Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[N:18]([CH3:33])[N:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)[CH:21]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:33][N:18]1[C:17]([CH2:16][O:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:6]([CH2:5][C:4]([OH:34])=[O:3])[CH:7]=[CH:8]3)=[CH:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:24][CH:23]=2)=[N:19]1
Reactant: CCOC(=O)Cn1ccc2cc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C)ccc21
Agent: [Li+]
Agent: [OH-]
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1COc1ccc2c(ccn2CC(=O)O)c1

Procedure:
In analogy to the procedure described for example 1 f], {5-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain {5-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid as yellow foam.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:29][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH2:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:7]=2[C:6]=1[CH3:30])=[O:4].[OH-].[Na+]>C(O)C.ClCCl.Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:12]2[C:7]3[C:6]([CH3:30])=[C:5]([C:3]([OH:4])=[O:2])[S:29][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:15]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:16]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OCC3CCOCC3)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OCC3CCOCC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl-4-(4-fluoro-2-((tetrahydro-2-H-pyran-4-yl)methoxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (82 mg) and NaOH (2M; 0.5 ml) was dissolved in ethanol (2 ml). The reaction was stirred at room temperature overnight. Then the reaction mixture was diluted with dichloromethane and HCl (2M). The suspension was filtered, washed with brine and ether. The residue was dried in vacuo over P2O5.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18](N)=[O:19])=[CH:16][C:4]=2[CH2:3]1.C([OH:24])C.[OH-].[K+]>O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([OH:24])=[O:19])=[CH:16][C:4]=2[CH2:3]1
Reactant: CCO
Reactant: CC(C(N)=O)c1ccc2c(c1)CC(=O)c1ccccc1S2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)CC(=O)c1ccccc1S2
Reaction time: 6 h
Yield: 64 %

Procedure:
To a mixture of 150 mg of 2-(10,11-dihydro-10-oxodibenzo[b,f]-thiepin-2-yl)-propionamide and 2 ml of ethanol was added 400 mg of potassium hydroxide in 2 ml of water, and the mixture was refluxed with stirring for 6 hours. After the completion of the reaction, ethanol was removed by distillation to obtain a residue to which was added water. The residue was washed with ethyl acetate, and an alkaline layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain a brown oil substance, which was chromatographed over 4 g of silica gel and eluted with benzene-chloroform (1:1) to obtain a light yellow oil substance. This substance was recrystallized from benzene-n-hexane, thereby obtaining 96 mg (yield: 64%) of 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as pale yellow crystals having a melting point of 130.5°-131.5° C.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[N:12]=1.C(OCC)(=O)C>CN(C=O)C.O>[C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([S:1][C:2]2[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=2)[N:12]=1)#[N:18]
Reactant: Cn1ccnc1S
Reactant: N#Cc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ccnc1Sc1cccc(C#N)n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 263.6 %

Procedure:
2-Mercapto-1-methyl-1H-imidazole (0.91 g, 7.94 mmol) and sodium hydride (60% in oil, 0.35 g, 8.66 mmol) were dissolved in DMF (30 ml), and 2-chloro-6-cyanopyridine (1.05 g, 3.00 mmol) was added thereto. The reaction mixture was stirred at 70° C. for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (1.71 g, ca. 100%) as pale yellow crystals.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:24][C:25]([CH3:32])([CH:30]=O)[C:26]([O:28][CH3:29])=[O:27].C(C1(C(OC)=O)CCC1)=O>>[CH:1]1([CH2:5][O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([CH2:24][C:25]([CH3:32])([CH3:30])[C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH2:23]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: c1cc(OCC2CCC2)c2c(OCC3CCNCC3)noc2c1
Reactant: COC(=O)C(C)(C)C=O
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C(C)(C)CN1CCC(COc2noc3cccc(OCC4CCC4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-(cyclobutylmethoxy)-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 17, Step 4) and methyl 2,2-dimethyl-3-oxopropanoate (Tetrahedron Asymmetry 2003, 14, 3371-3378) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutan-carboxylate.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH:7]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C1COCC1>[CH:7]1([NH:12][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)CBr
Reactant: NC1CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CNC1CCCC1
Reaction time: 8 h
Yield: 68.3 %

