Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:14]([S:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[C:10]([F:13])[CH:11]=[N:12][C:2]=1[O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([S:16][CH2:14][CH3:15])[CH:18]=1)[CH3:8]
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Reactant: CCSc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(F)cnc1Oc1cccc(SCC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
Ethyl 2-chloro-5-fluoro-nicotinate (J. Med. Chem. 1993, 36, 2676, M. Winn et. al.) (5.0 g, 24 mmol), 3-ethylsulfanylphenol (3.8 g, 24 mmol) and caesium carbonate (7.98 g, 24 mmol) were suspended in dioxan (50 ml) and the reaction was heated to 100° C. and stirred at this temperature under nitrogen for 8 h. The reaction was cooled to room temperature, filtered and the solid washed with ethyl acetate (50 ml). The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with cyclohexane:ethyl acetate (95:5) to give 5-fluoro-2-(3-ethylsulfanyl-phenoxy)-nicotinic acid ethyl ester (1.16 g).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[CH2:15][CH2:14]1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (2.5 g, 16 mmol), N-methylpiperazine (2 mL, 18 mmol) and potassium carbonate (2.7 g, 19 mmol) in DMSO (7 mL) was stirred and heated at 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature and then diluted with ethyl acetate (100 mL), washed with water (3×30 mL), brine, dried (MgSO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with dichloromethane—40% methanol/dichloromethane (gradient) to afford the desired title compound as a yellow solid, 3.67 g, 97%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1(/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][O:30]CC3C=CC=CC=3)=[CH:21][CH:20]=2)[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC(OC)(C)C>CO.CN(C=O)C.C([O-])(O)=O.[Na+].[OH-].[OH-].[Pd+2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:23][CH:24]=2)[CH2:10][O:11][C:12]([CH3:16])([CH3:15])[O:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(/C=C/c2ccc(C#CCCCOCc3ccccc3)cc2)COC(C)(C)OC1
Agent: [Pd+2]
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Solvent: COC(C)(C)OC
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(CCc2ccc(CCCCCO)cc2)COC(C)(C)OC1
Yield: 72.5 %

Procedure:
Palladium hydroxide on carbon (20%) (36 mg, 0.05 mmol) was added to a solution of 18 (0.361 g, 0.71 mmol) in MeOH (8 mL). Hydrogen was bubbled through the suspension with stirring until 18 was completely consumed and converted to a polar substance (monitored by TLC:hexanes/EtOAc 2:1). The mixture was filtered through a short pad of silica gel and concentrated under vacuum. To a solution of the resulting yellow oil in dry DMF (5 mL) were added 2,2-dimethoxypropane (90.5 mg, 0.84 mmol) and camphorsulfonic acid (10 mg, 0.043 mmol). After the mixture was stirred at room temperature for 1 day, it was diluted with saturated aqueous NaHCO3 solution (15 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layer was washed sequentially with saturated aqueous NaHCO3 solution (2×20 mL), water (2×20 mL), and brine (20 mL), and was then dried (Na2SO4). The solvent was removed under vacuum, and the residue was purified by chromatography (hexanes/EtOAc 8:1 to 2:1) to give 19 (217 mg, 72%). 1H NMR δ 7.15-7.05 (m, 4H), 5.09 (s, 1H), 3.89 (d, 2H, J=11.6 Hz), 3.67 (d, 2H, J=11.6 Hz), 3.60 (t, 2H, J=6.8 Hz), 2.60-2.50 (m, 4H), 2.40 (br s, 1H), 1.96 (t, 2H, J=8.0 Hz), 1.65-1.36 (m, 21H); 13C NMR δ 154.7, 139.9, 139.0, 128.2, 128.0, 98.2, 79.1, 66.1, 62.4, 51.5, 35.5, 33.5, 32.4, 31.2, 28.4, 28.2, 27.2, 25.3, 19.7. HRMS m/z: calcd for C24H40NO5 (MH+), 422.2901; found, 422.2904.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:12]([C:2]2[CH:11]=[CH:10][CH:5]=[CH:4][CH:3]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: COC(=O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 140.7 %

