Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][O:5][C:6]1[C:7]([C:22](OC)=[O:23])=[C:8]([C:18]([O:20][CH3:21])=[O:19])[C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[N:10][CH:11]=1.C[O-].[Na+]>CO>[OH:23][C:22]1[C:7]2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[N:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:3]([O:2][CH3:1])=[O:26]
Reactant: COC(=O)CCc1ncc(OCC(=O)OC)c(C(=O)OC)c1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCc1ncc2oc(C(=O)OC)c(O)c2c1C(=O)OC
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a solution of dimethyl 5-(2-methoxy-2-oxoethoxy)-2-(3-methoxy-3-oxopropyl)pyridine-3,4-dicarboxylate (2.20 g, 5.96 mmol) in methanol (60 mL) was added sodium methoxide (0.805 g, 14.9 mmol) at 80° C., and the mixture was stirred for 30 min. The resulting precipitate was collected by filtration, washed with methanol, and dissolved in 1M hydrochloric acid (10 mL). The mixture was extracted with ethyl acetate and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by recrystallization (ethyl acetate/diisopropyl ether) to give the title compound (1.35 g, yield 67%).
Reaction SMILES: [H-].[Na+].C(O[C:6]([C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=[C:11]([Cl:20])[S:10][C:9]=1[NH:21][C:22](=[O:26])[CH2:23][C:24]#[N:25])=[O:7])C.Cl>O1CCCC1>[Cl:20][C:11]1[S:10][C:9]2[NH:21][C:22](=[O:26])[C:23]([C:24]#[N:25])=[C:6]([OH:7])[C:8]=2[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([Br:19])=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1c(NC(=O)CC#N)sc(Cl)c1-c1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(O)c2c(-c3ccc(Br)cc3)c(Cl)sc2[nH]c1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of NaH (1.33 g, 33.2 mmol, 60% dispersion in mineral oil) in tetrahydrofuran (60 mL) at room temperature was added a solution of 4-(4-bromophenyl)-5-chloro-2-(2-cyano-acetylamino)-thiophene-3-carboxylic acid ethyl ester (5.26 g, 12.3 mmol) in tetrahydrofuran (60 mL) over 15 minutes. The reaction was stirred at room temperature for 12 h, and 1 N HCl was added (15 mL). The reaction was then concentrated under reduced pressure, and the resulting solid was triturated with water (15 mL) and diethyl ether (20 mL) to provide the titled compound. MS (APCI) m/e 381 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.CC1C=C(C=C(C)C=1)N.Br[C:20]1[O:24][CH:23]=[C:22]([C:25]([OH:27])=[O:26])[CH:21]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:20]2[O:24][CH:23]=[C:22]([C:25]([OH:27])=[O:26])[CH:21]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(S)c1
Reactant: O=C(O)c1coc(Br)c1
Agent: Cc1cc(C)cc(N)c1
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Sc2cc(C(=O)O)co2)c1

Procedure:
3,5-Dimethylthiophenol (4.33 g., 31.4 mmoles; prepared from 3,5-dimethylaniline by the procedures of Tarbell and Fukushima, Org. Synth. III, 809) and cuprous oxide (2.25 g., 15.7 mmoles) were reacted in 40 ml. of dimethylformamide at 140° C. for three hours. The mixture was cooled slightly and 5-bromofuran-3-carboxylic acid (3.0 g., 15.7 mmoles) in 40 ml. of dimethylformamide added. The mixture was refluxed for approximately 16 hours. Isolation of crude product as an oil was according to the procedure of Example 16 below. The oil was chromatographed on silica gel with ethyl acetate-1/hexane-5/5% acetic acid as eluant. Product was recovered by evaporation of clean, middle fractions and trituration with water (706 mg.). Recrystallization from methanol/water gave purified 5-(3,5-dimethylphenylthio)furan-3-carboxylic acid (440 mg., m.p. 82°-86° C., m/e 248).
Reaction SMILES: Br[C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[CH2:11][C:12]1([N:25]=[C:26]=[O:27])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C([Li])(C)(C)C>C1COCC1>[C:7]([N:6]1[C:2]2[C:26](=[O:27])[NH:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14][CH2:13]3)[CH2:11][C:3]=2[CH:4]=[N:5]1)([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cnn(C(C)(C)C)c2Br)(N=C=O)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Cc1cnn(C(C)(C)C)c1C(=O)N2
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 74.1 %

