Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cccc(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(F)c2)cc1
Yield: 25.3 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3-fluorophenyl)ethanol (prepared as described in Preparation 13), 3.44 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 60 ml of absolute methanol and 3.6 g of sodium cyanoborohydride, 1.18 g of the title compound were obtained as crystals, melting at 52° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].COC(OC)[N:13]([CH3:15])C.[NH2:18]N>C(O)C>[NH:18]1[C:1]([C:4]2[CH:9]=[N:8][CH:7]=[CH:6][N:5]=2)=[CH:2][CH:15]=[N:13]1
Reactant: COC(OC)N(C)C
Reactant: NN
Reactant: CC(=O)c1cnccn1
Solvent: CCO
Product: c1cnc(-c2ccn[nH]2)cn1
Reaction time: 3 h
Yield: 94 %

Procedure:
2-Acetylpyrazine (10 mmol, 1.22 g) is reacted with N,N-Dimethylformamide dimethyl acetal (15 mmol, 1.99 ml) without any solvent at 100° C. for 10 hrs. Extraction with methylene chloride and water is carried out and the organic layer is concentrated to obtain solids. The yield is 94%. The obtained product is dissolved in ethanol and then added with hydrazine (23.5 mmol, 1.14 ml). The reaction is carried out for 3 hrs at 90° C. The reaction solution is concentrated and extracted by methylene chloride and water. The product is rinsed by n-hexane and some ethanol. The product pzp is thus obtained and the yield is 83%. 1H NMR (400 MHz, CDCl3): δ 9.11 (s, 1 H), 8.55 (s, 1 H), 8.50 (d, 1 H, J=2.8 Hz), 7.69 (d, 1 H, J=1.6 Hz), 6.93 (d, 1 H, J=2.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]2[N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[C:15](=[O:17])[NH:8][C:4]=2[N:5]=[CH:6][CH:7]=1
Reactant: Cc1ccnc(N)c1-n1cccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccnc2[nH]c(=O)c3cccn3c12
Temperature: 25 °C

Procedure:
4-Methyl-3-(1H-pyrrol-1-yl)pyridine-2-amine (1.0 g, 5.8 mmol) and triphosgene (2.6 g, 8.7 mmol) were dissolved in 100 mL of toluene. The mixture was refluxed for 3 hours, then cooled to room temperature. The red solid was collected after filtration and washed with CH3CN 0.5 g (43%). The material was used directly for the next step reaction without purification. 1H NMR (400 MHz, DMSO) δ 11.64 (s, 1H), 8.15 (dd, J=1.4, 2.9 Hz, 1H), 8.13 (d, J=4.9 Hz, 1H), 7.20-7.08 (m, 2H), 6.75 (dd, J=2.9, 3.9 Hz, 1H), 2.81 (s, 3H).
