Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([S:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:12][C:11]1[CH:13]=[CH:14][C:8]([S:7][CH:4]2[CH2:3][CH2:2][N:1]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:29])([F:30])[F:31])=[CH:21][CH:22]=3)[CH2:6][CH2:5]2)=[CH:9][CH:10]=1
Reactant: Nc1ccc(SC2CCNCC2)cc1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc(SC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
4-(Piperidin-4-ylthio)aniline (6.69 mmol, 1.3946 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (6.69 mmol, 2.256 g), and potassium carbonate (13.39 mmol, 1.850 g) were combined in acetonitrile (20 mL) and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, and partitioned between dichloromethane and water. The organic layer was separated, dried, and concentrated under vacuum. The residue was purified by silica column chromatography (eluting with 2.5-5% methanol/dichloromethane gradient) to afford the title compound (1.93 g). MS m/z 465.0 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:11][N:12]([CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3C=CC=CC=3C2=O)[CH:13]=1.NN.C(Cl)Cl.C(#N)C>C(O)C>[NH2:17][CH2:16][CH2:15][CH2:14][N:12]1[CH:13]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:10]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:11]1
Reactant: CC(C)(C)OC(=O)c1cn(CCCN2C(=O)c3ccccc3C2=O)cc1-c1ccc(Cl)cc1Cl
Agent: NN
Solvent: CCO
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1cn(CCCN)cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 87 %

Procedure:
The Pthalimido Pyrrole 4 (1 eq) was dissolved in ethanol and hydrazine (3 eq) at room temperature under nitrogen. Upon heating to reflux, the reaction generated a white precipitate. Stir at reflux until complete (˜2 h) by TLC (CH2Cl2/acetonitrile (95:5 v/v), the UV active product was at Rf=0.2) and LCMS. Upon reaching completion, the reaction was allowed to cool to room temperature and the precipitate was vacuum-filtered off using a medium to fine cintered-glass filter. The filtrate was concentrated under reduced pressure to a gummy solid. The crude material was taken up in ethanol/EtOAc (1:1 v/v), stirred and the precipitate was filtered off in the same fashion as before. The filtrate was concentrated under reduced pressure and than dried in vacuo for 10-15 min. This process of adding ethanol/EtOAc, filtering and concentrating was done one more time or as needed to remove the majority of the white precipitate and residual hydrazine. The product was then dried in vacuo overnight. The material was used without further purification. Once dried, the reaction yielded the product as a glass (˜87% yield over 2 steps).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[O:5])[CH3:2].[Br:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[C:36]([Cl:41])[CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C.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]>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:38][C:37]1[CH:39]=[CH:40][C:34]([Br:33])=[CH:35][C:36]=1[Cl:41])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c2cnccc2n1C
Reactant: Nc1ccc(Br)cc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(Nc2ccc(Br)cc2Cl)c2cnccc2n1C
Temperature: 25 °C
Yield: 34.6 %

Procedure:
A degassed solution of 1-methyl-3-(nonafluorobutane-1-sulfonyloxy)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (500 mg, 0.99 mmol), 4-bromo-2-chloroaniline (246 mg, 1.19 mmol), Pd2dba3 (91 mg, 0.10 mmol), Xantphos (114 mg, 0.20 mmol) and DBU (352 μl, 2.48 mmol) in toluene (8 ml) was subjected to microwave irradiation at 120° C. for 5 minutes. The reaction mixture was cooled to ambient temperature then diluted with ethyl acetate (100 ml). The resultant solution was washed with water (30 ml), dried (Na2SO4) and concentrated in vacuo to give an oil. The oil was purified by flash chromatography (Si-PPC, cyclohexane:ethyl acetate, gradient 90:10 to 0:100) to afford the title compound as a yellow solid (140 mg, 35%). 1H NMR (CDCl3, 400 MHz) 8.75 (d, J=1.0 Hz, 1H), 8.41 (d, J=6.1 Hz, 1H), 7.68 (s, 1H), 7.54 (d, J=2.3 Hz, 1H), 7.19-7.27 (m, 2H), 6.94 (d, J=8.8 Hz, 1H), 4.44 (q, J=7.2 Hz, 2H), 3.99 (s, 3H), 1.44 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4].CN(C)C=O.[OH:14][C:15]1[C:20]2[C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:26]=3[C:27]([CH3:30])([CH3:29])[O:28][C:19]=2[CH:18]=[C:17]([CH:31]([CH3:39])[CH:32]([CH3:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:16]=1.C(N(CC)CC)C>O>[OH:14][C:15]1[C:20]2[C:21]3[CH2:22][N:23]([CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4])[CH2:24][CH2:25][C:26]=3[C:27]([CH3:29])([CH3:30])[O:28][C:19]=2[CH:18]=[C:17]([CH:31]([CH3:39])[CH:32]([CH3:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:16]=1
Reactant: NC(=O)NC(=O)CCl
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1
Reaction time: 24 h