Procedure:
A solution of methyl bromoacetate (17.4 mL, 188 mmol) in THF (40 mL) was dropwise added to a solution of cyclopentylamine (18.6 mL, 188 mmol) and triethylamine (26.1 mL, 188 mmol) in THF (150 mL) at 0° C. Following addition, the reaction was allowed to reach room temperature and was stirred overnight. The triethylammonium salts were filtered and rinsed with scant THF. The combined filtrates were concentrated in vacuo. The desired product was distilled from the residuals under reduced pressure to yield 20.2 g of compound 225 (68% yield). 1H NMR (500 MHz, CDCl3) δ ppm 3.73 (s, 3 H) 3.41 (s, 2 H) 3.00-3.13 (m, J=12.90, 6.39, 6.39 Hz, 1 H) 1.77-1.87 (m, 2 H), 1.67-1.74 (m, 2 H) 1.48-1.59 (m, 2 H) 1.29-1.41 (m, 2 H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([O:9][S:11](=[O:13])(=[O:12])[NH2:14])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Oc1cc(F)cc(F)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cc(F)cc(F)c1

Procedure:
Using the procedure of Example 84, the title compound was prepared using a mixture of 9.9 g (0.076 mole) of 3,5-difluorophenol and 7.0 ml (0.08 mole) of chlorosulfonyl isocyanate in 50 ml of toluene. The solid product was recrystallized from benzene to yield 11.7 g (74%) of white solid, mp 85°-88° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=3)=[C:20]([C:38]([F:41])([F:40])[F:39])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:43]>C(O)C>[ClH:43].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=2)=[C:20]([C:38]([F:39])([F:40])[F:41])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: COc1ccc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)cc1OC
Agent: Cl
Solvent: CCO
Product: COc1ccc(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)cc1OC
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Compound 18-3 (1.00 g) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (580 mg) as a pale-yellow powder.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:15])[C:5]1=[O:16].S(Cl)([Cl:19])=O>ClC(Cl)Cl>[Cl:19][CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:15])[C:5]1=[O:16]
Reactant: Cn1c(=O)n(CCO)c(=O)c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)n(CCCl)c(=O)c2ccccc21
Yield: 95 %

Procedure:
A mixture of 4.5 parts of 3-(2-hydroxyethyl)-1-methyl-2,4(1H,3H)-quinazolinedione, 8 parts of thionyl chloride and 75 parts of trichloromethane was stirred and refluxed for 5 hours. The reaction mixture was evaporated, yielding 4.5 parts (95%) of 3-(2-chloroethyl)-1-methyl-2,4(1H,3H)-quinazolinedione as a residue (intermediate 171).
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[SH:8][CH2:9][CH:10]([CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:11]([OH:13])=[O:12]>C(OC(=O)C)(=O)C>[C:2]([N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][CH:10]([CH2:9][SH:8])[C:11]([OH:13])=[O:12])[CH2:16][CH2:17]1)(=[O:1])[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)C(CS)CC1CCNCC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(CC(CS)C(=O)O)CC1
Yield: 80.2 %

Procedure:
A solution of 2-Mercaptomethyl-3-piperidin-4-yl-propionic acid TFA salt (0.1 g, 0.32 mmol) in acetic anhydride (2 mL) was stirred over night under argon and then concentrated under reduced pressure. Purification by HPLC (10→50% acetonitrile, 0.1% TFA in water) gave the title compound (63 mg, 80%).
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[F:20])(=O)C.C[O-].[Na+]>CO>[F:20][C@@H:7]1[C@@H:6]([CH2:5][OH:4])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a round-bottomed flask equipped with a magnetic spinbar and rubber septum was added 40 mg (0.1399 mmoles) 1-(5-O-acetyl-3-fluoro-2,3-dideoxy-β-D-erythro -pentofuranosyl)thymine, 9.1 mg (0.1679 mmoles) NaOMe powder and MeOH (1.4 mL). The mixture was allowed to stir for @2 hours at room temperature. The solvent was removed in vacuo and the resulting residue was purified by silica gel flash-chromatography to yield 1-(3-fluoro-2,3-dideoxy-β-D-erythro-pentofuranosyl)thymine (85%, 29 mg) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]=[C:15]3[C:10](=[N:11][CH:12]=[N:13][C:14]3=[O:17])[N:9]=2)=[C:4]([N:18]([CH3:20])[CH3:19])[CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]=[C:15]3[C:10](=[N:11][CH:12]=[N:13][C:14]3=[O:17])[N:9]=2)=[C:4]([N:18]([CH3:20])[CH3:19])[CH:3]=1)(=[O:23])[CH3:22]
Reactant: CN(C)c1cc(N)ccc1C1=NC2=NC=NC(=O)C2=N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C2=NC3=NC=NC(=O)C3=N2)c(N(C)C)c1

