Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Li+].[Br-].[I:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][Zn+].Cl[Si](C)(C)C.[CH3:18][C:19]([CH:21]=[CH2:22])=[O:20].S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl-].[NH4+]>O1CCCC1>[I:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][CH2:22][CH2:21][C:19](=[O:20])[CH3:18]
Reactant: [Zn+]Cc1ccccc1I
Reactant: C=CC(C)=O
Agent: C[Si](C)(C)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)CCCc1ccccc1I
Temperature: 21 °C
Reaction time: 0.25 h

Procedure:
A suspension of dry lithium chloride (6.4 g, 150 mmol) and cuprous cyanide (6.72 g, 75 mmol) in anhydrous tetrahydrofuran (75 ml) was stirred under nitrogen for 15 min at 21° C. and then cooled to −73°. A 0.5M solution of 2-iodobenzylzinc bromide in tetrahydrofuran (150 ml, 75 mmol) was added dropwise over 40 min below −65° C. and the temperature was allowed to rise to −7° C., stirred at this temperature for 0.5 h and then cooled back to −68° C. Chlorotrimethylsilane (19 ml, 150 mmol) was added over 10 min and stirring continued for a further 15 min. A solution of methylvinylketone (6.25 ml, 75 mmol) in anhydrous tetrahydrofuran (150 ml) was dried over anhydrous sodium sulphate and then added to the reaction over 25 min. The mixture was stirred in an acetone/cardice bath for 19 h, reaching −30° C., and then without cooling for 3 h. Aqueous ammonium chloride solution (200 ml) was added carefully and the reaction mixture was extracted with ether (2×200 ml). The combined organic layers were washed with water (200 ml) (a white solid was filtered off and discarded) and saturated brine (200 ml), dried over anhydrous magnesium sulphate and evaporated. The resulting oil was dissolved in cyclohexane (200 ml), solid was filtered off, and the filtrate was evaporated to give an oil (17.6 g). A 2 g portion was purified by flash chromatography on a 90 g Biotage cartridge eluting with an 8:1 mixture of cyclohexane and toluene to give the title compound as a liquid (1.112 g).
Reaction SMILES: [C-:1]#[N:2].[K+].CO.Cl.CN([CH2:10][CH:11]1[CH2:16][S:15][C:14]2[S:17][CH:18]=[CH:19][C:13]=2[C:12]1=[O:20])C>O>[O:20]=[C:12]1[CH:11]([CH2:10][C:1]#[N:2])[CH2:16][S:15][C:14]2[S:17][CH:18]=[CH:19][C:13]1=2
Reactant: [C-]#N
Reactant: CN(C)CC1CSc2sccc2C1=O
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#CCC1CSc2sccc2C1=O
Yield: 86.1 %

Procedure:
To a solution of 25.3 g of potassium cyanide in 100 ml of water is added 400 ml of methanol and to the solution is added 41 g of 5-dimethylaminomethyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one hydrochloride with stirring. The mixture is stirred for 3 hours at 45°-50° C. and then concentrated under reduced pressure. To the residue is added water and the mixture is extracted with chloroform. The extract is washed with water, dried over magnesium sulfate and the chloroform is distilled off. The residue is subjected to chromatography on silica gel and eluted with chloroform to give 28 g of 4-oxo-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-acetonitrile as pale brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[N:4]([CH2:12][CH2:13][CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([CH3:27])([O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:12][CH2:13][CH3:14])[C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:2]2[CH3:1])[CH3:26])[CH3:22]
Reactant: CCCn1c(-c2ccccc2)c(C)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(-c2ccccc2)c(C)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 3-methyl-2-phenyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: C[O:2][P:3]([CH2:7][NH:8][CH:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[O:11])([O:5]C)=[O:4]>Br>[P:3]([CH2:7][NH:8][CH:9]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][CH:28]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])([OH:5])([OH:4])=[O:2]
Reactant: COP(=O)(CNC(Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC(=O)OC(C)(C)C)OC
Agent: Br
Product: O=C(O)CCNC(=O)C(Cc1ccc(-c2ccccc2)cc1)NCP(=O)(O)O

