Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH:3]=[CH2:4].[F:6][C:7]1[CH:8]=[C:9]([CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:14]=O)[CH:10]=[CH:11][CH:12]=1.[OH-].[K+]>C(OCC)C.C(O)C.C(OCC)(=O)C.O>[F:6][C:7]1[CH:8]=[C:9]([C:13]2([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:14][CH2:1][C:2](=[O:5])[CH2:3][CH2:4]2)[CH:10]=[CH:11][CH:12]=1
Reactant: C=CC(C)=O
Reactant: O=CC(c1cccc(F)c1)c1cccc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Butenone (50.4 cc) is added to a solution of bis(3-fluorophenyl)acetaldehyde (144.5 g) in ethyl ether (500 cc), and then, after cooling to 0° C., a solution of potassium hydroxide (13.9 g) in ethanol (89 cc) is added dropwise. The reaction mixture is stirred for 2 h at 0° C. and then for 16 hours at 25° C. and diluted with ethyl acetate (300 cc) and water (500 cc). The aqueous phase is washed with ethyl acetate (300 cc). The combined organic phases are washed with a saturated sodium chloride solution (500 cc), dried over magnesium sulphate and concentrated under reduced pressure (2.7 kPa). The residue is chromatographed (in two runs) on silica gel (particle size 0.04-0.063 mm, columns 8.5 cm in diameter, 34 cm high), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (90:10). 4,4-Bis(3-fluorophenyl)cyclohexanone (90.3 g) is obtained in the form of white crystals. M.p. 95° C.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][C:27]([CH3:32])=[CH:28][C:29](Cl)=[O:30]>ClCCl>[CH3:26][C:27]([CH3:32])=[CH:28][C:29]([N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH2:2]1)=[O:30]
Reactant: CC(C)=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNc2ccccc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=CC(=O)N1CCN(C(=O)OC(C)(C)C)Cc2ccccc21
Temperature: 25 °C
Yield: 95.1 %

Procedure:
1 g (4.04 mmol) of tert-butyl 2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate was dissolved in 20 mL of dichloromethane and treated with 1.54 mL (8.86 mL) of triethylamine followed by 0.53 mL (4.83 mmol) of 3-methylbut-2-enoyl chloride. The reaction mixture was stirred over night at room temperature, poured onto water (50 mL) and extracted three times with 50 mL of dichloromethane each. The organic phases were combined, washed with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica (eluent: 5-10% methanol in dichloromethane) to yield 1.27 g of the title compound as a white solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O.[NH2:33][NH2:34].O>CN(C=O)C>[CH2:24]([C:23]1[C:3]2[C:4](=[O:22])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cc1ccccc1)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccccc3)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 105 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-hydroxy-3-phenylacetyl-1-(3-trifluoromethylphenyl)-1,8-naphthyridine-2(1H)-one (212 mg, 0.50 mmol) produced in Synthesis Example 2 in DMF (4 mL) was added hydrazine monohydrate (purity of 80%, 80 μL), and the mixture was stirred at 100 to 110° C. for 3 hours. To the reaction solution was added water. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-benzyl-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (172 mg, yield 82%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:19](=[C:20]([F:23])[C:21]=1[F:22])[N:18]1[CH2:24][C@@H:25]([CH3:29])[O:26][C@@H:27]([CH3:28])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2)(=O)[CH3:2].Cl.[NH2:31][OH:32]>CO>[F:22][C:21]1[C:20]([F:23])=[C:19]2[C:6]([CH2:7][C:8]3([C@H:17]4[C@H:27]([CH3:28])[O:26][C@H:25]([CH3:29])[CH2:24][N:18]42)[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]3=[O:14])=[CH:5][C:4]=1/[C:1](=[N:31]/[OH:32])/[CH3:2]
Reactant: CC(=O)c1cc2c(c(F)c1F)N1C[C@@H](C)O[C@@H](C)[C@@H]1C1(C2)C(=O)NC(=O)NC1=O
Reactant: NO
Agent: Cl
Solvent: CO
Product: C/C(=N\O)c1cc2c(c(F)c1F)N1C[C@@H](C)O[C@@H](C)[C@@H]1C1(C2)C(=O)NC(=O)NC1=O
Temperature: 85 °C

