Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[NH:22]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([N:22]3[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:23]3)[N:3]=2)=[N:13][C:14]=1[O:20][CH3:21]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)nc1OC
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)OC(C)(C)C)C3)nc3scnc23)nc1OC
Temperature: 95 °C
Reaction time: 24 h
Yield: 51.8 %

Procedure:
To a stirred solution of 5-chloro-N-(5,6-dimethoxypyridin-2-yl)thiazolo[5,4-d]pyrimidin-7-amine (344 mg, 1.06 mmol), tert-butyl pyrrolidin-3-ylcarbamate (289 mg, 1.55 mmol), X-Phos (256 mg, 0.53 mmol) and Cs2CO3 (1.3 g, 3.9 mmol) in 120 mL of dioxane at room temperature under nitrogen was added Pd2(dba)3 (138 mg, 0.24 mmol) in one portion. Then the reaction was stirred at 95° C. under nitrogen for 24 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (2:1)) to give tert-butyl 1-(7-(5,6-dimethoxypyridin-2-ylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamate (260 mg, 51.7%) as an oil. LC-MS: 474.2 [M+H]+, tR=1.67 min.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17].C(=O)(O)[O-].[Na+]>C(O)C>[O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][N:13]([CH2:24][CH2:23][C:22]3[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=3)[CH2:12][CH2:11]2)[CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: O=C1c2ccccc2CC12CCNCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccccc2CC12CCN(CCc1ccc([N+](=O)[O-])cc1)CC2
Yield: 56.2 %

Procedure:
A mixture of 0.60 g (3.0 moles) 1,3-dihydro-1-oxospiro[2H-indene-2,4'-piperidine], 0.71 g (3.1 mmoles) 4-nitrophenethyl bromide, and 0.28 g (3.3 mmoles) sodium bicarbonate in 3 ml ethanol was heated at reflux for 6 hours. The solvent was removed in vacuo and the residue was partitioned between 20 ml ethyl acetate and 5 ml dilute bicarbonate solution. The layers were separated and the aqueous layer was extracted with 20 ml ethyl acetate. The combined extract was washed wth 5 ml water and brine, dried, and the solvent was removed in vacuo to give 1.08 g crude product as a gum. This was purified by flash chromatography on silica gel eluting with methanol:chloroform (2:98). The material obtained was crystallized from 1:10 methylene chloride:ether to give 0.61 g (58%) product, m.p. 187°-188° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].NC(N)=[S:15]>CC(C)=O>[SH:15][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: NC(N)=S
Solvent: CC(C)=O
Product: COC(=O)c1cccc(CS)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 3-bromomethylbenzoate (6.9 g, 30 mmol; Lancaster) in dry acetone (10 mL) was added via dropwise addition a solution of thiourea (2.28 g, 30 mmol) in dry acetone (40 mL) at room temperature. After 15 minutes the precipitated thiouronium salt was collected by filtration; the solids were washed with acetone and dried. The thiouronium salt was dissolved in H2O (65 mL) and the pH was adjusted to 10.5 by the addition of 10% NaOH. The mixture was refluxed for 2 hours. After cooling to room temperature the solution was extracted with EtOAc and the organic layer was discarded. The aqueous solution was acidified to pH 1.5 and extracted three times with EtOAc. The organic extracts were dried (MgSO4), filtered and the solvent evaporated. The crude acid was then dissolved in anhydrous MeOH (125 mL), cooled to 0° C., and dry HCl gas was bubbled through the solution for 30 minutes. The reaction was then left for two days at room temperature. The mixture was concentrated in vacuo and the product was purified by flash column chromatography (silica, 5% EtOAc in hexane) providing a colorless oil: 1H NMR (250 MHz, CDCl3) δ 8.00 (s, 1H, 2-phenyl), 7.91 (d, J=7.6 Hz, 1H, 6-phenyl), 7.52 (d, J=7.6 Hz, 1H, 4-phenyl), 7.39 (dd, J=7.6 Hz, 1H, 5-phenyl), 3.92 (s, 3H, methyl ester), 3.78 (d, J=7.7 Hz, 2H, SCH2), 1.79 (t, J=7.7 Hz, 1H, SH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[CH:15]([CH:17]=O)=[O:16].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[CH:17][CH:15]=[O:16]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=CC=O
Solvent: O
Solvent: CC(=O)O
Product: O=CC=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (5 g) in acetic acid was added dropwise to a mixture of 40% aqueous glyoxal (50 ml) and water (400 ml). The mixture was stirred at room temperature for 2 hours and solid collected by filtration. A sample was recrystallised from ethanol to give 2-(2,6-dichloro-4-trifluoromethylphenylhydrazono)acetaldehyde, m.p. 131°-133°. This crude product (2.85 g) in ethanol (30 ml) was added to a solution of hydroxylamine hydrochloride (0.7 g) in water (10 ml), which had been neutralized with sodium acetate (0.82 g). The mixture was stirred at room temperature and then extracted with ethyl acetate. The extract was washed with brine, dried and evaporated to 2-(2,6-dichloro-4-trifluoromethylphenylhydrazono)acetaldehyde oxime. This was then treated with copper sulphate, in a similar manner to Example 1, to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole 1-oxide, m.p. 153°-154°, which in turn was treated with trimethyloxonium tetrafluoroborate and sodium methanethiolate, in a similar manner to Example 3, to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylthio-2H-1,2,3-triazole, m p. 100°-101°. (Compound 11)
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[O:4].Cl.[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=O>O>[C:3]([NH:2][N:1]=[C:8]([CH3:10])[C:7]([OH:12])=[O:11])(=[O:4])[NH2:5]
Reactant: CC(=O)C(=O)O
Reactant: NNC(N)=O
Agent: Cl
Solvent: O
Product: CC(=NNC(N)=O)C(=O)O