Procedure:
A solution of tert-butyl 4-((5-bromo-1-tert-butyl-1H-pyrazol-4-yl)methyl)-4-isocyanatopiperidine-1-carboxylate (225 mg, 0.51 mmol) in THF (10 mL) was cooled to −78° C. and t-butyl lithium (0.6 mL, 1.7 M in pentane) was added, dropwise, over 2 minutes. The mixture was stirred 30 minutes at −78° C., warmed to 0° C., and then quenched with saturated aqueous NH4Cl (20 mL). The mixture was stirred 30 minutes at room temperature, diluted with water (25 mL), and then extracted with ethyl acetate (2×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (12-100% ethyl acetate/heptane, 10 g silica gel) to yield 137 mg of tert-butyl 1′-tert-butyl-7′-oxo-1′,4′,6′,7′-tetrahydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridine]-1-carboxylate as a colorless solid. +ESI (M-tBu) 307.2; 1H NMR (400 MHz, DMSO-d6, δ): 7.74 (s, 1H), 7.30 (s, 1H), 3.51 (m, 2H), 3.20 (m, 2H), 2.79 (s, 2H), 1.64 (s, 9H), 1.56 (t, J=5.8 Hz, 4H), 1.38 (s, 9H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([CH:24]=1)[CH:22]=[O:23].C(Cl)Cl>CN(C)C(=O)C.O>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)=[C:21]([CH:24]=1)[CH:22]=[O:23]
Reactant: COc1ccc(O)cc1
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Oc2ccc(Cl)cc2C=O)cc1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
At the room temperature, anhydrous Na2CO3 (16 g, 0.15 mol) was added into a mixture of 4-methoxy-phenol (14.8 g, 0.12 mol) and 5-chloro-2-fluoro-benzaldehyde (16 g, 0.10 mol) in N,N-Dimethylacetamide (100 mL). After the mixture was refluxed for 3 h, it was cooled to room temperature. Then DCM and water were added. The organic phase was separated, washed with aqueous NaOH (1 N) and brine, dried over anhydrous Na2SO4 and concentrated to give the title compound (16 g).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6]1)=[O:4].CCN(C(C)C)C(C)C.Cl[C:25]([O:27][CH3:28])=[O:26].[Li+].[OH-]>>[CH2:11]([CH:7]1[CH2:6][CH:5]([C:3]([OH:2])=[O:4])[CH2:10][CH2:9][N:8]1[C:25]([O:27][CH3:28])=[O:26])[CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(CC(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC(C(=O)O)CC1CC(C)C

Procedure:
The compound was prepared as described in Reference Compound 1, Step 3 from crude 2-isobutyl-piperidine-4-carboxylic acid methyl ester (2.6 g, 13.0 mmol), DIPEA (4.55 mL, 26.1 mmol) and methyl chloroformate (1.31 mL, 17.0 mmol) and subsequently LiOH (1.3 equivalents) which yielded crude 2-isobutyl-1-(methoxycarbonyl)piperidine-4-carboxylic acid. MS m/z 242 (M−H)−.
Reaction SMILES: [CH2:1]([C:4]1(C(O)=O)[C:9](=[O:10])[CH2:8][CH2:7][S:6][CH2:5]1)[CH2:2][CH3:3].N1CCOCC1>O1CCCC1.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>[CH2:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH2:7][S:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1(C(=O)O)CSCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCCC1CSCCC1=O

Procedure:
To a stirred solution of 3-propyl-tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (0.272 g, 1.1 mmol) in 5.0 mL dry tetrahydrofuran at room temperature was successively added morpholine (0.979 g, 1.12 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (0.064 g, 0.055 mmol). Stirring was continued until the thin layer chromatography indicated the completion of reaction at which point the reaction mixture was evaporated and the crude product was purified by flash column chromatography on silica gel eluted eluted with hexane:ether (19:1) to give 0.163 g of 3-propyl-tetrahydrothiopyran-4-one.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH:28]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([CH3:39])[CH3:38])[C:32]=1[N:40]=[C:41]=[O:42])([CH3:30])[CH3:29]>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:16][CH:15]=2)[C:41]([NH:40][C:32]2[C:31]([CH:28]([CH3:29])[CH3:30])=[CH:36][CH:35]=[CH:34][C:33]=2[CH:37]([CH3:39])[CH3:38])=[O:42])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCc1ccc(NCc2ccc(OCCCC)cc2)cc1
Product: CCCCCCCCc1ccc(N(Cc2ccc(OCCCC)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 35.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-butoxyphenylmethyl)(4-octylphenyl)amine (1.65 g) and 2,6-diisopropylphenyl isocyanate (1.05 g) as starting materials, N-(4-butoxyphenylmethyl)-N′-(2,6-diisopropylphenyl)-N-(4-octylphenyl)urea (0.92 g) was obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]1=O.Cl>C1COCC1.CO>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: CC1Cc2c(cccc2-c2ccccn2)C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC1=Cc2cccc(-c3ccccn3)c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.7 %