Procedure:
A solution of 1.50 g. (0.011 mole) of chloroacetylurea in 25 ml. of dimethylformamide was added dropwise to a stirred solution of 3.57 g. (0.01 mole) of 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine in 20 ml. of dimethylformamide and 1.11 g. (0.011 mole) of triethylamine. After stirring for 24 hours, 65 ml. of water was added dropwise to the stirred mixture. The solid was filtered and recrystallized from acetonitrile, m.p. 131°-133°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1cc(I)ccc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(I)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-fluoro-5-iodobenzoic acid (Aldrich, 5.27 g, 19.8 mmol) in CH2Cl2 (35.0 mL) was added oxalyl chloride (14.9 mL, 29.7 mmol, 1M solution in CH2Cl2) followed by 2 drops of DMF via syringe. Gas evolution was initiated and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was then quenched with sat. aq. NH4Cl solution and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give crude 2-fluoro-5-iodobenzoyl chloride which was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>C1(C)C=CC=CC=1.C1COCC1>[C:8]1([C:5]2[CH:6]=[CH:7][C:2]([B:29]([OH:34])[OH:30])=[CH:3][CH:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Brc1ccc(-c2cccc3ccccc23)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OB(O)c1ccc(-c2cccc3ccccc23)cc1
Temperature: -60 °C
Yield: 68.9 %

Procedure:
Under an argon gas atmosphere, a mixture of 208.8 g (737.4 mmol) of 1-(4-bromophenyl) naphthalene and 2.1 L of dehydrated THF was cooled down to −60 degrees C., and added with 567 mL (884.9 mmol) of hexane solution of 1.56M n-butyllithium in drops while being stirred. Then, the reaction mixture was stirred for two hours at −60 degree C. 416 g (2.21 mol) of triisopropyl borate was dropped into the reaction solution at −60 degrees C. Subsequently, the reaction mixture was stirred for 17 hours at room temperature. The reaction mixture was further added with solution of hydrochloric acid to be stirred for one hour at room temperature. After the reaction, the reaction mixture was further added with toluene, so that aqueous phase thereof was eliminated. After organic phase thereof was dried with magnesium sulfate, the solvent was distilled away under reduced pressure. By recrystallizing the obtained solid by toluene, 126 g of 4-(1-naphthyl)phenylboronic acid was obtained at an yield of 67%.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>CCO>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:1][N:7]1[C:11](=[O:12])[C:10]2[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=[O:13]
Reactant: NCc1ccco1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1Cc1ccco1

