Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([O:19]C)[CH:10]=[CH:9][C:8]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24].[CH2:26](Cl)Cl>>[OH:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([OH:19])[CH:10]=[CH:9][C:8]=1[CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: COc1ccc(CCC(=O)O)c(OC)c1-c1ccccc1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: COC(=O)CCc1ccc(O)c(-c2ccccc2)c1O
Reaction time: 8 h
Yield: 94 %

Procedure:
BBr3 (4.72 g, 1.78 ml, 18.9 mmol) was carefully added through a syringe over 5 min to a stirred solution of dimethoxy acid 4c (1.35 g, 4.7 mmol) in anhydrous CH2Cl2 (20 ml). Resulted mixture was magnetically stirred for 8 h and concentrated under vacuum. The residue was co-evaporated with toluene (2×20 ml), dissolved in methanol (20 ml) and HCl gas was bubbled into the solution for 2 min. The material obtained after evaporation of the solvent was partitioned between cold water (30 ml) and ethyl acetate (100 ml). The organic phase was washed with saturated NaHCO3 (2×10 ml), brine (20 ml), dried over MgSO4 and concentrated. The resultant crude product was chromatographed on a short silica gel column eluting with ethyl acetate. Pure product fractions were concentrated to afford 1.2 g (94%) of 5c as a tan oil. 1H NMR(DMSO-d6): δ 8.95 (s, 1H), 7.82 (s, 1H), 7.24-7.36 (m, 5H), 6.83 (d, J=8.2 Hz, 1H), 6.38 (d, J=8.2 Hz, 1H), 3.59 (s, 3H), 2.75 (t, J=8.0 Hz, 2H), 2.52 (t, J=8.0 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=2[CH2:13][CH:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:4][CH:3]=1.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:30].[Na+].C(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[CH2:29]([N:10]([CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:11]1[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=1[CH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:30]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Oc1ccc(CCNc2ccccc2CC2CCc3cc(O)ccc3C2)cc1
Agent: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN(CCc1ccc(O)cc1)c1ccccc1CC1CCc2cc(O)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a solution of 6-{2-[2-(4-hydroxyphenyl)ethylamino]benzyl}-5,6,7,8-tetrahydronaphthalen-2-ol (1.0 g) in tetrahydrofuran (15 ml) were sequentially added acetic acid (in catalytic amounts), sodium triacetoxyborohydride (2.8 g) and acetaldehyde (572 mg), and the solution was stirred overnight at room temperature. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (730 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.C(O)C.Cl.[N-:25]=[C:26]=[O:27].[K+]>O>[C:17]([C:8]1[CH:7]=[C:6]([C:4]2[NH:25][C:26](=[O:27])[NH:2][CH:3]=2)[CH:11]=[C:10]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:9]=1[OH:16])([CH3:19])([CH3:20])[CH3:18]
Reactant: CC(C)(C)c1cc(C(=O)CN)cc(C(C)(C)C)c1O
Reactant: [N-]=C=O
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(-c2c[nH]c(=O)[nH]2)cc(C(C)(C)C)c1O
Reaction time: 2 h
Yield: 43.3 %

Procedure:
To a mixed solution of 1.2 g of 4-(2-aminoacetyl)-2,6-di-tert-butylphenol hydrochloride, 10 ml of ethanol, and 0.3 ml of concentrated hydrochloric acid was added a solution of 0.64 g of potassium isocyanate in 3 ml of water at room temperature. After stirring the mixture for 2 hours, 0.3 ml of concentrated hydrochloric acid was added thereto and the resultant mixture was refluxed for 2 hours. The reaction mixture thus obtained was poured into water and the precipitates formed were recovered by filtration. The reaction product was then recrystallized from aqueous ethanol to provide 0.5 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-4-imidazoline.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[C:4]1[C:5]([N+:24]([O-])=O)=[CH:6][C:7]([N+:21]([O-])=O)=[C:8]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:9]=1)[CH3:2].C([O-])=O.[NH4+]>O1CCOCC1.CO.[Pd]>[NH2:24][C:5]1[C:4]([N:3]([CH2:27][CH3:28])[CH2:1][CH3:2])=[CH:9][C:8]2[NH:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[N:21][C:7]=2[CH:6]=1
Reactant: CCN(CC)c1cc(NC(=O)c2ccccc2OC)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CO
Product: CCN(CC)c1cc2[nH]c(-c3ccccc3OC)nc2cc1N