Procedure:
To a solution of (2R,4S,4aS)-rel-8-acetyl-9,10-difluoro-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione (Intermediate 12, 250 mg, 0.63 mmol) in MeOH, was added hydroxylamine hydrochloride (88 mg, 1.3 mmol) and the mixture heated to 85° C. for 12 hours. After cooling to room temperature, solvent was removed, and the residue was purified via normal phase HPLC (95:5: Hexane:IPA) to give the title compound as a racemic mixture in the form of a pale yellow solid. Yield: 50 mg (20%).
Reaction SMILES: [C:1]([S:5][CH2:6][CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:20]([O:27][C:28](=[O:31])[CH2:29][NH2:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C1COCC1>[CH2:20]([O:27][C:28](=[O:31])[CH2:29][NH:30][C:8](=[O:10])[CH:7]([CH2:6][S:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)SCC(Cc1cccc(Br)c1)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)SCC(Cc1cccc(Br)c1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a 25 ml pear-shaped flask containing 2-(S-t-butylsulfanylmethyl)-3-(3-bromophenyl)propionic acid (0.22 g, 0.665 mmol) and THF (7 ml), at 0° C. were added dropwise a solution of glycine benzyl ester hydrochloride (0.134 g, 0.665 mmol) and a solution of triethylamine (93 μl, 67.3 mg, 0.665 mmol) in CH2Cl2 (7 ml), followed by dropwise additions of a solution of HOBT (0.102 g, 0.665 mmol) in THF (5 ml) and a solution of 1,3-dicyclohexyl carbodiimide (0.164 g, 0.796 mmol) in CH2Cl2 (6 ml). The ice/water cooling bath was removed and the mixture was stirred at room temperature overnight. After concentration under reduced pressure, the residue was partitioned between water and CH2Cl2, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography eluting with 0 to 50% ether in hexane to give 2-[3-(3-bromophenyl)-2-(S-t-butylsulfanylmethyl)propionylamino]acetic acid benzyl ester as a colorless viscous oil, 0.25 g, 79% yield. HPLC purity: 100%. 1H NMR (CDCl3) δ 1.29 (s, 9H), 2.51 (m, 1H), 2.64 (m, 1H), 2.85 (m, 3H), 4.02 (m, 2H), 5.16 (s, 2H), 5.95 (m, 1H), 7.12 (m, 2H), 7.35 (m, 7H); MS (ES+) [M+H+]: 478, 480; (ES−) [M−H+]: 476, 478.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=2)=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: Cc1ccc(CCOc2ccc([N+](=O)[O-])cn2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(CCOc2ccc(N)cn2)cc1
Yield: 94.8 %

Procedure:
2-(4-Methylphenethyloxy)-5-nitropyridine (3.7 g) and 1.7 g of 5% palladium charcoal were suspended in 37 ml of ethanol, and catalytic reduction was carried out until 1.1 liters of hydrogen were absorbed. After removal of the catalyst by filtration, the solvent was distilled out under reduced pressure. The crystals were collected on a glass filter and washed with ether to give 3.1 g of 2-(4-methylphenethyloxy)-5-aminopyridine as yellow crystals. Yield, 84.9%. M.P., 64.5°-65° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[N:15]([CH:16]=2)[CH:14]=[CH:13][S:12]3)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:17](OC(=O)C)(=[O:19])[CH3:18].S(=O)(=O)(O)O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17](=[O:19])[CH3:18])[CH:14]=[CH:13][S:12]3)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cccc(-c2cn3ccsc3n2)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)c1c(-c2cccc(C#N)c2)nc2sccn12
Temperature: 135 °C
Yield: 74 %

Procedure:
To a mixture of 6-(3-cyanophenyl)-imidazo[2,1-b]thiazole (5.50 g, 24.4 mmol) and acetic anhydride (50 mL) was added 0.6 mL of concentrated sulfuric acid. The reaction mixture was heated at 135° C. for 5 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (100 mL), washed with water (50 mL×2), saturated aqueous sodium bicarbonate solution (50 mL×2), water (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Product was purified by flash chromatography on silica gel eluting with 40% ethyl acetate in hexane to yield 4.8 g (74%) of the title compound as a light yellow solid. LCMS: 268 [M+H].
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)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.COCCOC>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Reactant: COc1ccccc1B(O)O
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: [Na+]
Solvent: COCCOC
Product: COc1ccccc1-c1cccc2c1/C(=C/c1ccc[nH]1)C(=O)N2
Temperature: 100 °C

