Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=1.[C:27]1([CH:33]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:34][NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[C:38]=2[Cl:47])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:47][C:38]1[C:39]([C:43]([F:44])([F:45])[F:46])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:35]([CH2:34][CH:33]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:14][CH2:13][CH2:12][CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:26])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1cccc(CCCCOS(=O)(=O)c2ccc(C)cc2)c1
Reactant: FC(F)(F)c1cccc(CNCC(c2ccccc2)c2ccccc2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)Cc1cccc(CCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 50 °C
Yield: 31 %

Procedure:
A mixture of {3-[4-(toluene-4-sulfonyloxy)butyl]phenyl}acetic acid methyl ester, (2,2-diphenylethyl)-(2-chloro-3-trifluoromethylbenzyl)amine (73 mg, 0.19 mmol), and potassium carbonate (26 mg, 0.21 mmol) in acetonitrile (5 ml) was stirred and heated to 50° C. for 5 hr. The reaction was cooled, diluted with water, and extracted with diethyl ether. The organic extracts were washed with water, dried, and the solvent removed. The residue was chromatographed over silica gel (hexane/methylene chloride/Diethyl ether:60/40/5) to give the title compound as an oil (35 mg, 31%). MS (ESI) 594.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH:29](=O)[CH:30]([CH3:32])[CH3:31]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][N:20]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(CC(C)C)C3)cc1

Procedure:
Method as described for example 26 using (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 7) and iso-butyraldehyde as starting materials. Purified by prep HPLC (low pH).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Na+].[I-].[H-].[Na+].[CH3:18][O:19][C:20]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[C:25]([OH:32])[CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21]>CN(C=O)C.C(Cl)Cl>[CH3:18][O:19][C:20]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[C:25]([O:32][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21]
Reactant: COC(=O)c1ccc2cccc(O)c2n1
Reactant: CCCCCCCCCCCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1cccc2ccc(C(=O)OC)nc12
Reaction time: 8 h
Yield: 14 %

Procedure:
In a first step, dodecyl bromide (767 μL, 3.2 mmol), NaI (478 mg, 3.2 mmol) and NaH (76 mg, 3.2 mmol) were added to a solution of 8-hydroxyl-quinoline-2-carboxylic acid methyl ester (2.11 mmol) stirring in DMF (dry, 10 mL), and the red reaction was allowed to stir overnight. The crude material resulting from removal of solvents by rotary evaporation was taken into DCM, washed with water, dried over Na2SO4, and filtered. The resulting solution was evaporated to dryness and the desired intermediate, 8-dodecyloxy-quinoline-2-carboxylic acid methyl ester, was obtained by HPLC (isocratic, 75% acetonitrile, 25% water) yielding 169 mg (about 14% yield). This intermediate was in turn deprotected using LiOH in THF/H2O as described in the method of Example 336 to yield the title compound, which was utilized further without additional purification or characterization.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([NH:12][NH2:13])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[CH3:24][N:25]=[C:26]=S.C(O)C>CN(C=O)C>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:24]([NH:25][CH3:26])=[N:13][NH:12][C:8]=2[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)cc(NN)n(Cc2ccc(OC)cc2)c1=O
Reactant: CN=C=S
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(OC)cc2)c1=O
Yield: 53 %

Procedure:
A solution of 3-butyl-6-hydrazino-1-(4-methoxybenzyl)-uracil (2.0 g, 6.3 mM) and methyl isothiocyanate (1.36 ml, 20 mM) in DMF (20 ml) was stirred at 120° C. for 20 hours. To the solution was added ethanol (20 ml) and the mixture was cooled to give crude crystals. Recrystallization from DMF/ethanol gave colorless crystals (1.2 g, 53%), m.p. 292°-294° C.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:9][C:10]1[C:11](=[O:18])[C:12]([Cl:17])=[CH:13][C:14](=[O:16])[CH:15]=1.Cl.C(OCC)(=O)C>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:14]1([OH:16])[CH:15]=[C:10]([Cl:9])[C:11](=[O:18])[C:12]([Cl:17])=[CH:13]1)[CH3:8]
Reactant: O=C1C=C(Cl)C(=O)C(Cl)=C1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)C=C(Cl)C(=O)C(Cl)=C1
Yield: 74 %

