Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[OH-].[K+]>CN(C=O)C>[Cl:5][CH2:4][CH2:3][CH2:2][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: ClCCCn1ccc2ccccc21
Temperature: 20 °C
Reaction time: 15 h
Yield: 70.6 %

Procedure:
To a solution of 1-bromo-3-chloropropane (2.00 g, 12.7 mmol) in DMF (7.0 mL) was added indole (500 mg, 4.24 mmol) followed by powdered KOH (262 mg, 4.66 mmol) at 20° C. The reaction mixture was then stirred for 15 h at 20° C. The reaction was quenched by addition of H2O and the product was extracted with Et2O. The organic solution was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. 1-(3-Chloro-1-propyl)indole (580 mg, 71%) was isolated by flash chromatography on a silica gel column by elution with EtOAc/Hexanes a pale yellow oil. 1H NMR (CDCl3, 300 MHz) δ2.28 (qu, 2H, J=6.3 Hz), 3.46 (t, 2H, J=6.2 Hz), 4.36 (t, 2H, J=6.6 Hz), 6.51 (d, 1H, J=3.3 Hz), 7.09-7.18 (m, 2H), 7.20-7.25 (m, 1H), 7.38 (d, 1H, J=8.5 Hz), 7.64 (d, 1H, J=7.7 Hz) ppm.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[Cl:20][C:17]([F:19])([F:18])[S:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:33]3[CH:32]=[N:31][CH:30]=[C:29]([F:28])[CH:34]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Example 185 using (R)-5-bromo-N-(4-((chlorodifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 217.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white foam. HPLC (Condition 4) tR=5.69 min, UPLC-MS (Condition 3) tR=1.09 min, m/z=495.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.77 (m, 1H) 1.79-1.89 (m, 1H) 2.87 (d, J=11.34 Hz, 1H) 3.20 (m, J=11.10, 4.50 Hz, 2H) 3.33-3.44 (m, 1H) 4.19 (br. s, 1H) 4.86 (d, J=3.13 Hz, 1H) 7.66 (d, J=8.60 Hz, 2H) 7.82 (d, J=9.78 Hz, 1H) 7.91 (d, J=8.60 Hz, 2H) 8.06 (d, J=1.00 Hz, 1H) 8.50 (s, 1H) 8.58 (d, J=2.35 Hz, 1H) 8.77 (d, J=1.95 Hz, 1H) 10.27 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15].C(N(CC)CC)C.[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>CN(C1C=CN=CC=1)C.CN(C)C=O>[F:1][C:2]1[C:7]([S:8]([NH:11][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15]
Reactant: C=C(C)C(=O)Cl
Reactant: NS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(C)C(=O)NS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Yield: 61.9 %

Procedure:
Using 24.7 g (0.1 mol) of pentafluorobenzene-sulfonamide, 1.2 g (0.01 mol) of 4-(N,N-dimethylamino)pyridine, 22.3 g (0.22 mol) of triethylamine, 13.5 g (0.12 mol) of methacryloyl chloride, and 100 ml of dimethylformamide, reaction was conducted in the same manner as in Synthesis Example 1. As a result, 19.5 g of N-(pentafluorobenzene-sulfonyl)methacrylamide was obtained (yield, 61.9%; light-yellow crystals; m.p., 133-133.5° C.).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([O:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)=[O:7])(C)(C)C.[C:35]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:40]=[CH:39][C:38](C(O)=O)=[CH:37][CH:36]=1.C(P(=O)(OCC)OCC)#N>C(N(CC)CC)C>[C:35]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:40]=[CH:39][C:38]([C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([O:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=3)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=2)=[O:7])=[CH:37][CH:36]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1ccc(C(C)C)cc1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)Oc1ccc(C(C)C)cc1
Yield: 74.7 %