Procedure:
Furfurylamine (5.70 mL, 61.8 mmol) and phthalic anhydride (10.0 g, 90.9 mmol) were heated to 120° C. for approximately 45 min. The reaction mixture was cooled to it and then suspended in EtOH. The resulting suspension was filtered to afford the title compound i-1a. 1HNMR (500 MHz, CDCl3): δ 7.88 (dd, 2H, J=3.2, 5.3 Hz), 7.73 (dd, 2H, J=3.0, 5.5 Hz), 6.38 (d, 1H, J=3.2 Hz), 6.32 (m, 1H), 4.88 (s, 2H).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([NH:7][C:8](=[N:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])SC)#[N:6]>C(#N)C>[CH2:1]([NH:4][C:8]([NH:7][C:5]#[N:6])=[N:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])[CH:2]=[CH2:3]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: C=CCN
Solvent: CC#N
Product: C=CCNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
Reaction of allylamine and N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea by the procedure of Example 11 afforded the title compound, m.p. 113°-114° C. (from acetonitrile).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[C:16]([CH:17]3[CH2:19][CH2:18]3)=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([F:20])[CH:8]=2)[CH2:2]1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[C:21]([N:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[C:16]([CH:17]3[CH2:19][CH2:18]3)=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([F:20])[CH:8]=2)[CH2:2]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(C2CC2)c(OCC2CNC2)cc1F
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C2CC2)c(OCC2CN(C(=O)c3ccccc3)C2)cc1F
Temperature: 20 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
To a mixture of methyl 4-(azetidin-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate (50 mg, 0.18 mmol), benzoyl chloride (28 mg, 0.20 mmol), and triethylamine (36 mg, 0.36 mmol) in DCM (10 mL) was stirred at 20° C. for 1 hour. The mixture was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to get a crude product (70 mg, 99%) which was used in the next step without further purification. LCMS (ESI) m/z: 384.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[Br:15][C:16]1[C:17](Cl)=[N:18][CH:19]=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:25]=[C:16]([Br:15])[C:17]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:18][CH:19]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Product: COC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)c(Br)c1
Yield: 37 %

Procedure:
As described for example 5, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (3.60 mg, 19.0 mmol) was converted using methyl 5-bromo-6-chloronicotinate instead of 6-chloronicotinonitrile to the title compound (SiO2, heptane:ethyl acetate=90:10 to 60:40, 2.83 g, 37%) which was obtained as a white solid. MS: m/e=403.3/405.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:6]([O:8][CH3:9])=[O:7].O>CO.C1COCC1.[C].[Pd]>[NH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(N)c(OC)c1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 104.1 %

Procedure:
To a solution of methyl 3-methoxy-4-nitrobenzoate (150 g) in methanol (600 mL) and THF (300 mL) was added 10% palladium-carbon (a 50% water-containing product, 15 g), and the reaction liquid was stirred at 50° C. to 64° C. under a hydrogen pressure of 0.9 MPa for 6.5 hours. The reaction liquid was allowed to stand to cool to room temperature and then filtered on celite, followed by concentrating the resultant filtrate under reduced pressure to provide 134 g of the title compound. The physical property values thereof agreed with reported values (CAS#41608-64-4).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[S:24]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)([O:27][CH2:28][CH:29]1[O:31][CH2:30]1)(=[O:26])=[O:25]>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:30][CH:29]([OH:31])[CH2:28][O:27][S:24]([C:32]4[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=4)(=[O:26])=[O:25])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Reactant: Cc1ccc(S(=O)(=O)OCC2CO2)cc1
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(O)COS(=O)(=O)c4ccc(C)cc4)CC3)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32.4 %

