Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:14])[N:3]=1.[NH2:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:14][C:4]1[N:3]=[C:2]([NH:15][C:16]2[CH:21]=[C:20]([CH:19]=[CH:18][N:17]=2)[C:22]#[N:23])[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=1
Reactant: N#Cc1ccnc(N)c1
Reactant: Clc1cc(C2CCOCC2)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1ccnc(Nc2cc(C3CCOCC3)cc(Cl)n2)c1
Temperature: 80 °C
Yield: 54.5 %

Procedure:
To a 25 mL round-bottomed flask charged with 2,6-dichloro-4-(tetrahydro-2H-pyran-4-yl)pyridine (1.20 g, 5.20 mmol, 1.00 equiv), 2-aminopyridine-4-carbonitrile (620 mg, 5.20 mmol, 1.00 equiv), cesium carbonate (2.40 g, 7.20 mmol, 1.40 equiv), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (170 mg, 0.260 mmol, 0.0500 equiv), and tris(dibenzylidineacetone)dipalladium(0) (120 mg 0.130 mmol, 0.0250 equiv) was added 1,4-dioxane (10 mL) under nitrogen atmosphere. The reaction was then heated to 80° C. for 16 h after which the mixture was cooled to room temperature, diluted with ethyl acetate (15 mL) and washed with water (2×15 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (40:60 ethyl acetate/heptane) afforded the desired product as a yellow solid (892 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6), δ: 10.38 (s, 1H), 8.49 (d, J=5.3 Hz, 1H), 7.94 (s, 1H), 7.63 (s, 1H), 7.34-7.23 (dd, J=4.0, 2.0 Hz, 1H), 6.98 (d, J=1.1 Hz, 1H), 3.95 (dd, J=11.9, 4.0 Hz, 2H), 3.44 (td, J=11.9, 2.4 Hz, 2H), 2.82 (tt, J=12.0, 3.6 Hz, 1H), 1.77-1.70 (m, 2H), 1.69-1.61 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[C:4]([N:27]([CH:36]2[CH2:41][C:40]([CH3:43])([CH3:42])[NH:39][C:38]([CH3:45])([CH3:44])[CH2:37]2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[N:3]=1.[NH2:46][CH2:47][CH2:48][CH2:49][CH:50]([CH2:56][NH2:57])[CH2:51][CH2:52][CH2:53][CH2:54][NH2:55]>C1(C)C(C)=CC=CC=1>[CH2:28]([N:27]([C:4]1[N:5]=[C:6]([N:8]([CH:9]2[CH2:10][C:11]([CH3:17])([CH3:18])[NH:12][C:13]([CH3:15])([CH3:16])[CH2:14]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:7]=[C:2]([NH:46][CH2:47][CH2:48][CH2:49][CH:50]([CH2:56][NH:57][C:2]2[N:3]=[C:4]([N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:36]3[CH2:37][C:38]([CH3:44])([CH3:45])[NH:39][C:40]([CH3:43])([CH3:42])[CH2:41]3)[N:5]=[C:6]([N:8]([CH:9]3[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12][C:13]([CH3:15])([CH3:16])[CH2:14]3)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:7]=2)[CH2:51][CH2:52][CH2:53][CH2:54][NH:55][C:2]2[N:3]=[C:4]([N:27]([CH:36]3[CH2:37][C:38]([CH3:44])([CH3:45])[NH:39][C:40]([CH3:43])([CH3:42])[CH2:41]3)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[N:5]=[C:6]([N:8]([CH:9]3[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12][C:13]([CH3:15])([CH3:16])[CH2:14]3)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:7]=2)[N:3]=1)[CH:36]1[CH2:37][C:38]([CH3:45])([CH3:44])[NH:39][C:40]([CH3:42])([CH3:43])[CH2:41]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: NCCCCC(CN)CCCN
Reactant: CCCCCCCCN(c1nc(Cl)nc(N(CCCCCCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Solvent: Cc1ccccc1C
Product: CCCCCCCCN(c1nc(NCCCCC(CCCNc2nc(N(CCCCCCCC)C3CC(C)(C)NC(C)(C)C3)nc(N(CCCCCCCC)C3CC(C)(C)NC(C)(C)C3)n2)CNc2nc(N(CCCCCCCC)C3CC(C)(C)NC(C)(C)C3)nc(N(CCCCCCCC)C3CC(C)(C)NC(C)(C)C3)n2)nc(N(CCCCCCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1

