Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[NH:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:24]3[CH:23]=[C:22]([CH3:21])[NH:26][N:25]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)n[nH]1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1cc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)n[nH]1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-methyl-1H-pyrazole-3-carboxylic acid as starting materials, MS (LC/MS): 409.2 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[C:20]([CH:33]=2)[C:21]([NH:23][C@@H:24]([CH2:29][CH2:30][S:31][CH3:32])[C:25]([O:27]C)=[O:26])=[O:22])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)=[C:20]([CH:33]=2)[C:21]([NH:23][C@@H:24]([CH2:29][CH2:30][S:31][CH3:32])[C:25]([OH:27])=[O:26])=[O:22])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1cc(OC(Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSCC[C@H](NC(=O)c1cc(OC(Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.9 %

Procedure:
A solution of methyl (2S)-2-{5-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfanylbutyrate (140 mg, 0.24 mmol) in methanol (5 ml) was treated with sodium hydroxide (190 mg, 4.7 mmol) in water (1 ml) and the mixture stirred at ambient temperature for 6 hours. The mixture was acidified to PH1 with 1M HCl and evaporated to dryness. The residue was washed with water (3×2 mL) and the resulting gum was triturated with diethyl ether to give the title compound as a white solid (43 mg). 1H NMR (DMSO-d6, 300 MHz) δ: 1.85-2.05 (5H,m); 2.4-2.6 (signed partially obscured by solvent signals, m); 2.6-2.75 (2H,m); 2.75-2.86 (2H,m); 4.4-4.48 (1H, m); 4.64.7 (2H,m); 5.82 (1H,t); 6.76-6.86 (2H,m); 6.96-7.08 (3H,m); 7.12-7.28 (4H,m); 7.44-7.5 (2H,dd); 7.62 (1H,s); 7.69 (1H,s); 8.58 (1H,t); 9.12 (1H,s). MS (ES+) m/z 580.3 (MH+) Anal.calculated for C31H31F2N3O4S.HCl.0.9NaCl C, 55.7; H, 4.8; N, 6.3%; Found: C, 55.9; H, 4.8; N, 6.1%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C@H:22]([CH2:26][C:27]3[CH:35]=[C:34]([CH3:36])[C:33]4[C:29](=[CH:30][N:31]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:32]=4)[CH:28]=3)[C:23](O)=[O:24])=[O:20])[CH2:15][CH2:14]1)=[CH:7]2.C(N(CC)C(C)C)(C)C.[N:54]1([CH:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C@H:22]([CH2:26][C:27]3[CH:35]=[C:34]([CH3:36])[C:33]4[C:29](=[CH:30][N:31]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:43])([CH3:42])[CH3:44])[N:32]=4)[CH:28]=3)[C:23](=[O:24])[N:63]3[CH2:64][CH2:65][CH:60]([N:54]4[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]4)[CH2:61][CH2:62]3)=[O:20])[CH2:17][CH2:18]1)=[CH:7]2
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4cccc(F)c4[nH]c3=O)CC2)C(=O)O)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4cccc(F)c4[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
(R)-2-(4-(8-Fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)propanoic acid (105 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (3 mL). N,N-Diisopropylethylamine (100 μL, 0.57 mmol) was added to the mixture followed by o-benzotriazol-1-yl-N,N,N′-tetramethyluronium tetrafluoroborate (65 mg, 0.20 mmol). The reaction was stirred at room temperature for 5 min. 4-Piperidinopiperidine (41 mg, 0.22 mmol) was added to the mixture. The reaction was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetae (25 mL), washed successively with water (3×), and brine. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The title compound was obtained without further purification as white solid in 96% yield. Mass spec.: 773.3 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[CH:18]=[CH:17][S:16][C:12]3=[CH:13][N+:14]=2[O-])=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH3:37]>CS(C)=O>[CH2:36]([N:38]1[CH2:43][CH2:42][N:41]([C:13]2[N:14]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=[C:11]3[CH:18]=[CH:17][S:16][C:12]=23)[CH2:40][CH2:39]1)[CH3:37]
Reactant: COc1ccc(-c2cc3ccsc3c[n+]2[O-])cc1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CS(C)=O
Product: CCN1CCN(c2nc(-c3ccc(OC)cc3)cc3ccsc23)CC1
Temperature: 0 °C