Procedure:
A solution of t-butyl N-[2-(dimethylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionate (0.38 g, 0.78 mmol) in 30% HBr/glacial HOAc is stirred at room temperature for 6.5 hours. After concentration to about 1/10 volume, ether (40 mL) is added and the solid filtered. The solid is then suspended in water (3 mL), filtered off and washed with water to obtain N-[2-(phosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionic acid, m.p. 242°-244° dec.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:15][CH:14]=1
Reactant: BrCc1ccc(CBr)cc1
Reactant: O=C1NCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C1c2ccccc2CN1Cc1ccc(CBr)cc1
Yield: 49.3 %

Procedure:
2,3-Dihydroisoindol-1-one (350 mg, 2.63 mmol), 1,4-bis-bromomethylbenzene (3.78 g, 14.3 mmol), Cs2CO3 (3.60 g, 11.1 mmol), in acetonitrile (20 mL), was stirred together at room temperature for 5 hours and 80° C. for 20 minutes. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the product was purified by column chromatography (30% EtOAc/Hexanes) to afford a white solid (410 mg, 49%). 1H NMR (300 MHz, CDCl3): δ 7.92 (d, 1H), 7.49-7.55 (m, 2H), 7.37-7.42 (m, 3H), 7.28-7.31 (m, 2H), 4.82 (s, 2.03), 4.49 (s, 2H), 4.31 (s, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[CH:22]=[CH:23][CH3:24])=[CH:17][CH:16]=1)(=[O:9])[CH3:8].CC(O)[C:28]#[N:29]>CO>[C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[CH2:22][CH:23]([C:28]#[N:29])[CH3:24])=[CH:17][CH:16]=1)(=[O:9])[CH3:8]
Reactant: CC(O)C#N
Reactant: CC=CC(=O)c1ccc(CCCCNC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NCCCCc1ccc(C(=O)CC(C)C#N)cc1
Yield: 79.9 %

Procedure:
1.1 ml of a 10% sodium carbonate aqueous solution was added to 15 ml of a methanol solution containing 510 mg of 4-[4-(acetylamino)butyl]-1-(2-butenoyl)benzene and 1.69 g of acetocyanhydrin, and the mixture was refluxed under heating for 2 hours. The solvent was removed, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol (40:1)) to obtain 450 mg of 4-[4-(acetylamino)butyl]-1-(3-cyanobutanoyl)benzene.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[OH-].[K+].Cl[CH2:12][CH:13]=O.Cl>CO>[O:7]1[C:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]=2[CH:13]=[CH:12]1
Reactant: O=CCCl
Reactant: O=C1CCCC(=O)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCCc2occc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
In methanol (40 mL) was dissolved 11.2 g (0.100 mol) of 1,3-cyclohexanedione, an aqueous solution (8 mL) containing 6.60 g (0.100 mol) of 85% potassium hydroxide was added dropwise to the solution, and the resulting mixture was stirred at room temperature for 30 minutes. This mixture was cooled in an ice bath, 21.6 g (0.110 mol) of 40% chloroacetaldehyde aqueous solution was added to the mixture with stirring and the resulting mixture was stirred at room temperature overnight. To the reaction mixture was added dropwise 2 mol/L hydrochloric acid aqueous solution, and the resulting mixture was stirred at room temperature for 30 minutes and extracted with ether. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 8.63 g (0.0635 mol, Yield: 63.5%) of 6,7-dihydro-1-benzofuran-4(5H)-one.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][NH:3]1.[Cl:25][CH2:26][CH2:27][N:28]=[C:29]=[O:30]>ClCCl>[Cl:25][CH2:26][CH2:27][NH:28][C:29]([N:3]1[CH:2]([CH3:1])[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4]1)=[O:30]
Reactant: O=C=NCCCl
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Solvent: ClCCl
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=O)NCCCl)OCO3
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
A mixture of 1.0 g (3.07 mmol) of (±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine, 25 ml of dry dichloromethane and 0.62 g (5.88 mmol of 2-chloroethyl isocyanate was stirred at room temperature for 24 h, then concentrated. The residue was purified by refluxing in ethanol to yield 1.25 g (94%) of the title compound, Mp.: 222-223° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][CH:12]([N:15]([C:17]4[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=4)[CH3:16])[C:9]=3[CH:10]=2)[N:5]=[C:4]([CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[NH:3]1.[H-].[Na+].[CH3:39]N(C=O)C>>[CH3:39][N:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][CH:12]([N:15]([C:17]4[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=4)[CH3:16])[C:9]=3[CH:10]=2)[N:5]=[C:4]1[CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CN(c1ccc(C(=O)OC(C)(C)C)cc1)C1CCc2cc3nc(CN4CCCCC4)[nH]c(=O)c3cc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CN(c1ccc(C(=O)OC(C)(C)C)cc1)C1CCc2cc3nc(CN4CCCCC4)n(C)c(=O)c3cc21
Reaction time: 0.02 h
Yield: 91 %