Procedure:
In a similar manner to that described in Example 73, a reaction was carried out using ethyl 3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-(4-isopropylphenoxy)propionate (723 mg), which is the product of Reference example 25, biphenyl-4-carboxylic acid (303 mg), diethyl cyanophosphonate (0.25 ml) and triethylamine (0.47 ml) and the reaction mixture was treated to give the title compound (630 mg) as a yellow oil.
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([NH2:32])[C:26]=1[N+:33]([O-:35])=[O:34]>CC(O)C>[Cl:31][C:30]1[C:25]([N:12]2[CH2:11][CH2:10][N:9]([CH2:1][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:14][CH2:13]2)=[C:26]([N+:33]([O-:35])=[O:34])[C:27]([NH2:32])=[N:28][CH:29]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: c1ccc(CCN2CCNCC2)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Cl)c(N2CCN(CCc3ccccc3)CC2)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
1-Phenethylpiperazine (0.100 g, 0.52 mmol, 1.1 eq) was suspended in iPrOH (1 mL). DIPEA (0.13 mL, 0.79 mmol, 1.5 eq) was added followed by 4,5-dichloro-3-nitropyridin-2-amine (0.099 g, 0.48 mmol, 1 eq). The mixture was heated and stirred at 65° C. overnight. The mixture was cooled to room temperature and filtered. The bright yellow solid was washed with iPrOH (3×2 mL), Et2O (2×2 mL) and dried to give the title compound as a bright yellow solid (0.112 g, 64%); 1H-NMR (500 MHz, DMSO-d6): δ 2.53-2.63 (m, 6H), 2.71-2.78 (m, 2H), 3.06 (m, 4H, piperazine N(CH2)2), 6.95 (s, 2H, NH2), 7.15-7.21 (m, 1H), 7.22-7.31 (m, 4H), 8.06 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.31 min—362/364 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][OH:30].[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][O:30][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: OCCc1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccccc2F)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 70.5 %

Procedure:
1.02 g of p-toluensulfonyl chloride (5.35 mM), 1.24 ml of diisopropyl ethylamine (7.13 mM) and 86 mg of 4-(dimethylamino)pyridine (0.71 mM) were added to the reaction solution (3.57 mM) containing 500 mg of 2-(2-fluoro-phenyl)-ethanol (3.57 mM) dissolved in methylene chloride solution with stirring for 6 hrs at 0° C. under Ar atmosphere, and then the reaction mixture was stirred for 12 hrs at room temperature. The resulting mixture was neutralized with ammonium chloride, extracted with ethyl acetate and washed with saturated NaCl solution to separate into an organic layer and water layer. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:7) as an eluant to give 740 mg of toluen-4-sulfonate-2-(2-fluoro-phenyl)-ethyl ester (u) (yield: 70%).
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9](=[O:28])(=[O:27])[CH2:10][C:11]3[C:15]([C:16]([O:18]CC)=[O:17])=[N:14][N:13]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:12]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[OH-:29].[Na+].OO>CCO>[NH2:2][C:1]([C:3]1[C:8]2[S:9](=[O:28])(=[O:27])[CH2:10][C:11]3[C:15]([C:16]([OH:18])=[O:17])=[N:14][N:13]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:12]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:29]
Reactant: [OH-]
Reactant: CCOC(=O)c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1c(C#N)cccc1-2
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cccc2c1S(=O)(=O)Cc1c(C(=O)O)nn(-c3ccccc3)c1-2
Reaction time: 2 h