Procedure:
39.4 mg of 1-ethyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-3-quinoline carboxylic acid were mixed with 50 ml of N,N-dimethylformamide in a round flask of 100 ml and slowly stirred at room temperature for 20 minutes. 14.4 mg of glycidyl tosylate were added thereto, it was stirred at room temperature, and then washed with 30.0 ml of N,N-dimethylformamide. The reactants were held at 80° C. for 5 hours and then stirred at 25° C. for 10 minutes. The reactants were crystalized through column chromatography (20 gm silica, 10% ethylacetate/hexane), filtered, and then dried to give 11.2 mg of 1-ethyl-6-fluoro-1,4-dihydro-7-{4-[2-hydroxy-3-(toluene-4-sulfonyloxy)-propyl]-1-piperazinyl}-4-oxo-3-quinoline carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>>[N:11]1([C:2]2[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: CC(=O)c1ccc(Cl)nc1
Product: CC(=O)c1ccc(-n2ccnc2)nc1
Temperature: 125 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a 25 mL vial which contained 1-(6-chloro-pyridin-3-yl)-ethanone (1.5 g, 10 mmol.) was added 1H-imidazole (3 g, 50 mmol.) at rt. The mixture was stirred at 120-130° C. for 2 h and cooled to rt. The contents were poured into 150 mL ice-water solution and extracted with EtOAc (3×100 mL). The combined organic layers was washed with water (3×50 mL), brine (50 mL) and dried over Na2SO4. The solvent was removed under vacuum to yield the crude which was purified by column to afford desired 1-(6-imidazol-1-yl-pyridin-3-yl)-ethanone (1.25 g, 67%).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([NH:5][C:6]1[NH:11][C:10]2=[N:12][CH:13]=[CH:14][C:9]2=[C:8]([OH:15])[N:7]=1)=[O:4].IN1C(=O)CCC1=O.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.OC1C2C(I)=CNC=2N=C(NC(=O)C(C)(C)C)N=1.[Pd](Cl)Cl.O.C(#N)C>[OH:15][C:8]1[C:9]2[C:14]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])=[CH:13][NH:12][C:10]=2[N:11]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:17])([CH3:16])[CH3:1])[N:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2ccnc-2[nH]1
Agent: Cl[Pd]Cl
Agent: CC(C)(C)C(=O)Nc1nc(O)c2c(I)c[nH]c2n1
Agent: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1nc(O)c2c(C#C[Si](C)(C)C)c[nH]c2n1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
To a solution of 20.0 g (85.4 mmol) of 2-(2,2-dimethylpropionyl)amino-4-hydroxypyrrolo[2,3-d]pyrimidine in 160 mL of dry DMF stirred in a dry atmosphere was added 38.2 g (187.8 mmol) of BSA and the mixture was heated to 40° C. for 3 hours. After cooling to about 0° C. in an ice bath there was added 23.1 g (102.5 mmol) of N-iodosuccinimide as a solid. The mixture was stirred at 0° C. for 15 minutes, then allowed to warm to ambient temperature overnight. To the resulting mixture, maintained under a nitrogen atmosphere, was added sequentially 12.6 g (128 mmol) of (trimethylsilyl) acetylene, 17.3 g (171 mmol) of triethylamine, 3.25 g (17.1 mmol) of cuprous iodide, and a preformed mixture prepared by adding 1.51 g (8.5 mmol) of palladium (II) chloride and 4.48 g (17.1 mmol) of triphenylphosphine to 40 mL of DMF. The resulting solution was stirred at ambient temperature for 2 hours. At this point, HPLC analysis of an aliquot indicated complete conversion of the in situ-derived N-(4-hydroxy-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropionamide. The reaction mixture was poured into 500 mL of acetonitrile and 12 mL of water was added, causing the product to precipitate. After stirring for about 15 minutes, the product was filtered, washed with acetonitrile, and dried, affording 18.6 g (66%) of N-[4-hydroxy-5-(trimethylsilyl) ethynyl-7H-pyrrolo [2,3-d]pyrimidin-2-yl]-2,2-dimethyl propionamide as a light tan solid, mp>300° C. NMR δ0.18 (s, 9H), 1.22 (s, 9H), 7.33 (s, 1H), 10.9 (br s, 1H), 11.8 (br s, 1H), 11.9 (br s, 1H); IR (KBr) 3229, 2155, 1678, 1658, 1619, 1434, 1244, 1180, 1069 cm-1 ; UV (EtOH) 285 nm (ε15,400 ), 250 nm (ε16,000). Anal. Calcd for C16H22N4O2Si: C, 58.15; H, 6.71; N, 16.95. Found: C, 57.58; H, 6.87; N,16.96.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH2:4][C@@:5]1([OH:28])[C:10](=[O:11])[O:9][CH2:8][C:7]2[C:12]([N:14]3[C:26](=[CH:27][C:6]1=2)[C:25]1[C:16](=[CH:17][C:18]2[C:23]([N:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15]3)=[O:13]>CO>[CH2:4]([C:5]1([OH:28])[C:6]2[CH:27]=[C:26]3[N:14]([CH2:15][C:16]4[C:25]3=[N:24][C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:17]=4)[C:12](=[O:13])[C:7]=2[CH2:8][O:9][CH:10]1[OH:11])[CH3:3]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1(O)c2cc3n(c(=O)c2COC1O)Cc1cc2ccccc2nc1-3
Temperature: 55 °C
Reaction time: 16 h

