Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[CH2:17][CH2:16][CH2:15][C:14]3[C:13]([C:18]#[N:19])=[CH:12][CH:11]=[CH:10][C:9]2=3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]=[C:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][CH:31]=O)=[CH:29][C:24]=2[CH2:23][O:22]1.CC(O)=[O:35]>C(Cl)Cl.CO>[O:35]=[C:6]1[CH2:5][N:4]([CH2:31][CH2:30][C:28]2[CH:29]=[C:24]3[C:25](=[CH:26][CH:27]=2)[C:21](=[O:20])[O:22][CH2:23]3)[CH2:3][CH2:2][N:1]1[CH2:7][CH:8]1[CH2:17][CH2:16][CH2:15][C:14]2[C:13]([C:18]#[N:19])=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: N#Cc1cccc2c1CCCC2CN1CCNCC1
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cccc2c1CCCC2CN1CCN(CCc2ccc3c(c2)COC3=O)CC1=O
Reaction time: 2 h

Procedure:
A solution of 5-(Piperazin-1-ylmethyl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (30 mg, 0.11 mmol) in 2 mL DCM/MeOH (1/1) was added (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (0.11 mmol), AcOH (6.6 mg, 0.11 mmol) and the reaction mixture was stirred for 2 hours, and then NaBH3CH (14 mg, 0.22 mmol) was added. The resulting mixture was stirred overnight at ambient temperature. The product was purified by prep-TLC (DCM/MeOH=20:1) to afford the desired product. 1H-NMR (400 MHz, MeOD) δ ppm 7.76 (d, J=8.0 Hz, 1H), 7.44-7.51 (m, 4H), 7.24 (t, J=8.0 Hz, 1H), 5.33 (s, 2H), 3.74-3.80 (m, 1H), 3.32-3.45 (m, 3H), 3.22-3.27 (m, 1H), 3.20 (d, J=2.4 Hz, 2H), 2.96-3.03 (m, 3H), 2.73-2.85 (m, 5H), 1.93-2.02 (m, 1H), 1.75-1.84 (m, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11].O.[C:13](=O)([O-])[O-].[Na+].[Na+].[CH2:19](O)[CH3:20]>>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:20]=[CH:19][CH:13]=[N:11]1
Reactant: COc1ccccc1NN
Reactant: O=C([O-])[O-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccccc1-n1cccn1

Procedure:
200 mg of 2-methoxyphenyl hydrazine hydrochloride was dissolved in 5 ml of ethanol, and 189 μl of malonaldehyde bisdimethylacetal was added and heated at reflux for 2 hours. To the reaction mixture was added 50 ml of water, neutralized with a saturated aqueous solution of sodium carbonate, and extracted with 60 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield 179.4 mg of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5].C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH2:17]([NH:16][C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([C:4](=[O:5])[CH2:3][CH2:2][NH:1][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=[CH:19][C:9]=2[N:10]=1)=[O:15])[CH3:18]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCNC(=O)Nc1nc2ccc(C(=O)CCN)cc2s1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(C(=O)CCNC(=O)c3ccccc3)cc2s1
Reaction time: 0.08 h
Yield: 27.7 %