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To the solution of 5-(diethylamino)-2,4-dinitro-1-(2-methoxybenzoyl)aminobenzene (388 mg, 1.0 mmol) in 10 mL of 1,4-dioxane and 10 mL of methanol, was added ammonium formate (1.5 g) and 10% Pd/C (200 mg) under nitrogen atmosphere. The reaction mixture was stirred for 30 min. The Pd/C and excess ammonium formate were filtered. Conc. HCl (10 mL) was added to the filtrate. After heating at 75° C. for 18 h, the reaction mixture was basified to pH 8 with saturated K2CO3 solution. The reaction mixture was diluted with 200 mL of ethyl acetate, washed with brine, and dried over anhydrous MgSO4. The reaction mixture was filtered and concentrated in vacuo to afford the crude product (280 mg, 90% yield). The crude product was then purified by column chromatography on silica gel using EtOAc as the eluant to afford the desired product (188 mg, 61% yield) as a brown solid: 1H-NMR (300 MHz, CDCl3) δ 1.01 (t, 6H, J=7.2 Hz), 3.01 (q, 4H, J=7.2 Hz), 4.05 (s, 3H), 6.92 (s, 1H), 7.03 (d, 1H, J=8.1 Hz), 7.11 (t, 1H, J=8.1 Hz), 7.36 (t, 1H, J=6.9), 7.41 (s, 1H), 8.52 (d, 1H, J=7.8 Hz); ESI MS m/z 311.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](Br)[CH:9]=2)[CH:4]=1.[Li]CCCC.[F:19][C:20]([F:29])([F:28])[CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:24]1([OH:27])[CH2:23][CH2:22][CH:21]([C:20]([F:28])([F:29])[F:19])[CH2:26][CH2:25]1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: O=C1CCC(C(F)(F)F)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(C3(O)CCC(C(F)(F)F)CC3)ccc2c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) anhydrous solution of 2-methoxy-6-bromonaphthalene (1.52 g, 6.40 mmol) in THF (40 mL) was added n-BuLi (6.9 mL of a 2.5 M solution in hexanes, 6.9 mmol). The mixture was stirred at −78° C. under a nitrogen atmosphere for 15 min, then 4-(trifluoromethyl)cyclohexanone (0.88 g, 5.3 mmol) was added slowly to the reaction mixture. The bath was allowed to warm to room temperature and the reaction mixture was quenched with saturated NH4Cl (aq). The resultant mixture was extracted with EtOAc/hexanes. The organic layer was evaporated in vacuo and the crude residue was purified by flash chromatography on silica gel using gradient elution (0% to 20% EtOAc/hexanes, 150 mL; 20% to 35% EtOAc/hexanes, 204 mL; 35% to 75% EtOAc/hexanes, 381 mL) to provide Isomer A as the faster-eluting product and Isomer B as the slower-eluting product.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1.Cl>>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:35])=[O:34])[CH:28]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1)CC2

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and pyridine-3-sulfonyl chloride; hydrochloride. White solid. MS (ESI): 456.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:21]3[CH:20]=[N:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(OC)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 2-methoxy-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)O.C(Br)(Br)(Br)[Br:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[Br:22]
Reactant: COC(=O)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl[3,5-bis(trifluoromethyl)phenyl](hydroxy)acetate (300 mg, 0.993 mmol) was dissolved in CH2Cl2 (10 mL). The solution was cooled to 0° C. and CBr4 (659 mg, 1.986 mmol) was added followed by PPh3 (521 mg, 1.986 mmol). After 1 hour, the reaction was warmed to room temperature and stirred at room temperature for 1 hour. The reaction was filtered through a short plug of silica gel with CH2Cl2. The filtrate was concentrated and the residue was purified by flash chromatography with 5% EtOAc/hexanes to afford methyl[3,5-bis(trifluoromethyl)phenyl](bromo)acetate. Rf=0.24 (5% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 8.02 (s, 2H), 7.87 (s, 1H), 5.41 (s, 1H), 3.83 (s, 3H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([CH3:16])=[C:9]([C:13]([NH2:15])=[O:14])[NH:10][C:11]=1[CH3:12])=O.[N+]([O-])(O)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>COCCO>[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]2[N:32]=[C:5]([C:7]3[C:8]([CH3:16])=[C:9]([C:13]([NH2:15])=[O:14])[NH:10][C:11]=3[CH3:12])[CH:4]=[CH:3][N:31]=2)=[CH:27][CH:28]=1
