]CC5C=CC=CC=5)=[O:33])=[CH:28][CH:27]=4)=[C:19]([F:42])[C:18]=3[F:43])=[C:11]([F:44])[C:10]=2[F:45])=[CH:6][C:5]=1[O:48]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:47]=[CH:46][C:7]([O:8][C:9]2[C:10]([F:45])=[C:11]([F:44])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]([OH:34])=[O:33])=[CH:30][CH:31]=4)=[C:19]([F:42])[C:18]=3[F:43])=[C:13]([F:16])[C:14]=2[F:15])=[CH:6][C:5]=1[OH:48]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc([N+](=O)[O-])c(OCc5ccccc5)c4)c(F)c3F)c(F)c2F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc(C(=O)O)cc4)c(F)c3F)c(F)c2F)cc1O
Reaction time: 8 h
Yield: 91 %

Procedure:
49.9 g of the 4-(4-nitro-3-benzyloxyphenoxy)-4′-(4-benzyloxycarbonylphenoxy)octafluorobiphenyl (0.065 mol) prepared as described in Example 2 are dissolved in 400 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 5 g of Pd/C (palladium/carbon) are then added to the solution. The mixture is then hydrogenated using hydrogen at a pressure of 1 bar at room temperature in an autoclave with vigorous stirring; the reaction is terminated after 3 days. The yellow-beige solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates in crystalline form. The reaction product is then separated off and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 91%).
Reaction SMILES: [CH2:1]([Sn:5]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[CH:7]=[C:8]([C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[NH:27]1[CH:31]=[C:30]([CH2:32][CH2:33][N:34]2[C:38](=[O:39])[CH2:37][NH:36][C:35]2=[S:40])[N:29]=[CH:28]1.N1CCCCC1>ClCCl>[NH:27]1[CH:31]=[C:30]([CH2:32][CH2:33][N:34]2[C:38](=[O:39])/[C:37](=[CH:17]/[C:15]3[O:16][C:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=4)=[CH:13][CH:14]=3)/[NH:36][C:35]2=[S:40])[N:29]=[CH:28]1
Reactant: O=C1CNC(=S)N1CCc1c[nH]cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(C=O)o2)c1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(/C=C3\NC(=S)N(CCc4c[nH]cn4)C3=O)o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
5-(3-(Tributylstannyl)phenyl)furan-2-carbaldehyde (65 mg, 0.14 mmol) synthesized by the same method as in Example 4 and 3-(2-(1H-imidazol-4-yl)ethyl)-2-thioxoimidazolidin-4-one (32 mg, 0.15 mmol) synthesized by the same method as in Example 3 were dissolved in dichloromethane (7 mL), piperidine (20 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) overnight. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform/methanol (9/1 (volume ratio)) as an eluent, to give labeling precursor 3 in a yield of 42 mg (yield 45.9%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].[H-].[Na+].[CH3:17][O:18][CH2:19]Cl>CN(C=O)C>[CH3:17][O:18][CH2:19][O:14][C:5]1[CH:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COCCl
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 2-nitro-5-trifluoromethylphenol (400 mg) in DMF (4.0 ml), sodium hydride (77 mg) was added at 0° C. in a stream of argon. The mixture was stirred for 30 minutes After stirring, methoxymethyl chloride (147 μl) was added dropwise thereto. The mixture was stirred for 20 minutes. The reaction mixture was quenched by iced water and extracted with ethyl acetate. The layer containing ethyl acetate was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=20:1) to give the title compound (353 mg) having the following physical data.
Reaction SMILES: [Mg].C(Br)CC(C)C.CCCCCBr.C[O:15][CH:16]([C:22]([CH3:26])=[CH:23][CH2:24][CH3:25])[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20].CC(=CCC)C=O.Cl>CCOCC>[CH3:20][CH:19]([CH2:18][CH2:17][CH:16]([OH:15])[C:22]([CH3:26])=[CH:23][CH2:24][CH3:25])[CH3:21]
Reactant: CCC=C(C)C(CCC(C)C)OC
Agent: CCC=C(C)C=O
Agent: Cl
Agent: [Mg]
Solvent: CCCCCBr
Solvent: CCOCC
Solvent: CC(C)CCBr
Product: CCC=C(C)C(O)CCC(C)C
Temperature: 10 °C