Procedure:
5-(4-Methoxyphenyl)thieno[2,3-c]pyridine-6-oxide (3.0 g) was reacted with phosphorus oxychloride (15 ml) at 100° C. for 3 hr. The reaction mixture was poured into ice-water, neutralized with sodium carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine and dried. The extract was filtered through silica gel, and the column was washed with ethyl acetate. The filtrates were combined and concentrated. The resulting 7-chloro-5-(4-methoxyphenyl)thieno[2,3-c]pyridine (2.1 g) was reacted reacted in N-ethylpiperazine (5 ml) and dimethyl sulfoxide (20 ml) with potassium carbonate (5.0 g) at 100° C. for 1 day. The reaction solution was evaporated, and the resulting residue was partitioned between ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with water and dried. Then, the solvent was removed, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 0.93 g of the title compound of as a pale brown oil.
Reaction SMILES: [O:1]([CH:8]1[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.Cl>[O:1]([CH:8]1[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(Oc2ccccc2)CC1
Yield: 92.1 %

Procedure:
Step 2 A solution of 8-phenoxy-1,4-dioxaspiro[4.5]decane (0.460 g, 1.963 mmol) in THF (5.0 mL) and 3 M hydrochloric acid (5 mL) was stirred at rt for 2 days. The mixture was extracted with EtOAc, and the organic phase was washed with brine, dried and concentrated to provide 4-phenoxycyclohexanone as a colorless oil (0.344 g, 92%). 1H NMR (500 MHz, chloroform-d) δ 7.22-7.27 (2 H, m), 6.87-6.94 (3 H, m), 4.62-4.66 (1 H, m), 2.59-2.68 (2 H, m), 2.19-2.30 (4 H, m), 1.96-2.04 (2 H, m). Mass spectrum m/z 191.1 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=4[N:19](C(C)=C)[C:18]3=[O:30])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O>C(O)C>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=4[NH:19][C:18]3=[O:30])[CH2:10][CH2:9]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccc(C)cc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9.6 parts of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one, 24 parts of a hydrochloric acid solution, 50 parts of water and 96 parts of ethanol is stirred first for a while at about 50° C. and further for 30 minutes at room temperature. The reaction mixture is evaporated and the oily residue is triturated in 2-propanone. The hydrochloride salt is filtered off and the free base is liberated in the conventional manner with ammonium hydroxide in water. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The semi-solid residue is crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-5-methyl-2H-benzimidazol-2-one; mp. 178.3° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:17])=[C:11]([CH2:13][C:14]([O-:16])=O)[N:12]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24](O)[CH:23]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH3:17])=[C:11]([CH2:13][CH2:14][O:16][C:26]3[CH:27]=[C:22]([CH2:21][C:20]([O:19][CH3:18])=[O:30])[CH:23]=[CH:24][C:25]=3[CH3:28])[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(C)c(O)c1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CC(=O)[O-]
Product: COC(=O)Cc1ccc(C)c(OCCc2nc(-c3ccc(Br)cc3)oc2C)c1

Procedure:
By the same procedure as Example 31 and Example 32 using [2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]acetate instead of the compound prepared in Example 30 and methyl(3-hydroxy-4-methylphenyl)acetate instead of methyl(2-fluoro-3-hydroxyphenyl)acetate, the title compound having the following physical data was obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][NH:14]1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:35])[O:33][CH3:34]>ClCCl>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][N:14]1[C:32]([O:33][CH3:34])=[O:35]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(C(F)(F)F)cc2C)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)cc2C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
Methyl 2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-4-carboxylate hydrochloride (8.2 g, 24.28 mmol) and DIPEA (10.60 mL, 60.69 mmol) were dissolved in dichloromethane (100 mL). Methyl carbonochloridate (2.257 mL, 29.13 mmol) was added and the reaction stirred at room temperature for 1 h. DCM (100 mL) was added. The organic phase was washed twice with 1 M HCl and water, dried over Na2SO4 and evaporated to yield dimethyl 2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (8.9 g, quant.). MS m/z 360 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.[H-].[Na+].Br[CH2:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:24]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])[CH:23]=1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: BrCc1cccc(-c2ccccc2)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccc2)c1
Temperature: 60 °C