Procedure:
To a solution of Ethyl 6-cyano-1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide (100 mg, 0.254 mmol) in EtOH (10 mL) is added an aq. solution of NaOH (10%, 1 mL) and 30% hydrogen peroxide (2 mL) at 100° C. and the heating is continued for another 2 h. The reaction mixture is evaporated under vacuum, acidified with HCl (1.5 N) and extracted with EtOAc. The organic layer is separated, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound. MS (ESI+): 384.0.
Reaction SMILES: CC1(C)COC(=O)[C@@H]1[C:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][C@@H:9]2[C:16]([O-:18])=[O:17].[OH-].[Li+]>O1CCCC1.O>[CH:8]12[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]1)[CH2:10][C@@H:9]2[C:16]([OH:18])=[O:17]
Reactant: CC1(C)COC(=O)[C@@H]1C12CCC(CC1)C[C@@H]2C(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1CC2CCC1CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of formula (VIIa) (Intermediate 3, 18.0 g, 67.7 mmol) was dissolved in tetrahydrofuran (100 mL) and the resulting solution cooled to 5–10° C. A solution of lithium hydroxide (7 g) in water (140 mL) was added slowly, maintaining the reaction temperature to below 25° C. and the mixture was stirred for 24 hours at room temperature, then concentrated in vacuo until most of tetrahydrofuran had been removed. Concentrated HCl was added drop-wise to adjust the pH to 2, water (60 mL) was added and the slurry stirred at 0–10° C. for one hour. The precipitate was isolated by filtration, and dried in a vacuum oven. The crude product of formula (IIIa) was used without any further purification (9.35 g, 90%).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:28](=O)[C:27]5[C:26]([C:37]([O:39]C)=O)=[CH:25][CH:24]=[CH:23][C:22]=5[NH:21]4)=[CH:16][CH:15]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.[NH2:42][NH2:43]>>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[NH:21][C:22]5[C:27]6[C:28](=[N:42][NH:43][C:37](=[O:39])[C:26]=6[CH:25]=[CH:24][CH:23]=5)[CH:29]4[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:16][CH:15]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1ccc(C(=O)N3CCN(C(=O)C4CC4)CC3)cc1)N2
Reactant: NN
Solvent: O
Product: O=C(c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1)N1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
A mixture of methyl 2-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (300 mg, 0.55 mmol) and hydrazine monohydrate (3 mL) was stirred room temperature for 3 h. The resulting mixture was evaporated under reduced pressure to 10 mL and then filtered; the filtrate was concentrated to give the crude product. The crude product was purified by pre-HPLC to give 8-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as a white solid (4 mg, yield 19%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.71-0.74 (m, 4H), 1.97 (t, 1H), 3.46-3.76 (m, 8H), 4.36 (dd, 1H), 4.83 (dd, 1H), 7.13-7.23 (m, 6H), 7.30 (d, 2H), 7.38 (t, 3H), 7.47 (s, 1H), 7.59 (t, 1H), 12.17 (s, 1H); LC-MS (ESI) m/z: 520 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][NH:5][C:4](=[S:17])[NH:3]1.C([O-])([O-])=O.[K+].[K+].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38]Cl)=[CH:34][CH:33]=2)=[CH:27][C:26]=1[C:40]([F:43])([F:42])[F:41]>CC(C)=O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:33]=[CH:34][C:35]([CH2:38][S:17][C:4]3[NH:5][CH:6]=[C:7]([CH2:8][C:9]4[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=4)[C:2](=[O:1])[N:3]=3)=[CH:36][CH:37]=2)=[CH:27][C:26]=1[C:40]([F:41])([F:42])[F:43]
Reactant: N#Cc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cc1
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.6 %

Procedure:
To a suspension of 4-[(4-oxo-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)methyl]benzonitrile (70 mg, 0.288 mmol) and K2CO3 (41.3 mg, 0.299 mmol) in acetone (6 mL), which was stirred at room temperature for 5 min was added 1-chloro-4-{[4-(chloromethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (60 mg, 0.187 mmol) under argon. The mixture was heated at 60° C. for 3 h. Purification via MDAP then afforded the title compound (31 mg, 0.059 mmol, 31.4% yield). LCMS: rt=3.98 min, [M+H+]=528
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23].[CH:26]1(OCCO[Si](C)(C)C)[CH2:28][CH2:27]1.C(O)(=O)C.[C-]#N.[BH4-].[Na+]>CO>[CH:26]1([N:19]2[CH2:20][CH2:21][CH:17]([NH:16][C:14]([C:12]3[S:13][C:9]([S:8][C:7]4[C:6]([Cl:25])=[CH:5][N:4]=[CH:3][C:2]=4[Cl:1])=[C:10]([N+:22]([O-:24])=[O:23])[CH:11]=3)=[O:15])[CH2:18]2)[CH2:28][CH2:27]1
Reactant: C[Si](C)(C)OCCOC1CC1
Reactant: O=C(NC1CCNC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Agent: [BH4-]
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NC1CCN(C2CC2)C1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Yield: 5.4 %