Procedure:
24.6 g (0.65 mol) of NaBH, were added in portions at 0° C. to a solution of 132 g (0.59 mol) of 2-methyl-4-(2-pyridyl)-1-indanone in 1000 cm3 of THF/methanol 2:1 and the mixture was stirred for 18 hours at room temperature. The reaction mixture was poured onto 1000 g of ice, admixed with concentrated aqueous HCl to a pH of 1 and extracted a number of times with Et2O. The combined organic phases were washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution. The solvent was removed under reduced pressure and the crude product was taken up in 1000 cm3 of toluene, admixed with 4.5 g of p-toluenesulfonic acid and heated under reflux for 2 hours using a water separator. Distillation at 0.1 mbar and 145° C. gave 84 g (69%) of 2-methyl-7-(2-pyridyl)indene as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][C:36]([CH3:42])([CH2:40][OH:41])[C:37](O)=[O:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:37](=[O:38])[C:36]([CH3:42])([CH3:35])[CH2:40][OH:41])[CH2:4][CH2:5]1)=[O:27]
Reactant: CC(C)(CO)C(=O)O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C(C)(C)CO)CC2)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 85.2 %

Procedure:
A solution of N-(trans-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (250 mg, 0.666 mmol) in dimethylformamide (5 ml) and triethylamine (278 μl, 2.0 mmol) was treated with 2,2-dimethyl-3-hydroxy propanoic acid (86 mg, 0.73 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (99 mg, 0.73 mmol) and 1-hydroxybenzotriazole (114 mg, 0.73 mmol). The reaction mixture was stirred under nitrogen at room temperature for 36 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium hydrogen carbonate solution (10 ml) and ethyl acetate (15 ml) and the aqueous phase was extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with water (2×10 ml), brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. Trituration of the residue with diethylether (5 ml) gave the title compound (270 mg) as a white solid.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[N:12][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])=[CH:13][N:12]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)C(Cl)Cl)cn1
Reaction time: 1 h

Procedure:
Dichloroacetyl chloride, 97% (2.0 ml, 0.03 mol) was added over a period of 30 seconds to a mixture of 5-amino-2-methoxypyridine (3.7 g, 0.03 mol), pyridine (5.0 ml) and methylene chloride (100 ml). The reaction was exothermic and allowed to stand at room temperature for one hour. The reaction was then washed with 5% sodium carbonate solution (2×100 ml), dried over anhydrous magnesium carbonate, filtered, and evaporated in vacuo to give a solid that was triturated with hexane to yield 6.4 g of the title compound, m.p. 104°-107° C. The title product was identified by infrared (IR), nuclear magnetic resonance (NMR) and mass spectrocopy (MS) analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.ClCC(OC(=O)CCl)=O.[CH2:19]([N:21](CC)CC)[CH3:20].O>C1C=CC=CC=1>[NH2:21][CH2:19][CH2:20][NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(N)cn1
Agent: O=C(CCl)OC(=O)CCl
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(NCCN)cn1
Reaction time: 3 h

