Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:39])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:17]([CH2:28][O:29]C4CCCCO4)[CH:16]=3)=[C:12]([C:36]#[N:37])[CH:11]=[N:10][N:9]2[CH:38]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:39])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:17]([CH2:28][OH:29])[CH:16]=3)=[C:12]([C:36]#[N:37])[CH:11]=[N:10][N:9]2[CH:38]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)c(COC4CCCCO4)c3)c2c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)c(CO)c3)c2c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a solution of 394 (30 mg, 0.057 mmol) in CH2Cl2 (1 ml) was added TFA (300 μl). The mixture was stirred at rt for 30 min, concentrated and purified by silica gel flash column chromatography to give the title compound (11 mg, 44%) (30% EtOAc—Hexanes). LCMS Found: (M+H)+=443.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.7 %

Procedure:
Under argon condition, 4-bromobenzoic acid methyl ester (500 mg, 2.33 mmol), bis(triphenylphosphine)palladium dichloride (Pd(PPh3)2Cl2; 86.1 mg, 0.116 mmol), triphenylphosphine (PPh3; 18.3 mg, 0.0698 mmol), trimethylsilyl acetylene (TMS acetylene; 493 μL, 3.49 mmol), and triethylamine (Et3N; 486 μL, 3.49 mmol) were dissolved in 10 mL of dry THF and the reaction mixture was stirred for 20 minutes at room temperature. To this cuprous iodide (CuI; 8.86 mg, 0.0465 mmol) was again added and the mixture was stirred for 15 hours at room temperature. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure and then 20 mL of n-pentane was added to the residue. The mixture was filtered through celite pad to remove the precipitate. The resulting solution was concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 503 mg (2.16 mmol, 93%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[N:17][CH:18]=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:26]=C)[CH:3]=1.CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[CH:26]([C:4]1[CH:3]=[C:2]([CH3:1])[C:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[N:17][CH:18]=2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[O:30]
Reactant: CC(C)=O
Reactant: C=Cc1cc(C)c(Cc2ccc(-c3ccnc(C)c3)nc2)cc1C(=O)OC
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(-c3ccnc(C)c3)nc2)c(C)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-methyl-5-((2′-methyl-[2,4′-bipyridine]-5-yl)methyl)-2-vinylbenzoate (0.11 g) in a mixed solvent of acetone (2.00 mL)-acetonitrile (2.00 mL)-water (2.00 mL) were added osmium oxide (fixed catalyst I) (0.04 g) and sodium periodate (0.33 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.11 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([CH3:14])[C:5]2[NH:6]C(=O)O[C:9](=[O:10])[C:4]=2[CH:3]=1.[C:15]([O:19][CH3:20])(=[O:18])[NH:16][NH2:17].CO>O>[NH2:6][C:5]1[C:12]([CH3:14])=[CH:13][C:2]([Cl:1])=[CH:3][C:4]=1[C:9]([NH:17][NH:16][C:15]([O:19][CH3:20])=[O:18])=[O:10]
Reactant: Cc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Reactant: COC(=O)NN
Solvent: CO
Solvent: O
Product: COC(=O)NNC(=O)c1cc(Cl)cc(C)c1N
Yield: 60.2 %