Procedure:
22.3 g of hydrochloric acid semicarbazide was dissolved in 100 ml of water, and 13.9 ml of pyruvic acid was added to the solution while stirring. Precipitated crystals were filtered out, washed, and dried to obtain 21 g of 2-carbamoylhydrazonopropionic acid having a melting point of 201° C. (decomposed).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO.O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(C)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 96.3 %

Procedure:
A solution of 89A (0.36 g, 1.8 mmol) and aqueous sodium hydroxide (1N, 3 mL, 3 mmol) in a mixture of methanol (1.5 mL) and tetrahydrofuran (3 mL) was heated at 80° C. for 1 h and at rt for 2 h. An additional portion of sodium hydroxide solution (1 mL) was added and the mixture was heated at 80° C. for 5 min. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and acidified with hydrochloric acid (1N). The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo to give 89B (0.314 g, 94%) as a white solid. LCMS: 182 (M+1)
Reaction SMILES: [NH3:1].CC(O)C.Cl[C:7]([C:34]1[CH:39]=[CH:38][C:37]([I:40])=[CH:36][CH:35]=1)([C:28]1[N:32]([CH3:33])[CH:31]=[N:30][N:29]=1)[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]1[N:18]=[N:19][N:20]=[C:13]1[N:12]=[C:11]2[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([C:7]([C:34]4[CH:35]=[CH:36][C:37]([I:40])=[CH:38][CH:39]=4)([C:28]4[N:32]([CH3:33])[CH:31]=[N:30][N:29]=4)[NH2:1])[CH:9]=3)[N:14]3[N:18]=[N:19][N:20]=[C:13]3[N:12]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: N
Reactant: Cn1cnnc1C(Cl)(c1ccc(I)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cn1cnnc1C(N)(c1ccc(I)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Temperature: 60 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
NH3/iPrOH (45 ml) was added dropwise at 5° C. to a mixture of 7-[chloro(4-iodophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-5-(3-chlorophenyl)-tetrazolo[1,5-a]quinazoline (0.0076 mol) in THF (45 ml). The mixture was brought to room temperature, poured out into a pressure vessel, stirred at 60° C. for 6 hours, cooled and poured out into ice water. The precipitate was filtered off and dried under a vacuum, yielding 1.6 g of a first batch of 5-(3-chlorophenyl)-α-(4-iodophenyl)-α-(4-methyl-4H-1,2,4-triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine (35%) The aqueous layer was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (1.7 g) was purified by column chromatography over silica gel (eluent: toluene/iPrOH/NH4OH 84/15/1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 1.03 g (23%) of a second batch of 5-(3-chlorophenyl)-α-(4-iodophenyl)-α-(4-methyl-4H-1,2,4-triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine. A sample (0.23 g) was crystallized from CH3CN, the precipitate was filtrated and dried yielding 0.09 g of 5-(3-chlorophenyl)-α-(4-iodophenyl)-α-(4-methyl-4H-1,2,4-triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine, mp. 238° C.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>CN(C=O)C>[C:10]1([N:9]([CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
NaH (0.220 g, 5.54 mmol) was dissolved in anhydrous DMF (2 mL) under argon and cooled to 0° C. To it was added diphenylamine (0.0.750 g, 4.43 mmol) dissolved in anhydrous DMF (2 mL). The reaction was stirred for 15 min at 0° C. followed by the addition of methyl 4-(bromomethyl)benzoate (1.02 g, 4.43 mmol) in anhydrous DMF (2 mL). The reaction was stirred for 2 h at 60° C. and then quenched by the addition of H2O (20 mL). The organic products were extracted with EtOAc (3×30 mL), washed with H2O (2×30 mL), brine (15 mL), dried with Na2SO4, filtered and concentrated in vacuo. The title compound was purified using automated column chromatography method 1 (0.746 g, 53%). 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J=8.2 Hz, 2H), 7.45 (d, J=7.7 Hz, 2H), 7.27 (m, 4H), 7.07 (d, J=7.9 Hz, 4H), 6.98 (t, J=7.3 Hz, 2H), 5.06 (s, 2H), 3.92 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 166.9, 147.8, 144.8, 130.0, 129.4, 128.9, 126.5, 121.7, 120.7, 56.3, 52.0. ESI-LRMS: [M+H]+=318 m/z.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1(C)C=CC=CC=1>[F:10][C:5]1[CH:4]=[CH:3][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cc(-c2ccccc2)ccc1F