Procedure:
A solution of 1-(6-(3-aminopropanoyl)-2-benzothiazolyl)-3-ethylurea (0.033 g, 0.10 mmol) in 1 mL anhydrous DMF was treated with triethylamine (0.028 mL, 0.20 mmol, 2.0 eq) at room temperature. It was stirred for about 5 min, followed by the addition of benzoyl chloride (0.014 mL, 0.12 mmol, 1.2 eq). It was stirred for about 2.5 hours, quenched with MeOH, filtered, concentrated, and purified by HPLC to give the desired compound 0.011 g (28%). LC/MS 396.7 (M+1); LC retention time 2.74 min.
Reaction SMILES: ClCCCC([O:11]C(=O)C)CCCCC.C([O:18][CH:19]([CH2:37][CH2:38][CH2:39][CH:40]=[CH2:41])[CH2:20][CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[C:24]#[N:25])(=O)C>>[OH:18][C@H:19]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:20]#[C:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:24]#[N:25].[OH:18][C@H:19]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:20]#[C:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:24]([NH2:25])=[O:11]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: C=CCCCC(CCCN(C#N)CCCCCCC(=O)OCC)OC(C)=O
Product: CCCCC[C@@H](O)C#CCN(C#N)CCCCCCC(=O)O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)C(N)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-aceotoxy-8nonane. The product of Step A is thus ethyl 7-[N-(4-acetoxy-8-nonenyl)cyanamido]heptanoate. The subsequent steps yield 7-[N-(4-hydroxy-8-nonenyl)cyanamido]heptanoic acid (B) and 7-[1-(4-hydroxy-8-nonenyl)ureido]heptanoic acid (C).
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1.C(N(CC)CC)C.C(Cl)Cl>CN(C=O)C>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:21][C:22]3[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: Nc1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccc(CO)cc1)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
A solution of 6-(cyclohexyl-cyclopropylmethyl-amino)-pyrimidine-4-carboxylic acid (Intermediate 13, 1.00 g; 3.63 mmol) in dry DMF (100 ml) was treated with polymer-supported Mukaiyama reagent, prepared as described in “S. Crosignani et al. Org. Lett. 2004, 6(24), 4579-4582” (2987 mg; 6.54 mmol), 4-aminobenzyl alcohol (Fluka, 492 mg; 3.99 mmol) and triethylamine (1.52 ml; 10.9 mmol). The reaction mixture was then stirred at room temperature for 18 hours. DCM was added and the product was filtered through an SPE column (Isolute NH2, 10g) and the column washed with DCM. The mixture was concentrated then rediluted in EtOAc. The organic phase was washed 5 times with brine, dried over MgSO4 and the solvent removed under vacuum to give the title compound (990 mg, 72%).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[C:15]([CH3:16])=[C:14]([OH:17])[C:13]([CH3:18])=[CH:12][C:10]=1[OH:11].C(O[CH:23]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=O)C>CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C(O)C>[CH3:18][C:13]1[C:14](=[O:17])[C:15]([CH3:16])=[C:9]([CH3:8])[C:10](=[O:11])[C:12]=1[CH:23]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CCCCC(OC(C)=O)c1cccs1
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1cccs1
Temperature: 60 °C
Yield: 74.8 %

Procedure:
D-Camphor-10-sulfonic acid (0.1 g) was added to a toluene solution (50 ml) of 2,3,5-trimethylhydroquinone (3.1 g, 0.02 mole) and ethyl 6-acetoxy-6-(2-thienyl)hexanoate (5.6 g, 0.02 mole), and the mixture was heated at 60° C. for 6.5 hours, with stirring. After cooling, ethanol (100 ml) and a 10% aqueous solution (20 ml) of ferric chloride were added to the reaction solution, followed by stirring for 10 minutes. The reaction product was extracted with isopropyl ether, and the organic layer was washed with water, dried (over magnesium sulfate) and concentrated under reduced pressure. The residue was chromatographed on a silica gel column, and elution was performed with isopropyl etherhexane (1:1) to give ethyl 6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-(2-thienyl)hexanoate (5.6 g, 76%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 2 to 8 were prepared.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12](Cl)=[O:13].C([O-])([O-])=O.[K+].[K+]>CCCCCCC.CCOC(C)=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:12](=[O:13])[CH2:11][O:9][C:3]=2[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C1COc2cc(F)ccc2N1
Yield: 93.1 %