Procedure:
Under, nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. A solution of 0.59 g (3.33 mmol) of 2,6-dichloro-p-benzoquinone in 3 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3) afforded 0.76 g of the desired product (NMR yield 74%; internal standard trioxane). As a purified product, 0.48 g of the desired product was obtained (yield 54%).
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)[CH2:2][CH3:3].[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]=2)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: CCCc1csc(N)n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: CCCc1csc(NS(=O)(=O)c2cccc(Cl)c2C)n1
Yield: 39 %

Procedure:
The title compound was prepared from 4-propyl-1,3-thiazol-2-ylamine (METHOD I) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellow solid, 90 mg (39% yield): mp 169° C.; HRMS Calcd (found) for C13H15ClN2O2S2 M/Z 330.0263 (330.0251).
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:24])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[N:17]2)[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[CH:27]1([C:30]2[S:31][C:32]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[C:33]([C:35](Cl)=[O:36])[N:34]=2)[CH2:29][CH2:28]1>C1COCC1.O>[C:3]([O:7][C:8](=[O:24])[N:9]([C:10]1[N:11]=[C:12]([CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[N:17]2)[O:13][CH:14]=1)[C:35]([C:33]1[N:34]=[C:30]([CH:27]2[CH2:28][CH2:29]2)[S:31][C:32]=1[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:36])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1nc(C2CC2)sc1-c1ccccc1
Reactant: CC(=O)c1ccn(Cc2nc(NC(=O)OC(C)(C)C)co2)n1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccn(Cc2nc(N(C(=O)OC(C)(C)C)C(=O)c3nc(C4CC4)sc3-c3ccccc3)co2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(3-acetyl-pyrazol-1-ylmethyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (76 mg, 0.25 mmol) in THF (1.0 mL) was added to a suspension of NaH (27 mg, 0.61 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 2-cyclopropyl-5-phenyl-thiazole-4-carbonyl chloride in THF (1.0 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 16 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.20. LC-MS-conditions 02: tR=1.11 min, [M+H]+=534.30.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:19]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)=[N:4][CH:5]=[C:6](N2C(=O)C3C(=CC=CC=3)C2=O)[CH:7]=1.[Br:37]C1C([C@@H](N[S@](C(C)(C)C)=O)CC2C=C(F)C=C(F)C=2)=NC(Br)=CC=1>>[Br:1][C:2]1[C:3]([C@@H:19]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)=[N:4][C:5]([Br:37])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Reactant: CC(C)(C)[S@](=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(Br)ccc1Br
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(Br)ccc1Br