Procedure:
Sodium borohydride (14 g, 370 mmol) is added in portions to a suspension of (S)-(+)-camptothecin (14 g, 40 mmol, that may be obtained using different commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis.)), in methanol (750 ml) and the resulting mixture is heated slowly to 55° C. so as to obtain a clear solution that is then agitated for 16 hours at ambient temperature. The solvent is then evaporated under reduced pressure, the residue is recovered in water (250 ml), neutralized by the addition of acetic acid (21 ml) and left alone for 2 hours at 4° C. The resulting suspension is filtered and washed successively with cold water, acetone and diethyl ether, which, after drying under reduced pressure, permits obtaining the sought compound in the form of a white solid, m.p. 280° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C@@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]1=S)C1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[CH2:28]([O:27][C:25]([N:8]1[CH2:12][CH2:11][CH:10]([C@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCN(Cc2ccccc2)C1=S
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 14 h
Yield: 64 %

Procedure:
To 50 ml of a dichloromethane solution of 2.984 g (9.90 mmol) of 1-benzyl-3-[(1R,2S )-2-t-butoxycarbonylcyclopropyl]pyrrolidine (isomer B1) was added 2.83 ml (19.82 mmol) of benzyl chloroformate at room temperature, and the mixture was stirred at the same temperature for 14 hours. To the reaction mixture was further added 1.98 ml (13.86 mmol) of benzyl chloroformate, followed by refluxing for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 2.188 g (64.0%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[S:23][CH:24]=[C:25]([CH2:27][C:28]([O-:30])=[O:29])[N:26]=2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[S:23][CH:24]=[C:25]([CH2:27][C:28]([OH:30])=[O:29])[N:26]=2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Sc2nc(CC(=O)[O-])cs2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Sc2nc(CC(=O)O)cs2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A mixture of ethyl [2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-thiazolylacetate (330 mg), lithium hydroxide hydrate (89.0 mg), tetrahydrofuran (3 ml), water (2 ml) and methanol (2 ml) was stirred at room temperature for 4 hrs. 1N Hydrochloric acid (2.2 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give [2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-thiazolyl]acetic acid (215 mg, yield 69%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 180–181° C.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:4][C:3]1=[O:12].C(N(CC)CC)C.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22].CCCCCCC>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:20][Si:21]([CH3:23])([CH3:22])[O:1][C@H:2]1[C@@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:4][C:3]1=[O:12]
Reactant: O=C1N[C@H](c2ccccc2)[C@@H]1O
Reactant: C[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)O[C@@H]1C(=O)N[C@@H]1c1ccccc1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Optically active (+)-cis-3-hydroxy-4-phenyl-azetidin-2-one (3.4 g, 20.8 mmol) was dissolved in THF (30 mL) along with triethylamine (5.8 g, 57.4 mmol) and DMAP (76 mg, 0.62 mmol) at 0° C. Trimethylsilyl chloride (2.4 g, 22 mmol) was added dropwise and the mixture stirred for 30 min. TLC (3:1 ethyl acetate:heptane) showed complete conversion to the less polar product. The mixture was diluted with ethyl acetate (30 mL), washed with saturated aqueous sodium bicarbonate (15 ml), brine (15 ml), and dried over sodium sulfate (5 g). The sodium sulfate was filtered and the filtrate was concentrated and solvent exchanged with heptane (50 mL) to give a white powder. The powder was collected via vacuum filtration through a Buchner funnel and dried under vacuum (<1 mmHg) at ambient temperature to a constant weight of 3.45 g (72% yield). mp: 120 to 122° C., [α]22578=+81.9 (MeOH, 1.0), 1H NMR (400 MHz, CDCl3) δ (ppm): −0.08 (s, 9H), 4.79 (d, J=4.4 Hz, 1H), 5.09 (dd, J=4.4, 2.7 Hz, 1H), 6.16 (bm, 1H), 7.3 to 7.4 (m, 5H).