Reactant: Cc1[nH]c(C(N)=O)c(C)c1C(=O)C=CN(C)C
Reactant: N=C(N)Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1[nH]c(C(N)=O)c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Temperature: 120 °C
Yield: 22.2 %

Procedure:
4-(3-Dimethylamino-acryloyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid amide (100 mg, 0.43 mmol), 4-fluorophenylguanidine nitrate (139 mg, 0.65 mmol) and K2CO3 (94 mg, 0.68 mmol) were partially dissolved in 2-methoxyethanol (5 mL) and heated at 120° C. for 18 h. The mixture was concentrated in vacuo and purified by SiO2 chromatography (EtOAc/MeOH gradient elution). The crude product was triturated in iPr2O to afford the title compound (31 mg) as a buff solid. M.p. 93.5–96.8° C. MS: [M+H+]=326.9 (C17H16FN5O requires 325.3). 1H-NMR (DMSO-d6) δ: 2.36 (s, 3H, CH3), 2.39 (s, 3H, CH3), 6.79 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 6.92 (br. s, 2H, NH), 7.07 (t, 2H, J=8.5 Hz, Ph-H), 7.76–7.78 (m, 2H, Ph-H), 8.36 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.41 (s, 1H, NH), 11.24 (br. s, 1H, NH).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]3[O:40][CH:39]=[CH:38][C:37]=3[CH:41]=2)O1.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[O:40]1[C:36]2[CH:35]=[CH:34][C:33]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)=[CH:41][C:37]=2[CH:38]=[CH:39]1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4occc4c3)n2n1
Temperature: 110 °C
Yield: 34.8 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 80 mg, 0.232 mmol), 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (73.6 mg, 0.302 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16 mg, 22 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.774 mL of 1,4-dioxane and 0.387 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (60-70% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (34.4 mg, 35%). 1H NMR (DMSO-d6) δ: 11.13 (s, 1H), 8.36 (d, J=1.5 Hz, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.89-8.00 (m, 4H), 7.78 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.6 Hz, 2H), 7.10 (dd, 1H), 6.34 (s, 1H), 5.13 (s, 1H), 2.35 (s, 3H), 1.39 (s, 6H); ESI-MS: m/z 452.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[CH2:43](Br)[CH:44]=[CH2:45]>CCOCC>[CH2:45]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][O:27][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:35]([CH3:37])[CH3:36])[CH:44]=[CH2:43]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO[Si](C(C)C)(C(C)C)C(C)C)[nH]c2c1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCn1c(-c2ccccc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-(2-{[(triisopropylsilyl)oxy]methyl}phenyl)-1H-indole-6-carboxylate in DMF (0.13 M) NaH (2 eq.) was added. After 20 min. allyl bromide (1.5 eq.) was added and the mixture stirred at RT for 2 h, diluted with Et2O, washed with sat aq. NH4Cl and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was subjected to flash chromatography (PE:EtOAc, 10:1). After evaporation of the solvents the product was obtained as yellow solid (67%).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(OO)(=[O:16])C.O>C(Cl)Cl>[C:8]1([CH2:7][CH:1]2[CH2:6][CH2:5][CH:4]3[CH:3]([O:16]3)[CH2:2]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1=CCC(Cc2ccccc2)CC1
Reactant: CC(=O)OO
Solvent: ClCCl
Solvent: O
Product: c1ccc(CC2CCC3OC3C2)cc1

Procedure:
A 500 mL round bottom flask equipped with a stirrer bar was charged with 9.55 g (0.056 mol) of (3-cyclohexen-1-ylmethyl)benzene, and 90 mL of methylene choride. Peracetic acid (17.5 g, 35 wt. % in acetic acid; 0.073 mol) in methylene chloride (70 mL) was added dropwise to the above mixture over 25 min. in an ice bath. After the above mixture was reacted at room temperature for 7 hrs., 200 mL of water was added to the above reaction mixture, the water layer was extracted with chloroform (2×150 mL). The organic layer was combined, washed with saturated sodium carbonate solution (2×150 mL), then with water (2×150 mL), and dried with sodium sulfate. The solvent was evaporated and the residue was vacuum distilled to give pure product.