Procedure:
5-amino-2-methoxypyridine(3.18 g), chloroacetic anhydride(6.56 g), and triethylamine(7.09 ml) were stirred in benzene(55 ml) for 1 hour while being cooled with ice. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum. To the solution of the residue in dimethylformamide(20 ml) was added potassium phthalimide(5.21 g) and then the mixture was refluxed with stirring for 3 hours. After a large amount of water was added thereto, the depositing crystal was collected by filtration. The solution of the crystal in ethanol(120 ml), with hydrazine monohydrate(2.56 ml) was refluxed with stirring for 2 hours and then concentrated under a vacuum. The residue, with water added thereto, was acidified with sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum. The solution of the residue in tetrahydrofuran(40 ml) was dropped into the suspension of lithium aluminium hydride(2.63 g) in tetrahydrofuran(40 ml) while being cooled with ice and the mixture was stirred at room temperature for 2 hours. A small amount of water was added thereto and the resulting deposit was filtrated out. The filtrate was concentrated under a vacuum, thereby yielding 2.12 g of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1([Cl:20])[CH:9]2[CH:3]1[C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[N:6](C=O)[C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=12.[OH-].[Na+].Cl>C(O)C>[Cl:20][C:2]1([Cl:1])[CH:3]2[CH:9]1[C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[NH:6][C:5]1[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=12
Reactant: O=CN1c2ccccc2C2C(c3ccccc31)C2(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ClC1(Cl)C2c3ccccc3Nc3ccccc3C21
Yield: 7.3 %

Procedure:
At 50° C, a solution comprising 18.25 g. (0.06 mole) of 1,1-dichloro-1a,10b-dihydrodibenzo(b,f)cycloprop(d)azepine-6(1H)-carboxaldehyde, 16.8 g. (0.42 mole) of sodium hydroxide and 319 g. of ethanol is stirred for 4.5 hours and, then, the reaction mixture is neutralized with conc. HCl. Ethanol is distilled off, water is added and extracted with ethyl acetate. The ethyl acetate extract is washed with water and dried with anhydrous sodium sulfate, followed by the distillation of the solventto dry up under reduced pressure. The residue is then recrystallized from benzene to give 12.0 g. (yield 7.30 %) of 1,1-dichloro-1,1a,6,10b-tetrahydrodibenzo(b,f)cycloprop(d)azepine. Meltingpoint: 162°-163° C
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:33])[NH:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NC(=O)C2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(C1CCCOC1)Oc1ccc(Br)cc12
Temperature: 120 °C
Yield: 38.2 %

Procedure:
A suspension of 6-bromo-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (300 mg, 0.79 mmol) and Lawesson's Reagent (319 mg, 0.79 mmol) in dry 1,4-dioxane (4 mL) was heated at 120° C. for 30 minutes in microwave. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(tetrahydro-2H-pyran-3-yl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (120 mg, 40%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[C:5]([C:14]#[N:15])=[C:4]([C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:3]=1[C:25]#[N:26].[H-].[Na+].C(#N)C.O.[CH:33]1(O)[CH2:36]C[CH2:34]1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([CH3:13])[C:9]([O:11][CH:12]2[CH2:36][CH2:33][CH2:34]2)=[O:10])[C:5]([C:14]#[N:15])=[C:4]([C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:3]=1[C:25]#[N:26]
Reactant: COC(=O)C(C)c1nc(N)c(C#N)c(-c2ccc3c(c2)OCO3)c1C#N
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C(=O)OC1CCC1)c1nc(N)c(C#N)c(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
Methyl 2-[6-amino-4-(1,3-benzodioxol-5-yl)-3,5-dicyano-2-pyridinyl]propionate (from Example 6) (100 mg, 0.29 mmol) in cyclobutanol (5 ml) is heated under reflux with a catalytic amount of sodium hydride for 2.5 hours. The product is isolated by RP-HPLC (Kromasil column 250 * 20 mm, C18, 10 μm; acetonitrile/water gradient: 3 minutes 10%, then within 30 minutes to 80%, flow rate: 25 ml*min−1).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH:2]=[CH2:3].[CH3:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1)[NH2:26]>>[CH3:22][C:23]1[CH:24]=[C:25]([NH:26][C:8]2[N:7]=[C:6]3[N:5]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:4]([CH2:1][C:2]#[CH:3])[C:12](=[O:13])[C:11]3=[CH:10][N:9]=2)[CH:27]=[CH:28][C:29]=1[N:30]1[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]1
Reactant: Cc1cc(N)ccc1N1CCN(C)CC1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1ccccn1
Product: C#CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)c(C)c3)nc2n1-c1ccccn1

Procedure:
17.0 mg of the entitled compound was obtained as a yellow solid in the same manner as in Example 113-1 to 113-2, for which, however, 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one obtained in Example 29-1 was used in place of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 113-1, and 3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.
Reaction SMILES: C1(C)C=CC(S(O)=O)=CC=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]C(=O)OCC=C)=[CH:15][CH:14]=1>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.C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1
Reactant: C=CCOC(=O)Nc1ccc(OC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)O)cc1
Solvent: ClCCl
Product: COc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78.8 %