Procedure:
5-Bromo-2-fluorobenzonitrile (53) (500 mg, 2.54 mmol) was coupled to phenylboronic acid (335 mg, 2.75 mmol) with Cs2CO3 (1.63 g, 5.00 mmol) in toluene (4 mL) in a microwave at 140° C. for 30 minutes. Water was added and the organics extracted several times with EtOAc, dried (MgSO4), filtered and the solvent concentrated in vacuo. The crude product was purified by Flash Master Jones Chromatography using a 25 g silica cartridge and eluting with 10% EtOAc in heptane to yield the title compound. Yield: 375 mg, 76%; LC-MS tr 1.63 min; HPLC Purity: 97%; MS (ES+) m/z not detectable (M+H)
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]1([C:14]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][S:17](=O)[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[C:8]1([C:14]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=[CH:16][S:17][CH2:18][CH2:19]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S1CCC(c2ccccc2)(c2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: C1=CC(c2ccccc2)(c2ccccc2)CCS1
Yield: 83.3 %

Procedure:
3.95 cm3 of acetic anhydride are added to a suspension of 2.7 g of 4,4-diphenyltetrahydrothiapyran 1-oxide in 30 cm3 of anhydrous toluene. The mixture is refluxed for 20 hours and concentrated to dryness at 60° C. under reduced pressure (2.7 kPa and then 0.13 kPa). The oily residue is crystallized from diisopropyl oxide, the crystals are drained and dried. 2.1 g of 3,4-dihydro-4,4-diphenyl-2H-thiapyran are obtained in the form of white crystals; melting point 78° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[C:10]([I:36])=[C:11]([CH2:25][CH:26]([O:32][C:33](=[O:35])[CH3:34])[CH2:27][O:28][C:29](=[O:31])[CH3:30])[C:12]([I:24])=[C:13]([NH:16][C:17](=[O:23])[CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:14]=1[I:15])=[O:7])(=[O:3])[CH3:2].[C:37]([O:40][CH2:41][CH2:42]Br)(=[O:39])[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[C:14]([I:15])=[C:13]([N:16]([CH2:42][CH2:41][O:40][C:37](=[O:39])[CH3:38])[C:17](=[O:23])[CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:12]([I:24])=[C:11]([CH2:25][CH:26]([O:32][C:33](=[O:35])[CH3:34])[CH2:27][O:28][C:29](=[O:31])[CH3:30])[C:10]=1[I:36])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCBr
Reactant: CC(=O)OCC(=O)Nc1c(I)c(CC(COC(C)=O)OC(C)=O)c(I)c(NC(=O)COC(C)=O)c1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)OCCN(C(=O)COC(C)=O)c1c(I)c(CC(COC(C)=O)OC(C)=O)c(I)c(NC(=O)COC(C)=O)c1I
Yield: 12 %

Procedure:
3,5-Bis-(acetoxyacetamido)-2,4,6-triiodo-(2,3-diacetoxypropyl)benzene, Example 71 a, was alkylated using 2-bromoethyl acetate in the presence of cesium carbonate according to the general procedure given in Example 25a. The reaction product was purified by HPLC to give the two products. 5-Acetoxyacetamido-3-[N-(2-acetoxyethyl)-acetoxyacetamido]-2,4,6-triiodo-(2,3-diacetoxypropyl)benzene was isolated in 12% yield.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH:4]=[C:5]1[C:10](=[O:11])[C:9](=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[CH2:8][NH:7][CH2:6]1>C(O)C.[Pd]>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH:9]1[C:10](=[O:11])[CH:5]([CH2:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=2[F:1])[CH2:6][NH:7][CH2:8]1
Reactant: O=C1C(=Cc2ccccc2F)CNCC1=Cc1ccccc1F
Agent: [Pd]
Solvent: CCO
Product: O=C1C(Cc2ccccc2F)CNCC1Cc1ccccc1F
Reaction time: 16 h

