Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].CC(C)([O-])C.[K+].O1CCCC1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]=[C:29](OP(N3CCOCC3)(N3CCOCC3)=O)[CH2:28][N:27]=[C:26]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[Cl:52])[C:25]=2[CH:53]=1>O.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[CH:2]=[N:1][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:29]3[CH2:28][N:27]=[C:26]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[Cl:52])[C:25]=2[CH:53]=1
Reactant: O=P(OC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)(N1CCOCC1)N1CCOCC1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 1.41 g (0.0125 mole) of ethyl isocyanoacetate, 1.4 g (0.0125 mole) of potassium t-butoxide and 125 ml of tetrahydrofuran was stirred at room temperature for 10 minutes. Following the addition of 5.23 g (0.01 mole) of 7-chloro-5-(2-chlorophenyl)-2-[bis-(morpholino)-phosphinyloxy]-3H-1,4-benzodiazepine stirring was continued for 1/2 hr. The reaction mixture was acidified with glacial acetic acid, diluted with 250 ml of water and extracted with three 100 ml portions of methylene chloride. The methylene chloride extracts were washed with saturated sodium bicarbonate solution, dried and evaporated. The crystalline residue was collected and washed with ether to give product with mp 215°-220°. The material was recrystallized from methylene chloride/ethyl acetate for analysis, mp 225°-228°.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH3:31])=[O:29])[C:10]([S:13]([CH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19])(=[O:15])=[O:14])([CH3:12])[CH3:11])=[O:7])(C)(C)C.Cl.ClC(O[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=O>O1CCOCC1>[CH2:37]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH3:31])=[O:29])[C:10]([S:13]([CH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19])(=[O:15])=[O:14])([CH3:11])[CH3:12])=[O:7])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Reaction time: 12 h
Yield: 39.9 %

Procedure:
A solution of 1.0g (2.19mmol) of (RS)-α-[[[(R)-2-(1-tert-butoxyformamido)-2-(methoxycarbonyl)-1,1-dimethylethyl]sulfonyl]methyl]hydrocinnamic acid was added dropwise at room temperature to 10 ml of 1.4 M hydrogen chloride in dioxan and stirred for a further 12 hours. After evaporation of the solvent under reduced pressure there was obtained a colourless foam which, without further purification and characterization, was dissolved in 8.5 ml of 1N sodium hydrogen carbonate solution and treated with 0.44 ml (3.07 mmol) of benzyl chloroformate. The thus-obtained suspension was stirred at room temperature for 12 hours. Subsequently, it was extracted twice with 250 ml of ether each time, the combined ether extracts were dried over magnesium sulphate and evaporated under reduced pressure. For purification, the oily crude product (1.05 g) was chromatographed on 50 g of silica gel firstly with methylene chloride then with a 95:5 mixture of methylene chloride and methanol as the eluent. There were obtained 430 mg of (RS)-α-[[[(R)- 2-(1-benzyloxyformamido)-2-(methoxycarbonyl)-1,1-dimethylethyl]sulfonyl]methyl]hydrocinnamic acid as a colourless foam, MS: 493 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH:19]([N:23]2[CH:27]=[C:26]([C:28]3[C:29]4[CH:36]=[CH:35][N:34](COCC[Si](C)(C)C)[C:30]=4[N:31]=[CH:32][N:33]=3)[CH:25]=[N:24]2)[CH2:20][C:21]#[N:22])[CH2:14][CH2:13]1.C(N(CC)CC)C.FC(F)(F)C(O)=O.C(N)CN>C(#N)C.CO.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH:19]([N:23]3[CH:27]=[C:26]([C:28]4[C:29]5[CH:36]=[CH:35][NH:34][C:30]=5[N:31]=[CH:32][N:33]=4)[CH:25]=[N:24]3)[CH2:20][C:21]#[N:22])[CH2:14][CH2:13]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CC4CCNCC4)c3)ncnc21