Procedure:
A quantity of 0.6 gm of 8-(4-amino-2-dimethylamino-phenyl)purin-6-one is heated to 150° C. in 5 ml of acetic anhydride for one hour. The mixture is evaporated to dryness in vacuo and recrystallized from acetone/ether.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:8][C:4]1[N:3]=[C:2]([NH:1][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(N)n1
Reactant: Brc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2ccccc2)n1
Temperature: 10 °C
Yield: 35.7 %

Procedure:
To a flask were added 2.2 g of 2-amino-6-methylpyridine, 3.1 g of bromobenzene, 2.7 g of sodium tert-butoxide, and 50 ml toluene. The mixture was purged thoroughly with nitrogen and 62 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthalenehthalene and 22 mg of palladium acetate were added. The reaction mixture was heated to 10° C. for 16 hours, and then cooled to 22 C. After quenching with 50 ml water, the product was extracted with 20 ml ethyl acetate, and washed with 15 ml water. The product was extracted with 50 ml of 1M hydrochloric acid, and then basified with aqueous ammonium hydroxide. Following extraction with 20 ml ethyl acetate, the product was purified by silica gel chromatography using a gradient from 10% ethyl acetate in hexane to 15% ethyl acetate in hexane, resulting in 1.3 g of a yellow-orange oil.
Reaction SMILES: BrCC(N(CC)CC)=O.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[CH:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27](Cl)(=[O:29])=[O:28])=[N:25][CH:26]=1)([CH3:20])[CH3:19]>>[C:14]1([CH3:17])[CH:15]=[CH:16][C:11]([NH:10][S:27]([C:24]2[CH:23]=[CH:22][C:21]([CH:18]([CH3:20])[CH3:19])=[CH:26][N:25]=2)(=[O:28])=[O:29])=[CH:12][CH:13]=1
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Agent: CCN(CC)C(=O)CBr
Product: Cc1ccc(NS(=O)(=O)c2ccc(C(C)C)cn2)cc1

Procedure:
prepared by reaction of 2-bromo-N,N-diethylacetamide with p-toluidine and 5-isopropyl-pyridine-2-sulfonyl chloride; in contrast to the general procedure the intermediate 5-isopropyl-pyridine-2-sulfonic acid p-tolylamide was isolated and crystallized from methanol/water 10/1
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+:19].[O:20]1CCOCC1>O>[NH2:3][C:4]1[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:20])=[O:1].[Na+:19]
Reactant: O=C1Cc2cccc(Nc3ccccc3)c2N1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)[O-])cccc1Nc1ccccc1

Procedure:
A mixture of 2-oxo-7-anilinoindoline (3 g.), sodium hydroxide (1.07 g.), dioxane (10 ml.) and water (50 ml.) was refluxed under heating for 22 hours with stirring. After cooling, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was dissolved in ethanol under heating and filtered. The filtrate was evaporated under reduced pressure and the oily residue was crystallized with ethyl acetate, collected by filtration, washed with ethyl acetate and dried to give powdery crystals of the captioned compound (1.8 g.). mp 195° to 200° C.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1.CO.[Pd]>[C:11]1([C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(CCc1ccccc1)c1ccccc1