Procedure:
According to the general procedure A, methyl 4-chlorobenzoate (88 mg, 0.52 mmol) reacted with aniline (57 mg, 0.61 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and K3PO4 (260 mg, 1.23 mmol) in DME at 100° C. for 24 h to give the title compound (111 mg, 96%) as a solid: 1H-NMR (400 MHz, CDCl3): δ 7.94 (d, 2H, J=7.6 Hz), 7.35 (t, 2H, J=6.0 and 7.6 Hz), 7.19 (d, 2H, J=7.6 Hz), 7.08 (t, 1H, J=7.6 Hz), 7.01 (d, 2H, J=8.8 Hz), 6.27 (bs, 1H), 3.89 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 166.97, 148.06, 140.75, 131.36, 129.37, 122.91, 120.74, 120.27, 114.41, 51.65. GC/MS(EI): m/z 227 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1Br)=[O:4].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>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.C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)c1sccc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 34.4 %

Procedure:
3-Bromothiophene-2-carboxylic acid methyl ester (1.0 g, 4.5 mmol, 1.0 eq.), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (1.4 g, 4.5 mmol, 1.0 eq.), THF (50 mL) and Na2CO3 (9 mL, 18 mmol, 4.0 eq.) were combined. The mixture was degassed and purged with nitrogen (3×). PdCl2(PPh3)2 (10.1 g, 0.14 mmol, 0.03 eq.) was added, and the mixture was again degassed and purged with nitrogen (3×), then heated at 80° C. overnight. The mixture was then cooled and the layers were separated. The THF layer was diluted with EtOAc (50 mL), washed with saturated aqueous NaCl (20 mL) and dried over Na2SO4. The material was filtered and applied onto a silica gel column and purified by chromatography with PE/EtOAc (20:1˜10:1) to yield 4-(2-methoxycarbonylthiophen-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (0.5 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[Cl:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[Cl:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccc(Cl)cc1Cl
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccc(Cl)cc2Cl)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 33.1 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (0.690 g, 0.004 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (2.1 g, 0.016 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2,4-dichloro-phenoxy)-but-2-enoic acid ethyl ester (1.20 g, 0.003 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,4-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (410 mg, 27%) as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=[C:11]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[C-:33]#[N:34].[Na+].O>CS(C)=O>[C:33]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=[C:11]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)#[N:34]
Reactant: BrCCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
1-(8-Bromooctyl)-2,4,5-triphenylimidazole (4 g) in dimethylsulphoxide (30 ml) was added dropwise to a mixture of sodium cyanide (0.5 g) in dry dimethylsulphoxide (30 ml). The reaction mixture was stirred at 50° C. for 2 h, cooled and poured into water (400 ml). The aqueous was extracted with diethyl ether (4×100 ml), the extracts were combined, washed with water (100 ml), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Chromatography on silica gel eluted with a dichloromethane:methanol gradient and recrystallisation from ether gave 1-(8-cyanoctyl)-2,4,5-triphenylimidazole (1.1 g, 31%) as a white solid, m.p. 72°-73°. Found: C, 83.10; H, 7.21; N, 9.69%; C30H31N3 requires: C, 82.90; H, 7.19; N, 9.57%.
Reaction SMILES: C(Cl)Cl.C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([C:21]2[CH:22]=[C:23]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:30][CH:29]=3)[C:24]([Cl:27])=[CH:25][CH:26]=2)=[O:20])[CH2:13][CH2:12]1)=O)(C)(C)C.FC(F)(F)C(O)=O>O>[NH:11]1[CH2:12][CH2:13][CH:14]([CH2:17][NH:18][C:19]([C:21]2[CH:22]=[C:23]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)[C:24]([Cl:27])=[CH:25][CH:26]=2)=[O:20])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2ccc(Cl)c(-c3ccc(-c4ccccc4)cc3)c2)CC1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CCNCC1)c1ccc(Cl)c(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To an oven dried 10 mL round bottom flask was added 5 mL of DCM, 20 mg (0.04 mmol) of 331, 1.5 mL trifluoroacetic acid (TFA), and 50 μL H2O. The reaction solution was stirred for 1 hour and quenched with 1 mL of saturated NaHCO3. The product was taken up in 20 mL of DCM and the organic solution further washed with water (3×15 mL) and dried over Na2SO4. The organic solution was rotary evaporated to provide 16.0 mg of the product as a pale tan oil (99.0% yield). 1H NMR 400 MHz DMSO-d6: δH 8.71 (1H, dd, J=2.7, 3.1 Hz), 8.48 (1H, br s), 8.07 (1H, br s), 7.90 (1H, s), 7.83-7.30 (10H, m); 3.28-1.16 (11H, m); MS (ES+) m/z 405 (M+H); HPLC (214 nm), rt 4.94 min, 99.8%.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]([C:17]1[N:18]=[C:19]([N:22]2[CH2:25][CH:24]([OH:26])[CH2:23]2)[S:20][CH:21]=1)=[O:16])[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]([C:17]1[N:18]=[C:19]([N:22]2[CH2:23][CH:24]([O:26][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:25]2)[S:20][CH:21]=1)=[O:16])[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.1 %