Procedure:
2-Amino-5-flourophenol (111MF10) (10.3 g, 81 mmol), 2-chloroacetyl chloride (10.1 g, 89 mmol) and K2CO3 (23.5 g, 170 mmol) were mixed according to GP1. CC (SiO2; Heptane/EtOAc 4:1-4) to give the title compound (111MF12) (12.6 g, 93%); 1H NMR (DMSO) δ 10.68 (s, 1H), 6.83-6.91 (m, 2H), 6.75-6.80 (m, 1H), 4.57 (s, 2H); 13C NMR (DMSO) δ 164.2, 157.8 (d, J=238.6 Hz), 144.0 (d, J=12.4 Hz), 123.9 (d, J=2.7 Hz), 116.3 (d, J=9.6 Hz), 108.6 (d, J=22.7 Hz), 104.0 (d, J=26.5 Hz), 66.7.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[C:35]([O:38]CC)(=[O:37])[CH3:36].Cl.[C:42]([O:45]CC)(=[O:44])[CH3:43]>C(O)C>[C:42]([OH:45])(=[O:44])/[CH:43]=[CH:36]/[C:35]([OH:38])=[O:37].[F:1][C:2]1[C:3]([CH2:25][NH:26][CH3:27])=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)cn1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCO
Product: CNCc1cn(S(=O)(=O)c2ccc(OC)nc2)c(-c2cccnc2F)c1F
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methoxypyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (124 mg) was dissolved in ethyl acetate (1 mL) and ethanol (1 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a free base (57.1 mg). A solution of the obtained free base (57.1 mg) in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (24 mg) in ethanol (2 mL), and the mixture was concentrated under reduced pressure. The obtained crystal was recrystallized from a mixed solvent of ethanol-water=20:1 to give the title compound as colorless crystals (yield 24.4 mg, 33%).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[C:13]1([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+]>C1(C)C(C)=CC=CC=1.CO>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:21]1[CH2:20][C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:24][CH2:23][CH2:22]1
Reactant: BrCC1COc2ccccc2O1
Reactant: c1ccc(-c2cccnc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CO
Product: C1=C(c2ccccc2)CN(CC2COc3ccccc3O2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (500 mg, 2.18 mmol) and 3-phenyl-pyridine (339 mg, 2.18 mmol) in xylene (2 ml) was refluxed for 4 h. After cooling, the solvent was decanted to give the crude oily pyridinium salt, which was dissolved in MeOH (5 ml). NaBH4 (330 mg, 4 eq) was added in small portions to the cooled mixture. After stirring for 2 h at RT, MeOH was evaporated, water was added and the mixture extracted with EtOAc. Drying (Na2SO4) and evaporation gave the crude product, which was purified by flash chromatography (heptane/EtOAc).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>CCOCC>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:23][CH:22]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: FC(F)(F)c1ccc(NC(=S)Nc2ncccc2OCc2ccccc2)cc1