Procedure:
A solution of 6-(2,6-dimethoxyphenyl)piperidin-2-one (70 mg; 0.29 mmol; 1.0 equiv.) in anh. DMF (3 ml) was treated at rt with NaH (60% dispersion in mineral oil; 71 mg; 1.78 mmol; 6.0 equiv.), and 3-(bromomethyl)-1,1′-biphenyl (110 mg; 0.44 mmol; 1.5 equiv.). The resulting mixture was then heated to 60° C., under nitrogen, for 1 h. The reaction mixture was allowed to cool to rt, and a solution of aq. sat. NaHCO3 (10 ml) was added. After extractions with AcOEt (2×20 ml), the mixed organic layers were further washed with brine (10 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by preparative HPLC afforded 1-([1,1′-biphenyl]-3-ylmethyl)-6-(2,6-dimethoxyphenyl)piperidin-2-one as a colorless oil. LC-MS (conditions A): tR=0.95 min.; [M+H]+: 402.16 g/mol.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:24][CH2:23][CH2:22]2)=[CH:17][C:16]=1[F:25])=[O:4].[OH-].[Na+]>O.C(O)(=O)C>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:6]3[C:7]4[N:8]([CH:11]=[N:12][CH:13]=4)[CH:9]=[CH:10][C:5]=3[C:3]([OH:4])=[O:2])=[C:16]([F:25])[CH:17]=2)[CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)c1ccn2cncc2c1Nc1ccc(C2CCC2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccn2cncc2c1Nc1ccc(C2CCC2)cc1F
Temperature: 60 °C
Yield: 102.9 %

Procedure:
A suspension of 8-(4-cyclobutyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid methyl ester (150 mg, 0.46 mmol) and 1M NaOH (1.5 mL, 1.5 mmol) in IMS (2 mL) was heated at 60° C. for 2 hours. The reaction mixture was then cooled to room temperature, diluted with water and glacial acetic acid was added to adjust pH to 4. The precipitate was filtered off and dried in a drying pistol at 40° C. for 18 hours to afford the title compound as a cream solid (154 mg, 99%). 1H NMR (DMSO-d6):10.53 (1 H, s), 8.34 (1 H, s), 7.74 (1 H, d, J=7.3 Hz), 7.35 (1 H, t, J=8.3 Hz), 7.24 (1 H, d, J=11.2 Hz), 7.13(1 H, d, J=8.1 Hz), 7.01 (1H, d, J=9.3 Hz), 6.23 (1H, s), 3.61 (1 H, m), 2.38 (2 H, m), 2.14 (2 H, m), 1.99 (1 H, m), 1.84 (1 H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[F:19][C:20]1[CH:27]=[CH:26][C:23]([NH:24][CH3:25])=[CH:22][C:21]=1[C:28]([F:31])([F:30])[F:29]>>[CH3:25][N:24]([C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)[CH:5]=[CH:4][N:3]=1)[C:23]1[CH:26]=[CH:27][C:20]([F:19])=[C:21]([C:28]([F:31])([F:29])[F:30])[CH:22]=1
Reactant: Fc1ccc(-c2ccnc(Cl)n2)cc1C(F)(F)F
Reactant: CNc1ccc(F)c(C(F)(F)F)c1
Product: CN(c1ccc(F)c(C(F)(F)F)c1)c1nccc(-c2ccc(F)c(C(F)(F)F)c2)n1
Temperature: 126 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A round-bottom flask was charged with 1.03 g of 2-chloro-4-(4-fluoro-3-trifluoromethylphenyl)-pyrimidine and 0.82 g of 4-fluoro-3-trifluoromethyl-N-methylaniline and heated to 126° C. for 1.5 h. The reaction mixture melted and subsequently thickened. After standing overnight, the mixture was partitioned between 20 mL of EtOAc and 20 mL of NaHCO3. The organic phase was separated, dried, filtered and evaporated. The crude product was adsorbed onto silica gel and eluted with 50% EtOAc/heptane to yield 0.67 g of an oil which solidified on standing: m.p. 83-84° C.
Reaction SMILES: C([N:11]1[CH2:29][CH2:28][CH2:27][C@H:12]1[C:13]([NH:15][C:16]([C:24]([OH:26])=[O:25])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])(OCC1C=CC=CC=1)=O.CCOCC.[BrH:35].CC(O)=O>>[BrH:35].[NH:11]1[CH2:29][CH2:28][CH2:27][C@H:12]1[C:13]([NH:15][C:16]([C:24]([OH:26])=[O:25])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14]
Reactant: O=C(O)C(=Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)C(=Cc1ccccc1)NC(=O)[C@@H]1CCCN1
Yield: 74 %