Procedure:
69.5 g (2.9 g-atoms) of magnesium are placed in 500 ml of absolute ether Subsequently, a solution of 438 g of isoamyl bromide, which contains about 1.5% of n-amyl bromide in accordance with gas chromatography, in 1.2 1 of absolute ether is added dropwise so that the exothermic reaction keeps the ether constantly at the boiling point After completion of the addition, the mixture is held at reflux temperature for a further 30 minutes. The Grignard solution is then cooled to 10° C. 236.5 g (2.41.mol) of 2-methyl 2-pentenal in 600 ml of absolute ether are then added dropwise within 40 minutes, the temperature then lying permanently between 10° C. and 20° C. In order to complete the reaction, the mixture is held at reflux temperature for a further 1 hour. The mixture is subsequently added to ice, decomposed with aqueous hydrochloric acid, the ethereal solution is washed neutral with soda and saturated sodium chloride solution and thereupon dried. The crude product (480 g) remaining behind after distillation of the solvent is fractionally distilled over a Widmer column and gives 312 g of 2,6-dimethyl-6-nonen-5-ol (III) of boiling point 62° C./0.05 Torr, nD25 =1.4479, which contains 1.5% of 4-methyl-3-decen-5-ol in accordance with gas chromatography (Carbowax, 130° C.).
Reaction SMILES: [H-].[Na+].[CH2:3]=[C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][N:5]1[C:19](=[O:23])[CH2:20][CH2:21][CH3:22].CN(C=[O:28])C>>[C:19]([N:5]1[CH2:6][C:7]2[C:8](=[O:28])[C:9]3[CH:10]=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][C:14]=3[NH:15][C:16]=2[C:4]1=[CH2:3])(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CN(C)C=O
Reactant: C=C1c2[nH]c3ccc(OC)cc3c2CCN1C(=O)CCC
Agent: [H-]
Agent: [Na+]
Product: C=C1c2[nH]c3ccc(OC)cc3c(=O)c2CN1C(=O)CCC
Reaction time: 6 h
Yield: 40 %

Procedure:
NaH (1.5 eq; 60% suspension in oil) is added to a solution of 1-methylene-2-butyryl-6-methoxy-1,2,3,4-tetrahydro-β-carboline (160 mg; 0.6 mmol) in DMF (3 ml). The mixture is stirred under an oxygen atmosphere for 6 hours. The DMF is then distilled off under reduced pressure. The crude product is washed several times with ethyl acetate. After filtration and drying, 2-butyryl-7-methoxy-3-methylene-9-oxo-1,3,4,9-tetrahydropyrrolo[3,4-b]quinoline is obtained (yield=40%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH:6]12[CH2:12][CH:9]([CH:10]=[CH:11]1)[CH:8]=[CH:7]2.C([O:15]CC)C>>[CH:2]12[CH2:1][CH:9]([CH:10]=[CH:11]1)[CH:8]1[CH:3]2[CH:6]([CH2:12][OH:15])[CH2:7]1
Reactant: CCOCC
Reactant: C1=CC2C=CC1C2
Reactant: C=CC[Mg]Br
Product: OCC1CC2C3C=CC(C3)C12
Yield: 73 %

Procedure:
The procedure of Example I was repeated on a larger scale by reacting 195 mmoles of allylmagnesium bromide in diethyl ether with 218 mmoles of bicyclo[2.2.1]hepta-2,5-diene at 125° C. for 3 hours. After the oxidation and hydrolysis, distillation gave tricyclo[4.2.1.02.5 ]non-7-en-3-yl-methanol (b.p. 97°-99° C. at 1 mm Hg) in 73 percent yield based on the allylmagnesium bromide.
Reaction SMILES: C(OC([N:6]1[CH:15]=[C:14]([CH:16]=[O:17])[C:13]2[C:8](=[CH:9][C:10]([O:26][CH3:27])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:12]=2)[CH:7]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH3:37])[CH:30]=1)=O)C.[OH-].[K+].C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>CO>[C:23]([O:22][CH2:21][CH2:20][CH2:19][O:18][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:26][CH3:27])[CH:7]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH3:37])[CH:30]=1)[NH:6][CH:15]=[C:14]2[CH:16]=[O:17])(=[O:25])[CH3:24]
Reactant: CCOC(=O)N1C=C(C=O)c2cc(OCCCOC(C)=O)c(OC)cc2C1Cc1cccc(OCC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1cccc(CC2NC=C(C=O)c3cc(OCCCOC(C)=O)c(OC)cc32)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 109.2 %

Procedure:
To a solution of 6-(3-acetoxy-propoxy)-1-(3-ethoxy-benzyl)-4-formyl-7-methoxy-1H-isoquinoline-2-carboxylic acid ethyl ester (130 mg, 0.25 mmol) in methanol (3.5 mL) was added powdered potassium hydroxide (85.5 mg, 1.53 mmol) at room temperature. The mixture was stirred at room temperature for 14 hrs. The solvent was evaporated and the residue was diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (2×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane, 75% ethyl acetate/hexane, ethyl acetate) afforded 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-1,2-dihydro-isoquinoline-4-carbaldehyde (120 mg, 42% yield).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][S:5][C:6](SC)=[CH:7][C:8]([C:10]1[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=1[Cl:21])=O>C(O)C>[Cl:21][C:11]1[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:15]([Cl:16])[C:10]=1[C:8]1[CH:7]=[C:6]([S:5][CH3:4])[NH:3][N:2]=1
Reactant: NN
Reactant: CSC(=CC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl)SC
Solvent: O
Solvent: CCO
Product: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Reaction time: 0.75 h