Procedure:
A mixture of 1.05 g of 6-chloro-8-methyl-1H-benzo[d]-1,3-oxazine-2,4-dione, 0.46 g of methyl carbazate and 20 ml of methanol was heated to reflux for 3 hours. After the reaction mixture was allowed to cool to around room temperature, water was poured thereto and the mixture was extracted with ethyl acetate three times. The resulting organic layer was concentrated under reduced pressure, and the residue was washed with toluene to obtain 0.77 g of N-(2-amino-5-chloro-3-methylbenzoyl)-N′-methoxycarbonylhydrazine of the formula:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:22][C:11]2[CH2:12][CH2:13][C:14]3[CH:15]=[N:16][C:17]([S:20][CH3:21])=[N:18][C:19]=3[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1.CC(C)=O>[C:1]([O:5][C:6]([C:8]1[S:22][C:11]2=[CH:12][CH:13]=[C:14]3[C:19]([N:18]=[C:17]([S:20][CH3:21])[N:16]=[CH:15]3)=[C:10]2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2c(n1)-c1cc(C(=O)OC(C)(C)C)sc1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CSc1ncc2ccc3sc(C(=O)OC(C)(C)C)cc3c2n1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
2-Methylsulfanyl-5,6-dihydro-thieno[2,3-h]quinazoline-8-carboxylic acid tert-butyl ester (9.0 g, 26.91 mmol) and DDQ (12.22 g, 53.82 mmol) were suspended/dissolved in dry dioxane (100 mL) and heated at reflux for 1 hour. Further DDQ (12.22 g, 53.82 mmol) was added and the resulting suspension was heated at reflux for 1.5 hours. After cooling to room temperature the mixture was concentrated under reduced pressure and then partitioned between EtOAc and saturated Na2CO3. The aqueous layer was further extracted with EtOAc (3×200 mL) and the combined organics were washed with saturated Na2CO3 (2×250 mL) and brine (1×200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The deep brown gum obtained was redissolved in hot acetone, silica (˜60 mL) was added and the resultant suspension was concentrated under reduced pressure. The solid obtained was subjected to column chromatography (gradient elution, 20-30% acetone in hexanes, ˜600 mL silica) giving a light brown solid (6.50 g, 73% yield).). MS (ES+) 333. δH (CDCl3) 1.7 (9H, s), 2.8 (3H, s), 7.8 (1H, d), 7.9 (1H, d), 8.8 (1H, s), 9.2 (1H, s)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15](B(O)O)=[CH:14][C:13]=1[CH3:21].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([C:2]2[C:3]([CH3:9])=[CH:4][CH:5]=[C:6]([NH2:8])[N:7]=2)=[CH:14][C:13]=1[CH3:21]
Reactant: Cc1ccc(N)nc1Cl
Reactant: COc1ncc(B(O)O)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ncc(-c2nc(N)ccc2C)cc1C
Temperature: 80 °C
Reaction time: 12 h
Yield: 29.7 %

Procedure:
6-Chloro-5-methylpyridin-2-amine (1.426 g, 10 mmol), 6-methoxy-5-methylpyridin-3-ylboronic acid (2.0 g, 12 mmol) and Pd(PPh3)4 (577.8 mg, 0.5 mmol) were combined in a flask. DME (100 mL) was added followed by aqueous Na2CO3 (10.00 mL of 2 M, 20.0 mmol). The flask was fitted with a condenser and heated at 80° C. for 12 hours under N2 atmosphere. More Pd(PPh3)4 (577.8 mg, 0.5 mmol) was added, the condenser was removed and the flask was fitted with a rubber stopper. N2 (g) was flushed through the flask and the reaction was stirred at 80° C. for an additional 12 hours under N2(g) balloon. The reaction mixture was filtered through a bed of Celite, the Celite was washed with ethyl acetate and the combined filtrates were concentrated. The residue was purified by column chromatography (30-100% ethyl acetate-Hexanes) to yield 680 mg of the product as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.66 (s, 1H), 7.29 (d, J=8.3 Hz, 1H), 6.37 (d, J=8.3 Hz, 1H), 5.75 (s, 2H), 3.91 (s, 3H), 2.18 (s, 3H), 2.14 (s, 3H). ESI-MS m/z calc. 229.1. found 230.5 (M+1)+. Retention time 0.91 minutes.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](Cl)=O)=[CH:16][C:3]1=2.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].N1C=CC=CC=1.Cl.[NH2:45][OH:46]>COCCOCCOC>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH:18]=[N:45][OH:46])=[CH:16][C:3]1=2
Reactant: O=C(Cl)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: NO
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: c1ccncc1
Solvent: COCCOCCOC
Product: O=C1c2ccccc2COc2ccc(CC=NO)cc21
Temperature: -78 °C

