Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([OH:11])[CH:4]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]Cl.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:4]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: COCCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1cc(OC)ccc1C=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 4-methoxy-2-hydroxybenzaldehyde (6.5 g, 40 mmol), MEM-chloride (10.0 g, 80 mmol) and diisopropylethylamine (21 mL, 120 mmol) in dichloromethane (200 mL) was stirred at 25° C. for 14 h. The reaction mixture was concentrated to a small volume, diluted with diethyl ether (200 mL) and filtered through a short path of silica gel. The filtrate was concentrated to give crude 4-methoxy-2-(methoxyethoxy)methoxy-benzaldehyde which was pure enough for use in the next step.
Reaction SMILES: N1C=CN=C1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10](=[O:24])[N:11]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]2)[N:12]=1.[H-].[Na+].[NH2:27][C:28]1[C:33]2[CH2:34][CH2:35][O:36][C:32]=2[C:31]([C:37](N2C=CN=C2)=[O:38])=[CH:30][C:29]=1[Cl:44]>C1COCC1>[NH2:27][C:28]1[C:33]2[CH2:34][CH2:35][O:36][C:32]=2[C:31]([C:37]([O:23][CH2:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][N:11]3[C:10](=[O:24])[CH:9]=[CH:8][C:7]([Cl:6])=[N:12]3)[CH2:17][CH2:18]2)=[O:38])=[CH:30][C:29]=1[Cl:44]
Reactant: O=c1ccc(Cl)nn1CCCN1CCC(CO)CC1
Reactant: Nc1c(Cl)cc(C(=O)n2ccnc2)c2c1CCO2
Agent: [H-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C(=O)OCC2CCN(CCCn3nc(Cl)ccc3=O)CC2)c2c1CCO2
Reaction time: 0.17 h
Yield: 42.6 %

Procedure:
1H-imidazole (2.72 g) was added to a solution of 6-chloro-2-[3-[4-(hydroxymethyl)-1-piperidinyl]propyl]-3(2H)-pyridazinone (2.62 g) in THF (100 ml). NaH (60%, 0.4 g) was added, under nitrogen atmosphere. The mixture was stirred for 10 minutes. 1-[(4-Amino-5-chloro-2,3-dihydro-7-benzofuranyl)carbonyl]-1H-imidazole (2.64 g) was added and the resulting reaction mixture was stirred for 15 minutes at room temperature. The solvent was evaporated. The residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/hexane/(CH3OH/NH3) 50/45/5). The desired fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE with a drop of ACN. The precipitate was filtered off, washed and dried, yielding 1.88 g (39%) of [1-[3-(3-chloro-6-oxo-1(6H)-pyridazinyl)propyl]-4-piperidinyl]methyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate (compound 21, mp: 137° C.) In a similar way, [1-[3-(3-methyl-6-oxo-1(6H)-pyridazinyl)propyl]-4-piperidinyl]-methyl 7-amino-6-chloro-1,3-benzodioxole-4-carboxylate (compound 22) was also prepared.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([N:12]2[C:17](=[O:18])[C:16]3[C:19]([C:23]([F:26])([F:25])[F:24])=[N:20][CH:21]=[CH:22][C:15]=3[NH:14][CH:13]2[C:27]2[C:32]([OH:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]>CC(C)CC(=O)C.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([N:12]2[C:17](=[O:18])[C:16]3[C:19]([C:23]([F:24])([F:25])[F:26])=[N:20][CH:21]=[CH:22][C:15]=3[N:14]=[C:13]2[C:27]2[C:32]([OH:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(Cc1ccc(F)c(F)c1)N1C(=O)c2c(ccnc2C(F)(F)F)NC1c1ncccc1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(=O)CC(C)C
Product: CC(Cc1ccc(F)c(F)c1)n1c(-c2ncccc2O)nc2ccnc(C(F)(F)F)c2c1=O
Temperature: 90 °C