Procedure:
To a solution of tert-butyl 4-[N-[4-oxo-2-(piperidin-1-yl)methyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-methylamino]benzoate (0.060 g, 0.123 mmol) in anhydrous DMF (3 ml) under argon was added a dispersion of NaH in mineral oil (60% w/w) (0.0060 g, 0.147 mmol) and the reaction mixture was stirred for 1 min. Mel (15 μL, 0.246 mmol) was then added via syringe and the reaction mixture was stirred for a further 2 hours. The reaction mixture was then partitioned between a saturated aqueous solution of sodium bicarbonate (40 ml) and ethyl acetate (75 ml) and the organic phase was then successively washed with a saturated aqueous solution of sodium bicarbonate (30 ml), brine (30 ml), then dried (Na2SO4) and concentrated under reduced pressure to afford the title compound (0.056 g, 91%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH2:20][OH:21])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(Cl)Cl>[C:14]([O:13][C:11]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH:20]=[O:21])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A 2 L, 3-necked round bottomed flask equipped with an overhead stir and a N2 inlet was charged with a solution of oxalyl chloride (130 mL, 0.26 mol) in DCM (250 mL). The solution was cooled to −78° C., and a solution of DMSO (20 mL, 0.28 mol) in DCM (30 mL) was added dropwise. After 30 minutes, a solution of (S)—N-Boc-prolinol (40 g, 0.20 mol) in DCM (200 mL) was added dropwise. After 30 minutes, TEA (140 mL, 1.00 mol) was added to the solution, and the flask was transferred to an ice/water bath and stirred for another 30 minutes. The reaction mixture was diluted with DCM (200 mL) and washed successively with H2O, 1M HCl, saturated NaHCO3, and brine. The DCM layer was dried over Na2SO4, filtered, and concentrated to afford crude (S)-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (40 g) as an oil, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:14]O>>[F:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(F)c1I
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(C)c(I)c1F
Temperature: 80 °C

Procedure:
To the solution of 2-fluoro-3-iodo-4-methylbenzoic acid (450 mg, 1.6 mmol, 1.0 eq) in methanol (5 ml), catalytic amount of conc.HCl (0.1 ml) was added. The resultant solution was heated to reflux at 80° C. for overnight. Methanol was evaporated. To this residue, water was added and the aqueous layer was extracted thrice with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulphate, filtered and evaporated to afford methyl 2-fluoro-3-iodo-4-methylbenzoate. Yield: 450 mg (95%). 1H NMR (400 MHz, DMSO): δ 2.49 (s, 3H), 3.85 (s, 3H), 7.30-7.32 (d, 1H, J=7.84 Hz), 7.76-7.80 (t, 1H, J=7.82 Hz). LCMS: (ES+) m/z=295 (M+H).
Reaction SMILES: [CH3:1][C:2](=[CH2:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH:5]=O.Cl.[NH2:15]O>C(O)C>[CH3:1][C:2](=[CH2:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][C:5]#[N:15]
Reactant: NO
Reactant: C=C(C)C(CC=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: C=C(C)C(CC#N)c1ccccc1
Yield: 37.2 %