Procedure:
Chalcone (compound 1) (37.6 mmol) was dissolved in 250 ml of toluene (in some cases 25 ml of MeOH was added to insure a complete dissolution) and 400 mg of 10% Pd/C (0.01 eq) was added to the mixture. The compound was hydrogenated at 45 psi in a Parr apparatus for 40 min to 3 hrs to form 1,3-diphenylpropan-1-one (compound 2), during which time the reaction mixture was periodically checked for the starting material by TLC (Hex:EtOAc=1:1) to prevent over-reduction. Upon completion of reduction the reaction mixture was filtered through a short pad (2-3 inch) of silica gel and solvent was removed in vacuo to afford a crude product, which was either sufficiently pure to use in the next step or was purified by recrystallization from MeOH or Hex:EtOAc=3:1 or, in the case where over-reduction has occurred, by silica gel column chromatography using Hex:EtOAc=5:1 as an eluent.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([CH2:8][CH:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[N:6][CH:7]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCC1CN2C=NC=C(Br)C2=N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCc1cn2cncc(Br)c2n1
Temperature: 90 °C
Reaction time: 24 h
Yield: 43.7 %

Procedure:
8-Bromo-2-ethyl-2,3-dihydroimidazo[1,2-c]pyrimidine (3.0 g) was dissolved in toluene (60 mL), then activated manganese (IV) dioxide (3.5 g) was added thereto, and the mixture was heated under stirring at 90° C. for 1 day. Manganese (IV) oxide was filtered off through Celite, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10) to give the title compound (1.3 g) as white crystals.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][C:4](=[O:8])[CH2:5][CH:6]=[CH2:7].O.O.O.O.O.O.O.O.O.[S-2:18].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH3:7][CH:6]1[CH2:5][C:4](=[O:8])[CH2:3][CH:2]([CH3:1])[S:18]1
Reactant: C=CCC(=O)CC=C
Reactant: [S-2]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CC(=O)CC(C)S1
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.5 %

Procedure:
1,6-Heptadien-4-one (0.50 g, 4.54 mmol) was dissolved in toluene (8 mL) and water (4 mL). Sodium sulfide nonahydrate (1.09 g, 4.54 mmol) was dissolved in water (4 mL) and added to the solution above and stirred at room temp. After 5 h, the aqueous layer was saturated with potassium carbonate and extracted with diethyl ether. The combined organics were washed with brine, dried MgSO4, and concentrated. The crude compound was purified on a Combiflash silica column with 0-10% EtOAc/hexanes to give 0.193 g (29%) of the title compound.
Reaction SMILES: [CH3:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4].ClCl.[OH-].[Na+].[C-:12]#[N:13].[Na+]>CO.C(=O)([O-])O.[Na+]>[C:12]([CH2:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4])#[N:13]
Reactant: CC(=O)C(C)(C)C
Reactant: [C-]#N
Agent: ClCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(=O)CC#N
Yield: 85.2 %

Procedure:
To a solution of pinacolone (100.16 g, 1 mol) in methanol (300 ml) is introduced gaseous chlorine (70.91 g, 1 mol) at 15-20° C. over a period of 1 hour. The reaction mixture is neutralized with a 48% solution of sodium hydroxide in methanol (285 ml) and then aqueous solution of sodium hydrogen carbonate (4.20 g) in that order. After dilution with methanol (40 ml), the resulting mixture is mixed with an aqueous solution (137 ml) of sodium cyanide (58.81 g, 1.2 mol) and refluxed for 1 hour. The methanol is evaporated under atmospheric pressure over a period of 1.5 hours. The residue is mixed with a 4% aqueous sodium hydroxide (650 g) solution and shaken with benzene (300 ml) to remove neutral material (10.78 g). Hydrochloric acid (35%) (92.60 g) is poured into said alkaline aqueous layer below 15° C., and the mixture is shaken with benzene (750 ml). The benzene layer is washed with water, then mixed with an aqueous solution (44 ml) of sodium hydrogen carbonate (0.66 g), and the benzene layer is evaporated under atmospheric pressure. A solution of the residue is adjusted to pH 7.0 by stirring with benzene (142 ml), water (30 ml) then 35% hydrochloric acid (0.37 g). The benzene layer is dried and concentrated to give cyanopinacolone (106.70 g) as crystals melting at 64° to 67° C. Yield is 85 %. The product contains only 0.09% of 2-hydroxy-2-t-butylsuccinonitrile as a contaminant.
Reaction SMILES: C(OC[N:10]1[C:18]2[C:17]([O:19]C(C)(C)C)=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:24][NH:25][CH:26]([CH2:34][O:35]COC)[CH:27]([OH:33])[CH2:28][O:29]COC)=[CH:11]1)C1C=CC=CC=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:35][CH2:34][CH:26]([NH:25][CH2:24][C:12]1[C:13]2[N:14]=[CH:15][NH:16][C:17](=[O:19])[C:18]=2[NH:10][CH:11]=1)[CH:27]([OH:33])[CH2:28][OH:29]
Reactant: COCOCC(O)C(COCOC)NCc1cn(COCc2ccccc2)c2c(OC(C)(C)C)ncnc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]cnc2c(CNC(CO)C(O)CO)c[nH]c12
Reaction time: 0.17 h