Procedure:
To a solution of 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (700 mg, 1.75 mmol) (obtained as described in Reference Example 36(4)) in methylene chloride (35 ml) were added methanesulfonyl chloride (406 μl, 5.25 mmol) and triethylamine (736 μl, 5.25 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (895 mg, yield 100%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9]C(OC(C)(C)C)=O)=[CH:4][C:3]=1[F:17].[Cl:18][C:19]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])=[CH:26][C:20]=1[C:21]([N:23]=[C:24]=[O:25])=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:18][C:19]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])=[CH:26][C:20]=1[C:21]1[NH:23][C:24](=[O:25])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:17])[CH:4]=2)[N:9]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(Cl)c(F)c1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(Cl)c(F)c3)c(=O)[nH]2)c1)C(F)(F)F
Yield: 37104.1 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using tert-butyl 2-(4-chloro-3-fluorophenyl)hydrazinecarboxylate (Intermediate-71, 0.828 g, 0.003 mmol), 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 1.3 g, 0.043 mmol), DCM (20 mL), trifluoro acetic acid (5.0 mL) to afford 0.500 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 4.45 (d, 2H), 7.48 (d, J=15.0 Hz, 1H), 7.68-7.83 (m, 3H), 7.85 (d, 1H), 7.99 (d, J=17.1 Hz, 1H), 10.08 (d, J=12.0 Hz, 1H), 12.73 (s, 1H).
Reaction SMILES: O=S(Cl)Cl.[CH2:5]([O:7][C:8]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]2)=[CH:13][C:9]=1[C:10](N)=[O:11])[CH3:6].OC1C=CC([C@H]2CC[C@H](CCC)CC2)=CC=1.C(Cl)(Cl)Cl.[OH-].[K+]>>[CH2:5]([O:7][C:8]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:18][CH2:19][C@H:20]([CH2:23][CH2:24][CH3:25])[CH2:21][CH2:22]2)=[CH:13][C:9]=1[CH:10]=[O:11])[CH3:6]
Reactant: CCC[C@H]1CC[C@H](c2ccc(OCC)c(C(N)=O)c2)CC1
Agent: CCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCC[C@H]1CC[C@H](c2ccc(OCC)c(C=O)c2)CC1

Procedure:
18 g of SOCl2 is added, at 80°, to a suspension of 28.9 g of 2-ethoxy-5-(trans-4-propyl-cyclohexyl)-benzamide [obtainable, for example, by reaction of trans-1-(4-hydroxyphenyl)-4-propyl-cyclohexane with chloroform/KOH to give 2-ethoxy-5-(trans-4-propylcyclohexyl)-benzaldehyde, oxidation to the acid, reaction with SOCl2 to give the chloride and reaction with NH3 ] in 100 ml of toluene. After the mixture has been stirred at 80° for 6 hours, cooled and poured into water, 2-ethoxy-5-(trans-4-propyl-cyclohexyl)-benzonitrile of m.p. 32° is obtained.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([NH:9][C:10]([O:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6].O.[OH-].[Li+]>C1COCC1.CO.O>[C:13]12([O:12][C:10]([NH:9][C@@H:4]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:3]([OH:23])=[O:2])=[O:11])[CH2:14][CH:15]3[CH2:16][CH:17]([CH2:18][CH:19]([CH2:21]3)[CH2:20]1)[CH2:22]2
Reactant: COC(=O)[C@@H](NC(=O)OC12CC3CC(CC(C3)C1)C2)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[C@H](NC(=O)OC12CC3CC(CC(C3)C1)C2)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.1 %