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCC(CC1CCN(C(=O)c2ccc(F)cc2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Fluoro benzoyl chloride (94.7 mg, 0.597 mmol), 4-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (from example 5, step 4; 0.250 g, 0.498 mmol), and triethylamine (208 μL, 0.00149 mol) were dissolved in acetonitrile (2.5 mL). The mixture was stirred at RT for 1 h. Solvents were evaporated. The crude product was treated with DCM (3 mL) and trifluoroacetic acid (3 mL, 0.04 mol) for 30 min, and evaporated to dryness under reduced pressure. To the resultant residue was added methanol (5 mL) and ethylenediamine (0.5 mL, 0.007 mol) and the resulting mixture was stirred at RT for 30 min. After being concentrated under reduced pressure, the residue was purified on RP-HPLC (XBridge C-18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH, at flow rate 60 mL/min) to give the desired product. LCMS calculated for C25H25FN7O(M+H)+: m/z=458.2; Found: 458.0. NMR (300 MHz, CD3OD) δ 9.01 (1H, s), 8.90 (1H, s), 8.54 (1H, s), 7.89 (1H, d, J=3.6 Hz), 7.42 (2H, m), 7.31 (1H, d, J=3.6 Hz), 7.17 (2H, m), 4.98 (1H, m), 4.55 (1H, m), 3.52 (2H, m), 3.16 (2H, m), 2.73 (1H, m), 2.25 (2H, m), 2.03 (1H, m), 1.88 (2H, m), 1.38 (1H, m), 1.28 (1H, m) ppm.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[CH3:10].C1C(=O)N(Br)[C:13](=[O:14])C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][O:14][CH3:13])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C)c(Br)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COCc1cc(C)c(Br)c(C)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 15.4 %

Procedure:
2-bromomesitylene (5.00 g) was dissolved in carbon tetrachloride (50 mL). NBS (4.45 g) and benzoyl peroxide (182 mg) were added to the solution, and the mixture was stirred at 80° C. for three hours. The reaction mixture was returned to room temperature and filtered. The solid collected by filtration was washed with n-heptane. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane). The resulting fraction was concentrated under reduced pressure. The residue was dissolved in THF (120 mL). Sodium methoxide (28% solution in methanol, 9.35 mL) was added to the solution, and the mixture was stirred at 80° C. for four hours. The reaction mixture was returned to room temperature and concentrated under reduced pressure. Water was added to the residue, followed by extraction with DCM. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 5%). The resulting fraction was concentrated under reduced pressure, and the residue was purified again by NH silica gel column chromatography (n-heptane) to give the title compound (880 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCOC(=O)c1csc(-c2cccc(OC)c2)n1
Temperature: 25 °C

Procedure:
A suspension of 3-methoxyphenyl boronic acid (0.25 g, 1.65 mmol), ethyl 2-bromothiazole-4-carboxylate (0.33 g, 1.4 mmol), PdCl2(dppf)2 (0.11 g) and 2M Na2CO3 (aq) (2 mL) in DME (10 mL) was heated to reflux for 20 h. The mixture was cooled to RT, filtered, concentrated by rotary evaporation and purified on silica gel (6:1 hexanes/EtOAc and 4:1 hexanes/EtOAc) to afford the title compound as a light-brown oil. EI-MS m/z 264 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].Cl[Sn]Cl.Cl>Cl>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:10]
Reactant: Nc1ccc(F)cc1Br
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: NNc1ccc(F)cc1Br
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
Commercially available 2-bromo-4-fluoroaniline 1 (2.36 ml, 20.75 mmol) was added to a stirring solution of concentrated hydrochloric acid (40 ml) that was cooled to −5° C. This solution was allowed to age while stirring for 10 minutes. An aqueous solution of NaNO2 was added over 15 minutes. SnCl2/HCl (10.40 g, 46.1 mmol, 10 ml HCl) was added over 15 minutes and aged for an additional 30 minutes to 1 hour. The mixture was filtered and washed with dichloromethane. The resulting solid was dissolved in 1.0M HCl and extracted 3 times with dichloromethane. The organic layer was vacuum dried overnight to give 3.53 g (83% yield). 1H NMR (400 MHz, CDCl3): 7.169 (dd, J=8 Hz, J=2.8 Hz 1H), δ 7.076 (dd, J=5.2 Hz, J=9.2 Hz, 1H), 6.982 (td, J=8.4 Hz, J=2 Hz 1H), δ 5.540 (bs, 1H), δ 3.590 (bs, 1H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[O:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)[CH2:6]1.[N+]([O-])(O)=O.C(Cl)Cl.[NH4+].[OH-]>C(Cl)Cl>[N+:1]([C:11]1[CH:10]=[C:9]([CH:7]2[CH2:8][O:5][CH2:6]2)[CH:14]=[CH:13][C:12]=1[NH:15][C:16](=[O:18])[CH3:17])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C2COC2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C2COC2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