Procedure:
3-(1-(3,4-difluorophenyl)propan-2-yl)-2-(3-hydroxypyridin-2-yl)-5-(trifluoromethyl)-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (5.90 g, 12.7 mmol) was dissolved in 500 mL of 4-methyl-2-pentanone. To this solution, manganese dioxide was added (16.6 g, 191 mmol) and the mixture was heated to 90° C. for 1 hour. The reaction was cooled, filtered through Celite and washed with CH2CL2. The filtrate was collected and concentrated in vacuo as a yellow solid which was purified by silica gel chromatography to afford the racemic mixture 3-(1-(3,4-difluorophenyl)propan-2-yl)-2-(3-hydroxypyridin-2-yl)-5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][C:12]([O:14]C)=[O:13])=[C:9]2[C:4]([N:5]([CH3:19])[C:6](=[O:18])[N:7]([CH3:17])[C:8]2=[O:16])=[N:3]1.OS(O)(=O)=O>O1CCOCC1.O>[CH3:1][N:2]1[C:10]([CH2:11][C:12]([OH:14])=[O:13])=[C:9]2[C:4]([N:5]([CH3:19])[C:6](=[O:18])[N:7]([CH3:17])[C:8]2=[O:16])=[N:3]1
Reactant: COC(=O)Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc2c(c1CC(=O)O)c(=O)n(C)c(=O)n2C

Procedure:
A mixture of Step 6 intermediate (1.0 g, 3.755 mmol) and 6 N H2SO4 (9.3 ml) in dioxane (9.3 ml) stirred at reflux temperature for 2 h to give a homogeneous pale yellow solution. This solution was cooled, diluted with water and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water, dried over Na2SO4 and concentrated. The residue obtained was triturated in diethyl ether, solid obtained was collected by filtration to give 330 mg of the product as a white solid; 1H NMR (300 MHz, DMSO-d6): δ 3.17 (s, 3H), 3.34 (s, overlapping with DMSO, 3H), 3.79 (s, 3H), 4.11 (s, 2H), 12.95 (br s, 1H) and 1H NMR (300 MHz, CDCl3): δ 3.39 (s, 3H), 3.50 (s, 3H), 3.88 (s, 3H), 4.10 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].C([O-])([O-])=O.[Na+].[Na+].[NH2:48][C:49]1[C:50]([C:56]([NH:58][C:59]2[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=2)=[O:57])=[N:51][C:52](Br)=[CH:53][N:54]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:48][C:49]1[C:50]([C:56]([NH:58][C:59]2[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=2)=[O:57])=[N:51][C:52]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:4][CH:3]=2)=[CH:53][N:54]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCc1ccc(Br)cc1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
A mixture of the product of step (ii) (9.84 g, 30 mmol), bis(pinacolato)diboron (11.4 g, 45 mmol), KOAc (9 g, 90 mmol) and Pd(dppf)Cl2 (1 g, 1.5 mmol) in dioxane (200 mL) was stirred and degassed with N2 (×3). The mixture was stirred at 80° C. under a N2 atmosphere for 3 hours. The reaction mixture was cooled to room temperature. Water (25 mL) and Na2CO3 (10 g, 90 mmol) were added to the mixture. The mixture was stirred for 10 minutes before the product of step (v) (7.9 g, 27 mmol) and Pd(dppf)Cl2 (0.5 g, 0.7 mmol) were added. The resulting solution was degassed again with N2 (×3). The reaction mixture was stirred at 90° C. under a N2 atmosphere for additional 10 hours. Na2SO4 was added, filtered and the filtrate concentrated in vacuo. The crude product was purified by column chromatography with PE:EtOAc=5:1 to 3:1 as eluent to afford the subtitle compound (vi) as a yellow solid (7.8 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[S:5][CH:6]=1.[CH3:17][S-:18].[Na+]>CN(C=O)C.[Cu](I)I>[CH3:17][S:18][C:2]1[N:3]=[C:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[S:5][CH:6]=1
Reactant: O=c1[nH]c2ccccc2n1-c1nc(Br)cs1
Reactant: C[S-]
Agent: I[Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1csc(-n2c(=O)[nH]c3ccccc32)n1
Temperature: 140 °C
Reaction time: 20 h