Procedure:
4-Methyl-3-phenyl-4-pentenal (15.27 g; 0.077 mol) and hydroxylamine hydrochloride (8.1 g; 0.116 mol) were heated together in 95% ethyl alcohol (125 ml) at reflux under nitrogen for 3 hours. Ethyl alcohol was removed on the rotavapor and the residue partitioned between n-heptane and water (100 ml each). The aqueous phase was reextracted with n-heptane (100 ml). Each organic phase was washed with 5% aqueous HCl, water, aqueous saturated NaHCO3 and brine (100 ml each). Combined extracts were dried over anhydrous sodium sulfate. The product was purified by column chromatography on silica gel (eluting with heptane/ethyl acetate 10:1 to 5:1) followed by bulb-to-bulb distillation. 4.9 g of the desired product were obtained (0.0285 mol; yield=37%).
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[Cl:11][C:12]1[S:16][C:15]([CH2:17][C@H:18]2[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)=[O:24])[CH2:19]2)=[CH:14][CH:13]=1>>[N:4]1[N:3]([CH2:7][C:8]([N:21]2[CH2:22][C@H:18]([CH2:17][C:15]3[S:16][C:12]([Cl:11])=[CH:13][CH:14]=3)[CH2:19][C@H:20]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)=[O:24])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: O=C(O)Cn1nccn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)s2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)s2)CN1C(=O)Cn1nccn1
Yield: 58 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride and (2S,4S)-4-((5-chlorothien-2-yl)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 66, (2S,4S)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-((5-chlorothien-2-yl)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (58.3 mg, 58%). 1H-NMR (400 MHz, CDCl3): σ 9.14 (s, 1H), 7.72 (s, 2H), 7.42 (d, 2H), 7.00 (t, 2H), 6.95-6.90 (m, 4H), 6.75 (d, 1H), 6.61 (d, 1H), 5.39 (s, 2H), 4.86 (d, 1H), 3.62 (dd, 1H), 3.19 (t, 1H), 3.03-2.85 (m, 2H), 2.83-2.77 (m, 1H), 2.72 (dd, 1H), 1.72-1.64 (m, 1H). MS (EI) for C26H23ClFN5O3S. found 540.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:11][C:3]1[CH:4]=[C:5]([CH:8]([OH:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(C(C)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C(C)O)cc1N
Temperature: 25 °C
Reaction time: 7 h
Yield: 97.8 %

Procedure:
To a solution of 1-(4-methyl-3-nitrophenyl)ethan-1-ol (1.96 g) in ethyl acetate (55 mL) was added 10% palladium on carbon (56.5% water included, 901 mg), and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite (registered trademark) pad. The filtrate was concentrated under reduced pressure to obtain the title compound (1.60 g). 1H-NMR (CDCl3) δ ppm: 1.47 (3H, d, J=6.4 Hz), 1.73 (1H, br s), 2.16 (3H, s), 3.63 (2H, br s), 4.80 (1H, q, J=6.4 Hz), 6.66-6.75 (2H, m), 7.02 (1H, d, J=7.3 Hz).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[NH:9][N:8]=[CH:7]2.[CH2:14]1COCC1>>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[N:9]([CH3:14])[N:8]=[CH:7]2
Reactant: C1CCOC1
Reactant: Fc1cc2[nH]ncc2cc1Br
Agent: [H-]
Agent: [Na+]
Product: Cn1ncc2cc(Br)c(F)cc21
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (8.84 g, 221 mmol) in THF (50 mL) was added dropwise a solution of 5-bromo-6-fluoro-1H-indazole (CAS 105391-70-6, 44.1 g, 201 mmol) in THF (200 mL) at 5° C. After 15 min at 5° C., Mel (31.7 mL, 221 mmol) was added at 5° C. and the RM was stirred between 0° C. and 5° C. for 1.5 h. The reaction was quenched with 0.5 M HCl and extracted with EtOAc. The organic phases were combined, washed with brine, dried over Na2SO4 and evaporated under vacuo. The 2 isomers formed were separated by MPLC with heptane and EtOAc to afford the title compound as a yellow solid (tR 5.07 min (conditions 1), NMR in DMSO-d6: 8.14 (d, 1H); 8.04 (s, 1H); 7.79 (d, 1H); 4.00 (s, 3H)).
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=2[CH3:1])[CH2:16][CH2:15]1
Reactant: Cc1c(C=O)cccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1c(CN2CCN(C)CC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2-Methyl-3-nitrobenzaldehyde (J. Org. Chem. 1981, 46, 1752-1755) (1.0 g, 6.1 mmol) was dissolved in DCE and N-methylpiperazine and HOAc were added followed by sodium triacetoxyborohydride. The reaction was stirred at rt for 1 h and was then quenched with 5% K2CO3 solution. The reaction mixture was extracted (3×) with ethyl acetate, dried over magnesium sulfate, filtered, concentrated onto silica gel and flash chromatographed to give the title compound (1.6 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.69 (d, J=7.7 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.34 (t, J=7.9 Hz, 1H), 3.48 (s, 2H), 2.16-2.42 (m, 1H), 2.10 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([Br:18])[S:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>C(O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([Br:18])[S:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Br)c1nc2sc(Br)cc2c(=O)n1Cc1ccccc1
Reactant: CN(C)CCN
Solvent: CCO
Product: CCC(NCCN(C)C)c1nc2sc(Br)cc2c(=O)n1Cc1ccccc1