Procedure:
To a solution of compound 1 (300 mg, 0.96 mmol) in ethanol, 10 mg of 5% Pd/C was added. The reaction mixture was stirred for 16 h under hydrogen gas at atmospheric pressure. Pd/C was filtered, and the solvent was evaporated to dryness. Compound 11 was obtained as a white solid (285 mg, 95% yield). Rf (30:70 methanol:chloroform)=0.20. 1H NMR (300 MHz, CDCl3): δ 7.25-6.90 (m, 8H, Ar—H), 3.60-2.50 (m, 10H, NCH2CHCH2). 13C NMR (75 MHz, CDCl3): 175.10, 161.05 (d, J=250.0), 131.34 (d, J=4.3), 128.68 (d, J=8.3), 124.28 (d, J=15.5), 115.48 (d, J=21.6), 48.55, 46.54, 25.52. ESI Mass calculated for C19H20F2NO (M+H)+316.15. found 316.20.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[C:14]2[C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]([CH3:18])([CH3:17])[C:9]=2[CH:8]=CC=1CO.[CH2:23]1C[O:26][CH2:25][CH2:24]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:24]([CH:25]([C:3]1[CH:4]=[CH:5][C:14]2[C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]([CH3:17])([CH3:18])[C:9]=2[CH:8]=1)[OH:26])#[CH:23]
Reactant: C1CCOC1
Reactant: CC1(C)CCC(C)(C)c2c1ccc(CO)c2C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 1 h

Procedure:
29.9 g (92.5 mmol) of α-trimethylsilylethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol and 100 ml of THF were introduced into a round-bottomed flask and 103.8 ml (114.2 mmol) of a tetrabutylammonium fluoride solution (1.1M in THF) were added dropwise. Stirring was carried out at room temperature for one hour and the reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of ethyl acetate and hexane (1/4). After evaporating the solvents, 18.1 g (79%) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol, with a melting point of 56°-57° C., were recovered.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N:21]=[C:22]=[O:23])(C)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:22]([NH2:21])=[O:23])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC1CCCNC1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC1CCCN(C(N)=O)C1
Temperature: 25 °C
Reaction time: 3.35 h
Yield: 70.3 %

Procedure:
3-(2-tert-Butoxycarbonylaminoethyl)piperidine (500 mg, 2.19 mmoles) was dissolved in anhydrous dichloromethane (10 mL) and trimethylsilylisocyanate (2.96 mL, 21.9 mmoles) was added. The mixture was stirred under argon at 25° C. for 3.35 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered, evaporated to dryness and chromatographed on a silica gel column (15×5 cm) using 5% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 3-(2-tert-butoxycarbonylaminoethyl)piperidine-1-carboxamide (417.7 mg, 70%): FABMS: m/z 272.0 (MH+); HRFABMS: m/z 272.1979 (MH+). Calcd. for C13H26O3: m/z 272.1974; δH (CDCl3) 1.16 (1H, m, CH2), 1-30-1.60 (5H, m, CH/CH2), 1.46 (9H, s, —COOC(CH3)3), 1.68 (1H, m, CH2), 1 84 (1H, m, CH2), 2.54 (1H, dd, CH2), 2.73 (1H, m, CH2), 3.08 (1H, m, CH2), 3.42 (1H, m, CH2), 4.02 (1H, m, CH2), 4.10 (1H, m, CH2), 4.84 (1H, m, NH) and 4.96 ppm (2H, bm, CONH2); δC (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 25.2, 31.7, 34.9, 37.3, 44.6, 50.3; CH: 32.9; C: 79.5, 156.4, 158.2.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([NH:19][CH3:20])=[O:18])[C:11]([C:25]([CH3:27])=[CH2:26])=[CH:10][N:9]=2)=[CH:5][C:4]([CH3:28])=[N:3]1.N#N>C(O)C.O=[Pt]=O>[CH3:1][N:2]1[C:6]([NH:7][C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([NH:19][CH3:20])=[O:18])[C:11]([CH:25]([CH3:26])[CH3:27])=[CH:10][N:9]=2)=[CH:5][C:4]([CH3:28])=[N:3]1
Reactant: C=C(C)c1cnc(Nc2cc(C)nn2C)cc1Nc1ccccc1C(=O)NC
Agent: O=[Pt]=O
Agent: N#N
Solvent: CCO
Product: CNC(=O)c1ccccc1Nc1cc(Nc2cc(C)nn2C)ncc1C(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 61.3 %