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (2.34 g, 0.0117 mol), 4-trifluoromethylphenyl isothiocyanate (2.85 g, 0.014 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with ether to induce crystallisation of the product. Yield 3.06 g (65%), m.p. 165°-167 ° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:38][C:39]1[C:40]([CH3:45])=[N:41][O:42][C:43]=1[CH3:44]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:38][C:39]4[C:40]([CH3:45])=[N:41][O:42][C:43]=4[CH3:44])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: Cc1noc(C)c1CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(Cc5c(C)noc5C)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (83 uL, 0.6 mmol) in DMF (1.5 mL), was added 4-(chloromethyl)-3,5-dimethylisoxazole (35 mg, 0.24 mmol). The mixture was stirred at room temperature for 3 hours. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to afford 5-Chloro-N2-(4-(1-((3,5-dimethylisoxazol-4-yl)methyl)piperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid. 1H NMR (400 MHz, MeOD-d4) 8.12 (s, 1H), 7.75 (d, 1H), 7.03 (s, 1H), 6.27 (s, 1H), 4.25 (s, 2H), 3.69-3.67 (m, 2H), 3.27-3.20 (m, 3H), 2.54 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 2.10-1.95 (m, 4H); ESMS m/z 525.1 (M+H+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[S:5]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH:7]=[C:6]1[C:13]([O-:15])=[O:14].Cl[C:17]([C:19]1[CH:20]=[C:21]([CH2:25][C:26]#[N:27])[CH:22]=[CH:23][CH:24]=1)=[O:18].Cl.[CH2:29](Cl)Cl>>[CH3:29][O:14][C:13]([C:6]1[S:5][C:9]2[S:10][C:11]([C:17]([C:19]3[CH:20]=[C:21]([CH2:25][C:26]#[N:27])[CH:22]=[CH:23][CH:24]=3)=[O:18])=[CH:12][C:8]=2[CH:7]=1)=[O:15]
Reactant: N#CCc1cccc(C(=O)Cl)c1
Reactant: ClCCl
Reactant: O=C([O-])c1cc2ccsc2s1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)c1cc2cc(C(=O)c3cccc(CC#N)c3)sc2s1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
Anhydrous aluminium chloride (167.5 g) is added in small portions over a period of 11/2 hours to a mixture of methyl (thieno[2,3-b]thiophene-2-carboxylate (49.5 g) and 3-chloroformyl-phenylacetonitrile (44.8 g) in methylene chloride (1250 cc) at 20°-30° C. The reaction mixture is stirred for 17 hours at a temperature of about 20° C., then hydrolysed, with care, by the slow addition of an N aqueous solution of hydrogen chloride (500 cc), the internal temperature being kept at about 20° C. by external cooling with an ice bath. The aqueous phase is decanted off and extracted three times with methylene chloride (total 600 cc). The combined methylene chloride solutions are washed three times with distilled water (total 240 cc), dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (2 g), filtered and evaporated. The residue is taken up in boiling acetonitrile (250 cc). After cooling for 1 hour at 4° C., the resulting crystals are filtered off, washed three times with iced acetonitrile (total 60 cc), and dried under reduced pressure (20 mm Hg) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. 3-(5-Methoxycarbonyl-thieno[2,3-b]thien-2-yl)carbonyl-phenylacetonitrile (74.7 g), melting at 184° C., is thus obtained.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[Cl:14])=[N+:2]=[N-:3].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:14][C:5]1[CH:6]=[C:7]([C:10]([F:12])([F:13])[F:11])[CH:8]=[CH:9][C:4]=1[N:1]1[C:24]([NH2:25])=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[N:3]=[N:2]1
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(CC#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nnn(-c3ccc(C(F)(F)F)cc3Cl)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-2-chloro-4-trifluoromethyl-benzene (1.00 g, 1 eq) and commercial (4-methoxy-phenyl)-acetonitrile (0.797 g, 1.2 eq) in ethanol (10 ml) kept under nitrogen, a solution of sodium methoxide (0.366 g, 1.5 eq) in ethanol (10 ml) is added drop-wise (20 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (40 ml), washed with water (2×50 ml), dried over MgSO4 and evaporated to dryness. The yellow solid residue (1.20 g) is purified by flash chromatography using 60-120 mesh silica gel and eluting with 15% ethylacetate in hexane, to afford the title compound as a white solid (0.324 g, 30% yield). M.p. 130.0-130.7° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[SH:15][CH:16]([CH3:20])[C:17](O)=[O:18].C(=O)([O-])[O-].[NH4+:25].[NH4+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[NH:25][C:17](=[O:18])[CH:16]([CH3:20])[S:15]2)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: [NH4+]
Reactant: CC(S)C(=O)O
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: COc1cc(C2NC(=O)C(C)S2)cc(OC)c1OC
Temperature: 80 °C
Yield: 78 %

Procedure:
A mixture of 19.6 g of 3,4,5-trimethoxybenzaldehyde, 10.6 g of 2-mercaptopropionic acid and 6 g of ammonium carbonate in 250 ml of benzene was refluxed for 3 hours at 80° C. in a flask provided with a Dean-Stark apparatus and the thus distilled water was removed. The crystals which separated out from the reaction mixture after reaction was over and on cooling the reaction mixture, were collected by filtration and recrystallized from benzene to give 22.2 g of colourless and aciculates melting at 133° to 134° C. in a yield of 78%.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])C(C)C.C[C:21]([CH3:24])([O-:23])[CH3:22].[Li+].C([O:30]C[C@@H]1CO1)(C)(C)C>CN(C)C=O>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH2:9][CH2:8][N:7]1[CH2:22][C@@H:21]([CH2:24][OH:30])[O:23][C:6]1=[O:5]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC[C@@H]1CO1
Reactant: COc1ccccc1OCCNC(=O)OCC(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1ccccc1OCCN1C[C@@H](CO)OC1=O