Procedure:
A solution of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetyl chloride (15.00 g) in 150 ml of dry diglyme was stirred at -78° C. under nitrogen as lithium tri-tert-butoxyaluminohydride (104.6 ml of a 0.5M solution in diglyme) was added slowly dropwise over one hour. The reaction was stirred ten minutes at -78° C. and then quenched with 3 ml of glacial acetic acid added slowly dropwise. After warming the reaction to room temperature 50 ml of pyridine and 2 equiv. of hydroxylamine hydrochloride (7.27 g) was added and the slurry stirred at 50° C. for two hours. The solvent was evaporated using high vacuum and the residue taken up in chloroform and 1N HCl. The layers were separated and the aqueous phase extracted with chloroform. The combined organic phases were dried (MgSO4), filtered, and evaporated. The residue was purified by flash chromatography (silica; 5:2 hex-EtOAc) and recrystallized from ethyl acetate-hexane to give 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetaldoxime, as crystals, m.p. 132°-134° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)=[CH:7][CH:6]=[C:5](F)[N:4]=1)[CH3:2].O.[NH2:24][NH2:25].C([O-])(O)=O.[Na+]>CC(O)C>[CH2:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)=[CH:7][CH:6]=[C:5]([NH:24][NH2:25])[N:4]=1)[CH3:2]
Reactant: NN
Reactant: CCc1nc(F)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCc1nc(NN)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
2-Ethyl-6-fluoro-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.15 g, 0.51 mmol) was suspended in 2-propanol (1.0 mL) in a screw-cap reaction vessel. Hydrazine hydrate (0.12 mL, 2.5 mmol) was added, the reaction vessel was sealed and the mixture was stirred at 90° C. for 18 h. Sat. NaHCO3 (aq) (20 mL) was added and the mixture was extracted wth EtOAc (4×35 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 2-ethyl-6-hydrazinyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.15 g, 96%) as a light yellow solid that was used in the next step without further purification. MS (ESI) m/z: 311.2 (M+H+).
Reaction SMILES: C[O:2][CH:3]([O:10][CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12](N(CC)CC)C>CC(C)=O.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:2][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:12][CH2:11][O:10]1
Reactant: COC(OC)c1ccccc1
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: OC1OCCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 605.4 %

Procedure:
To a stirred solution of crude product from step 5 (1.89 g; 5.49 mmol) in a mixture of acetone (80 ml) and water (25 ml) was added p-toluene sulfonic acid monohydrate (70 mg; 0.37 mmol). After stirring at room temperature for 3 hours, triethylamine (2 ml; 1.43 mmol) was added and stirred for 5 minutes. The mixture was evaporated until volume went down to 10 ml. A mixture of acetone (80 ml) and water (15 ml) was added followed by addition of p-toluene sulfonic acid monohydrate (70 mg; 0.37 mmol). After 3.5 hours, triethylamine (3 ml; 2.15 mmol) was added, evaporated to a small volume, extracted with ether (3×100 ml). The extract was washed with brine (50 ml), dried over MgSO4 and evaporated yielding quite pure 1-hydroxyisochroman (1.3 g; 94%), (MP. 136°-138° C.). NMR (CDCl3 ; 300 MHz) δ:2.32 (3H, s, CH3O), 2.51 (1H, dd, J=12.4, 17.5 Hz, H-4), 2.97 (1H, d, J=3.5 Hz; --OH), 3.06 (1H, dd, J=4.1, 17.5 Hz, H-4), 3.77, 3.82 (3H, s each, ArOCH3), 4.70 (1H, dd, J=4.1, 12.4 Hz, H-3), 6.22 (1H, d, J=3.4 Hz, 1H), 6.71, 6.76, (1H, d each, J=9.0 Hz, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[S:6][C:7]([CH:10]=[N:11][OH:12])=[CH:8][N:9]=1.[Cl:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]([Cl:19])=[N:11][OH:12])=[CH:8][N:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(Oc2ncc(C=NO)s2)c(Cl)c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ncc(C(Cl)=NO)s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
To a solution of Example 30C (12 g, 42 mmol) in N,N-dimethyl formamide (80 mL) was added N-chlorosuccinimide (5.6 g, 42 mmol). The mixture was stirred at ambient temperature for 16 hours, water (1000 mL) was added and the resulting suspension was filtered. The solids were dried in a vacuum oven to provide 12.8 g of the title compound (95%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.82 (s, 3H) 7.04 (dd, J=8.82, 2.94 Hz, 1H) 7.26 (d, J=2.94 Hz, 1H) 7.54 (d, J=9.19 Hz, 1H) 7.66 (s, 1H) 12.48 (s, 1H); MS (ESI) m/z 319.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19]([CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[CH:18][N:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)[N:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][N:17]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:32][CH:33]=2)[N:16]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1nn(Cc2ccc(Oc3ccccc3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
After a mixture of ethyl 3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazol-4-yl]propionate (800 mg), 1N sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazol-4-yl]propionic acid (740 mg, yield: 97%). This was recrystallized from acetone-hexane. Melting point: 120–121° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[C:19]([N:22]1[CH2:27][CH2:26][CH:25]([C:28](Cl)=[O:29])[CH2:24][CH2:23]1)(=[O:21])[CH3:20]>>[CH3:18][O:17][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:28]([CH:25]3[CH2:24][CH2:23][N:22]([C:19](=[O:21])[CH3:20])[CH2:27][CH2:26]3)=[O:29])[S:3][C:4]=2[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:9][CH:8]=1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C3CCN(C(C)=O)CC3)nc12

