Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:14])[C:5]2[NH:9][C:8]([CH:10]([F:12])[F:11])=[N:7][C:6]=2[CH:13]=1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([Cl:14])[C:5]2[N:9]=[C:8]([CH:10]([F:11])[F:12])[N:7]([C:20]3[N:21]=[C:16]([Cl:15])[N:17]=[C:18]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[N:19]=3)[C:6]=2[CH:13]=1
Reactant: Nc1cc(Cl)c2[nH]c(C(F)F)nc2c1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Nc1cc(Cl)c2nc(C(F)F)n(-c3nc(Cl)nc(N4CCOCC4)n3)c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 28.4 %

Procedure:
6-Amino-4-chloro-2-difluoromethylbenzimidazole (500 mg, 2.3 mmol) was dissolved in acetone (50 ml), 2,4-dichloro-6-morpholino-1,3,5-triazine (542 mg, 2.3 mmol) was added at −15° C., and potassium carbonate (500 mg) was further added. After having elevated the temperature gradually to room temperature, the mixture was stirred at room temperature for 5 hours. The solvent was evaporated under vacuum, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:4) to afford 2-(6-amino-4-chloro-2-difluoromethylbenzimidazol-1-yl)-4-chloro-6-morpholino-1,3,5-triazine (272 mg, yield 28%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([C:23]1[CH:31]=[CH:30][C:26]2[CH:27]=[CH:28][O:29][C:25]=2[CH:24]=1)[N:7](CC1C=CC=CC=1)[C@@H](C1C=CC=CC=1)C)[CH3:2]>CCO.O.CC(O)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@H:6]([NH2:7])[C:23]1[CH:31]=[CH:30][C:26]2[CH2:27][CH2:28][O:29][C:25]=2[CH:24]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1ccc2ccoc2c1)N(Cc1ccccc1)[C@H](C)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C[C@H](N)c1ccc2c(c1)OCC2
Reaction time: 18 h

Procedure:
A mixture of the dibenzylamine 6-5 (1.19 g, 2.78 mmol) in EtOH/H2O/AcOH (26 mL/3 mL/1.0 mL) was degassed with argon and treated with Pd(OH)2 (1.19 g). The mixture was placed under 1 atm of H2. After stirring for 18 h, the mixture was diluted with EtOAc, and filtered through celite. The filtrate was concentrated and the residue purified by flash chromatography (10% ethyl acetate/dichloromethane) to give the ester 6—6 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]3[CH:17]=2)[CH:5]=[CH:6][CH:7]=1.[F:18][CH:19]1[CH2:22][N:21]([C:23]([C:25]2[CH:26]=[N:27][N:28]([CH3:33])[C:29]=2[C:30](O)=[O:31])=[O:24])[CH2:20]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:12]3[N:13]=[C:14]([NH:16][C:30]([C:29]4[N:28]([CH3:33])[N:27]=[CH:26][C:25]=4[C:23]([N:21]4[CH2:20][CH:19]([F:18])[CH2:22]4)=[O:24])=[O:31])[CH:15]=[CH:10][N:11]3[CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc2nc(-c3cccc(F)c3)cn2cn1
Reactant: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)O
Product: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)Nc1ccn2cc(-c3cccc(F)c3)nc2n1

Procedure:
The title compound was prepared in analogy to example 82 from 2-(3-fluorophenyl)imidazo[1,2-c]pyrimidin-7-amine (100 mg) and 4-(3-fluoroazetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (100 mg, 440 μmol). Yellow solid (76 mg, 39%).
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([OH:10])[C@H:4]1[O:9][C:7](=[O:8])[CH2:6][CH2:5]1>[2H]C(Cl)(Cl)Cl>[Br:1][CH2:2][C@H:3]([OH:10])[C@@H:4]1[O:9][C:7](=[O:8])[CH2:6][CH2:5]1
Reactant: O=C1CC[C@@H]([C@H](O)CBr)O1
Agent: [2H]C(Cl)(Cl)Cl
Product: O=C1CC[C@H]([C@@H](O)CBr)O1