Procedure:
A solution of 3-benzyl-6-bromo-2-(1-bromopropyl)thieno[2,3-d]pyrimidin-4(3H)-one (2-6, 35 mg, 0.079 mmol, 1 equiv) and N,N-dimethylethylenediamine (21 mg, 0.237 mmol, 3 equiv) in ethanol (5 mL) was heated at reflux for 18 h. The reaction was concentrated, and the residue was partitioned between EtOAc and brine. The organic layer was dried (MgSO4) and concentrated to provide 3-benzyl-6-bromo-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one (2-8) as a yellow gum. MS(M+1)=449.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:24]([F:27])([F:26])[F:25])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([N:22]=O)[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[NH4+].[Cl-]>CO.O.C(Cl)Cl.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:24]([F:25])([F:26])[F:27])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([NH2:22])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=NN1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: NN1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-nitrosoindoline (0.1 g, 0.2 mmol) in MeOH(10.0 mL) was added zinc powder (77.5 mg) and NH4Cl (36.9 mg, 0.69 mmol) in water (2.0 mL). The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with CH2Cl2 and the CH2Cl2 layer was washed with water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (0.08 g): ESIMS m/z 404.86 ([M+H]+).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)([OH:7])[CH3:6])#[N:2].[Cl:21]Cl>C(O)(=O)C>[C:1]([CH2:3][CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)([OH:7])[CH3:6])#[N:2]
Reactant: CC(O)(CCC#N)c1ccc(Oc2ccccc2)cc1
Reactant: ClCl
Solvent: CC(=O)O
Product: CC(O)(CCC#N)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
2.76 g. of 1-cyano-3-(4-phenoxy-phenyl)-butan-3-ol are dissolved in 20 ml. of acetic acid, a solution of 0.8 g. of chlorine in 20 ml. of acetic acid is added dropwise at 20° while stirring, the mixture is stirred for a further one hour and evaporated and the residue is worked up in the customary manner to give 1-cyano-3-(4-p-chlorophenoxy-phenyl)-butan-3-ol, m.p. 68° - 70°.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH2:24][CH2:25][CH3:26])[C:16]2=[O:27])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH2:24][CH2:25][CH3:26])[C:16]2=[O:27])=[CH:13][CH:14]=1
Reactant: CCCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncccc21
Agent: [Pd]
Solvent: CCO
Product: CCCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reaction time: 3 h
Yield: 93.4 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.5 g) and 10% Pd—C (0.444 g) in EtOH (40 mL) was hydrogenated under balloon pressure at room temperature for 3 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 3-(4-hydroxyphenyl)-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.05 g) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:5]([CH3:8])([CH3:6])[CH3:4])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chlorophenylacetic acid (10.0 g, 58.6 mmol) in CH2Cl2 was added 2-Cert-butyl-1,3-diisopropyl-isourea (50 g, 250 mmol) dropwise at −10° C. The mixture was stirred at room temperature overnight, then the precipitate was, removed by filtration. The filtrate was washed with 1M HCl (aq) and saturated NaCl (aq), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 2% EtOAc/petroleum ether to afford the title compound: 1H NMR (CD3OD, 300 MHz) δ 7.26-7.30 (m, 2H), 7.18-7.21 (m, 2H), 3.49 (s, 2H), 1.43 (s, 9H).