Procedure:
The title compound was prepared according to the 2 step method presented for the synthesis of compound 30E of Example 30 utilizing 42D.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:12]=[C:13]([C@:17]2([CH3:37])[CH2:22][CH2:21][N:20]([CH2:23][C@H:24]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:25]([O:27][CH3:28])=[O:26])[CH2:19][C@@H:18]2[CH3:36])[CH:14]=[CH:15][CH:16]=1)(=O)C.O>CO>[OH:10][C:11]1[CH:12]=[C:13]([C@:17]2([CH3:37])[CH2:22][CH2:21][N:20]([CH2:23][C@H:24]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:25]([O:27][CH3:28])=[O:26])[CH2:19][C@@H:18]2[CH3:36])[CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)CN1CC[C@@](C)(c2cccc(OC(C)=O)c2)[C@@H](C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H](Cc1ccccc1)CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
Potassium carbonate (1.46 g, 0.0105 mol, 3 eq) was added to a solution of 5a (1.49 g, 0.0035 mol, 1 eq) in methanol (15 mL) (see FIGS. 2 and 3). The suspension was stirred under nitrogen for 2 h. Water (200 mL) was added and the suspension was extracted with ethyl acetate (200 mL). The organic solution was washed with brine (100 mL), separated and dried over sodium sulfate. Evaporation of the solvent afforded the methyl ester 6a as a solid (1.17 g, 87% yield). Rf 0.30 (hexane/EtOAc=8:2). 1H NMR δ (CDCl3) 0.70 (d, 3H), 1.25 (s, 3H), 1.51 (d, 1H), 1.94 (m, 1H), 2.20-2.50 (m, 3H), 2.60-3.00 (m, 5H), 3.55 (s, 3H), 6.64 (d, 2H), 6.75 (s, 1H), 6.85 (s, 1H), 7.10-7.35 (m, 7H); [M+H]+382.2,: tR=3.42 min; purity: 99%. (Chiral purity determination; HPLC conditions: column Chiralcel OD 4.6×250 mm; flow: 1 mL/min; mobile phase: 92.5% hexane/7.5% isopropanol; λ=254 nM; Inj. Vol: 20 μL; 6a (reference standard): tR=27.97 min; 6b (reference standard): tR=25.36 min; result: 6a/6b=98.7/1.3 (% area pic calculation)].
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[CH3:12][O:13][C:14](=[O:31])[C:15]1[CH:20]=[C:19]([N:21]([C:23](=[O:25])[CH3:24])[CH3:22])[C:18]([C:26]([F:29])([F:28])[F:27])=[CH:17][C:16]=1[NH2:30]>O1CCOCC1>[CH3:12][O:13][C:14](=[O:31])[C:15]1[CH:20]=[C:19]([N:21]([C:23](=[O:25])[CH3:24])[CH3:22])[C:18]([C:26]([F:27])([F:29])[F:28])=[CH:17][C:16]=1[NH:30][C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3]
Reactant: COC(=O)c1cc(N(C)C(C)=O)c(C(F)(F)F)cc1N
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(N(C)C(C)=O)c(C(F)(F)F)cc1NC(=O)Oc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4-chlorophenyl chloroformate (26 mg, 1.1 eq.) is slowly added to a solution of 5-(acetyl-methyl-amino)-2-amino-4-trifluoromethyl-benzoic acid methyl ester (36 mg, 0.12 mmoles) in dioxane (0.2 ml). The solution is stirred at 80° C. for 2 hours. The solution is evaporated to yield 5-(acetyl-methyl-amino)-2-(4-chloro-phenoxycarbonylamino)-4-trifluoromethyl-benzoic acid methyl ester after repeated trituration with hexane. Used tel quel for the next step.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.C(O)CC>O>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[N:13]2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccccc1F
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CCCO
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccccc1F
Temperature: 4 °C
Yield: 55.5 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2-fluorobenzoic acid (11.2 g), N,N'-carbonyldiimidazole (12.9 g) and 2-amino-7-chloro-1,8-naphthyridine (8.9 g). The product produced by precipitation in water (13.6 g; m.p. 218° C.) is dissolved in boiling 1-propanol (450 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with 1-propanol (3×20 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-2-fluorobenzamide (8.3 g) is produced, m.p. 222° C. EXAMPLE 14
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[O:15][CH2:14][C:13]([CH3:18])([CH3:17])[C:12]=2[CH:11]=[C:10](Br)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[B:30](OC)([O:33]C)[O:31]C>O1CCCC1>[CH2:1]([C:8]1[C:16]2[O:15][CH2:14][C:13]([CH3:18])([CH3:17])[C:12]=2[CH:11]=[C:10]([B:30]([OH:33])[OH:31])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)COc2c(Cc3ccccc3)cc(Br)cc21
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC1(C)COc2c(Cc3ccccc3)cc(B(O)O)cc21

Procedure:
Following General Procedure A and using 7-benzyl-5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 39, 1.57 g, 4.81 mmol), 15 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (5.64 mL, 9.6 mmol) and trimethyl borate (1.02 mL, 9.6 mmol), the title compound was obtained as a foam that was used as such for the next step without purification and characterization.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[C:23]4[O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:31])[CH:5]=[CH:4][N:3]=1.[OH:32][CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1>>[CH:21]1[C:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][C:23]=2[C:18]([C:16]([NH:15][C:13]2[CH:12]=[CH:11][C:10]([CH3:31])=[C:9]([CH:14]=2)[NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:32][CH:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[N:7]=2)=[O:17])=[CH:19][CH:20]=1
Reactant: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1Nc1ccnc(Cl)n1
Reactant: CN1CCC(O)CC1
Product: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1Nc1ccnc(OC2CCN(C)CC2)n1

Procedure:
Using an analogous procedure to that described in Example 8, 2-chloro-4-[5-(4-dibenzofuranylcarbonylamino)-2-methylanilino]pyrimidine was reacted with 4-hydroxy-N-methylpiperidine. The reaction mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent followed by increasingly polar mixtures of methylene chloride and methanol containing 1% aqueous ammonium hydroxide solution. There was thus obtained the title compound; NMR Spectrum: (DMSOd6) 1.56 (m, 2H), 1.84-2.1 (m, 4H), 1.97 (s, 3H), 2.17 (s, 3H), 2.53 (m, 2H), 4.78 (m, 1H), 6.22 (d, 1H), 7.18 (d, 1H), 7.38-7.58 (m, 4H), 7.77 (d, 1H), 7.86 (m, 2H), 7.93 (d, 1H), 8.19 (d, 1H), 8.28 (d, 1H); Mass Spectrum: M+H+ 507.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:31])[NH:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:14])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])[CH:26]=[CH:27][CH:28]=1
Reactant: CCCN(CCC)C(=O)CN(C(=O)CN)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: CCCN(CCC)C(=O)CN(C(=O)CNC(=O)Nc1cccc(C)c1)c1ccccc1
Yield: 44.8 %