Procedure:
The product from Example 1.5 (104 mg, 0.195 mmol) was stirred in DCM (10 ml) at −78° C. and boron tribromide (1.0M in DCM, 1.95 ml) added dropwise. The reaction was stirred at −78° C. for 45 minutes before addition of methanol (10 ml). The solvents were evaporated and the residue co-evaporated with methanol (2×). The residue was partitioned between water and DCM and the aqueous layer evaporated. The residue was stirred in methanolic ammonia for 10 minutes and then evaporated on to silica and purified by flash silica chromatography, eluting with 5:4.5:0.5 DCM:methanol:ammonia giving the title compound as a white solid (27 mg, 52%). 1H NMR (300 MHz, CDCl3) 2.76 (1H, q, J 5.2 Hz), 3.48 (1H, dd, J 6.3, 11.9 Hz), 3.60 (2H, m), 3.70 (2H, m), 3.85 (2H, ABq), 7.34 (1H, s), 7.78 (1H, s); 13C NMR (75 MHz, CDCl3) 40.2, 59.8, 59.8, 63.5, 71.2, 113.1, 117.5, 129.2, 142.4, 143.5, 155.4; m/z (ES+) 537 (2MH+, 20%), 269 (MH+, 100%); HRMS (ESI+) C11H16N4O4 requires 269.1241. found 269.1250. The product, compound 1.6, is a 1:1 mixture of the enantiomers of Examples 17 and 18 below.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:33])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc2c(c1)C1(CC(c3ccccc3)O2)NC(=O)NC1=O
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)C1(CC(c3ccccc3)O2)NC(=S)NC1=O
Yield: 16.6 %

Procedure:
A suspension of 6-methyl-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (200 mg, 0.65 mmol) and Lawesson's Reagent (263 mg, 0.65 mmol) in anhydrous 1,4-dioxane (8 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-methyl-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (35 mg, 17%). 1H-NMR (CDCl3): 2.28 (s, 3H), 2.47 (d, 1H), 2.51 (d, 1H), 5.30 (s, 1H), 6.92 (s, 1H), 6.70 (d, 2H), 7.10 (m, 1H), 7.41 (m, 1H), 8.18 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][CH:6]=1.[CH2:9]([O:11][P:12]([O:16]CC)[O:13][CH2:14][CH3:15])[CH3:10]>>[CH2:9]([O:11][P:12]([CH2:7][C:4]1[S:3][C:2]([Br:1])=[CH:6][CH:5]=1)(=[O:16])[O:13][CH2:14][CH3:15])[CH3:10]
Reactant: ClCc1ccc(Br)s1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(Br)s1)OCC
Temperature: 140 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
2-Bromo-5-chloromethylthiophene described in Preparation Example 141 (7.3 g, 34.5 mmol) and triethylphosphite (6.35 g, 38.2 mmol) were stirred at 140° C. for 3 hours. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50), and the title compound (8.82 g, 31.2 mmol, 90.3%) was obtained as a reddish brown oil.