Procedure:
Hydrazine monohydrate (0.51 ml) was added dropwise to a solution of 3.6 g of 3,3-bis[methylthio]-1-(2,6-dichloro-4-trifluoromethylphenyl)-2-propen-1-one (17) in 40 ml of ethanol at room temperature, and the mixture was stirred for 45 minutes and then refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel (eluent: ether/hexane=2/5) to afford 3.3 g of the desired compound in the form of white crystals.
Reaction SMILES: C1(C)C=CC=CC=1.[H-].[Br:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[CH2:13][CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16].Cl>CO>[Br:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[CH2:13][CH:14]([CH2:15][OH:16])[CH2:20][OH:21]
Reactant: CCOC(=O)C(Cc1cccc(Br)c1)C(=O)OCC
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: OCC(CO)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
To an ice-cooled 94 ml of 1.0 M diisobutylalminium hydride toluene solution was added dropwise 5.41 g of diethyl (3-bromobenzyl)malonate at 15° C. or less under argon flow. The mixture was stirred for 30 minutes under ice-cooling, warmed to room temperature and stirred for 2 hours. The reaction solution was ice-cooled, and 21 ml of methanol was added dropwise slowly, then 41 ml of 2 N hydrochloric acid was added dropwise. The mixture was stirred for 20 minutes at room temperature. The reaction solution was filtered to remove insolubles, extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, chloroform: methanol=10:1) to provide 1.96 g of the objective compound as white crystals. M.p. 61-63° C.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1O.Cl.[CH3:13][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][CH:24]([CH2:26][CH2:27][CH2:28][C:29]([OH:33])([CH:31]=[CH2:32])[CH3:30])[CH3:25])[CH3:20])[CH3:15]>[Cl-].[Zn+2].[Cl-].C(OCC(C)C)(=O)C>[CH3:9][C:8]1[C:7]([OH:10])=[C:6]([CH3:11])[C:5]2[CH2:32][CH2:31][C@:29]([CH2:28][CH2:27][CH2:26][C@@H:24]([CH2:23][CH2:22][CH2:21][C@@H:19]([CH2:18][CH2:17][CH2:16][CH:14]([CH3:13])[CH3:15])[CH3:20])[CH3:25])([CH3:30])[O:33][C:3]=2[C:2]=1[CH3:1]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OCC(C)C
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 3 h
Yield: 101.7 %

Procedure:
To a mixture consisting of 23.3 g (0.153 mol) of 2,3,5-trimethylhydroquinone, 17.5 g (0.128 mol) of zinc chloride, 50 ml of isobutyl acetate and 2.5 g of concentrated hydrochloric acid, 46.1 g (0.153 mol) of isophytol (purity: 98.3%) were added dropwise under stirring at 30°-40° C. over 3 hours. At the same temperature, the reaction mixture was stirred for additional 2 hours. After the reaction mixture was washed with 10 ml of water, the solvent was distilled off. Toluene (100 ml ) was added to the residue to dissolve the same. The resulting solution was washed successively with water, alkaline water and a saturated aqueous solution of NaCl, dried over magnesium sulfate and then concentrated under reduced pressure, whereby 67.0 g of the title compound were obtained as a brown oil (yield: 98.6%, GLC purity: 98.6%, α-tocopheryl acetate content: 0.2%, isobutyl acetate recovery rate: 92%).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([S:17][C:18]3[S:22][C:21]([NH2:23])=[CH:20][CH:19]=3)=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:24][CH3:25].[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>O1CCCC1>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([S:17][C:18]3[S:22][C:21]([NH:23][C:35]([NH:34][C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)=[O:36])=[CH:20][CH:19]=3)=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:24][CH3:25]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1cc2c(Sc3ccc(N)s3)ccnc2cc1OCCCN(C)C
Solvent: C1CCOC1
Product: COc1cc2c(Sc3ccc(NC(=O)Nc4ccc(F)cc4)s3)ccnc2cc1OCCCN(C)C
Yield: 6.2 %