Reaction SMILES: [N:1]([CH2:4][C:5]([NH2:7])=[O:6])=[N+:2]=[N-:3].[CH2:8]=[O:9].[OH-].[K+].Cl>>[N:1]([CH2:4][C:5]([NH:7][CH2:8][OH:9])=[O:6])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC(N)=O
Reactant: C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: [N-]=[N+]=NCC(=O)NCO
Temperature: 0 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A mixture of 2-azido-acetamide (1.40 g, 14 mmol), 30% aqueous (methanol free) formaldehyde (1.40 g, 14 mmol) and 1.0 N aqueous KOH (0.28 ml, 0.28 mmol) was stirred at 0° C for 4 hrs. To the reaction mixture 1.0 N aqueous HCl was added (pH=7) and the resulting mixture evaporated in vacuo. The residue was suspended in ethyl acetate (50 ml), the solution dried over magnesium sulfate, filtered and the filtrate concentrated to a volume of 5 ml. Chromatography on silica gel (63-200 μm, 18 g) with ethyl acetate afforded 2-azido-N-(hydroxymethyl)-acetamide as a colourless oil in 90% yield. NMR-spectrum in CDCl3: 3.6 (broad signal, 1H), 4.0 (s, 2H), 4.8 (d, 2H, J=6 Hz), 7.3 (broad signal 1H) ppm.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:17]([Si:21]([O:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([CH2:42]Br)[CH:36]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18]>CCCCCC.CN(C=O)C>[Si:21]([O:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([CH:36]=1)[CH2:42][N:13]1[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][C:12]1=[O:16])([C:17]([CH3:19])([CH3:20])[CH3:18])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)[Si](Oc1ccc(Cl)c(CBr)c1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion in mineral oil) (3.50 g, 0.0874 mmol) was washed with hexane, suspended in DMF (100 mL) at 0° C. with stirring under Ar, then treated with tert-Butyl-3-oxopiperazine-1-carboxylate (15.0 g, 0.728 mol). After 1 h, tert-butyl(3-bromomethyl-4-chlorophenoxy) diphenylsilane (33.34 g, 0.0728 mol) in DMF (50 mL) was added dropwise, and the reaction mixture was left to warm to room temperature overnight. The reaction mixture partitioned between EtOAc/hexane (50/50) and H2O, the aqueous layer washed with EtOAc/hexane, the organics combined, washed with H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound which was used without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[C:19]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)#[N:20]>O1CCOCC1>[C:19]([C:21]1[CH:22]=[C:23]([S:27]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)#[N:20]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cccc(C#N)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirring mixture consisting of tert-butyl 2-aminoethylcarbamate (Sigma-Aldrich, 832 mg), triethylamine (1.44 mL), and 1,4-dioxane (25 mL) was added 3-cyanobenzene-1-sulfonyl chloride (Compound 14, Sigma-Aldrich, 942 mg) and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 5% aqueous potassium hydrogen sulfate. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title intermediate (1.52 g), which was carried on without further purification.
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[NH2:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[N:10]=1>O1CCCC1>[Cl:1][S:2]([NH:5][C:6]([NH:8][C:9]1[N:10]=[C:11]([O:17][CH3:18])[CH:12]=[C:13]([O:15][CH3:16])[N:14]=1)=[O:7])(=[O:4])=[O:3]
Reactant: COc1cc(OC)nc(N)n1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: C1CCOC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Cl)n1
Reaction time: 0.5 h

Procedure:
A solution of 4.8 g of chlorosulfonyl isocyanate in 10 ml of tetrahydrofuran (THF) is added to a solution of 4.7 g of 2-amino-4,6-dimethoxypyrimidine in 80 ml of THF under ice cooling and stirred for 30 minutes to yield N-chlorosulfonyl-N'-(4,6-dimethoxy-2-pyrimidinyl)urea. A solution of 1.0 g of 2-methylpyrrolo[1,2-a]pyridine in 10 ml of THF and 1.0 g of aluminum chloride are added to the above mixture and stirred for an hour at room temperature. THF is distilled off. The residue after addition of water is extracted with ethyl acetate. The extract is dried and distilled to remove ethyl acetate. The residue is purified by silica gel chromatography (eluent: n-hexane-ethyl acetate) to give 0.71 g of the title compound (Compound No. 5) having mp. 197°-199° C. and 0.88 g of the title compound (Compound No. 6) having mp. 168°-169° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
