Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:9]3[CH:10]=[C:11]([C:15]#[N:16])[CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1.[CH3:25][Si:26]([CH3:33])([CH3:32])[CH2:27][CH2:28][O:29][CH2:30]Cl>CN(C=O)C.C(N(CC)C(C)C)(C)C>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:9]3[CH:10]=[C:11]([C:15]#[N:16])[CH:12]=[CH:13][C:14]=3[C:5]=2[N:4]([CH2:30][O:29][CH2:28][CH2:27][Si:26]([CH3:33])([CH3:32])[CH3:25])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: N#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(Br)n[nH]c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1nc(Br)c2nc(-c3c(F)cccc3F)c3cc(C#N)ccc3c21
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A 250 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 3.3 g of 3-bromo-5-(2,6-difluorophenyl)-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile in 85 ml of DMF, 10.6 ml of N,N-diisopropylethylamine and 3.2 ml of 2-(trimethylsilyl)ethoxymethyl chloride. After 5 h at RT, the mixture is poured into 8 volumes of ice-water. The aqueous phase is extracted with 3 times 200 ml of AcOEt, and the organic extracts are combined, washed with saturated NaCl solution, dried over MgSO4 and concentrated under RP. Purification is carried out by flash chromatography on silica gel (40-63 μm), eluting with a mixture of DCM and methanol (99.5/0.5 by vol.), to give on one hand 2.1 g of 3-bromo-5-(2,6-difluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile in the form of a white solid. MS (E/I): m/z=515 (M+); 1H NMR: −0.12 (s, 9H); 0.87 (t, J=8.0 Hz, 2H); 3.65 (t, J=8.0 Hz, 2H); 6.17 (s, 2H); 7.40 (t, J=8.0 Hz, 2H); 7.77 (m, 1H); 8.41 (broad s, 1H); 8.47 (dd, J=1.5 and 8.5 Hz, 1H); 8.77 (d, J=8.5 Hz, 1H). And, on the other hand, 1.2 g of 3-bromo-5-(2,6-difluorophenyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile (white solid). MS (E/I): m/z=515 (M+); 1H NMR: −0.05 (s, 9H); 0.90 (t, J=8.0 Hz, 2H); 3.73 (t, J=8.0 Hz, 2H); 5.92 (s, 2H); 7.38 (t, J=8.0 Hz, 2H); 7.76 (m, 1H); 8.24 (broad s, 1H); 8.34 (dd, J=1.5 and 8.5 Hz, 1H); 8.69 (d, J=8.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][NH:33][CH2:34][CH:35]([OH:38])[CH2:36][OH:37]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]([CH2:34][CH:35]([OH:38])[CH2:36][OH:37])[CH3:32])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNCC(O)CO
Product: CN(CC(O)CO)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(2,3-dihydroxy-propyl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and 3-Methylamino-propane-1,2-diol following General Procedure C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[CH:19](B1OB(C=C)OB(C=C)O1)=[CH2:20].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([CH:19]=[CH2:20])[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc(Cl)n2)cc1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1ncnc(Nc2ccc(C(F)(F)F)cc2)n1
Temperature: 90 °C
Yield: 16.5 %

Procedure:
To a solution of 4-chloro-N-(4-(trifluoromethyl)phenyl)-1,3,5-triazin-2-amine (0.5 g, 1.821 mmol) in dioxane (8 mL) and water (2 mL) were added trivinylboroxin (0.588 g, 3.64 mmol), cesium carbonate (1.780 g, 5.46 mmol). The reaction mixture was flushed with nitrogen for 10 min and Tetrakis (0.210 g, 0.182 mmol) was added. The reaction mixture was heated at 90° C. for 2 h then filtered through a pad of celite and washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel using 15% ethyl acetate in hexane to give N-(4-(trifluoromethyl)phenyl)-4-vinyl-1,3,5-triazin-2-amine as a white solid (0.08 g, 12.21% yield). LCMS: R.T.=1.14 min; [M+H]+=267.1.
Reaction SMILES: C(C([OH:13])(CC=C)C)C1C=CC=CC=1.C(=O)([O-])O[C:16]1([CH3:25])[CH2:21][CH2:20][CH:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1>>[CH:16]1([CH3:25])[CH2:21][CH2:20][CH:19]([CH:22]([CH3:24])[CH3:23])[CH:18]([OH:13])[CH2:17]1
Reactant: C=CCC(C)(O)Cc1ccccc1
Reactant: CC(C)C1CCC(C)(OC(=O)[O-])CC1
Product: CC1CCC(C(C)C)C(O)C1
Yield: 18 %