Reaction SMILES: [OH:1][C:2]1([CH3:8])[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18]>C(Cl)Cl>[C:16]([O:1][C:2]1([CH3:8])[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: CC1(O)CCSCC1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1(C)CCSCC1
Temperature: 0 °C
Yield: 65.3 %

Procedure:
To a 200-mL three-necked flask fitted with a stirrer bar coated with Teflon™, were added 5.95 g of 4-hydroxy-4-methyltetrahydrothiopyran (manufactured by SANKYO KASEI Co., Ltd.), 5.08 g of triethyl amine, and 50 mL of dried methylene chloride, and the mixture was stirred under nitrogen atmosphere at 0° C. To the mixture, 5.0 g of methacryloyl chloride was slowly added through a dropping funnel, and the resulted mixture was reacted at 0° C. for 30 minutes, allowed to warm to room temperature, and was further reacted for another 5 hours. After confirming loss of the starting material by TLC, the reaction solution was poured in a 300-mL separatory funnel, washed with 100 mL of water followed by with 100 mL of saturated NaCl solution (brine), and dried with anhydrous sodium sulfate. From the obtained solution, the solvent was removed by an evaporator, to obtain an oily crude product. The crude product was purified by silica gel chromatography using a mixed solution of n-hexane and ethyl acetate to give 5.89 g of 4-methyl-tetrahydro-2H-thiopyran-4-yl methacrylate (thiopyran derivative of the following formula 3) (yield: 59.4%).
Reaction SMILES: CO[C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:16]([S:17][CH3:18])=[C:15]3[C:10]([N:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:12](=[O:21])[N:13]([CH3:20])[C:14]3=[O:19])=[N:9]2)=[CH:5][CH:4]=1.BrCC1C=C[C:34]([S:37](C)(=[O:39])=[O:38])=CC=1>>[CH3:20][N:13]1[C:14](=[O:19])[C:15]2=[C:16]([S:17][CH3:18])[N:8]([CH2:7][C:6]3[CH:27]=[CH:28][C:3]([S:37]([CH3:34])(=[O:39])=[O:38])=[CH:4][CH:5]=3)[N:9]=[C:10]2[N:11]([CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:12]1=[O:21]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(Cn2nc3c(c2SC)c(=O)n(C)c(=O)n3CC(C)(C)C)cc1
Product: CSc1c2c(=O)n(C)c(=O)n(CC(C)(C)C)c2nn1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
The synthetic procedure of this compound is analogous to EXAMPLE 5 wherein 2-(4-methoxybenzyl)-5-methyl-3-(methylthio)-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione is used instead of 2-(4-methoxybenzyl)-5-methyl-7-neopentyl-3-(phenylthio)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione, and 1-(bromomethyl)-4-(methylsulfonyl)benzene is used instead of 1-(4-(bromomethyl)phenyl)-1H-1,2,4-triazole. MS (ESI) m/z 451.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]([C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[CH2:5][C:6](=O)[NH:7]2.[N+:20]([CH2:22][C:23]1[N:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[O:25][N:24]=1)#[C-:21]>>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]([C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[CH2:5][C:6]1[N:7]2[CH:21]=[N:20][C:22]=1[C:23]1[N:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[O:25][N:24]=1
Reactant: O=C1CN(C(=O)N2CCCC2)c2c(F)cccc2N1
Reactant: [C-]#[N+]Cc1noc(C(C)C)n1
Product: CC(C)c1nc(-c2ncn3c2CN(C(=O)N2CCCC2)c2c(F)cccc2-3)no1