Procedure:
To a solution of (S)-2-(Adamantan-1-yloxycarbonylamino)-3,3-dimethyl-butyric acid methyl ester (358 mg, 1.107 mmol) in THF (4 mL) and MeOH (4 mL) was added a pre-made solution of lithium hydroxide monohydrate (93 mg, 2.214 mmol) in water (4.00 mL). The cloudy white solution was stirred at rt for 5 hrs. The volatiles were removed, and the reaction mixture was diluted with dilute citric acid solution and extracted with EtOAc (3×10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to obtain a white solid (291.4 mg, 85%) as product. The crude material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:30]([NH:32][CH3:33])[CH3:31])=[N:9][C:10]=2[C:11]2[CH:29]=[CH:28][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:34]([OH:39])(=O)[C:35]#[C:36][CH3:37]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:30]([N:32]([CH3:33])[C:34](=[O:39])[C:35]#[C:36][CH3:37])[CH3:31])=[N:9][C:10]=2[C:11]2[CH:29]=[CH:28][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CN[C@@H](C)c1nc(-c2ccc(C(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)nccn12
Reactant: CC#CC(=O)O
Product: CC#CC(=O)N(C)[C@@H](C)c1nc(-c2ccc(C(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)nccn12
Yield: 33.4 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(1-(methylamino)ethyl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (intermediate 48) and 2-butynoic acid, to afford the title compound (11.5 mg, 33.4%). Data: UPLC(C) Rt: 2.54 min; m/z 522.2 (M+H)+.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[C:29]([C:34](O)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[C:29]([C:34]([N:2]3[C@H:3]([CH2:7][NH:8][C:9]([C:11]4[C:20]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:14]=[CH:13][CH:12]=4)=[O:10])[CH2:4][C@H:5]4[C@@H:1]3[CH2:6]4)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Reactant: O=C(O)c1ccccc1-c1cccc(Cl)c1
Product: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1ccccc1-c1cccc(Cl)c1)c1cccc2c1OCCO2

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 3′-chloro-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.43 min; [M+H]+=489.0.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([O-:13])=[O:12]>N1C=CC=CC=1>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([S:20]([O:1][C:2]2[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=2[CH3:10])(=[O:22])=[O:21])=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(O)c(=O)ccn1C
Solvent: c1ccncc1
Product: Cc1c(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c(=O)ccn1C
Yield: 50 %

Procedure:
3-Hydroxy-1,2-dimethylpyridin-4(1H)-one (0.2 g, 1.5 mmol) was reacted with 4-nitrobenzenesulfonyl chloride (0.488 g, 2.2 mmol) in 10 mL of pyridine to afford PZBG-3c in 50% yield (0.23 g, 0.7 mmol). 1H NMR (400 MHz, CDCl3) δ=8.41-8.34 (m, 4H), 7.26 (d, J=7.6 Hz, 1H), 6.33 (d, J=7.6 Hz, 1H), 3.67 (s, 3H), 2.53 (s, 3H). 13C NMR (100 MHz, CDCl3) 6=170.9, 150.9, 144.9, 143.2, 140.9, 140.1, 130.4, 124.0, 118.4, 41.9, 14.6. ESI-MS(+): m/z 325.11 [M+H]+, 346.96 [M+Na]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>CCO>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH:9]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cc(Br)c(F)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccccc1)c1cc(Br)c(F)cc1O
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
In a bottle were combined 1-(5-bromo-4-fluoro-2-hydroxyphenyl)ethanone (8.63 g, 37.15 mmol), benzaldehyde (3.94 g, 37.15 mmol), EtOH (96%, 45 mL) and NaOH (13.08 g, 327 mmol). The mixture was stirred vigorously for 0.5 h. and then filtered. The mixture was poured into HCl (1 N, 50 mL) and filtered. The solid was dried to give 1-(5-bromo-4-fluoro-2-hydroxyphenyl)-3-phenylprop-2-en-1-one (10.8 g, 91%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.Cl>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:24]5[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]5)=[CH:32][CH:31]=4)[N:7]=3)=[CH:12][NH:11][N:10]=2)=[CH:14][CH:15]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Clc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Agent: Cl
Product: CN1CCN(c2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
The solution of 150 mg (0.515 mMol) of 2-chloro-4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidine in 5 mL of 1,4-dioxanes (Merck p.a. 9671) at rt is treated with 99 mg of 4-(4-methyl-piperazin-1-yl)-phenylamine (0,515 mMol, 1 Eq.) and 235 mg (2.06 mMol; 202 μl; 4 Eq.) of HCl (32%) (Fluka puriss 84416). The yellow suspension is stirred for 24 h at 100° C. After cooling to rt, the supernatant is decanted and discarded. The smeary residue is treated with 10 ml of NaHCO3 satd. solution and 10 ml of ethyl acetates. The precipitated crude product is filtered off and dried at 60° C. under reduced pressure. The combined organic layers are re-extracted with water, dried (Na2SO4), and evaporated to obtain additional crude product. The combined crude products are purified by means of column chromatography over silica gel (Si60 (0,040-0,063 mm) Merck); eluting with CH2Cl2/CH3OH/NH4OH (9:1:0.1). Final purification is done by suspending the obtained beige crystals in CH2Cl2/CH3OH (1:1) to obtain {4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as pure crystals.