Procedure:
An 1H-NMR test carried out in the presence of a chiral shift-reagent [10 mg of compound No. 8 in deuterochloroform (0.6 ml) in the presence of Europhium (hfc)3 ] confirmed the absence of the 6-bromo-2,3,6-trideoxy-D-erythro-hexono-1,4-lactone enantiomer).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH:16]([C:26]([OH:28])=[O:27])[N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[C:7]=1[C:31]([O:33]C(C)(C)C)=[O:32])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH:16]([C:26]([OH:28])=[O:27])[N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[C:7]=1[C:31]([OH:33])=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(C(=O)O)n3ccc4ccccc43)C2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)O)n3ccc4ccccc43)C2SC1
Reaction time: 0.17 h

Procedure:
A solution of 3-[(acetyloxy)methyl]-7-[[2-carboxy-2-(1H-indol-1-yl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, tert-butyl ester (0.05 mole) in 10 ml of trifluoroacetic acid maintained at 0° C. is stirred for 10 minutes. The trifluoroacetic acid is removed under vacuum. The residue is treated with ethyl ether to give a solid material. Filtration gives the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][C:4]=1[CH2:5][N:6]([CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1.[CH3:43]O>S(=O)(=O)(O)O>[CH3:43][O:19][C:18](=[O:20])[CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:5][C:4]2[CH:35]=[CH:36][CH:37]=[C:38]([C:39]([F:40])([F:41])[F:42])[C:3]=2[Cl:2])[CH2:21][CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:12]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Yield: 93 %

Procedure:
To a solution of (3-{3[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-acetic acid hydrochloride salt (Example 1d, 0.1 g, 0.2 mmol) in methanol (2 ml) was added concentrated sulfuric acid (2 drops). After the resulting mixture was heated to reflux for 2 h solvent was removed under vacuum. The residue was dissolved in water and neutralized to pH=7. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with, brine, dried over magnesium sulfate, and concentrated in vacco to give 900 mg (93%) of the title compound as an oil. MS m/e 596.2 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:27][C:28]([CH3:31])=[N:29][N:30]=3)=[CH:22][CH:21]=2)[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])C1C=CC=CC=1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[O:27][C:28]([CH3:31])=[N:29][N:30]=3)=[CH:24][CH:25]=2)[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1
Solvent: CC(=O)O
Product: COC(=O)c1cc(O)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1
Yield: 76.5 %

Procedure:
Methyl 3-(benzyloxy)-5-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)benzoate (28 g, 72.1 mmol, 1 equiv.) (Intermediate 9) was debenzylated in acetic acid using 10% Pd/C (5.6 g) at 60 PSI in hydrogenation apparatus. After complete reaction, the reaction mixture was poured on ice and the solid obtained was filtered through Buckner funnel. The solid was washed with water and air-dried to furnish the title compound (18 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:18]([C:20]1[CH:21]=[C:22]([CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[C:29]=1[O:30][CH2:31]OCCOC)[C:23]([O:25][CH3:26])=[O:24])=[O:19]>>[CH2:31]([O:30][C:29]1[C:28]([C:2]2[CH:3]=[C:4]([S:10](=[O:12])(=[O:11])[NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1[CH:18]=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCOCOc1c(C=O)cc(C(=O)OC)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(S(=O)(=O)NC(C)(C)C)cc1Br
Product: COC(=O)c1cc(C=O)c(OCc2ccccc2)c(-c2cc(S(=O)(=O)NC(C)(C)C)ccc2OC)c1

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-N-tert-butyl-4-methoxybenzenesulfonamide and methyl 3-formyl-4-(2-methoxyethoxy-methoxy)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzoate, gave methyl 6-benzyloxy-5′-tert-butylsulfamoyl-5-formyl-2′-methoxy-biphenyl-3-carboxylate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[N:14]=[C:13]([C:25]#[N:26])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][C:13]([C:25]#[N:26])=[N:14]2)=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)nn2-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)nn2-c2ccc(N)cc2)cc1
Yield: 82.1 %