Procedure:
A solution of 0.5 g (0.00125 mole) of N-carbobenzoxy-L-prolyl-dehydrophenylalanine in 3 ml of 32% HBr/HOAc was treated as N-carbobenzoxy-L-prolyl-dehydrophenylalanine azlactone was treated in Example 7(a) except that the ether precipitated product was allowed to stand two days at room temperature before filtration and crystallization from methanol/ethyl acetate to yield 0.313 g (74%) of L-prolyl-dehydrophenylalanine hydrobromide, m.p. 227°-228.5° (dec.), RfA 0.45.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[C:18](O)=[N:19][CH:20]=[N:21][CH:22]=4)=[C:11]3[O:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:18]1[C:17]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9][O:10][C:11]=23)=[CH:22][N:21]=[CH:20][N:19]=1
Reactant: Oc1ncncc1-c1ccnc2c(-c3ccc(F)cc3)noc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2noc3c(-c4cncnc4Cl)ccnc23)cc1
Temperature: 90 °C
Yield: 100.6 %

Procedure:
A suspension of 5-(3-(4-fluorophenyl)isoxazolo[4,5-b]pyridin-7-yl)pyrimidin-4-ol (45 mg, 0.146 mmol) in phosphorus oxychloride (503 μl, 5.40 mmol) was heated at 90° C. for 1 h, then allowed to cool to room temperature. The solvent was evaporated to afford the title compound (48 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH:9]([O:11][CH3:12])[CH3:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[CH:16]2[CH2:20][CH2:21][CH:22]=[CH:23][CH:15]12.C(O)(=O)C>C(OCC)C>[Cl:1][C:2]1[C:8]([CH:9]([O:11][CH3:12])[CH3:10])=[CH:7][C:5]([N:6]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])=[C:4]([F:13])[CH:3]=1
Reactant: COC(C)c1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)C2CCC=CC12
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(C)c1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 40.8 %