Procedure:
To a solution of 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(pyrrolidin-3-yl)thiophene-2-carboxamide (0.20 g, 0.48 mmol), (2-cyclopropoxyethoxy)trimethylsilane (498 mg, 2.86 mmol) and acetic acid (286 mg, 4.77 mmol) in methanol (10 mL) under nitrogen, was added sodium borohydride cyanide powder (150 mg, 2.38 mmol) by small portion. The resulting reaction mixture was heated under reflux for 4 hours. After this time, the reaction mixture was passed through a celite cartridge and the organic solution was concentrated. The resulting residue was dissolved in ethyl acetate and was washed with sodium bicarbonate solution and brine. The organic layer was separated, dried (Na2SO4) and concentrated. The crude was purified by reverse phase HPLC to afford the titled product as a solid (12.0 mg, 5% yield) 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.87 (1H, d), 8.54 (1H, s), 4.23 (1H, m), 2.83 (2H, m), 2.07 (1H, m), 1.63 (2H, m), 1.23 (2H, m), 0.48 (2H, m), 0.38 (2H, m). MS m/z: 459.08, 461.07 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.BrCCCCCC[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][C:25]2[CH:24]=[CH:23][CH:22]=[C:19]3[C:20]([NH:16][C:17](=[O:26])[C:18]=23)=[O:21])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCCCCSc3ccc(Cl)cc3)cccc21
Temperature: 90 °C
Reaction time: 23 h

Procedure:
4-Chlorothiophenol (2.89 g, 20 mmol), N-(6-bromohexyl)-phthalimide (6.20 g, 20 mmol) and K2CO3 (5.53 g, 40 mmol) were suspended in DMF (50 mL) under an atmosphere of argon and stirred at 90° C. for 23 h. The solvent was evaporated under reduced pressure and the residue was partitioned between water (100 mL) and CH2Cl2 (150 mL). The aqueous layer was extracted with CH2Cl2 (2×100 mL), the combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the title compound, pure enough for further reactions.
Reaction SMILES: Cl[C:2]1[C:3]([OH:12])=[N:4][O:5][C:6]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22]O)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][O:12][C:3]1[CH:2]=[C:6]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[O:5][N:4]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1noc(-c2cccs2)c1Cl
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2cccs2)on1
Yield: 74.1 %

Procedure:
4-Chloro-3-hydroxy-5-(2-thienyl)isoxazole (0.50 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.40 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (0.57 g, 66%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([NH2:32])=[O:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[OH:36]/[N:35]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@H:10]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]([NH2:32])=[O:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(N3CCC(C(N)=O)CC3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(N3CCC(C(N)=O)CC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-1-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)piperidine-4-carboxamide and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow foam, MS (ESI+): m/z=457.5 ([M+H]+).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([O:15]CC=C)=[CH:7][C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:3])[CH3:2].C(O[C:27]1[C:32](C(C)(C)C)=CC(O)=C(OCC=C)[C:28]=1C(C)(C)C)(=O)C>CN(C)C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:9][C:8]([OH:15])=[C:7]([CH2:32][CH:27]=[CH2:28])[C:6]=1[C:19]([CH3:22])([CH3:20])[CH3:21])(=[O:3])[CH3:2]
Reactant: C=CCOc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Reactant: C=CCOc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Solvent: CN(C)c1ccccc1
Product: C=CCc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Temperature: 25 °C
Yield: 165 %