Procedure:
Following the general procedure of EXAMPLE 30 and making non-critical variations but using 5-fluoro-1,2,3,4-tetrahydro-4-[(pyrrolidino)carbonyl]quinoxalin-2-one (XXXII, EXAMPLE 29, 0.978 g) and 3-isocyanomethyl-5-isopropyl-1,2,4-oxadiazole (0.673 g) are convened to the title compound, mp 169°-170°; MS (m/z) at 396; IR (mineral oil) 1657, 1495, 1216, 1614 and 785 cm-1 ; NMR (CDCl3) 1.47, 1.86, 3.30, 3.34, 5.13, 7.08, 7.22, 7.38 and 8.12 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][C:23](=[O:36])[CH:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]([CH3:27])[CH3:26])[CH:17]=[CH:16][N:15]=2)[O:11][N:10]=1.C(N(CC)CC)C.[Cl:44][CH:45]([Cl:49])[C:46](Cl)=[O:47]>C(Cl)Cl>[Cl:44][CH:45]([Cl:49])[C:46]([N:20]([CH2:21][CH2:22][C:23](=[O:36])[CH:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]([CH3:27])[CH3:26])[C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[CH:13]=2)[CH:19]=1)=[O:47]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)CCNc1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
tert-Butyl 6-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-ylamino)-2-methyl-4-oxohexan-3-ylcarbamate (445 mg, 0.83 mmol) was dissolved in methylene chloride (10 mL) with triethylamine (140 μL, 1.0 mmol). The solution was cooled on an ice-water bath and then a solution of dichloroacetyl chloride (100 μL, 1.0 mmol) in methylene chloride (1 mL) was added dropwise. The reaction mixture was allowed to stir overnight while warming to room temperature. The solution was washed successively with water and saturated sodium bicarbonate solution, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 0.5:99.5 methanol:methylene chloride to provide tert-butyl 6-(2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamido)-2-methyl-4-oxohexan-3-ylcarbamate (185 mg) as a pink foam. 1H NMR (CDCl3): 8.85 (d, 1H), 7.91 (d, 1H), 7.61-7.35 (m, 5H), 7.18 (s, 1H), 6.11 (s, 1H), 5.02 (d, 1H), 4.28-4.08 (m, 2H), 3.15-2.82 (m, 3H), 2.20-2.10 (m, 1H), 1.42 (s, 9H), 1.08 (d, 3H), 0.85 ppm (d, 3H). MW=644 confirmed by LC-MS, tr=16.72 min (Method Y) MH+=642-646.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C1CCN2C(=NCCC2)CC1.Br[CH2:22][CH2:23][OH:24].C(Cl)[Cl:26]>>[ClH:26].[OH:24][CH2:23][CH2:22][O:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: ClCCl
Reactant: OCCBr
Reactant: CC(C)(C)OC(=O)NO
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NOCCO
Product: Cl
Temperature: 40 °C
Reaction time: 60 h
Yield: 70 %

Procedure:
The title compound was prepared according to the procedure described in WO2006/10094. To a mixture of t-butyl hydroxycarbamate (11.27 g, 85 mmol) and DBU (12.8 mL, 85 mmol) was added 2-bromoethanol (15 mL, 212 mmol) slowly, and the reaction mixture was stirred at 40° C. for 2.5 days. After cooling, the reaction mixture was diluted with DCM, and washed successively with cold 1N HCl aqueous solution, water, and brine. The organic layer was dried over anhydrous Na2SO4, purified by column chromatography (38% EtOAc in hexane) to afford 12.6 g (70%) of the title compound as a colorless syrup. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.95 (s br, 1H), 4.55 (t, 1H), 3.70 (t, 2H), 3.45-3.55 (m, 2H), 1.38 (s, 9H).