Procedure:
The method of Grignard and Chambret, Compt. rend. 182, 299(1926) was used to prepare 2-benzylpent-4-en-2-ol. The alcohol was converted to the 1-menthyl carbonate by a procedure like that of Example 4. Distillation of the extracted product through an 8-inch Vigreux column gave fractions boiling 25°-110°/0.04-0.6 mm, all having strong OH absorption in the infra-red. The residue was distilled through a short path and the fraction boiling 165°-6°/0.6-0.7 mm showed the following IR absorptions: no OH, strong carbonate (1750 and 1255 cm-1), vinyl (1655, 978, 913 cm-1), monosubstituted aromatic (750 shoulder, 697 cm-1). NMR analysis indicated 80% of the expected mixed ester, a yield of 18.0% from the alcohol. This product had very little odor, but on heating produced a menthol odor.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[NH:21]([C:23]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[S:24])[NH2:22].CN(C)C=O>Cl.O>[OH:1][C:2]1[C:3]([C:18](=[N:22][NH:21][C:23]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)=[S:24])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1nn(C)c(-c2cccc(C(F)(F)F)c2)c1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2cccc(C(F)(F)F)c2)c1O
Yield: 68.3 %

Procedure:
1-[4-Hydroxy-1-methyl-5-(3-trifluoromethylphenyl)-1H-pyrazol-3-yl]ethanone (0.229 mmol, 65.0 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.229 mmol, 48.3 mg) were stirred with dimethylformamide (2.5 mL) and three drops of concentrated hydrochloric acid at room temperature for 24 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. Chloroform/n-hexane was added to the resulting solid, and is the precipitated solid was recovered by filtration and dried by means of a vacuum pump to give the desired product as a yellow solid (74.7 mg, yield 68%).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][CH:9]=1.BrC(C)C.C1C=CC2C(=CC=CC=2O)C=1>CS(C)=O>[CH3:1][CH:2]([O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][CH:9]=1)[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCc2ccc(O)cc21
Agent: Oc1cccc2ccccc12
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)Br
Product: CC(C)Oc1ccc2c(c1)C(=O)CCC2
Temperature: 0 °C
Yield: 65 %

Procedure:
A suspension of 24.3 g (0.22 mole) of potassium tert-butoxide in 240 ml of dimethyl sulfoxide under a nitrogen atmosphere was stirred and cooled in a cold water bath while a solution of 29.2 g (0.18 mole) of 3,4-dihydro-7-hydroxy-1(2H)-naphthalenone in 400 ml of dimethyl sulfoxide was added dropwise over 45 minutes. The mixture was stirred at room temperature for an additional 45 minutes, and then 23.7 ml (31.0 g; 0.25 mole) of 2-bromopropane was added in one portion. After stirring for an additional 30 hours, the mixture was added to 2.0 kg of ice/water and extracted with dichloromethane (4×300 ml). The combined organic layers were back-washed with water (2×150 ml), dried (anhydrous magnesium sulfate), and evaporated (vacuum) to an oil residue. Flash chromatographic purification (silica gel, dichloromethane elution) of the residue yielded 24.0 g (65% yield) of the analytically pure ether product as an oil, suitable for conversion to the naphthol described in Example 4.
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH:5][CH:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C2C(CCCC2)CCC1>[CH3:13][CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:4][NH:5]1
Reactant: CC(NCCBr)c1ccccc1
Agent: Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCC2CCCCC2C1
Product: CC1NCCc2ccccc21
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 76 %