Procedure:
A solution of 28.3 g of 2-chloro-4,6-bis[N-octyl-N-(2,2,6,6-tetramethyl-4-piperidyl)amino]-1,3,5-triazine [prepared as described in Preparation 2(b)] and 1.0 g of 1,8-diamino-4-aminomethyloctane in 200 ml of xylene was refluxed for 10 hours. It was then treated as described in Example 1 to give a residue, which was purified by column chromatography through silica gel, eluted with a 20:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine, to give the desired Compound No. 14, in the form of crystals melting at 55°-60° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:25][CH:26]=C)[CH2:5][C@@H:6]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:29](O)(=[O:31])C.CSC>CO.C(Cl)Cl.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:25][CH:26]([O:31][CH3:29])[N:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@@H:6]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:5]1)=[O:28]
Reactant: C=CC[C@H](C[C@@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC
Reactant: CC(=O)O
Solvent: ClCCl
Solvent: CO
Solvent: CSC
Product: COC(=O)[C@@H]1CC(OC)N(C(=O)OCc2ccccc2)[C@@H](C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ozone gas was bubbled through a stirred, cold, (−78° C.) solution of (2R,4R)-4-allyl-2-benzyloxycarbonylamino-pentanedioic acid 1-tert-butyl ester 5-methyl ester (5.0 g, 12.8 mmol) in 100 mL of 10:1 methanol/methylene chloride, and 0.73 mL of acetic acid until a blue color persisted. Nitrogen gas was then bubbled through the solution until the blue color dissipated. The mixture was warmed to ambient temperature and dimethyl sulfide (2.8 mL, 3.83 mmol) was added. The mixture was stirred for 48 hours, diluted with methylene chloride, and washed with 10% aqueous sodium carbonate, brine, and the mixture was dried over sodium sulfate. Filtration and concentration of the filtrate provided (2R,4S)-6-methoxy-piperidine-1,2,4-tricarboxylic acid 1-benzyl ester 2-tert-butyl ester 4-methyl ester as a clear oil, which was used in the subsequent step without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([C:32](O)=[O:33])[CH2:27]1)(=[O:25])=[O:24]>>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([C:32]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[O:33])[CH2:27]1)(=[O:24])=[O:25]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(O)C1CCCN(S(=O)(=O)c2ccc3ccccc3c2)C1
Product: O=C(C1CCCN(S(=O)(=O)c2ccc3ccccc3c2)C1)N1CCN(c2ccncc2)CC1
Yield: 25 %

Procedure:
Using an analogous procedure to that described in Example 14, 1-(4-pyridyl)piperazine was reacted with 1-(2-naphthylsulphonyl)piperidine-3-carboxylic acid to give 1-[1-(2-naphthylsulphonyl)-piperidin-3-ylcarbonyl]-4-(4-pyridyl)piperazine as a foam in 25% yield;
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([NH2:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([S:39][CH3:40])[C:27]=1[C:28](Cl)=[O:29]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([NH:23][C:28](=[O:29])[C:27]2[C:31]([S:39][CH3:40])=[CH:32][C:33]([C:35]([F:38])([F:36])[F:37])=[CH:34][C:26]=2[O:25][CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)Cl
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1

Procedure:
In analogy to the procedure described for the synthesis of example 16, the title compound was prepared from rac-3-amino-3-phenyl-piperidine-1-carboxylic acid benzyl ester (example 29, step 1) and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoyl chloride (Example B.6).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[K+]>CCO.O>[N+:15]([C:13]1[CH:12]=[CH:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=2[CH:14]=1)([O-:17])=[O:16]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2s1
Yield: 85 %

Procedure:
10 g (39.8×10−3 moles) 5-nitrobenzo[b]thiophen-2-carboxylic acid ethyl ester in 250 ml of EtOH and 60 ml of H2O were reacted with 3.8 g (67.8×10−3 moles) of KOH at 60° C. for 2 hours, after which the potassium salt of the product was collected by filtration. A further fraction of the product was collected on adding isopropanol to the filtrate. The salt was dissolved in water and after acidulating the solution with HCl(c), the protonated form of the acid was precipitated out. It was purified by recrystallisation in H2O/EtOH. Yield: 85%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:11][C@H:10](O)[CH2:9]2)=[CH:4][C:3]=1[F:13].[NH3:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:11][C@H:10]([N:14]3[CH2:6][CH2:7][CH2:2][C@H:3]3[CH3:4])[CH2:9]2)=[CH:4][C:3]=1[F:13]
Reactant: O[C@H]1C[C@@H](c2ccc(Br)c(F)c2)C1
Reactant: N
Product: C[C@@H]1CCCN1[C@H]1C[C@H](c2ccc(Br)c(F)c2)C1