Procedure:
A mixture of 5-[4-(methylsulfonyl)phenyl]-1-(4-nitrophenyl)pyrazole-3-carbonitrile (1.1 g), iron powder (1.1 g) and ammonium chloride (0.11 g) in ethanol (20 ml) and water (7 ml) was refluxed for 1 hour. The solvent was evaporated, and the residue was filtered, washed with water and dissolved in hot ethyl acetate. The solution was filtered and the filtrate was concentrated. The residue obtained was recrystallized from ethyl acetate to give crystals of 1-(4-aminophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonitrile (0.83 g).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][CH2:14][OH:15]>CS(C)=O.C(OCC)(=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH2:13][CH2:14][OH:15])=[CH:6][CH:5]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: OCCCOc1ccc(Br)cc1
Reaction time: 2.5 h

Procedure:
Powdered sodium hydroxide (2.2 g) was added to a solution of 4-bromophenol (3.46 g) and 3-bromopropanol (2.36 ml) in DMSO (18 ml). The mixture was stirred vigorously at 20° for 2.5 h then diluted with ethyl acetate (100 ml) and washed with 2N hydrochloric acid (100 ml), water (100 ml×2) and brine. Concentration of the dried organic phase yielded the title compound (5.02 g) as a pale orange oil. T.l.c. (diethyl ether) Rf 0.32.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=1)([O-])=O>C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[Zn].[Cl-].[NH4+].O.C(O)C>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][CH2:11][NH:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(NCCc2cccnc2)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(NCCc2cccnc2)cc1

Procedure:
The N-(4-nitrophenyl)-N-(2-pyrid-3-ylethyl)amine (3) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.I[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu](I)I>[CH3:19][C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[C:1]1=[O:11]
Reactant: O=C1NCCc2cnccc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2cnccc2C1=O
Yield: 15.1 %

Procedure:
3,4-Dihydro-2,6-naphthyridin-1(2H)-one (I-67h: 45 mg, 0.304 mmol) was reacted with 3-iodo-4-methylpyridine (100 mg, 0.456 mmol), copper iodide (5.7 mg, 0.0304 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (12.95 mg, 0.0912 mmol) and potassium phosphate (193.3 mg, 0.912 mmol) in 1,4-dioxane (5 mL) to afford the crude product. Purification by column chromatography on silica gel (4% methanol in CHCl3), followed by preparative HPLC afforded 11 mg of the product (15.27% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[CH3:20]I>CN(C=O)C>[CH3:20][N:3]1[CH:4]=[CH:5][S:1]/[C:2]/1=[N:6]\[CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nccs2)CC1
Solvent: CN(C)C=O
Product: Cn1ccs/c1=N\C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 21 %

Procedure:
To a solution of tert-butyl 4-(1,3-thiazol-2-yl)amino-1-piperidinecarboxylate (2.5 g) obtained in Example 135b) in DMF (50 ml) was added methyl iodide (1.1 ml), and mixed at 80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform and an aqueous potassium carbonate solution. The organic layer was collected by separation, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified with silica gel column to obtain the title compound as a pale yellow solid (0.54 g, 21%).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[O:4]1[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3]1
Reactant: O=C1CCCCC1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: OCCN1CCOC12CCCCC2
Temperature: 80 °C
Reaction time: 12 h
Yield: 45.3 %