Procedure:
50.0 g(161.8 mmole) of N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example 5(2) above was suspended in 450 ml of decalin and then heated to 140° C. 64.70 g(485.4 mmole) of anhydrous aluminum chloride (AlCl3) was added thereto over 40 minutes. The reaction solution was stirred for a further 30 minutes at constant temperature, and then cooled to room temperature. The supernatant was removed and the lower layer was added to 800 g of ice-water with stirring. 150 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 1000 ml of ethyl acetate, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and then extracted three times, each time with 2100 ml of ethyl acetate. The extracts were combined, washed with 420 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 18.1 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[O:19][CH:18]([CH2:20][OH:21])[CH2:17][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.O.S(=O)(=O)(O)[OH:24]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[CH3:1][C:2]1[C:3]2[O:19][CH:18]([C:20]([OH:24])=[O:21])[CH2:17][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cc2c(-c3ccccc3)noc2c2c1OC(CO)C2
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc2c(-c3ccccc3)noc2c2c1OC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A portion (4.5 g) of the 7,8-dihydro-5-methyl-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-methanol prepared in Example 9 was dissolved in 150 ml of acetone. To the stirred solution, a mixture of chromium (VI) oxide (5.9 g), water (12 ml) and concentrated sulfuric acid (8.3 g) was added dropwise over time, and the resulting mixture was stirred for 2 hours at room temperature. After leaving the mixture to stand overnight, the insolubles were filtered off by suction. After distilling off the acetone, water was added and the mixture was subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized from acetone-water to yield 2.9 g of 7,8-dihydro-5-methyl-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7carboxylic acid. m.p. 210°-213° C. This compound exhibited a mass spectrum haivng a molecular ion peak at m/e 295.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].Br[CH2:13][CH2:14][CH2:15][OH:16].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[OH:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH3:10]
Reactant: OCCCBr
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(C)c1OCCCO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-hydroxy-3,5-dimethyl benzaldehyde (5.0 g, 33.29 mmol) in DMF (30 mL) were added 3-bromo propan-1-ol (5.56 g, 39.95 mmol) and Cs2CO3 (16.24 g, 50.0 mmol). Then, the reaction mixture was stirred at room temperature for 48 hours. Then, water was added and the products were extracted with ethyl acetate (2×250 mL). The combined organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. Removal of solvent gave 4-(3-hydroxypropoxy)-3,5-dimethyl benzaldehyde as a colorless liquid. Yield: 5.38 g (77%).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH:15]=1)([O:3]C)=[O:2].[OH-].[Na+]>CO.O>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH:15]=1)([OH:3])=[O:2]
Reactant: COC(=O)CCCCCSC1=CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCSC1=CCCC1=O
Yield: 51.9 %

Procedure:
2-(5-Carbomethoxypentylthio)cyclopent-2-en-1-one (133 mg) was treated with 0.8 ml of a 3 N aqueous solution of sodium hydroxide in 5 ml of methanol and 2 ml of water at room temperature for 45 minutes. After the reaction, the reaction mixture was extracted with diethyl ether. The aqueous layer was acidified with hydrochloric acid, and extracted with diethyl ether. The extracts were treated in a customary manner to afford 125 mg of a crude product. The crude product was chromatographed on a thin layer plate with diethyl ether/isopropyl ether/acetic acid (=75/30/3) to afford 65 mg of 2-(5-carboxypentylthio)cyclopent-2-en-1-one in a yield of 49%. The product had the following characteristics.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:30][C:31]1[CH:36]=[C:35](Cl)[N:34]=[C:33]([S:38][CH3:39])[N:32]=1.CO>O1CCOCC1>[CH3:39][S:38][C:33]1[N:32]=[C:31]([NH2:30])[CH:36]=[C:35]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[NH:11][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:14][N:13]=3)=[CH:16][CH:17]=2)[N:34]=1
Reactant: CSc1nc(N)cc(Cl)n1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CO
Product: CSc1nc(N)cc(Oc2ccc(-c3nnc(Nc4cccc(C(F)(F)F)c4)[nH]3)cc2)n1
Yield: 27.7 %

Procedure:
4-(5-{[3-(trifluoromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (101.7 mg, 0.31 mmol) was added, followed by 4-amino-6-chloro-2-(methylthio)-pyrimidine (60.3 mg, 0.34 mmol). The vial was capped and microwaved at 200° C. for 10 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water system with 0.01% of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHCO3. Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a white solid (39.5 mg).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[C:15]([S:19][S:20][CH2:21][C@H:22]1[C:26](=[O:27])[O:25][CH2:24][N:23]1[C:28]([O:30][CH2:31][CH:32]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])([CH3:18])([CH3:17])[CH3:16]>ClCCl>[CH:34]1[C:33]2[CH:32]([CH2:31][O:30][C:28]([N:23]([CH3:24])[C@@H:22]([CH2:21][S:20][S:19][C:15]([CH3:17])([CH3:16])[CH3:18])[C:26]([OH:27])=[O:25])=[O:29])[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)SSC[C@H]1C(=O)OCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](CSSC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.4 %

