Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2]1.[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][CH2:25][CH:26]([CH2:29][OH:30])[O:27][CH3:28]>>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][CH2:25][CH:26]([O:27][CH3:28])[CH2:29][O:30][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COC(CO)COC1CCCCO1
Reactant: CCCCCCCCCCCCCCC1CO1
Product: CCCCCCCCCCCCCCC(O)COCC(COC1CCCCO1)OC
Yield: 53.2 %

Procedure:
The epoxide (9) (4.8 g, 20 mmoles) as obtained in Example 4-1 was reacted with 7.6 g (40 mmoles) of 2-methylglycerol monotetrahydropyranyl ether in the same manner as Example 1-2 to give 4.58 g (53.2%) of the desired compound (10).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([O:34]CC)=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:37]([CH3:39])[CH3:38])[O:11][N:10]=1.C(O)C.[OH-].[Na+]>O1CCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][S:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([OH:34])=[O:33])[CH:26]=[CH:25]4)=[CH:20][CH:21]=2)=[C:12]([CH:37]([CH3:39])[CH3:38])[O:11][N:10]=1
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(SCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CSc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 100 °C
Yield: 93.8 %

Procedure:
A solution of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}thio)phenyl]-2-quinolinecarboxylate (20 mg, 0.033 mmol) in tetrahydrofuran (0.33 mL) was placed in a microwave reaction vial followed by ethanol (0.17 mL) and 1 N sodium hydroxide (0.050 mL). The tube was sealed then heated to 100° C. for ten minutes. The reaction mixture was then concentrated and the residue partitioned between tetrahydrofuran and brine. 1 N hydrochloric acid (0.050 mL) was added. The organic layer was separated and concentrated to yield 17 mg (94%) of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}thio)phenyl]-2-quinolinecarboxylic acid as an orange solid. 1H NMR (400 MHz, d6-DMSO): δ 8.57 (d, J=9 Hz, 1H), 8.35 (s, 1H), 8.20-8.10 (m, 3H), 7.76 (d, J=8 Hz, 2H), 7.63 (d, J=7 Hz, 2H), 7.58-7.7.54 (m, 1H), 7.42 (d, J=8 Hz, 2H), 3.95 (s, 2H), 3.24 (septet, J=7 Hz, 1H), 1.16 (d, J=7 Hz, 6H). HRMS (ESI) C29H22Cl2N2O3S calculated: 549.0806 [M+H]+, found: 549.0813 [M+H]+.
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[C:15]([F:35])=[CH:16][C:17]3[C:18]([CH:34]=2)=[N:19][C:20]2[N:21]([CH3:33])[CH:22]=[C:23]([C:28]([O:30]CC)=[O:29])[C:24](=[O:27])[C:25]=2[CH:26]=3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>[OH-].[K+].C(O)C>[CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[C:15]([F:35])=[CH:16][C:17]3[C:18]([CH:34]=2)=[N:19][C:20]2[N:21]([CH3:33])[CH:22]=[C:23]([C:28]([OH:30])=[O:29])[C:24](=[O:27])[C:25]=2[CH:26]=3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(Cc5ccccc5)C4)c(F)cc3cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(Cc5ccccc5)C4)cc3nc21
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
A suspension of (RS)-8-(3-benzyl-1-piperazinyl)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4dihydrobenzo[b][1,8]naphthyridine (2.65 g) in N aqueous potassium hydroxide (14 cc) and ethanol (20 cc) is heated to a temperature in the region of 80° C. for 20 minutes, treated at the same temperature with 5% strength acetic acid (32 cc) and stirred for 20 minutes. The insoluble matter is drained at approximately 80° C. and washed with water (2×20 cc), ethanol (2×20 cc) and ethyl ether (2×20 cc). After 2 recrystallizations in dimethylformamide (50 cc each time), (RS)-8-(3-benzyl-1-piperazinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (2.05 g) is obtained in the form of a yellow solid, decomposing at 270°-275° C.
Reaction SMILES: FC1C=C[C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[CH:19]([NH:21][CH3:22])[CH3:20])=CC=1.[C:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([N:21]([CH3:22])[CH:19]([C:9]2[N:8]([CH3:5])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH3:20])=[O:32])=[CH:34][CH:35]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CNC(C)c1nc2ccccc2c(=O)n1-c1ccc(F)cc1
Product: CC(c1nc2ccccc2c(=O)n1C)N(C)C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
In a similar manner as described above in Paragraph A, but replacing 3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one with 3-(4-fluorophenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one and 4-tert-butylbenzoyl chloride with the appropriate starting material, the following compounds were made:
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:44](COCC[Si](C)(C)C)[CH:43]=[N:42][C:5]=2[C:6]([CH2:33][C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:41])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[C:12]([F:30])[C:11]=1[O:31][CH3:32])#[N:2].C(=O)(O)[O-:54].[Na+]>S(=O)(=O)(O)O.O>[Cl:40][C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:41])[C:34]=1[CH2:33][C:6]1[C:5]2[N:42]=[CH:43][NH:44][C:4]=2[C:3]([C:1]([NH2:2])=[O:54])=[C:8]([NH:9][C:10]2[CH:15]=[C:14]([F:16])[C:13]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[C:12]([F:30])[C:11]=2[O:31][CH3:32])[N:7]=1
Reactant: COc1c(Nc2nc(Cc3c(Cl)cccc3Cl)c3ncn(COCC[Si](C)(C)C)c3c2C#N)cc(F)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1F
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1c(Nc2nc(Cc3c(Cl)cccc3Cl)c3nc[nH]c3c2C(N)=O)cc(F)c(N2CCNCC2)c1F
Temperature: 95 °C