Procedure:
A mixture of 1-(4-bromo-1,3-thiazol-2-yl)-1,3-dihydro-2H-benzimidazol-2-one from Step A (1.00 g, 3.38 mmol), sodium methanethiolate (710 mg, 10.13 mmol), and copper iodide (643 mg, 3.38 mmol) in DMF (6 mL) were heated at 140° C. An additional amount of sodium methanethiolate (474 mg, 6.76 mmol) was added to the mixture after 3 h and 16 h and the reaction continued stirring at 140° C. After 20 h, the cooled mixture was partitioned between saturated aqueous NaHCO3 (30 mL) and CHCl3 (50 mL). The aqueous phase was extracted further with CHCl3 (50 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=264 (M+1).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([CH3:14])[CH:11]([N:15]([CH3:17])[CH3:16])[CH:10]([CH3:18])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[CH3:16][N:15]([CH3:17])[CH:11]1[CH:10]([CH3:18])[CH2:9][NH:8][CH2:13][CH:12]1[CH3:14]
Reactant: CC1CN(Cc2ccccc2)CC(C)C1N(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1CNCC(C)C1N(C)C

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.5 g) and Mixtures A+B of 1-benzyl-4-dimethylamino-3,5-dimethylpiperidine (2.7 g, 10.1 mmol) in methanol (50 ml) was stirred in hydrogen atmosphere (1 atm.) at 60° C. for 48 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford Mixtures A+B of 4-dimethylamino-3,5-dimethylpiperidine. Yield 0.9 g (52.6%), C9H20N2, m/z 157 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[N:6][C:7]=1F.[NH:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([NH:38]C(=O)OC(C)(C)C)[CH2:33]1>>[Br:1][C:2]1[C:7]([N:32]2[CH2:37][CH2:36][CH2:35][C@H:34]([NH2:38])[CH2:33]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(F)n2)c2cc(-c3cccnc3)ncc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Product: N[C@H]1CCCN(c2nc(-c3n[nH]c4cnc(-c5cccnc5)cc34)ccc2Br)C1
Yield: 22.32 %

Procedure:
Following the procedures as described in Example 241 and starting with 3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (S)-tert-butyl piperidin-3-ylcarbamate, 289 was obtained as an off-white solid (17.8 mg, 22.32%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.31 (d, J=1.8 Hz, 1H), 9.23 (s, 1H), 9.03 (s, 1H), 8.60 (d, J=4.7 Hz, 1H), 8.46 (d, J=7.9 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.62 (dd, J=11.8, 7.1 Hz, 1H), 7.52 (dd, J=8.0, 4.8 Hz, 1H), 3.92 (d, J=10.0 Hz, 1H), 3.84 (d, J=11.7 Hz, 1H), 2.89 (dt, J=16.9, 10.7 Hz, 2H), 2.82-2.75 (m, 1H), 1.96 (d, J=12.6 Hz, 1H), 1.90-1.71 (m, 2H), 1.27 (dd, J=20.9, 9.6 Hz, 1H); ESI MS m/z=450.1 (M+1)
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([O:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C=O)c1OCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
2-Hydroxy-3-methylbenzaldehyde 20.0 g (147 mmol) prepared by the above 1-(1) was dissolved in dimethylformamide (DMF) (100 ml) and to the solution was added potassium carbonate 31.0 g (221 mmol) and thereto was dropped benzyl bromide 25.0 g (147 mmol). The reaction mixture was stirred for 2 hours at 20° C. After disappearance of the raw material, the reaction mixture was filtrated and the solvent was removed in vacuo and the residue was purified in the same manner as in the above 2-(1) to give 2-benzyloxy-3-methylbenzaldehyde 24.2 g (yield: 73%).
Reaction SMILES: [N+](C1C=C(S([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=3)(=[O:25])=[O:24])=[CH:18][CH:17]=2)(=O)=O)C=CC=1)([O-])=O.O[C:36]1[CH:43]=[CH:42][C:39]([CH:40]=[O:41])=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:32]([C:28]1[CH:27]=[C:26]([S:23]([O:22][C:19]2[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][O:13][C:36]3[CH:43]=[CH:42][C:39]([CH:40]=[O:41])=[CH:38][CH:37]=3)=[CH:21][CH:20]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCCc2ccc(OS(=O)(=O)c3cccc([N+](=O)[O-])c3)cc2)c1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCCc2ccc(OS(=O)(=O)c3cccc([N+](=O)[O-])c3)cc2)cc1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A mixture of 32.5 g (64 mmole) 4-([3-nitrophenylsulfonyl]oxy)phenethyl 3-nitrobenzenesulfonate, 8 g (65 mmole) p-hydroxybenzaldehyde and 20 g (145 mmole) potassium carbonate in 300 ml acetonitrile was refluxed for 10 minutes, then stirred at room temperature over night and thereafter refluxed for 30 minutes. The salts were filtered off and the solvent evaporated in vacuo. Dichloromethane and water were added, the phases were separated, the organic phase was dried and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using dichloromethane as eluent and crystallization in diisopropyl ether gave 23.5 g (yield 86%) of 4-[2-(4-formylphenoxy)ethyl]phenyl 3-nitrobenzenesulfonate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:17])(=[N:12][C:13](=[O:16])[CH2:14][CH3:15])=[O:11])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:17])(=[N:12][C:13](=[O:16])[CH2:14][CH3:15])=[O:11])=[CH:8][CH:9]=1
Reactant: CCC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCC(=O)N=S(C)(=O)c1ccc(N)cc1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 77.6 %