Procedure:
Triethylsilane (6.04 ml, 37.8 mmol) and trifluoroacetic acid (9 ml) were added to a solution of (R)-(9H-fluoren-9-yl)methyl 4-((tert-butyldisulfanyl)methyl)-5-oxooxazolidine-3-carboxylate (Compound 2b-B) (1.68 g, 3.78 mmol) in dichloromethane (18 ml), and the mixture was stirred at room temperature for one day. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→20/80→0/100) to afford (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(tert-butyldisulfanyl)propanoic acid (Compound 2c-B) (1.22 g, 72%).
Reaction SMILES: [C:1]([CH:9]=[C:10]([CH3:14])[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18]>>[C:1]([CH:9]=[C:10]([CH3:14])[C:11]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(=CC(=O)c1ccccc1)C(=O)O
Product: CC(=CC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
As for Example 8, 3-(benzoyl)-2-methylacrylic acid is coupled to L-proline to give 1-[3-benzoyl-2-methylacryloyl]-L-proline. The preceding compound is reacted with thiolacetic acid in carbontetrachloride to give the product of the example as a glass.
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11]([CH:13]([CH2:16][CH3:17])[CH2:14][OH:15])[CH3:12]>>[CH2:1]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([O:15][CH2:14][CH:13]([CH2:16][CH3:17])[CH2:11][CH3:12])[O:10][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:1][CH2:2][CH2:3][CH3:4])[O:15][CH2:14][CH:13]([CH2:16][CH3:17])[CH2:11][CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCC(CC)CO
Reactant: CCCC[Sn](=O)CCCC
Product: CCCC[Sn](CCCC)(OCC(CC)CC)O[Sn](CCCC)(CCCC)OCC(CC)CC
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A 500 ml recovery flask was charged with 59.8 g (0.15 mol) of dibutyltin oxide (manufactured by Aldrich Chemical Co., U.S.A., 98%) and 122 g (1.2 mol) of 2-ethyl-1-butanol (manufactured by Aldrich Chemical Co., U.S.A., 98%), whereby the flask contained the resulting white slurry mixture. The flask was attached to an evaporator (manufactured by Shibata Scientific Technology Ltd., Japan, R-144) connected to a thermoregulator-equipped oil bath (manufactured by Masuda Corporation, Japan, OBH-24), a vacuum pump (manufactured by ULVAC Inc., Japan, G-50A), and a vacuum controller (manufactured by Okano Works Ltd., Japan, VC-10S). The oil bath temperature was set at 140° C. The flask was immersed in the oil bath, whereupon rotation of the evaporator was started. Rotation was continued for about 30 minutes while stirring and heating under atmospheric pressure with the evaporator purge valve open. The evaporator purge valve was then closed, and the pressure in the system was gradually lowered to about 70 kPa using the vacuum pump and the vacuum controller. This state was maintained for 1 hour, after which the flask was removed from the oil bath. The reactant had turned a transparent liquid. The purge valve was gradually opened to return the system pressure to atmospheric pressure. The distillate was 3.6 g, transparent and had separated into 2 layers. Analysis of the distillate showed a water content of about 2.2 g. The flask was then removed from the oil bath and the purge valve was gradually opened to return the system pressure to atmospheric pressure. The flask yielded 175 g of reaction solution. Results of 119Sn, 1H and 13C-NMR analysis showed that, using dibutyltin oxide as a reference, the reaction solution contained about an 99% yield of 1,1,3,3-tetrabutyl-1,3-bis(2-ethyl-butyloxy)-distannoxane.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[NH:19]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:20]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:17]=[C:15]([N:19]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:20]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: c1cncc(OC2CCNC2)c1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CCC(Oc4cccnc4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.5 %

Procedure:
A 16 mL vial was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (40 mg, 0.16 mmol), DMF (3.8 mL), 3-(pyrrolidin-3-yloxy)pyridine hydrochloride (64 mg, 0.32 mmol; which may be prepared as described in Step 2), DIPEA (63 μL, 0.38 mmol) and HATU (72 mg, 0.19 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on chromatography column (eluent: dichloromethane/MeOH, 95/5) to give a beige solid. This solid was triturated in acetone and diethyl ether, filtered, washed with acetone and diethyl ether then dried to give the title compound (7.3 mg, 13%) as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.S(Cl)([Cl:19])=O.O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:19])=[C:4]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: OCc1ccc(Br)cc1OC1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: ClCc1ccc(Br)cc1OC1CCCCC1
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
To a solution of (4-bromo-2-cyclohexyloxyphenyl)methanol (5.46 g) in dichloromethane (16 ml) was added thionyl chloride (3.42 g) dropwise at 5° C. under nitrogen, and the mixture was stirred at the same temperature for 1.5 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated and dried in vacuo to give 4-bromo-1-chloromethyl-2-cyclohexyloxybenzene (5.59 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:13][NH2:14].[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([C:25](OCC)=[O:26])[N:24]=2)[CH:21]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([C:25]([NH:14][CH2:13][C:3]3[CH:4]=[C:5]([O:8][C:9]([F:11])([F:12])[F:10])[CH:6]=[CH:7][C:2]=3[F:1])=[O:26])[N:24]=2)[CH:21]=1
Reactant: NCc1cc(OC(F)(F)F)ccc1F
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(NCc1cc(OC(F)(F)F)ccc1F)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (2-fluoro-5-(trifluoromethoxy)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.