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.149 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (149 μL , 0.298 mmol), (Ph3P)4Pd (5 mg, 0.004 mmol) (Aldrich), and 2-methoxyphenylboronic acid (25 mg, 0.164 mmol) (Aldrich) in 4 mL of a 2:1 mixture of 1,2-dimethoxyethane:distilled water was heated at 100° C. under a nitrogen atmosphere for 18 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 20% ethyl acetate-hexanes elution) to provide a crude yellow solid. Recrystallization from chloroform-pentane yielded pure (Z)-1,3-dihydro-4-(2-methoxyphenyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Yield 37 mg, 79%) as yellow crystals (mp 223-225° C.).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:40]2[C@H:41]([CH3:64])[C@H:42]3[C@@H:59]([C@H:60]([OH:62])[CH3:61])[C:58](=[O:63])[N:43]3[C:44]=2[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[CH:51][CH:50]=2)=[O:46])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[CH2:17]([O:16][C:14]([C:12]1[N:13]=[C:9]([N:7]2[CH2:6][CH:5]([S:4][C:40]3[C@H:41]([CH3:64])[C@@H:42]4[C@@H:59]([C@H:60]([OH:62])[CH3:61])[C:58](=[O:63])[N:43]4[C:44]=3[C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[CH:51][CH:50]=3)=[O:46])[CH2:8]2)[S:10][CH:11]=1)=[O:15])[CH3:18]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CCOC(=O)c1csc(N2CC(SC(C)=O)C2)n1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
To a solution of 3-acetylthio-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (468 mg, 1.71 mmol) (obtained as described in Reference Example 1) in dimethylformamide (15 ml) was added hydrazine acetate (171.0 mg, 1.86 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1.5 hours. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.02 g, 1.72 mmol) in acetonitrile (30 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (1.5 ml, 8.61 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate) to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate as a pale yellow solid (752 mg, yield 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:9]([C:15]2[N:16]=[N:17][N:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:19]=2)[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[C:9]([C:15]2[N:16]=[N:17][N:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:19]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(C)(C)C)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)n1nnc(C(CO)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Reaction time: 2 h

Procedure:
To a stirred solution of ethyl 3,3-bis(4-fluorophenyl)-2-[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]-2-propenoate (2.0 g, 4.8 mmoles) in dry methylene chloride (10 mL) under argon at -78° C. was added 10 mL of diisobutylaluminum hydride solution (1.0 Molar solution in methylene chloride) over a period of three minutes. The reduction was allowed to proceed at -78° C. under argon for two hours. Analytical TLC eluted twice with 20% (v/v) ethyl acetate in hexanes showed no starting material at Rf =0.42 and a major spot at Rf =0.14 for desired product. The crude reaction mixture (at -78° C.) was diluted with 10 mL of 2N HCl followed by extractions with ethyl acetate (40 mL×2). The organic layers were combined, dried over MgSO4, evaporated under reduced pressure and dried under high vacuum at room temperature overnight to give the title compound which was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]3[CH2:18][CH2:17][CH2:16][C:11]3=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1.C([Sn](CCCC)(CCCC)[C:29]1[O:30][CH:31]=[CH:32][CH:33]=1)CCC>C1(C)C=CC=CC=1>[O:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]3[CH2:18][CH2:17][CH2:16][C:11]3=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: O=S1(=O)N=C2CCCN2c2ccc(Oc3cccc(Br)c3)cc21
Solvent: Cc1ccccc1
Product: O=S1(=O)N=C2CCCN2c2ccc(Oc3cccc(-c4ccco4)c3)cc21