Procedure:
The title compound was prepared using the procedure described in Example 1B except substituting the product from Example 22C for the product from Example 1A. 1H NMR (300 MHz, CD3OD) δ 1.12 (d, J=6 Hz, 3 H), 1.48 (m, 1 H), 1.78 (m, 2 H), 2.00 (m, 1 H), 2.23 (m, 1 H), 2.36 (m, 2 H), 2.59 (m, 3 H), 3 H), 3.03 (m, 1 H), 3.34 (m, 1 H), 3.48 (m, 1 H), 7.06 (dd, J=9 Hz, J=3 Hz, 1 H), 7.17 (dd, J=9 Hz, J=3 Hz, 1 H), 7.53 (t, J=9 Hz, 1 H); (DCl/NH3) m/z 312 (M+H)+.
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([O:15]CC=C)=[O:14])[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@H:25]([OH:27])[CH3:26])[C@H:4]([OH:29])[CH2:3]1.[OH-].[Li+].CO.Cl>C1COCC1>[Cl:1][C@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C@@H:5](/[CH:19]=[CH:20]/[C@@H:21]([OH:28])[CH2:22][CH2:23][CH2:24][C@H:25]([OH:27])[CH3:26])[C@H:4]([OH:29])[CH2:3]1
Reactant: C=CCOC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](O)C[C@H]1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](O)CCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@H](Cl)C[C@H]1O
Yield: 70 %

Procedure:
A solution of 77 mg (0.18 mmol) of ester 9 in 1.4 mL of THF was hydrolyzed with 400 uL (0.18 mmol) of aqueous lithium hydroxide (0.5M) and 0.4 mL of methanol at 25° C. for 5 h. The mixture was acidified by addition of 200 uL of 1.0M hydrochloric acid and the residual water was removed in vacuo. The residual products were purified by FCC on 10 g of silica gel eluted with 100% EtOAc, 5% methanol:95% EtOAc, then 10% methanol:90% ethyl acetate. Isolated from appropriate fractions was 49 mg of free acid 10 as an oil (70% yield); 1H NMR (acetone-d6): 1.11 (d, J=6.3 Hz, 3H), 1.45 (m, 6H), 1.67 (m, 2H), 1.91 (m, 1H), 2.09-2.37 (m, 8H), 2.86 (br s, 4H), 3.71 (m, 1H), 4.12 (m, 3H), 5.54 (m, 4H).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH2:8][CH2:9][N:10]2[C:14](=[CH:15][C:16](SC3C=CC=CC=3)=[O:17])[CH2:13][S:12][C:11]=12)=[O:6])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.FC(F)(F)C([O-])=O.[Ag+]>[CH:1]([O:4][C:5]([C:7]1[CH2:8][CH2:9][N:10]2[C:14](=[CH:15][C:16]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:17])[CH2:13][S:12][C:11]=12)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)C1=C2SCC(=CC(=O)Sc3ccccc3)N2CC1
Reactant: C1CCNCC1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)OC(=O)C1=C2SCC(=CC(=O)N3CCCCC3)N2CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
1.0 g of S-phenyl (7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo[2,1-b]thiazol-3-ylidene)thioacetate and 1.2 g of piperidine were suspended in 40 ml of tetrahydrofuran and 740 mg of silver trifluoroacetate was added thereto under stirring at room temperature. After 2 hours, the insoluble matters were filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography and recrystallized from ethanol. Thus 0.65 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([CH2:13][O:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)[CH2:11][O:10][C:9]2=[O:25])=[CH:4][CH:3]=1.Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([CH2:13][O:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[CH2:11][O:10][C:9]2=[O:25])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCC2COC(=O)N2c2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1ccc(OCC2COC(=O)N2c2ccc(Cl)cc2)cc1
Yield: 64 %