Procedure:
Synthesis of 4-Acetoxy-3,5-Di-tert-Butyl-2-(2-Propenyloxy)phenol 4-Acetoxy-3,5-di-tert-butyl-1-(2-propenyloxy)benzene (11.0 g) was dissolved in N,N-dimethylaniline (50 ml) and the solution was refluxed for 18 h under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (15% ethyl acetate in n-hexane) to afford 4-acetoxy-3,5-di-tert-butyl-2-(2propenyl)phenol [8.84 g (yield, 77%)] as a white solid.
Reaction SMILES: CN(CCN(C)C)C.[Li]C(CC)C.[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:24][CH3:25])[CH:16]=1.[CH3:26][S:27]SC>C1COCC1>[F:14][C:15]1[CH:23]=[C:22]([S:27][CH3:26])[C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:24][CH3:25])[CH:16]=1
Reactant: CSSC
Reactant: COc1cc(F)ccc1C(=O)O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1cc(F)cc(SC)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of TMEDA (1.95 mL, 12.9 mmol) in anhydrous THF (8 mL) was slowly added a solution of sec-BuLi (1.4 M solution in cyclohexane, 18.5 mL, 25.8 mmol) at −78° C., followed by a solution of 4-fluoro-2-methoxy-benzoic acid (44, 1.0 g, 5.88 mmol) in anhydrous THF (2 mL) at −78° C. under an atmosphere of N2. The mixture stirred at −78° C. for 2 h before a solution of dimethyl disulfide (2.1 mL, 23.5 mmol) in anhydrous THF (2 mL) was added slowly. The mixture was stirred at same temperature for 1 h before it was warmed up to room temperature and quenched with H2O. The crude mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL). Aqueous layer was collected and acidified with 2 M HCl, followed by extraction by EtOAc (2×20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Companion unit, 40 g Redisep column, 20% to 50% EtOAc/hexane) to give 4-fluoro-2-methoxy-6-(methylthio) benzoic acid as a white solid (46, 0.22 g, 17%): 1H NMR (300 MHz, CDCl3) δ 8.07 (dd, J=15.3, 4.5 Hz, 1H), 7.03 (t, J=8.7 Hz, 1H), 4.11 (s, 3H), 2.49 (s, 1H); MS (ESI+) m/z 217 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[CH2:16])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24]>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16][S:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH2:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1S
Reactant: C=C(NC(=O)OCc1ccccc1)C(=O)O
Solvent: CCO
Product: Nc1ccccc1SC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 49.4 %

Procedure:
23 g of α-benzyloxycarbonylaminoacrylic acid and 30 g of 2-aminobenzenethiol were dissolved in 20 ml of ethanol, and the resulting mixture was stirred at room temperature for an hour. After the solvent was distilled off, ether was added to the residue so as to cause crystallization. The precipitated crystals were separated by filtration and washed with ether to obtain 17.8 g of the desired compound. Its melting point was 150°-151° C.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[N:18]=[C:19]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[N:20]5[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=45)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:43](OC(=O)C)(=[O:45])[CH3:44]>C(Cl)Cl>[NH2:26][C:22]1[C:21]2[N:20]([C:19]([CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:43](=[O:45])[CH3:44])[CH2:30][CH2:29]3)=[N:18][C:17]=2[C:11]2[CH:10]=[C:9]3[C:14]([CH:15]=[CH:16][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8]3)=[CH:13][CH:12]=2)[CH:25]=[CH:24][N:23]=1
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Reaction time: 0.25 h

Procedure:
1-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-ylmethyl-imidazo[1,5-a]pyrazin-8-ylamine (100.00 mg, 0.23 mmol) in a dried 10 mL round-bottom flask was dissolved in 1.7 mL of methylene chloride and was charged with PS-DIEA (117.95 mg, 0.46 mmol). Acetic anhydride (Ac2O) (11 μL, 0.51 equiv) was added in one portion. After 15 min., another 5.5 μL of Ac2O (0.25 equiv) was added. After another 15 min., another 2.64 μL of Ac2O (0.12 equiv) was added. After another 15 min., another 11 μL of Ac2O (0.51 equiv) was added. The reaction was filtered through a fritted funnel, and the resins were rinsed multiple times with methylene chloride. The crude product was purified by silica gel flash chromatography (wetted with 100% EtOAc, eluted with 5% (7N NH3) in MeOH/EtOAc) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (1H, d, J=1.68), 8.28 (1H, d, J=8.20), 8.19 (2H, dd, J=1.51 Hz, J=1.18), 7.93 (3H, m), 7.53 (3H, m), 7.23 (1H, d, J=5.10), 7.12 (1H, d, J=5.76), 5.55 (2H, m), 4.67 (1H, d, J=13.28), 3.83 (1H, d, J=12.26), 3.06 (1H, m), 2.96 (2H, m), 2.56 (1H, m), 2.27 (1H, m), 2.10 (3H, s), 1.85 (2H, t), 1.31 (2H, m); MS (ES+): m/z 477.11/478.08 (40/20) [MH+]; HPLC: tR=2.11 min (OpenLynx, polar—5 min).