A solution of 90 g (774.8 mmol) of tetrahydropyran-4-methanol and 129.6 mL (929.76 mmol, 1.2 eq.) of triethylamine in 775 mL of anhydrous DCM was cooled to 0° C. with in an ice bath. Methanesulfonyl chloride (66.2 mL, 852.28 mmol, 1.1 eq.) of was then added dropwise over 60 minutes while maintaining the temperature around 0° C. The reaction mixture was stirred for 30 minutes at 0° C. and quenched with a saturated solution of sodium bicarbonate (800 mL). The aqueous layer was extracted with DCM (800 mL). The combined organic layers were washed with water (2×800 mL), brine (800 mL) and dried over sodium sulfate. After filtration and concentration in vacuo, a yellowish solid (146.1 g, 97%) was obtained corresponding to the methanesulfonic acid tetrahydropyran-4-ylmethyl ester.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][C:12](=O)[C:13](F)(F)F)[CH:3]=1.Br[CH2:19][C:20]1C=C[CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+]>O.CO.CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:19]=[CH:20][CH:21]=[C:22]([N+:26]([O-:28])=[O:27])[CH:23]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1sc(Br)cc1NCc1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (500 mg, 1.51 mmol), 1-(bromomethyl)-3-nitrobenzene (490 mg, 2.27 mmol), cesium carbonate (1.23 g, 3.78 mmol) and DMF (10 mL) was stirred at 70° C. for 1 h. Then, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 80:20 hexane/EtOAc) to give a yellow oil. A mixture of this oil, MeOH (5 mL), potassium carbonate (500 mg) and water (2.5 mL) was stirred at room temperature for 0.5 h. After removal of the solvent at reduced pressure, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the title compound (495 mg, 88%) was obtained as a yellow oil:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:32])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(Cl)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(Cl)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-chloro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=1.0 min; [M+H]+=411.11.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=O.[OH-].[Na+].O.[NH2:15][NH2:16]>O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]1[N:15]=[N:16][C:4]([C:3]2[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[N:15][N:16]=1
Reactant: NN
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc(F)c1-c1nnc(-c2c(F)cccc2F)nn1
Temperature: 0 °C
Yield: 164.8 %

Procedure:
9.05 g of 2,6-difluorobenzoyl chloride and a solution of 2.17 g of sodium hydroxide in 7.5 ml of water are simultaneously dropped into a solution of 1.25 g of hydrazine hydrate in 25 ml of water under stirring and cooling by ice-water. After addition, the white suspension is stirred at room temperature for 2 hours. After filtration the solid product is washed with water and recrystallized from glacial acetic acid to yield 6.3 g of desired product as white crystals.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Br:29])=[C:24]([CH3:30])[CH:23]=1)(=[O:20])[C:18]#[CH:19]>C1COCC1.[Cu]I>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:19]#[C:18][C:17]([O:21][C:22]2[CH:23]=[C:24]([CH3:30])[C:25]([Br:29])=[C:26]([CH3:28])[CH:27]=2)=[O:20])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: C#CC(=O)Oc1cc(C)c(Br)c(C)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(OC(=O)C#Cc2ccc([N+](=O)[O-])cc2)cc(C)c1Br
Temperature: 65 °C
Yield: 72.5 %

Procedure:
1-Iodo-4-nitrobenzene (550 mg, 2.17 mmol) in THF (4 mL) was degassed under reduced pressure at −78° C., and then nitrogen gas was introduced. To the solution was added K2CO3 (552 mg, 298.6 mmol), CuI (30 mg, 0.16 mmol) and PdCl2(Ph3P)2 (14 mg, 0.020 mmol), and the mixture was stirred at 65° C. 4-bromo-3,5-dimethylphenyl propiolate (6-1) (506 mg, 2.03 mmol) in THF (2.5 mL) was added by syringe pump over a period of 6 h. After being cooled to room temperature, the mixture was filtered and washed with EtOAc. The filtrate was concentrated and purified by silica gel column chromatography to give the title compound 7-1 (551 mg, 74% yield) as a brown solid.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7]([O:16][C:17]([CH3:19])=O)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[C:21]1(O)[CH:26]=CC=[CH:23][CH:22]=1>C(OCC)(=O)C>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([O:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:26][CH:19]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Reactant: Oc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)Oc1ccccc1