Procedure:
Working in a manner similar to that described in Example 1, but starting with 2-(2-amino-N-phenylacetamido)-N,N-dipropylacetamide (1.7 g) and 3-methylphenyl isocyanate (0.77 g), and after recrystallization in acetonitrile, 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}-N,N-dipropylacetamide (1.1 g), m.p. 182° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][CH3:20])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][N:19]([CH3:20])[C:7]([C:4]2[S:5][CH:6]=[C:2]([Br:1])[CH:3]=2)=[O:9])=[CH:15][CH:16]=1
Reactant: CNCCc1ccc(F)cc1
Reactant: O=C(O)c1cc(Br)cs1
Product: CN(CCc1ccc(F)cc1)C(=O)c1cc(Br)cs1

Procedure:
From 4-bromo-thiophene-2-carboxylic acid and 1.47 g of [2-(4-fluorophenyl)-ethyl]-methyl-amine (the compound of Preparation Example 14) (1.98 g), a colorless solid (2.53 g) was obtained, in the same way as Preparation Example 118-b).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[CH:22]=[N:21]2)=[CH:17][CH:16]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[N:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1cnn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1.34 g), 1 N aqueous sodium hydroxide solution (6 ml), ethanol (12 ml), and tetrahydrofuran (12 ml) was stirred at room temperature for two hours. After 1 N hydrochloric acid (6 ml) was added to the reaction mixture, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (1.21 g, yield: 97%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 124–125° C.
Reaction SMILES: [C:1](=[O:14])([O:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[O:2][CH2:3]Cl.[I-:15].[Na+]>C(#N)C>[C:1](=[O:14])([O:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[O:2][CH2:3][I:15]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)COC(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)COC(=O)OCI
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Chloromethyl tert-butoxycarbonylmethyl carbonate (6.45 g) was added to a solution of sodium iodide (16.5 g) in acetonitril (65 ml). After stirring at 40° C. for 4 hours the reaction mixture was cooled in ice, filtered and evaporated in vacuo. The residue was taken up in dichloromethane, washed with aqueous sodium bicarbonate and sodium thiosulfate, dried over magnesium sulfate, filtered and evaporated in vacuo. Purification on silica gel with hexane/ethyl acetate (3:1) as eluent gave the title compound as a colourless oil.
Reaction SMILES: [C:1]([O:4][C@H:5]([C:7]1[O:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][CH:18]=[C:17](Br)[C:16]=3[CH:21]=2)=[N:10][N:11]=1)[CH3:6])(=[O:3])[CH3:2].[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[C:1]([O:4][C@H:5]([C:7]1[O:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][CH:18]=[C:17]([C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:23]([F:22])([F:34])[F:35])[CH:26]=4)[C:16]=3[CH:21]=2)=[N:10][N:11]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CC(=O)O[C@@H](C)c1nnc(-c2ccc3occ(Br)c3c2)o1
Product: CC(=O)O[C@@H](C)c1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Yield: 75 %

Procedure:
In the same manner as in Reference Example 19 and using (1S)-1-[5-(3-bromo-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]ethyl acetate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and [3-(trifluoromethoxy)phenyl]boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 75%) was obtained as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=1[C:18]#[N:19]>CN(C)C=O>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=2)[C:17]=1[C:18]#[N:19]
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
4-(Trifluoromethyl)benzyl alcohol (1.15 g; 6.3 mmol) was added to a cooled (0° C.) slurry of sodium hydride (249.7 mg; 6.2 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature overnight. The reaction mixture was then added to a cooled (0° C.) solution of 2,6-difluorobenzonitrile in dimethylfomamide, stirred for 6 hours at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered, washed with water and dried to afford 804.4 milligrams of 2-fluoro-6-(4-trifluoromethylphenylmethoxy)-benzonitrile as waxy yellow solid. Yield 45%.