Procedure:
A solution of 1.30 g of methyl 4-[3-(4-chlorophenyl)-2-oxooxazolidin-4-yl]methoxybenzoate (compound 176) obtained in Example 22 in 18 ml of acetic acid and 10 ml of concentrated hydrochloric acid was refluxed with heating for 24 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was recrystallized from acetic acid-water to give 0.80 g of the title compound (compound 179) in a yield of 64%.
Reaction SMILES: [N+](C1C=CC(C[CH:9]2[C@@H:15]3[N:12]([C:13](=[O:19])[C@@H:14]3[C@@H:16]([OH:18])[CH3:17])[C:11]([C:20]([O-:22])=[O:21])=[C:10]2[S:23][CH2:24][CH2:25][NH:26]C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1)([O-])=O.O1CCOCC1.O.P([O-])([O-])([O-])=O>[Pd].C(O)C>[NH2:26][CH2:25][CH2:24][S:23][C:10]1[CH2:9][C@H:15]2[N:12]([C:13](=[O:19])[C@@H:14]2[C@@H:16]([OH:18])[CH3:17])[C:11]=1[C:20]([OH:22])=[O:21]
Reactant: C[C@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)C(Cc3ccc([N+](=O)[O-])cc3)[C@@H]12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: C[C@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SCCN)C[C@H]12
Reaction time: 2 h

Procedure:
A mixture of the ester (e3) (30 mg), 10% palladium on charcoal (50 mg), dioxan (4 ml), water (1 ml), ethanol (0.3 ml) and 0.05 M pH 7 phosphate buffer solution (1.3 ml) was shaken under hydrogen for 2h. The catalyst was removed by filtration of the mixture over Celite washing with water (10 ml) and the solution was then concentrated to a volume of about 10 ml. The aqueous solution was washed with ether (3×20 ml) and ethyl acetate (10 ml) before concentrating in vacuo to a volume of about 3 ml. The solution was loaded onto a column (80×12 mm) of XAD-2, which was then eluted with water to afford (5R, 6S)-3-(2-aminoethylthio)-6-[(s)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (e4) which was identified by the absorption at λmax (H2O) 297 nm in the uv spectrum.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:2]1.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22](O)=[O:23].CCN=C=NCCCN(C)C.C(O)CCC.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]([N:1]1[CH2:2][CH:3]([O:5][C:6]2[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:4]1)=[O:23]
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: Clc1nccnc1OC1CNC1
Agent: CCN=C=NCCCN(C)C
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1nc2ccccc2[nH]1)N1CC(Oc2nccnc2Cl)C1
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of 2-(azetidin-3-yloxy)-3-chloropyrazine (see PREPARATION P22.1; 0.38 g, 2.047 mmol), 1H-benzo[d]imidazole-2-carboxylic acid (0.37 g, 2.282 mmol), EDCI (0.392 g, 2.047 mmol), butanol (0.121 g, 0.790 mmol) and DCM (25 mL) was added DIPEA (0.62 mL, 3.56 mmol). After 2 hours, the crude reaction was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0% to 50% EtOAc in hexane, to provide (1H-benzo[d]imidazol-2-yl)(3-(3-chloropyrazin-2-yloxy)azetidin-1-yl)methanone (270 mg, 0.819 mmol, 40.0% yield), as a white solid. MS (ESI) m/z 330.0 (MH+). IC50 (uM) 1.375.
Reaction SMILES: [H-].[Na+].[C:3](=[O:7])([O-])[O:4][CH3:5].[C:8]1(=[O:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1>C1C=CC=CC=1>[O:17]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[C:3]([O:4][CH3:5])=[O:7]
Reactant: O=C1CCc2ccccc21
Reactant: COC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)C1Cc2ccccc2C1=O
Reaction time: 1 h
Yield: 17.8 %