The organic phase (upper phase) was isolated and the process was repeated with an additional 20 ml CH2Cl2. The organic extracts were combined, it was assumed the organic phase contained about 5 g (−80 mmol) of anhydrous HNO3. Using a 50 fold excess, this required about 25 ml of solution. The nitric acid solution was cooled in a ice bath. The N-(4-oxetan-3-ylphenyl)acetamide (21 0 mg, 0.70 mmol) was treated with 25 ml of the chilled HNO3/CH2Cl2 solution and was allowed to stir about 30 minutes. The reaction mixture was carefully poured into 45 ml 1 0% NH4OH solution and carefully shaken. The phases were separated and the aqueous phase was washed with 20 ml CH2Cl2. The combined organic phase was dried over Na2SO4, filtered and concentrated. The crude material was purified
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.C1(C(OC(C)(C)C)=O)CC1.BrCCCC[Cl:31].[Li+].CC([N-]C(C)C)C>>[Cl:31][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1
Reactant: ClCCCCBr
Reactant: CC(C)(C)OC(=O)C1(CCCCBr)CC1
Agent: CC(C)(C)OC(=O)C1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)(C)OC(=O)C1(CCCCCl)CC1

Procedure:
Compound 104a was prepared, likewise the procedure described for 103b, starting from t-butyl cyclopropanecarboxylate (Kohlrausch, K. W. F. et al. Z. Elektrochem. Angew. Phys. Chem, 1937, 43, 282-285) (12.5 g, 88 mmol), 1-bromo-4-chlorobutane (13.7 mL, 117 mmol) and LDA (prepared from BuLi (2.5M in hexanes, 37 mL, 92.5 mmol) and iPr2NH (12.3 mL, 88 mmol, distilled from NaOH)) to give, after purification by fractional distillation under reduced pressure, 104a (10.73 g 52%) as a colorless oil. bp: T=57-61° C. (p=0.001 mbar). 1H NMR: δ 3.52 (t, J=6.6 Hz, 2H), 1.76 (quintet, J=6.8 Hz, 2H), 1.64-1.54 (n, 2H), 1.51-1.46 (m, 2H), 1.42 (s, 9H), 1.12 (dd, J=6.6, 3.9 Hz, 2H), 0.60 (dd, J=6.6, 3.9 Hz, 2H). 13C NMR: δ 173.9, 80.0, 45.1, 33.6, 32.9, 28.2 (3×), 25.3, 24.2, 15.4 (2×). HRMS calcd for C12H22ClO2 (MH+): 233.1308, found: 233.1308.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH3:11][CH:12]([C:18]1[CH:19]=C(O)[CH:21]=[C:22]([CH:24]=1)[OH:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH3:11][CH:12]([C:18]1[CH:24]=[C:22]([OH:23])[C:21]2[C:2]3[CH2:6][CH2:5][S:4][C:3]=3[C:7](=[O:8])[O:9][C:10]=2[CH:19]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)C1SCCC1=O
Reactant: CCCCCC(C)c1cc(O)cc(O)c1
Product: CCCCCC(C)c1cc(O)c2c3c(c(=O)oc2c1)SCC3

Procedure:
Following a procedure similar to that described in Example 1B hereinabove, methyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate is reacted with 5-(2-heptyl)resorcinol to give 1,2-dihydro-7-(2-heptyl)-9-hydroxy-4-oxo-4H-thieno [2,3-c][1]benzopyran.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7]C.[CH3:23][O:24][C:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[C:27]([CH3:34])[N:26]=1>>[OH:7][C:6]1[N:5]([C:9]2[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=2)[N:4]=[CH:3][C:2]=1[C:29]1[CH:28]=[C:27]([CH3:34])[N:26]=[C:25]([O:24][CH3:23])[CH:30]=1
Reactant: COc1cc(B(O)O)cc(C)n1
Reactant: COCCCNC(=O)c1ccc(-n2ncc(Br)c2OC)nc1