Procedure:
A suspension of the product obtained in Step A (200 mg, 0.50 mmol), 222 μl (0.66 mmol) of 2-(tributylstannyl)furan and 30 mg (0.025 mmol) of tetrakistriphenylphosphine in 4 ml of toluene is refluxed for 45 minutes. The toluene is evaporated off in vacuo and the residue is chromatographed on SiO2 (CH2Cl2/acetone 96/4) to yield the title product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH:15]([CH3:17])[CH3:16])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>>[CH:15]([O:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1)([CH3:17])[CH3:16]
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)Oc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)Oc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 45 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 350. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.28 (m, 1H) 7.6 (m, 2H) 7.35 (m, 1H) 7.0 (m, 4H) 6.68 (m, 2H) 5.5 (m, 1H) 4.62 (m, 1H) 3.71 (m, 2H) 2.85 (m, 2H) 1.32 (d, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]([CH2:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=1.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][NH:28][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=3)[CH2:11][N:12]([CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=2)=[CH:32][CH:33]=1
Reactant: CS(=O)(=O)N(CCc1cccnc1)Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: CS(=O)(=O)N(CCc1cccnc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 19 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 504. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.4 (d, 1H) 8.3 (s, 2H) 8.0 (s, 1H) 7.9 (d, 1H) 7.5 (m, 3H) 7.2 (m, 1H) 7.0 (d, 2H) 6.9 (d, 1H) 6.7 (d, 2H) 5.5 (m, 1H) 4.4 (s, 2H) 3.7 (m, 2H) 3.4 (m, 2H) 2.8 (m, 7H).
Reaction SMILES: C(O[C@@H:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=O)C.B(F)(F)F.CCOCC.[C:44]1([SH:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(OCC)(=O)C>ClCCl>[C:9]([O:8][C@H:7]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:18][C@@H:5]([S:50][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=[O:11])[CH3:10]
Reactant: Sc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.82 g (0.008 Mol) of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranose was dissolved in 80 ml of anhydrous dichloromethane and stirred at 0° C. under an atmosphere of nitrogen. To this solution, 4.0 ml (0.032 Mol) of boron trifluoride diethyl etherate was slowly added. This was followed by 2.2 ml (0.021 Mol) of thiophenol. The resulting solution was stirred at 0° C. for 4 hr. and at RT for 2 hr. and then poured into a mixture of ethyl acetate (500 ml) and ice-cold saturated sodium bicarbonate solution (200 ml).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:20]=[C:13]3[N:14]=[C:15]([CH3:19])[CH:16]=[C:17](Cl)[N:12]3[N:11]=2)=[CH:6][CH:5]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CN1CCCC1=O>[CH3:19][C:15]1[CH:16]=[C:17]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[N:12]2[N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:21])=[CH:5][CH:6]=3)[CH:20]=[C:13]2[N:14]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc(-c2cc3nc(C)cc(Cl)n3n2)cc1
Solvent: CN1CCCC1=O
Product: Cc1cc(N2CCCC2)n2nc(-c3ccc(C(=O)O)cc3)cc2n1
Temperature: 80 °C
Yield: 80 %

Procedure:
To a solution of 4-(7-chloro-5-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-benzoic acid methyl ester (15.1 mmol) in 1-methyl-2-pyrrolidinone (50 ml) was added pyrrolidine (151 mmol) and the reaction heated at 80° C. for 72 hours. The resultant solid precipitate was filtered and dried under vacuum, then dissolved in 10% NaOH and the aqueous phase washed with ethyl acetate, acidified with conc. HCl, and the resultant precipitated white solid filtered and dried under vacuum to afford 4-(5-Methyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidin-2-yl)-benzoic acid. (3.9 g, 80% yield) MS m/z @323 (m+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:19])[N:12]([CH2:16][CH2:17][OH:18])[CH:13]([CH3:15])[CH3:14])[N:10]=2)[CH2:3]1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1.CO>CN(C)C=O>[Si:20]([O:18][CH2:17][CH2:16][N:12]([CH:13]([CH3:14])[CH3:15])[C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([OH:1])[CH2:3]2)[S:7][CH:8]=1)=[O:19])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)N(CCO)C(=O)c1csc(N2CC(O)C2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a solution of 3-hydroxy-1-{4-[N-(2-hydroxyethyl)-N-isopropyl-carbamoyl]-1,3-thiazol-2-yl}azetidine (1.33 g, 4.66 mmol) (obtained as described in Reference Example 59(2)) in dimethylformamide (40 ml) were added t-butyldimethylsilyl chloride (738 mg, 4.89 mmol) and imidazole (333 mg, 4.89 mmol) in an ice bath, and the mixture was stirred in the ice bath for 2 hours. After checking the completion of the reaction, methanol was added thereto and the mixture was stirred for 30 minutes. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) ethyl acetate as the eluant to afford 1-(4-{N-[2-(t-butyldimethylsilyloxy)-ethyl]-N-isopropyl-carbamoyl}-1,3-thiazol-2-yl)-3-hydroxyazetidine (1.26 g, yield 69%) as a pale yellow oil.