Procedure:
A solution of 2-[2-(2,5-dimethyl-2H-pyrazol-3-ylamino)-5-isopropenyl-pyridin-4-ylamino]-N-methyl-benzamide (0.13 g, 0.345 mmole, 1 eq) in ethanol (10 mL) was degassed with N2 and to this PtO2 (0.012 g, 0.052 mmole, 0.15 eq) was added. The resulting mixture was stirred at room temperature under H2 atmosphere with balloon pressure for 10 h. After completion of the reaction, it was filtered through a celite bed which was then washed with ethanol (10 mL). The filtrate was evaporated under reduced pressure to give a solid residue which was purified by washing with diethyl ether to give the title compound as a gray solid (80 mg, 61%). 1H-NMR (400 MHz, DMSO-d6): δ 1.24-1.26 (d, 6H, J=6.76 Hz), 2.05 (s, 3H), 2.75-2.76 (d, 3H, J=4.48 Hz), 2.89-3.10 (m, 1H), 3.53 (s, 3H), 5.96 (s, 1H), 6.67 (s, 1H), 6.85-7.10 (m, 1H), 7.40-7.50 (m, 2H), 7.65-7.67 (d, 1H, J=7.76 Hz), 7.86 (s, 1H), 8.36 (s, 1H), 8.60-8.70 (brs, 1H), 9.89 (s, 1H). LC-MS [M+H]+=379.2.
Reaction SMILES: [C:1]([CH2:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([CH2:12][C:13]2[O:14][C:15]3[C:22]([Cl:23])=[CH:21][C:20]([CH2:24][CH2:25][CH3:26])=[C:19]([O:27]C(=O)C)[C:16]=3[C:17]=2[CH3:18])=[CH:10][CH:9]=1)([O:3]CC)=[O:2].O.Cl>CO.[OH-].[Na+]>[C:1]([CH2:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([CH2:12][C:13]2[O:14][C:15]3[C:22]([Cl:23])=[CH:21][C:20]([CH2:24][CH2:25][CH3:26])=[C:19]([OH:27])[C:16]=3[C:17]=2[CH3:18])=[CH:10][CH:9]=1)([OH:3])=[O:2]
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OCC(=O)OCC)cc3)c(C)c2c1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1cc(Cl)c2oc(Cc3ccc(OCC(=O)O)cc3)c(C)c2c1O
Yield: 85.4 %

Procedure:
A solution of 2-(p-carboethoxymethoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran (133 mg; 0.28 mmole) in methanol (10 mL) and 10N sodium hydroxide (1 mL) was stirred at room temperature for a period of 30 minutes. Water was then added and the mixture was acidified with 6N hydrochloric acid. The solid was filtered, washed with water, and air-dried to yield 93 mg (82%) of 2-(p-carboxymethoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran, mp. 179°-180° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[N:24]1([CH2:29][CH2:30]O)[CH:28]=[CH:27][N:26]=[CH:25]1>>[N:24]1([CH2:29][CH2:30][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:17](=[O:18])[C:16]4[C:15]5[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=5)[NH:9][C:8]=4[C:7]([CH3:21])([CH3:22])[C:6]=3[CH:23]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: OCCn1ccnc1
Product: CC1(C)c2cc(OCCn3ccnc3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-imidazol-1-yl-ethanol.
Reaction SMILES: [Si:1]([O:8][CH:9]=[C:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:22][CH:23]([Cl:27])[C:24](Cl)=[O:25]>C1CCCCC1.C(Cl)Cl>[Si:1]([O:8][CH:9]=[C:10]1[CH:11]2[CH:12]([C:23]([Cl:27])([Cl:22])[C:24]2=[O:25])[CH:13]=[CH:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC=C1C=CC=C1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC=C1C=CC2C1C(=O)C2(Cl)Cl

Procedure:
A 3-neck, 5 L flask equipped with a heating mantle, a mechanical stirrer, an argon inlet, and a pressure-equalized dropping funnel was charged with the 6-(tert-butyldimethylsilyloxy)fulvene from the previous Preparation dissolved in 2 L of cyclohexane. After this solution was brought to reflux, 150 mL of triethylamine was added in one portion. Then, 100 mL of dichloroacetyl chloride was added dropwise to the refluxing mixture over a 1.5 hr period. The cooled reaction mixture was diluted with 1.5 L of methylene chloride and filtered to remove the triethylamine hydrochloride by-product. The dark solution of the crude reaction product could be stored as such for a few days. The solvent was removed by evaporation immediately before its use in the next reaction.