Procedure:
A mixture of 0.58 g (0.0029 mole) of 4-chloro-2-fluoro-5-(1-methoxyethyl)aniline, 0.82 g (0.0054 mole) of tetrahydrophthalic anhydride, and 15 ml of acetic acid was refluxed overnight. The acetic acid was then evaporated under reduced pressure, leaving a residue which was dissolved in diethyl ether. This solution was washed successively with water and an aqueous solution of sodium bicarbonate. The solution was dried, filtered, and the solvent was evaporated under reduced pressure leaving a residue. This residue was passed through a silica gel column, eluting with ethyl acetate/heptane (1/4). Appropriate fractions were combined, and the solvent was evaporated under reduced pressure, yielding 0.4 g of N-[4-chloro-2-fluoro-5-(1-methoxyethyl)phenyl]-3,4,5,6-tetrahydrophthalimide as a solid, m.p. 141°-44° C. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11]Br.C(=O)([O-])[O-].[K+].[K+]>>[Br:9][CH2:10][CH2:11][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: BrCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: BrCCOc1ccc(I)cc1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
A mixture of 4-iodophenol (15.0 g, 68.2 mmol) and 1,2-dibromoethane (50 ml, 580 mmol) and potassium carbonate (14.0 g, 0.1 mol) was stirred and refluxed for 22 h. After cooling to r.t., the mixture was filtered, washed with ethyl acetate and concentrated in vacuo. The residue was chromatographed on silica gel (Hexane/ethyl acetate 40:1 to 20:1) to afford the title compound (18.7 g, 84%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[CH3:29][O:28][C:20]1[CH:19]=[C:18]([NH:17][C:14]2[O:15][C:16]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:37](=[O:39])[CH3:38])=[CH:3][CH:4]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[N:13]=2)[CH:23]=[C:22]([O:24][CH3:25])[C:21]=1[O:26][CH3:27]
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(N)cc4)c3o2)cc(OC)c1OC
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Nc2nc3cccc(-c4ccc(NC(C)=O)cc4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.075 g (0.1927 mmol) [7-(4-amino-phenyl)-benzooxazol-2-yl]-(3,4,5-trimethoxy-phenyl)-amine (example 11), 0.027 ml triethylamine and 0.016 g (0.199 mmol) acetyl chloride in 4 ml dichloromethane is stirred for 1 h at room temperature. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, EtOAc) to afford the title compound as orange crystals. Rt=2.16 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 434 (M+1)+; m.p. 265-270° C.
Reaction SMILES: [CH3:1][C:2]1([OH:9])[CH2:4][CH:3]1[Si:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C:2]1([O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:4][CH:3]1[Si:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC1(O)CC1[Si](C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(OS(C)(=O)=O)CC1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
16 g (0.11 mole) of a trans isomer, a cis isomer or a trans/cis isomer mixture of 1-methyl-1-hydroxy-2-(trimethylsilyl)cyclopropane, prepared in Section (1) was dissolved in 150 ml of dichloromethane and 25 ml of triethylamine was added thereto. The reaction solution was cooled to 0° C., 16 g (0.14 mole) of methanesulfonylchloride was gradually added thereto and the mixture was vigorously stirred for 1 hour. 50 mL of a saturated aqueous NaHCO3 solution was added to the reaction mixture to complete the reaction. An organic layer was separated from the reaction solution, dried over anhydrous magnesium sulfate (MgSO4), and concentrated by distillation of the solvent. Although the concentrate may be used directly without any further purification, it was finely purified by vacuum distillation (55-60° C./0.1 mmHg). As a result, 21.4 g (0.0096 mole, yield: 87%) of 1-methyl-1-(methanesulfonyloxy)-2-(trimethylsilyl)cyclopropane was obtained as a trans isomer, a cis isomer and a mixture thereof.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[N:11]=[N:10][C:9]([CH3:12])=[C:8]2[N:13]=[CH:14][NH:15][C:7]=12.S(=O)(=O)(O)[OH:17]>O.C(O)(=O)C>[CH3:12][C:9]1[C:8]2[N:13]=[CH:14][NH:15][C:7]=2[C:6](=[O:17])[NH:11][N:10]=1
Reactant: Cc1nnc(N)c2[nH]cnc12
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1n[nH]c(=O)c2[nH]cnc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 4.00 g sodium nitrite in 15 ml of water is added dropwise at 50° C. to 2.20 g of 4-amino-7-methyl-3H-imidazo[4,5-d]pyridazine in a mixture of 30 ml acetic acid, 5 ml of water and 0.5 ml concentrated sulphuric acid. The reaction mixture is stirred for a further two hours at 50° C. and then heated to 90° C. for one hour. After cooling to ambient temperature the reaction mixture is diluted with 30 ml of water. The precipitate formed is suction filtered, washed with water, ethanol and diethyl ether and dried.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[OH:5][CH:6]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1>C1(C)C=CC=CC=1.O1CCOCC1>[CH:18]([N:17]1[CH2:16][CH:6]([CH2:7][O:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[O:5][C:1]1=[O:2])([CH3:20])[CH3:19]
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc(OCC(O)CNC(C)C)cn1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1ccc(OCC2CN(C(C)C)C(=O)O2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10 g of phosgene in 40 ml of toluene is added dropwise at 5°-10° C. to 15.6 g of 3-(2'-hydroxy-3'-isopropylamino-propoxy)-6-methyl-pyridine, dissolved in 75 ml of dioxane, in the presence of 8 ml of 2,6-lutidine,whilst stirring. The reaction mixture is stirred overnight at room temperature and is then evaporated in vacuo. The evaporation residue is rendered alkaline with a little concentrated sodium hydroxide solution and is extracted with 200 ml of ethyl acetate. The organic phase is evaporated, initially at approx. 20 mm Hg and then at 0.1 mm Hg/60° C. bath temperature. Approx. 50 ml of ether are added to the residue which remains, giving crystalline 3-isopropyl-5-[(6-methylpyridin-3-yloxy)methyl]-oxazolidin-2-one of melting point 86°-88° C.