Procedure:
Tetrakis(triphenylphosphine)palladium (30.3 mg, 26.2 μmol) was added to a methylene chloride solution (3.7 ml) of p-toluenesulfinic acid (64.3 mg, 0.411 mmol) and allyl N-(p-methoxyphenyl)carbamate (77.6 mg, 0.374 mmol) prepared in Preparation 7. The reaction mixture was stirred for 40 minutes at room temperature. The reaction solution was subjected to a silica gel chromatography to obtain p-anisidine (36.3 mg) with a yield of 79%.
Reaction SMILES: Cl[C:2](Cl)([CH2:8][C:9]([Cl:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[Na+].[H][H]>C(O)C.[Pt]>[Cl:12][C:9]([F:10])([F:11])[CH2:8][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)(Cl)CC(F)(F)Cl
Reactant: [H][H]
Agent: [Pt]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCC(F)(F)Cl
Yield: 75.2 %

Procedure:
25.5 g of ethyl 2,2,4-trichloro-4,4-difluorobutyrate are dissolved in 200 ml of absolute ethanol. 16.4 g of anhydrous sodium acetate and 2.0 g of 5% platinum/carbon catalyst are added and then gaseous hydrogen is passed in under atmospheric pressure until the hydrogen uptake is 2 equivalents. The catalyst is removed by filtration and the ethanol is removed by distillation and then the remaining oil is poured onto water, and the organic phase is separated off, dried with sodium sulfate, filtered and distilled under atmospheric pressure. 14.0 g of ethyl 4-chloro-4,4-difluorobutyrate are obtained in the form of a colourless oil of boiling point 154°-156° C.
Reaction SMILES: [CH:1]1([Si:6](OC)([O:9][CH3:10])[O:7][CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]([OH:17])([CH2:15][CH3:16])[CH3:14].C[Si](C)(C)Cl>C[O-].[Na+]>[CH:13]([O:17][Si:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([O:9][CH3:10])[O:7][CH3:8])([CH2:15][CH3:16])[CH3:14]
Reactant: CO[Si](OC)(OC)C1CCCC1
Reactant: CCC(C)O
Agent: C[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Product: CCC(C)O[Si](OC)(OC)C1CCCC1
Yield: 84.3 %

Procedure:
In a 100 ml three-neck flask provided with a magnetic stirrer were charged 10.3 g (0.0542 mole) of cyclopentyl trimethoxysilane, 40.3 g (0.543 mole) of sec-butyl alcohol and 33.7 mg (0.625 m mole) of sodium methoxide, which were then reacted with each other at room temperature for 2 hours under stirring. Then, trimethylchlorosilane was added to neutralize the alkali. Then, 10.6 g (0.0457 mole) of sec-butoxy cyclopentyl dimethoxysilane were obtained by vacuum distillation. Its structure was confirmed as in Example 1. FIGS. 1 and 2 are charts of 1H-NMR and IR, respectively. The yield was 84%.
Reaction SMILES: Cl[Si:2](Cl)([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[F:10][C:11]([F:17])([F:16])[S:12]([OH:15])(=[O:14])=[O:13].Cl>>[F:10][C:11]([F:17])([F:16])[S:12]([O:15][Si:2]([O:15][S:12]([C:11]([F:17])([F:16])[F:10])(=[O:14])=[O:13])([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4])(=[O:14])=[O:13]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CC(C)[Si](Cl)(Cl)C(C)C
Agent: Cl
Product: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(OS(=O)(=O)C(F)(F)F)C(C)C
Yield: 58.2 %

Procedure:
An oven-dried 100 mL-RB flask is charged with dichlorodiisopropylsilane (9.2 g, 0.05 mol). Then 15 g of trifluoromethanesulfonic acid (15 g, 0.10 mol) is added dropwise. The mixture is heated at 60° C. until no further HCl evolves. The residue is distilled to yield 12 g (60%) of the product as clear liquid. 1H NMR (500 MHz, CDCl3, in ppm) δ 1.58 (heptet, 2H, J=7.2 Hz), 1.24 (d, 12H, J=7.2 Hz).