Procedure:
Alternatively, N-t-Butoxycarbonyl-2-phenoxyglycine n-butyl ester was prepared by heating a mixture of 1.5 g. (0.005 mol.) of N-t-butoxycarbonyl-2-acetoxylglycine n-butyl ester and 0.5 g. (0.005 mol.) of phenol at 150° for 1 hour. The residue was dissolved in ethyl acetate and the resulting solution was washed with cold 10% aqueous sodium hydroxide, dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:15][O:14][C:13]2[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[C:19]([CH3:20])[C:12]=2[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:24][C:25]1[C:30](O)=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35].C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)Cl>O.C(OCC)(=O)C>[F:24][C:25]1[C:30]([O:22][C:21]([C:18]2[CH:17]=[CH:16][C:13]3[O:14][CH2:15][CH:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[O:11][C:12]=3[C:19]=2[CH3:20])=[O:23])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: Cc1c(C(=O)O)ccc2c1OC(CO[Si](C)(C)C(C)(C)C)CO2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc2c1OC(CO[Si](C)(C)C(C)(C)C)CO2
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added 3-(tert-butyldimethylsilyloxymethyl)-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid (0.72 g, 2.13 mmol) and ethyl acetate (11 mL). To this was added pentafluorophenol (0.82 g, 2.23 mmol) followed by 1 M dicyclohexylcarbodiimide in methylene chloride (2.34 mL, 2.34 mmol). This mixture was stirred at room temperature for four hours. A few milliliters of water were added and stirring continued for 10 min. The reaction was filtered, diluted with ethyl acetate, washed once with 1 N HCl, once with saturated aqueous sodium bicarbonate solution, once with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to give an oil. This oil was flash chromatographed on silica gel eluting with hexanes to give a clear colorless oil, 3-(tert-butyldimethylsilyloxymethyl)-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid pentafluorophenyl ester, (0.90 g, 1.78 mmol) in 84% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 0.10 (s, 6H), 0.90 (s, 9H), 2.50 (s, 3H), 3.90 (m, 2H), 4.14 (m, 1H), 4.24 (m, 1H), 4.40 (m, 1H), 6.83, (d, 1H), 7.86, (d, 1H); TLC Rf=0.88 (1:1 ethyl acetate/hexane).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:11]=1[C:12](O)=O>O>[C:10]1([CH3:9])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:11]=1[C:12]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Reactant: Nc1ccccc1N
Solvent: O
Product: Cc1cc(C)c(-c2nc3ccccc3[nH]2)c(C)c1
Temperature: 150 °C

Procedure:
2-Mesitylbenzimidazole was synthesized by dissolving 1.5 g 1,2-phenylene diamine (14 mmol) in 40 g of PPA at 120° C. To this solution, 2.1 g of 2,4,6-trimethylbenzoic acid (13 mmol) was added and the temperature was increased to 150° C. After 16 h the solution was cooled to 60° C. and poured into water forming an off-white precipitate. The precipitate was separated by filtration and washed thoroughly with water, yielding 2.6 g of light brown powder (85% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:19])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH3:18])[C:9]([CH3:17])=[C:10]([OH:16])[C:11]=2[CH3:15])[O:6]1)=[O:4].[C:20]([Si:24]([CH3:28])([CH3:27])OCl)([CH3:23])([CH3:22])[CH3:21].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1([CH3:19])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH3:18])[C:9]([CH3:17])=[C:10]([O:16][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:28])[CH3:27])[C:11]=2[CH3:15])[O:6]1)=[O:4]
Reactant: COC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: CC(C)(C)[Si](C)(C)OCl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(C)CCc2c(C)c(O[Si](C)(C)C(C)(C)C)c(C)c(C)c2O1