Procedure:
To a 50 mL flask containing diethanolamine (9.7 mL, 100 mmol) was added cyclohexanone (10.4 mL, 100 mmol, 1 eq.) and potassium carbonate (pulverized and dried at 160° C., 13.8 g, 100 mmol, 1 eq.). The reaction was stirred at 80° C. for 12 h. The reaction was cooled to room temperature and diluted with dichloromethane before filtering off potassium carbonate. The crude mixture diluted in cyclohexane was washed with water at 0° C. Drying with sodium sulfate and evaporation afforded the title product (8.4 g, 45% yield). 1H NMR (CDCl3, 400 MHz) d?(ppm): 3.91 (t, J=6.7 Hz, 2H); 3.60 (m, 2H); 3.00 (t, J=6.7 Hz, 2H); 2.70 (t, J=5.3 Hz, 2H); 1.72-1.50 (m, 7H); 1.43-1.30 (m, 2H); 1.21-1.04 (m, 1H). 13C NMR (CDCl3, 129.9 MHz) d?(ppm): 94.9; 63.2; 59.2; 50.3; 49.0; 32.6 (2C); 25.6; 23.3 (2C).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH:36][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1)[CH3:31]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)CCNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with beta-alanine ethyl ester hydrochloride using BOP reagent in tetrahydrofuran to give the title compound as a light brown solid, MS (ESI+): m/z=475.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17]Cl)[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:14][CH2:13][N:15]([CH2:19][CH3:20])[CH2:16][CH3:17])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCN(CC)CCCl
Reactant: Oc1ccc2nc(Cl)sc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.15 g (16.7 mmol) of 2-chloro-6-hydroxy-benzothiazole are dissolved in 50 ml of dimethylformamide and after the addition of 5.68 g (33 mmol) of 2-diethylamino-ethyl chloride-hydrochloride and 8.3 g (60 mmol) of potassium carbonate the mixture was stirred for 20 hours at ambient temperature. It was then added to water and extracted with ethyl acetate. The extracts are dried and evaporated down. The evaporation residue is purified by column chromatography on neutral aluminium oxide (eluant: petroleum ether/ethyl acetate=6:1). Yield: 3.9 g (81.7% of theory), oil, 1H-NMR spectrum (200 MHz, CDCl3, signals at ppm): 1.08 (t, 6H); 2.65 (q, 4H); 2.9 (t, 2H); 4.09 (t, 2H); 7.08 (dd, 1H); 7.24 (d, 1H); 7.8 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]([NH:5][C@H:6]([CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=1)[C:7]([OH:9])=[O:8])=[O:4]>CC(O)=O.[Pd]>[F:1][C:2]([F:27])([F:28])[C:3]([NH:5][C@H:6]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:16][CH:17]=1)[C:7]([OH:9])=[O:8])=[O:4]
Reactant: CCCCCCCCc1ccc(C(=O)C[C@@H](NC(=O)C(F)(F)F)C(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCc1ccc(CC[C@@H](NC(=O)C(F)(F)F)C(=O)O)cc1
Reaction time: 20 h