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3cc(C)nc(OC)c3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 212 using 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide and (2-methoxy-6-methylpyridin-4-yl)boronic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (quin, J=6.6 Hz, 2H) 2.30 (s, 3H) 3.18 (s, 3H) 3.22-3.30 (m, 2H) 3.32 (t, J=6.3 Hz, 2H) 3.79 (s, 3H) 7.16 (br. s., 1H) 7.31 (br. s., 1H) 8.31 (br. s., 1H) 8.33-8.53 (m, 2H) 8.61 (br. s., 1H) 8.82 (s, 1H) 13.35 (br. s., 1H). MS m/z 398 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:23]=[CH:22][C:10]([CH2:11][N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[CH:9][C:8]=2[O:24][CH3:25])[CH:5]=[CH:4][CH:3]=[N:2]1>C1COCC1.CCO.O>[N:1]1([CH2:6][C:7]2[CH:23]=[CH:22][C:10]([CH2:11][N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[CH:9][C:8]=2[O:24][CH3:25])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1cnn(Cc2ccc(Cn3cccn3)c(OC)c2)c1
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc(Cn2cc(C(=O)O)cn2)ccc1Cn1cccn1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a solution of crude ethyl 1-(4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzyl)-1H-pyrazole-4-carboxylate (998 mg, 29%, 0.85 mmol) in THF:EtOH:H2O 2:1:1 (15 ml), LiOH Monohydrate (107 mg, 2.55 mmol) was added and stirred for 12 h at 50° C. The reaction mixture was concentrated under reduced pressure. The remaining solid was taken up in ethyl acetate and extracted with water. The aqueous phase was acidified by adding aqueous HCl and extracted with ethy acetate. The organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude 1-(4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzyl)-1H-pyrazole-4-carboxylic acid. MS [M+H]+=313.
Reaction SMILES: [CH3:1][C:2]1([CH2:5]O)[CH2:4][CH2:3]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C1COCC1.[C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24]>C(Cl)Cl.N1CCCCC1.C(O)(=O)C>[CH2:29]([O:28][C:26](=[O:27])[C:25]([C:23]#[N:24])=[CH:5][C:2]1([CH3:1])[CH2:3][CH2:4]1)[CH3:30]
Reactant: CC1(CO)CC1
Reactant: CCOC(=O)CC#N
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)=CC1(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
To 1-methylcyclopropane-methanol (Aldrich, 1.13 mL, 11.6 mmol) in 50 mL CH2Cl2 was added neutral alumina (2.5 g) and then PCC (2.5 g, 11.6 mmol), and the mixture stirred 3 h at ambient temperature. The mixture was filtered through a 1 cm plug of silica gel under vacuum, and rinsed with Et2O. The filtrate was concentrated to ca. 5 mL total volume. To the residue was added THF (10 mL), ethyl cyanoacetate (1.2 mL, 11.3 mmol), piperidine (5 drops), and finally acetic acid (5 drops). The whole was stirred at ambient temperature overnight, then partitioned between Et2O and sat. aq. NaHCO3. The phases were separated and the organic phase washed with brine, dried (MgSO4), and concentrated. Flash chromatography of the residue (10→15% EtOAc/hexanes) provided 0.53 g (25%) of the ester as a colorless oil that crystallized on standing, mp 35–37° C. 1H NMR (CDCl3) δ 6.99 (s, 1H), 4.27 (q, J=7.3 Hz, 2H), 1.55 (s, 3H), 1.32 (t, J=7.3 Hz, 3H), 1.14 (s, 2H), 1.07 (s, 2H). 13C NMR δ. 170.44, 162.90, 115.17, 103.69, 62.52, 21.24, 21.07 (2C), 20.71, 14.35. Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C, 66.86; H, 7.47; N, 7.70.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([OH:14])[CH:4]([O:6][Si](C(C)(C)C)(C)C)[CH3:5].[F-].[K+].O.C(OCC)(=O)C>CO>[Cl:1][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([OH:14])[CH:4]([OH:6])[CH3:5]
Reactant: CC(O[Si](C)(C)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 10 h
Yield: 17 %

Procedure:
To a solution of 0.27 g (0.77 mmol) of 1-chloro-2-(2,4-difluorophenyl)-3-(tert-butyldimethylsilyloxy)butan-2-ol ((2S,3R)/(2R,3R)=91/9) in 3 mL of methanol was added 0.06 g (0.94 mmol) of potassium fluoride, and reaction was performed for 10 hours and then at 50° C. for another 25 hours. Next, 5 mL of water was added to stop the reaction, and extraction was performed with 10 mL of ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product as a colorless oil. The resulting crude product was quantitatively analyzed by HPLC (under the same HPLC measurement conditions as those in Example 6). Thereby, the title compound was obtained in a yield of 17% ((2S,3R)/(2R,3R)=95/5).