Procedure:
The reaction is carried out according to J. Med. Chem., 1970, 650. A suspension of 6.75 g of sodium hydride at 80% in oil and 45 g of methyl carbonate in 120 ml of benzene are mixed together. 11.9 g of 1-indanone dissolved in 100 ml of benzene are added, at 60° C., over 1 and a half hours and the mixture is then refluxed. After 1 hour, the benzene is distilled off. Xylene is added and the mixture is again refluxed. After 1 hour, it is cooled, 30 ml of AcOH are added and the resulting mixture is poured onto 200 ml of a water/ice mixture containing 30 ml of 1N HCl. The insoluble material is removed by filtration and the filtrate is extracted with Et2O. The extracts are washed with water, with saturated NaHCO3 solution, with water, with saturated NaCl solution and then dried over Na2SO4. The product is chromatographed on silica, eluting with EtOAc/hexane (1.3; v/v) in order to obtain 3.05 g of the expected compound.
Reaction SMILES: [Na].[CH3:2][CH2:3][O:4][C:5]([CH:7](P(OCC)(OCC)=O)[CH3:8])=[O:6].[CH2:17]([C:21]1[N:22]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:23]([CH:26]=O)=[CH:24][N:25]=1)[CH2:18][CH2:19][CH3:20]>C(O)C>[CH2:17]([C:21]1[N:22]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:23](/[CH:26]=[C:7](\[CH3:8])/[C:5]([O:4][CH2:3][CH3:2])=[O:6])=[CH:24][N:25]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Agent: [Na]
Solvent: CCO
Product: CCCCc1ncc(/C=C(\C)C(=O)OCC)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
Ethanol (5 mL) was treated with sodium metal (0.101 g, 0.0044 g-atom), then triethyl 2-phosphonopropionate (0.953 g, 0.004 mol) in ethanol (2 mL) was added. After 5 minutes a solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde (1.1 g, 0.004 mol) in ethanol (2 mL) was added to give an initial exotherm The reaction mixture was stirred at ambient temperature under argon for 2 hours, concentrated in vacuo and the residue partitioned between water and ethyl acetate. The extract was washed, dried, and concentrated. The crude product was flash chromatographed over silica gel with an ethyl acetate/hexane gradient to provide ethyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-methyl-2-propenoate (0.85 g, 59%) as an oil; NMR (NOE) was consistent with the structure.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].O>CN(C1C=CN=CC=1)C.C(#N)C>[CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([S:13](=[O:16])(=[O:15])[NH:14][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[O:25][CH3:24])=[CH:11][CH:12]=1)=[O:5]
Reactant: COc1ccccc1C(=O)Cl
Reactant: COCC(=O)Nc1ccc(S(N)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1ccc(S(=O)(=O)NC(=O)c2ccccc2OC)cc1
Reaction time: 2 h

Procedure:
8 g (33 mmol) of 2-methoxy-N-(4-sulfamoylphenyl)acetamide are introduced into 160 ml of acetonitrile at 0° C., and 6.63 g (66 mmol) of triethylamine and a catalytic amount of DMAP are added. 5.6 g (33 mmol) of 2-methoxybenzoyl chloride—dissolved in 20 ml of acetonitrile—are subsequently added at 0° C., and stirring is continued for 2 hours at this temperature. After a further 2 hours at room temperature, the mixture is transferred into water and the precipitate is filtered off with suction;
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:18]2[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:10]=1>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[C:11]([NH:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1)[N:10]=[C:9]2[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: Oc1ccccc1
Product: COc1cccc2c(Oc3ccccc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 10 was used, starting from phenol and (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methoxy-1-phenoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][C:8]=1[CH2:21][CH2:22][CH3:23])[CH3:2].[H][H]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH2:21][CH2:22][CH3:23])[CH3:2]
Reactant: [H][H]
Reactant: CCCc1cc(OCc2ccccc2)ccc1OCC(=O)OCC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1cc(O)ccc1OCC(=O)OCC
Yield: 57.3 %

Procedure:
A solution of (4-benzyloxy-2-propylphenoxy)acetic acid ethyl ester (0.60 g, 1.83 mmol) in THF (15 mL) is treated with 5% Pd/C (75 mg) and hydrogen (60 psi) at ambient temperature for 24 h. The mixture is filtered and concentrated. The crude product is purified by radial chromatography using 15% ethyl acetate in hexanes to give a tan solid (0.25 g, 57%). 1H NMR (400 MHz, CDCl3) δ 6.66 (d, J=2.9 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 6.57 (dd, J=8.8, 2.9 Hz, 1H), 4.56 (s, 1H), 4.40 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.63 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); MS (FIA) m/e 239 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][OH:11])=[N:6][CH:7]=1.C(O)(=O)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[N:6][CH:7]=1
Reactant: OCC#Cc1ccc(Br)cn1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: OCCCc1ccc(Br)cn1
Reaction time: 17 h
Yield: 82.4 %

Procedure:
To a suspension of 3-(5-bromo-2-pyridinyl)-2-propyn-1-ol (0.5 g) and dipotassium azadicarboxylate (3.66 g) in pyridine (40 ml) was added acetic acid (2 ml) and the mixture stirred at room temperature for 24 h, with further additions of acetic acid after 2 h (0.16 ml) and 17 h (2.16 ml). As reduction had only partially gone to completion, further dipotassium azadicarboxylate (3.2 g) and acetic acid (1.86 ml) were added, and stirring continued for 17 h. The mixture was quenched with water (15 ml) and evaporated in vacuo. The residue was co-evaporated with toluene (15 ml) and the residue partitioned between 8% sodium bicarbonate solution (60 ml) and ethyl acetate (60 ml) and the organic phase dried and evaporated in vacuo. The oily residue was purified by FCC using ether and ether-methanol (5%) eluants to afford the title compound as a yellow oil (0.42 g).