Procedure:
Using 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol and 1-acetyl-piperidine-4-carbonyl chloride the title compound was obtained as a white solid (22%), MS: m/e=419(M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[OH:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:8][C:6]1[CH:7]=[C:2]([O:24][C:15]2[CH:16]=[CH:17][C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:14]=2[Cl:13])[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:5]=1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: COC(=O)c1cc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)cc(Cl)n1
Temperature: 120 °C

Procedure:
A mixture consisting of 2.06 gm (0.01 mol) of methyl 4,6-dichloro-picolinate, 2.15 gm (0.011 mol) of chloro-4-trifluoromethyl-phenol, 1.5 gm of pulverized potassium carbonate and 5 ml of dimethylformamide was heated at 120° C. for one hour, while stirring. The mixture solidified. The solid mass was stirred and decanted several times with ice water, then acidified with acetic acid, and finally extracted with ethyl acetate. The organic phase was separated, washed with water and dried with sodium sulfate. The solvent was distilled off, and the residual oil was purified by chromatography on 40 gm of silicagel (eluant: Diisopropyl ether). 1.4 gm (38% of theory) of the title compound were obtained as a virtually colorless oil. Rf -value: 0.48 (prepared thin-layer chromatography plates manufactured by E. Merck, Darmstadt, Germany, with silicagel 60-F-254 Eluant: Acetone/diisopropyl ether 1:2; the spots are visible in ultraviolet light at 254 μm).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH2:5][CH:6]=1.[SH:7][CH2:8][C:9]([OH:11])=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH3:1][C:2]1([S:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][O:3]1
Reactant: O=C(O)CS
Reactant: CC1=CCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CC1(SCC(=O)O)CCCO1

Procedure:
A mixture of 2-methyl-4,5-dihydrofuran and 2-mercaptoacetic acid in THF are treated with a catalytic amount of para-toluene sulfonic acid according to the procedure in Example I.A.2. After removal of the solvent, S-(2-methyl-tetrahydrofuran-2-yl) mercaptoacetic acid is obtained. Alternatively, mercaptosuccinic acid is reacted with 2-methyl-4,5-dihydrofuran and then converted to a mercaptosuccinic anhydride derivative by a dehydrating agent such as dicyclohexyl carbodiimide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH:35]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CS(C)=O>[CH:35]1([N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=3)[CH:3]=[N:2]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: BrC1CCCCCC1
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2[nH]ncc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2c(cnn2C2CCCCCC2)c1
Temperature: 85 °C
Yield: 60 %