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([O:32][CH3:33])=[C:21]([NH:25]C(=O)OCC=C)[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([O:32][CH3:33])=[C:21]([CH:22]=[CH:23][CH:24]=2)[NH2:25])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1c(N)cccc1-c1nc(N2CCOCC2)sc1-c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To a solution of 2-propen-1-yl [3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]carbamate (40 g, 99 mmol) in DCM (500 mL), acetic acid (11.3 mL, 197 mmol) and Pd(PPh3)2Cl2 (1.3 g, 1.64 mmol) were added. Then tri-n-butyl tin hydride (37.3 mL, 145 mmol) was added dropwise to the mixture at 0° C. The mixture was stirred at rt for 30 min. The reaction was quenched by slow addition of saturated NaHCO3 (200 mL). The two layers were separated. The aqueous layer was extracted with DCM (400 mL×2). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether (500 mL) to afford the title compound of Step B (26.1 g, 79.1% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (d, J=5.5 Hz, 1H), 7.01 (dd, J=7.5 Hz, 8.1 Hz, 1H), 6.83 (dd, J=1.5 Hz, 8.2 Hz, 1H), 6.68 (dd, J=1.5 Hz, 7.5 Hz, 1H), 6.61 (d, J=5.5 Hz, 1H), 3.86-3.95 (br, 2H), 3.78-3.82 (m, 4H), 3.58-3.63 (m, 4H), 3.56 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:25])([CH3:24])[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19](F)[CH:18]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N:26]1([CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.O>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:24])([CH3:25])[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([N:29]5[CH2:28][CH2:27][N:26]([CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])[CH2:31][CH2:30]5)[CH:18]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: OCCOCCN1CCNCC1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccnc(F)c1
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccnc(N2CCN(CCOCCO)CC2)c1
Temperature: 105 °C

Procedure:
A mixture of (3E)-6-fluoro-3-[4-(2-fluoropyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one (50 mg, 0.15 mmol) and 2-(2-(piperazin-1-yl)ethoxy)ethanol (50 mg, 0.29 mmol) in 2 mL of DMSO was heated in 105° C. bath for 6 hours. The mixture was cooled to room temp and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-6-fluoro-3-[4-(2-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}pyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 64 mg, 89%.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].[N+:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].C(NC1C=C(C2C3N(C4C=CC=CC=4)C=NC=3C=C(C#N)C=2)C=CC=1)(=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:17]=[C:16]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:19]([O-:21])=[O:20])[CH:27]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)Nc1cccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)c1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1cc(-c2cccc([N+](=O)[O-])c2)c2c(c1)ncn2-c1ccccc1
Yield: 7.6 %

Procedure:
This was prepared from 5-cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), 3-nitrophenylboronic acid (84 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) in a similar manner to 7-(3-acetamidophenyl)-5-cyano-1-phenylbenzimidazole. Purification by a similar procedure afforded the title compound (13 mg, 8%) m/z, 341.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]4[CH2:33][C:32](=[O:34])[C:29]5([CH2:31][CH2:30]5)[CH2:28]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:35])[NH:6]2.[BH4-].[Na+]>CO>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]4[CH2:33][CH:32]([OH:34])[C:29]5([CH2:31][CH2:30]5)[CH2:28]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:35])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCCN1CC(=O)C2(CC2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
The above product from Example 2 (75 mg) was dissolved into MeOH (8 ml) and stirred at RT. NaBH4 (75 mg) was added to the reaction and stirred at RT for 30 min. The reaction was evaporated and purified by column chromatography to give title compound (60 mg). Mass: (M+1), 478