Procedure:
106 mg (0.41 mmol) (RS)—S-(4-nitrophenyl)-N-propionyl-S-methylsulfoximide is dissolved in 10 ml ethanol and treated with 20 mg palladium on activated charcoal (10% Pd). The mixture is stirred under hydrogen at normal pressure for 45 minutes at 23° C. The catalyst is filtered off and the solution concentrated. After chromatographic purification (silica gel, hexane/ethyl acetate (0-50% ethyl acetate)), 72 mg (77%) of the desired product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:60][C:61]1([CH3:73])[O:65][C@H:64]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([NH2:72])=[N:68]2)[CH2:63][O:62]1>CN(C)C=O.C(OCC)(=O)C>[CH3:60][C:61]1([CH3:73])[O:65][C@H:64]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([NH:72][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:68]2)[CH2:63][O:62]1
Reactant: Cc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.51 g, 1.59 mmol) in N,N-dimethylformamide (6.14 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.79 mL, 4.79 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.06 g, 2.39 mmol) and a solution of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.33 g, 1.67 mmol) in N,N-dimethylformamide (0.5 mL). The reaction was stirred at 25° C. over the weekend. At this time, the reaction was diluted with ethyl acetate (75 mL) and was washed with a saturated aqueous ammonium chloride solution (1×150 mL), a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 50-100% ethyl acetate/hexanes) afforded (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.70 g, 88%) as an orange solid: HR-ES-MS m/z calculated for C26H33N4O5F [M+H]+ 501.2508, observed 501.2507; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.24 (s, 3H), 1.30 (s, 3H), 1.35-1.64 (m, 2H), 1.66-1.86 (m, 1H), 2.31 (s, 3H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 3.96-4.14 (m, 3H), 4.20 (d, J=18.4 Hz, 1H), 4.30-4.40 (m, 1H), 4.59 (d, J=18.4 Hz, 1H), 4.83-4.93 (m, 2H), 6.43 (d, J=2.1 Hz, 1H), 7.08-7.20 (m, 1H), 7.27-7.38 (m, 2H), 7.60 (d, J=2.1 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]([NH2:16])(=[S:15])[CH3:14].CCCCCC.C(OCC)(=O)C>C(#N)C>[CH3:14][C:13]1[S:15][CH:2]=[C:3]([C:4]#[C:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:16]=1
Reactant: O=C(C#Cc1ccccc1)CCl
Reactant: CC(N)=S
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1nc(C#Cc2ccccc2)cs1
Yield: 13.2 %