Temperature: 25 °C
Yield: 99 %

Procedure:
Step a. A solution of 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid methyl ester (i, 41.9 mmol), t-butyl-dimethyl-silyloxy chloride (62.8 mmol), and imidazole (172.2 mmol) in 100 mL of DMF was stirred at 85-95° C. for 16 h, and cooled to room temperature. The solution was diluted with 200 mL of ethyl acetate, washed, in tandem, with H2O, 1% HCl, saturated NaHCO3, and brine, dried with Na2SO4, and concentrated. Purification by flash silica gel chromatography gave the product, 6-(t-butyl-dimethyl-silyloxy)-2,5,7,8-tetramethyl-chroman-2-carboxylic acid methyl ester (ii), as white solid in 99% yield. 1H NMR (300 MHz, CDCl3) δ 0.11 (s, 6H), 1.04 (s, 9H), 1.62 (s, 3H), 1.86-1.76 (m, 1H), 2.01 (s, 3H), 2.11 (s, 3H), 2.16 (s, 3H), 2.22-2.30 (m, 1H), 3.49-3.65 (m, 2H), 3.69 (s, 3H), 4.22 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][C:18]([C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])[CH3:19])[C:14](Cl)=[O:15]>O1CCOCC1.O.C(OC(=O)C)C>[CH3:12][N:13]([S:17][C:18]([C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])[CH3:19])[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: CN1C(=O)C(C)(C)SC1=NO
Reactant: CN(SC(C)(C)C(=O)c1ccccc1)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CN(SC(C)(C)C(=O)c1ccccc1)C(=O)ON=C1SC(C)(C)C(=O)N1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2.5g (0.015m) of 3,5,5-trimethyl-2-oximino-thiazolidin-4-one and 3.93g (0.015m) of N-methyl-N-(2-benzoyl-2-propanesulfenyl)carbamoyl chloride in 100 ml of dioxane was added 1.5g (0.015m) of triethylamine. After stirring at room temperature for 16 hours, the reaction mixture was diluted with water and the product isolated in ethylacetate. Recrystallized from isopropyl ether. Weight of the product 1.3g, m.p. 98°-100° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[CH:8][C:6]=2[N:7]=1.[C:19](Cl)(=O)C(Cl)=O.CN(C)C=O.[CH3:30][O:31][CH2:32][CH2:33][NH2:34]>ClCCl.C(N(CC)CC)C>[CH3:30][O:31][CH2:32][CH2:33][NH:34][C:11]([C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([CH3:19])=[N:7][C:6]=2[CH:8]=1)=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: COCCN
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNC(=O)c1cc2nc(C)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 in dichloromethane (2 ml) was added 2M oxalyl chloride solution in dichloromethane (0.75 ml) followed by 2 microdrops of dimethylformamide. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo to give a crude product. This crude product was stirred in dichloromethane (5 ml) and to it was added 2-methoxyethylamine (34.8 μL) and triethylamine (61.5 μL). The reaction mixture was stirred at room temperature overnight. It was then partitioned between dichloromethane and saturated sodium bicarbonate solution, the combined organics were dried (MgSO4) and the solvents removed in vacuo to give a crude residue. This was purified by flash chromatography to yield 2-Methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxylic acid (2-methoxy-ethyl)-amide (30 mg).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9][N:10]2[C:14](=O)[CH:13]([CH3:16])[NH:12][C:11]2=[O:17])=[CH:7][CH:6]=1.CO.Cl>O1CCCC1>[CH3:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH3:16])[NH:12][C:11]2=[O:17])=[CH:7][CH:6]=1
Reactant: COc1ccc(CN2C(=O)NC(C)C2=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN2CC(C)NC2=O)cc1
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
Under a nitrogen stream, sodium borohydride (0.65 g) was suspended in tetrahydrofuran (25 mL), boron trifluoride diethyl ether complex (2.63 mL) was added dropwise under ice-cooling, and the mixture was stirred at the same temperature for 15 min. Then, a solution of 3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione (2.00 g) described in Preparation Example 51 in tetrahydrofuran (25 ml) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 min and at room temperature overnight. To the reaction mixture were added dropwise methanol and 0.5N hydrochloric acid, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (1.16 g).