Procedure:
A mixture of 8.7 g (21.7 mmol) of 2-(R)-trifluoroacetamido-4-oxo-4-(4-octylphenyl)butanoic acid (from Example 12, Step A) and 1.75 g of 10% Pd/C in 25 mL of HOAc was hydrogenated at 40 psi for 20 h. The mixture was filtered through a pad of Celite; the flask and pad were rinsed with EtOAc. Toluene was added to the filtrate and the filtrate was concentrated to afford 9.0 of the title compound which was used without further purification.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12].[CH:21]1([C@@H:27]([NH2:29])[CH3:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH:21]1([C@@H:27]([NH:29][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:8]([O:7][CH3:6])[CH:9]=2)[CH3:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C[C@H](N)C1CCCCC1
Reactant: C#CCOc1ccc(C(=O)Cl)cc1OC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCOc1ccc(C(=O)N[C@@H](C)C2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
To a mixture of 10 ml of THF and 0.30 g of 3-methoxy-4-(2-propynyloxy)benzoyl chloride were added 0.21 g of (1S)-1-(cyclohexyl)ethylamine and 0.20 g of triethylamine in order at room temperature. The mixture obtained was stirred at room temperature for 4 hours. Then, ethyl acetate was added to the reaction mixture and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was washed with methyl tert-butyl ether and hexane to obtain 0.33 g of N-((1S)-1-cyclohexylethyl)-4-(2-propynyloxy)-3-methoxybenzamide (hereinafter, described as the compound 21 of the present invention) represented by the formula:
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[CH2:3][C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:5].C(NC1C=CC(S([N:40]=[N+:41]=[N-])(=O)=O)=CC=1)(=O)C.C(#N)C>C(N(CC)CC)C>[N+:40](=[C:3]([C:2](=[O:1])[C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:5])=[N-:41]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COc1cccc(OC(=O)CC(=O)c2cc(OC)c(OC)c(OC)c2)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cccc(OC(=O)C(=[N+]=[N-])C(=O)c2cc(OC)c(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
The procedure of Baumm et al, Synthetic Communication 1987, 17(14), 1709-1716, was used. To a stirred solution of 0.0561 g (0.156 mmol) of the product of Step 2 and 0.041 g (0.171 mmol) of 4-acetamidobenzenesulfonyl azide in 2 ml of anhydrous acetonitrile 0.065 ml (0.47 mmol) of triethylamine was added at 0° C. After stirring for 3 hours at room temperature the solvent was evaporated to dryness under reduced pressure and the residue was purified by flash column chromatography (silica gel, methylene chloride) to give 0.059 g (98% yield) of 3-methoxyphenyl 2-diazo-3-oxo-3-(3,4,5-trimethoxyphenyl)propanoate. This was dissolved in 2 ml of anhydrous methylene chloride and 3.5 mg (7.9 μmol) of rhodium (III) acetate was added at room temperature under nitrogen atmosphere. The resulting mixture turned deep green after 1 h of stirring at room temperature. After filtration through Celite and washing with fresh methylene chloride, the filtrate was evaporated to dryness under reduced pressure to give the title compound as an deep yellow crystals (0.049 g, 91%); 1H NMR (CDCl3) δ 3.8 (s, 3H, OMe); 3.9 (s, 6H, OMe); 3.94 (s, 3H, OMe); 6.58 (dd, 1H, CH aromatic, J=2.4 Hz; 8.6 Hz); 6.76 (d, 1H CH aromatic; J=2.4 Hz); 7.04 (s, 2H, CH aromatic); 7.25 (d, 1H, CH aromatic, J=8.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[CH:8](Cl)Cl.C[O-:21].[Na+]>>[CH3:1][C:2]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[CH:8]=[O:21]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(Cl)Cl)c1
Reactant: C[O-]
Agent: [Na+]
Product: Cc1ccc(C)c(OCc2ccccc2C=O)c1

Procedure:
As a process for producing 2-(aryloxymethyl)benzaldehyde, for example, the following method is described in JP 2009-215286 A (Example 5). In the method, 2-(2,5-dimethylphenoxymethyl)benzaldehyde is obtained by reacting 2-(2,5-dimethylphenoxymethyl)benzal chloride and sodium methoxide, and then a resulting acetal compound is extracted with xylene. Then, an organic layer obtained after liquid separation is mixed with an aqueous sulfuric acid solution to hydrolyze the acetal compound to obtain 2-(2,5-dimethylphenoxymethyl)benzaldehyde.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:12]([CH2:13][OH:14])=[CH:11][C:10]([C:15]#[N:16])=[CH:9][C:8]=1[NH:17][C:18]1[N:23]=[C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)[C:21]2=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:20]2[N:19]=1>C1COCC1>[CH3:1][S:2]([O:14][CH2:13][C:12]1[CH:11]=[C:10]([C:15]#[N:16])[CH:9]=[C:8]([NH:17][C:18]2[N:23]=[C:22]([NH:24][CH:25]3[CH2:27][CH2:26]3)[C:21]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:20]3[N:19]=2)[C:7]=1[Cl:6])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cc(CO)c(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1
Solvent: C1CCOC1
Product: CS(=O)(=O)OCc1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Temperature: 0 °C
Yield: 89.3 %

Procedure:
Added methanesulfonyl chloride (0.153 ml, 1.97 mmol) to an ice-cooled solution of 2-((2-chloro-5-cyano-3-(hydroxymethyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (300 mg, 0.788 mmol) in THF (20 ml). The bath was removed and after 15 min, water was added and the reaction was extracted with EtOAc. The organic extracts were washed with brine and dried with sodium sulfate. The solvent was removed to leave crude 2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)benzyl methanesulfonate (323 mg) as a tan solid