Procedure:
5-((7-[3-(Dimethylamino)propoxy]-6-methoxy-4-quinolyl}sulfanyl)-2-thiophenylamine (190 mg), para-fluorophenyl isocyanate (69 mg) and tetrahydrofuran (30 ml) were stirred together at room temperature for 30 minutes. The organic solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate, followed by ethyl acetate:methanol=10:1) using NH type silica gel. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue for solidification to obtain 16 mg of a yellowish-brown solid.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.C(O)(=O)C.[N:16]([O-])=O.[Na+].[C:20]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:21][C:22]([CH3:24])=O>[Zn].O>[CH2:27]([O:26][C:20]([C:21]1[C:3]([CH3:5])=[C:2]([C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[NH:16][C:22]=1[CH3:24])=[O:25])[CH3:28]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: 2.5 °C

Procedure:
Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket and an air condenser, were charged tertiary butyl acetoacetate (1.0 Kg; 6.3 mole) and acetic acid (3.0 Lt). The solution was cooled to 0-5° C. and a previously dissolved solution of sodium nitrite (0.436 Kg; 6.3 mole) in 640 mL DM water into an addition funnel and added to the flask at a rate that the temperature does not exceed 5° C. After the addition, the solution was maintained for 90 minutes at 0-5° C. and slowly brought the reaction mixture to room temperature (25-30° C.) over a period of 4 hours. At this temperature, ethyl acetoacetate (0.824 Kg; 6.3 mole) was charged at once followed by Zinc powder (0.94 Kg; 14.4 mole) in ten equal lots below 70° C. After addition of zinc powder, the reaction mixture was maintained for 1-2 hours at 65-70° C. The resulting solution was cooled to 60° C. and quenched in a carboy containing 25.0 Lt DM water under stirring. The product was extracted with ethyl acetate and separated using separating funnel. The organic layer was then clarified by treating the product solution with activated charcoal followed by filtration through hyflow. The solvent was then recovered by distillation under diminished pressure and the traces were removed by the addition of methanol (500 ml) to the distillation flask and continued distillation under diminished pressure. The resulting product was triturated in 95% aqueous methanol (1.5 L) at 0-5° C. for 2 hours to get a crystalline product of formula-II.
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH:9]=[N:8][C:7]([Cl:11])=[N:6][C:5]=2[NH:4][CH:3]=1.[Si:12]([O:19][C@@H:20]1[CH2:25][CH2:24][C@H:23](O)[CH2:22][CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(C=P(C)(C)C)#N>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:10]2[CH:9]=[N:8][C:7]([Cl:11])=[N:6][C:5]=2[N:4]([C@H:23]2[CH2:24][CH2:25][C@H:20]([O:19][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14])[CH2:21][CH2:22]2)[CH:3]=1
Reactant: Clc1ncc2c(Br)c[nH]c2n1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](O)CC1
Agent: CP(C)(C)=CC#N
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(Br)c3cnc(Cl)nc32)CC1

Procedure:
To a suspension of 5-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.13 g, 0.50 mmol) and cis-4-(tert-butyldimethylsilyloxy)cyclohexanol (0.23 g, 1.0 mmol) in toluene (8 mL) was added (cyanomethylene)trimethylphosphorane (CMMP; prepared according to Chem. Pharm. Bull. 2003, 51(4), 474-476.) (6.3 mL, 0.16 M in THF, 1.0 mmol). The resulting clear solution was refluxed for 16 h. The reaction mixture was washed with brine, and extracted with EtOAc (3×). The combined organic layer was dried (Na2SO4) and concentrated. The residue was purified on ISCO to provide the desired product (0.16 g, 72%). 1H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 7.27 (s, 1H), 4.70 (tt, J=12.2, 3.9 Hz, 1H), 3.69 (tt, J=10.5, 4.2 Hz, 1H), 2.09-1.99 (m, 3H), 1.86-1.71 (m, 2H), 1.66-1.54 (m, 3H), 0.90 (s, 9H), 0.08 (s, 6H). MS m/z 444.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([NH:29][CH2:30][CH2:31][N:32]1[C:36](=[O:37])[CH2:35][S:34][C:33]1=[O:38])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1CCCCC1.NCCN1C(=O)/C(=C/C2C=CC=CC=2)/SC1=O>>[NH2:29][CH2:30][CH2:31][N:32]1[C:36](=[O:37])/[C:35](=[CH:6]/[C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)/[S:34][C:33]1=[O:38]
Reactant: Cc1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1CCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NCCN1C(=O)S/C(=C\c2ccccc2)C1=O
Solvent: C1CCNCC1
Product: Cc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1

Procedure:
The title compound 30d was prepared from 4-methylbenzaldehyde (73 μL, 0.62 mmol), compound 29 (250 mg, 0.62 mmol) and piperidine (7.0 μL, 0.062 mmol) in a manner similar to that described for 30a in 36.0% (83 mg) yield as a cream solid.