Procedure:
Using N,N-dimethylformamide solution of isobutyl-2-(2-methoxyphenoxy)ethylcarbamate 26.7 g (0.1 mol), lithium-t-butoxide 1.60 g (0.02 mol) and (S)-2-t-butoxymethyl-oxiran 14.3 g (0.11 mol), the procedures as described in Example 1 were carried out to obtain the targeted product.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:24][N:25]1[CH2:30][CH2:29][CH2:28][NH:27][S:26]1(=[O:32])=[O:31]>N1C=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([N:27]3[CH2:28][CH2:29][CH2:30][N:25]([CH3:24])[S:26]3(=[O:32])=[O:31])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Reactant: CN1CCCNS1(=O)=O
Solvent: c1ccncc1
Product: CN1CCCN(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)S1(=O)=O
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.300 g, 0.80 mmol), 2-methyl-1,2,6-thiadiazinane 1,1-dioxide (0.144 g, 0.96 mmol) and Cu2O (0.086 g, 0.60 mmol) in pyridine (6.0 mL) were heated at reflux for 16 hr. The reaction was filtered and the solids washed with CHCl3 (100 mL). The filtrate was stirred for 1 hr with disodium ethylenediamine tetraacetate (0.5 g) in water (25 mL) in the presence of air. The organic extracts were stirred for 1 hr with disodium ethylenediamine tetraacetate (0.50 g in water 50 mL) in the presence of air. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The residue was purified by preparative HPLC (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:31])[C:26](OCC)=[O:27])=[CH:20][C:19]=1[F:32])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:31])[C:26]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:27])=[CH:20][C:19]=1[F:32])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)C(=O)Nc1ccc(OCc2ccccc2)c(F)c1
Product: O=C(NCCc1ccccc1)C(=O)Nc1ccc(OCc2ccccc2)c(F)c1
Yield: 98 %

Procedure:
Phenethyl-amine (33 mL, 520 mmol) was added to ethyl [(4-benzyloxy-3-fluorophenyl)amino](oxo)acetate (81 g, 260 mmol) and the mixture was sonicated at room temperature for 30 min. The resulting solid was filtered, washed with water and dried to give N-(4-benzyloxy-3-fluorophenyl)-N′-(2-phenylethyl)ethanediamide (100 g, 99%). 1H NMR (400 MHz, d6-DMSO): δ 10.72 (br s, 1H), 9.05 (m, 1H), 8.78 (m, 1H), 7.77 (m, 1H), 7.59 (m, 1H), 7.46-7.19 (m, 8H), 5.16 (m, 2H), 3.45 (m, 2H), 2.83 (m, 2H); IR (cm−1): 2980, 2883, 1653, 1522, 1506, 1441, 1385, 1221, 1122, 951, 808, 746, 696, 584; LC/MS (M+H=393).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[O:11][CH2:10][CH:9]([OH:12])[CH2:8][O:7]1.[H-].[Na+].[H][H].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH2:17]([O:12][CH:9]1[CH2:10][O:11][CH:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[O:7][CH2:8]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC1COC(c2ccco2)OC1
Reactant: [H][H]
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(COC2COC(c3ccco3)OC2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a stirred solution of 17 g of 2-(2-furyl)-5-hydroxy-1,3-dioxane in 150 ml of toluene was added over a period of twenty minutes 4.4 g of sodium hydride (54.7% in mineral oil). The mixture was allowed to stir for 1 hour to permit evolution of by-product hydrogen, after which time 12.7 g of benzyl chloride was added during 15 minutes. The reaction mixture was heated to 70° C and maintained thereat for ca. 21 hours. The reaction mixture was allowed to cool to room temperature and remain at that temperature for 4 days. The mixture was washed with two 250-ml volumes of water, which aqueous washes were combined and extracted with toluene (three 150-ml volumes) to recover product. The toluene solution was combined with the washed reaction mixture and the total mixture was dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 22.5 g of amber oil. The oil was washed with 25 ml of hexane, which procedure produced 17.5 g of clear oil. The clear oil was distilled and those fractions boiling at a bath temperature of 144°-154° C under 2 × 10-4 mm Hg (bath temp. 144°-147°; nD25 1.5349: bath temp. 148°-154°; nD25 1.5379) were combined (10.6 g) and a portion was submitted for elemental analysis. Upon refrigeration for ca. 48 hours, 0.5 g of crystalline 5-benzyloxy-2-(2-furyl)-1,3-dioxane precipitated, m.p. 58.5°-61° C.