Procedure:
Methyl 3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate (500 mg, 1.62 mmol, prepared in Synthetic Intermediate III(c)) was dissolved in 5 mL DMSO and NaHMDS (2.4 mL, 2.4 mmol, 1.0 M in THF) was added followed by bromocycloheptane (446 uL, 3.25 mmol). The reaction was heated overnight at 85° C. The reaction was quenched with TFA and purified by HPLC to give methyl 3-(1-cycloheptyl-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate (393 mg, 60%). (M+H)+=405.
Reaction SMILES: O(CC)[C:2]([S-])=[S:3].[K+].[NH2:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[OH:16]>CCO>[Br:15][C:13]1[CH:12]=[CH:11][C:10]2[O:16][C:2](=[S:3])[NH:8][C:9]=2[CH:14]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Product: S=c1[nH]c2cc(Br)ccc2o1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
Potassium ethyl xanthate (416 mg, 2.60 mmol) was added to a solution of 2-amino-4-bromophenol (244 mg, 1.30 mmol) in EtOH (3.24 mL). The reaction mixture was heated at reflux for 4 h. Upon cooling to RT the mixture was concentrated and the resulting residue was dissolved in water. Acetic acid was added until pH=5 and a white solid precipitated from the solution. The solid was filtered, washed with water and dried to afford 270 mg (90%) of a tan powder which was used without further purification: 1H NMR (d6-DMSO, 400 MHz) δ 14.02 (s, 1H), 7.47-7.38 (m, 3H); 13C (d6-DMSO, 400 MHz) δ 181.4, 148.1, 133.7, 127.1, 117.8, 118.8, 112.2; MS (Cl) m/z 229.8 (M−1); HPLC retention time=4.34 min.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:4]=1.Cl.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][N:13]=1>Cl.C(Cl)Cl.CO>[OH:9][C:7]1[C:6]([CH:18]([C:15]2[CH:14]=[N:13][C:12]([CH3:11])=[CH:17][CH:16]=2)[OH:19])=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: CSc1nccc(O)n1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CSc1ncc(C(O)c2ccc(C)nc2)c(O)n1

Procedure:
A mixture of 10.0 g (0.07 mol) of 2-methylthio-4-hydroxypyrimidine and 12.4 g (0.079 mol) of 2-methyl-5-formylpyridine hydrochloride in 75 ml of concentrated hydrochloric acid was heated at reflux for 1 hour. After working up as in Example 1 an oil is obtained which is taken up in methylene chloride-methanol then recrystallized from ethyl acetate to give 4-hydroxy-5-[(6-methyl-3-pyridinyl)hydroxymethyl]-2-methylthiopyrimidine; 9.3 g (50%), m.p. 140°.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-:15])=[O:14])[C:7]=1[CH3:16])(=O)C.[OH-].[Na+].O>CO>[CH3:16][C:7]1[C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1c(C)ccc([N+](=O)[O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO
Yield: 82.4 %

Procedure:
To a solution of 2,6-dimethyl-3-nitrobenzyl acetate (26.9 g) in methanol (266 ml) was added aqueous 1N sodium hydroxide solution (133 ml) at ambient temperature for 30 minutes. To the mixture was added water, and the precipitate was collected by filtration to give 2,6-dimethyl-3-nitrobenzyl alcohol (18.0 g) as pale yellow crystals.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[S:3].[OH-].[Na+].Cl[CH2:12][CH2:13][CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.O>CCO>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]=[C:2]([S:3][CH2:12][CH2:13][CH2:14][C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[N:4]=1
Reactant: Nc1cc[nH]c(=S)n1
Reactant: ClCCCc1c[nH]cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccnc(SCCCc2c[nH]cn2)n1

Procedure:
A mixture of thiocytosine (0.7 g.), sodium hydroxide(0.22 g.) and 4-(3-chloropropyl)imidazole (0.8 g.) was stirred in EtOH (8 ml.) and water (8 ml.) at room temperature for 16 hours and then heated under reflux for 2 hours. The solution was evaporated to dryness and the residue partitioned between dilute aqueous sodium hydroxide (20 ml.) and EtOAc (30 ml.). The EtOAc layer was evaporated to dryness to give 4-[3-(4-aminopyrimid-2-ylthio)propyl]imidazole as a brown gum which was used without further purification.