Procedure:
1-Chloro-4-phenyl-3-butyn-2-one (1.6 g, 9.1 mmol) was dissolved in dry acetonitrile (15 mL), treated with thioacetamide (680 mg, 9.1 mmol), and heated to reflux for 4 h. After cooling, the acetonitrile was removed in vacuo, and the residue was partitioned between water (50 mL) and ethyl acetate (150 mL). The organic phase was dried over Na2SO4, filtered, concentrated in vacuo, adsorbed onto silica gel, and purified by column chromatography on silica gel eluting with 99:1, 98:2, then 95:5 hexane:ethyl acetate to afford 2-methyl-4-(phenylethynyl)-1,3-thiazole (240 mg, 13% yield) as a red oil. 1H NMR (CDCl3, 300 MHz) δ 7.58–7.54 (m, 2H), 7.40–7.34 (m, 4H), 2.74 (s, 3H). MS (EI ionization) 199 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[C:9]1([CH2:15][N:16]2[CH2:20][CH:19]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F-].[Cs+]>C1COCC1.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>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([C:18]2[CH2:17][N:16]([CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:20][CH:19]=2)=[CH:7][N:6]=1
Reactant: CC1(C)OB(C2=CCN(Cc3ccccc3)C2)OC1(C)C
Reactant: Cc1ncc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ncc(C2=CCN(Cc3ccccc3)C2)cn1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
The title compound can be prepared through a coupling palladium mediated reaction, e.g. starting from 5-bromo-2-methylpyrimidine and 1-(phenylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole. For example, to a solution of 5-bromo-2-methylpyrimidine (1.3 eq.) in THF, 1-(phenylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole (1 eq.), tetrakis(triphenylphosphine)palladium(0) (5% mol) and cesium fluoride (4 eq.) may be added at room temperature. The resulting mixture should be stirred at 80° C. for 1.5 hours. After cooling the solvent should be evaporated under reduced pressure and the residue partitioned between dichloromethane and sodium hydroxyde (1M). The organic phase should be evaporated under reduced pressure and the crude product purified by flash chromatography to give the title compound.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:28])[NH:6][C:7]1[CH:13]=[CH:12][C:11]([O:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)(=[O:17])=[O:16])=[CH:10][C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH3:29][O:30][C:31]([NH:33][C:34](=[N:37][C:38]([O:40][CH3:41])=[O:39])SC)=[O:32].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([NH:4][C:5](=[O:28])[NH:6][C:7]1[CH:13]=[CH:12][C:11]([O:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=2)(=[O:16])=[O:17])=[CH:10][C:8]=1[NH:9][C:34]([NH:37][C:38]([O:40][CH3:41])=[O:39])=[N:33][C:31]([O:30][CH3:29])=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)N=C(NC(=O)OC)Nc1cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)ccc1NC(=O)NC(C)=O

Procedure:
14.6 g of 2-(3-acetylureido)-5-(3-trifluoromethylphenylsulfonyloxy)aniline, 12.4 g of N,N'-bismethoxycarbonyl-S-methylisothiourea and 75 mg of p-toluenesulfonic acid are stirred under reflux for two hours. After cooling down, the mixture is evaporated under reduced pressure, the residue is recrystallized from isopropanol and the crystals are stirred with cold ethyl acetate, filtered off with suction and washed, melting point 189° C., decomposition.
Reaction SMILES: [CH:1]([C@H:4]1[C:9]([O:10]C)=[N:8][C@@:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:12])[C:6]([O:20][CH3:21])=[N:5]1)([CH3:3])[CH3:2].Cl>C(OCC)C>[CH:1]([C@H:4]1[C:9](=[O:10])[NH:8][C@@:7]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([CH3:12])[C:6]([O:20][CH3:21])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC1=N[C@](C)(Cc2ccccc2)C(OC)=N[C@H]1C(C)C
Agent: Cl
Solvent: CCOCC
Product: COC1=N[C@@H](C(C)C)C(=O)N[C@]1(C)Cc1ccccc1
Reaction time: 2 h
Yield: 68.6 %

Procedure:
1.44 g of (2S,5R)-2,5-dihydro-2-isopropyl-3,6-dimethoxy-5-benzyl-5-methylpyrazine in 30 ml of diethyl ether were treated at room temperature with 25 ml of 0.2 N HCl in diethyl ether. After 2 h, the mixture was evaporated under reduced pressure. Distillation of the residue yielded 0.94 g (69%) of crude (2S,5R)-2,5-dihydro-2-isopropyl-6-methoxy-5-benzyl-5-methyl-3-pyrazinone, boiling point 170° C./0.005 torr.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:33]=[CH:32][C:16]3[N:17]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:19][C:15]=3[CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:38][O:39][C:40](=[O:47])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]Br.O>CN(C)C=O>[CH3:38][O:39][C:40](=[O:47])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:34])[F:35])=[CH:4][CH:5]=1)(=[O:10])=[O:11])[C:13]1[CH:33]=[CH:32][C:16]2[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:19][C:15]=2[CH:14]=1
Reactant: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
150 mg of 4-(trifluoromethyl)-N-(1,2-diphenyl-1H-benzimidazol-5-yl)benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 11 mg of sodium hydride and stirred for 30 minutes at 20° C. 88 mg of 6-bromohexanoic acid methyl ester was added, it was allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was digested with diisopropyl ether.