Procedure:
To a solution of the product of Example 52D (130 mg, 0.17 mmol) in concentrated sulfuric acid (5 mL) at 0° C. was added water (1 mL) and the mixture was heated at 95° C. for 20 minutes. After cooling to ambient temperature, the mixture was diluted with water (3 mL), adjusted to pH 8-9 with saturated sodium bicarbonate solution and extracted with dichloromethane (3×20 mL). The combined organic phase was concentrated and the residue was purified by preparative HPLC using a gradient of 10/90 to 80/20 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 12.35 (s, 1 H), 9.61 (s, 1 H), 8.97 (s, 2 H), 8.66 (s, 1 H), 7.91 (s, 1 H), 7.74-7.66 (m 1 H), 7.56-7.53 (m, 2 H), 7.43-7.37 (m, 1 H), 4.77 (s, 2 H), 3.82 (s, 3 H), 3.21 (m, 8 H). MS: 562 (M+H+).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH2:17]([N:19]([CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)[CH2:20][CH3:21])[CH3:18]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:27]([C:26]2[CH:30]=[CH:31][C:23]([CH2:22][N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])=[CH:24][CH:25]=2)[OH:28])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CCN(CC)Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CCN(CC)Cc1ccc(C(O)=C2C(=O)N(C(C)=O)c3ccc(C(C)=O)cc32)cc1

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-diethylaminomethyl-benzoic acid
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15].[CH2:31]([O:33][C:34](=[O:68])[C@@H:35]([O:65][CH2:66][CH3:67])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44]/[CH:45]=[C:46](/[C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:59]=[CH:58][C:57](/[C:60](/[CH3:64])=[CH:61]/[CH2:62]O)=[CH:56][CH:55]=3)=[CH:50][CH:49]=2)\[CH3:47])=[CH:39][CH:38]=1)[CH3:32]>C1COCC1.O.C(OCC)(=O)C>[CH2:21]([O:20][C:18](=[O:19])[C@@H:17]([O:16][CH2:14][CH3:15])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:62]/[CH:61]=[C:60](/[C:57]2[CH:56]=[CH:55][C:54]([C:51]3[CH:52]=[CH:53][C:48](/[C:46](/[CH3:47])=[CH:45]/[CH2:44][O:43][C:40]4[CH:39]=[CH:38][C:37]([CH2:36][C@H:35]([O:65][CH2:66][CH3:67])[C:34]([O:33][CH2:31][CH3:32])=[O:68])=[CH:42][CH:41]=4)=[CH:49][CH:50]=3)=[CH:59][CH:58]=2)\[CH3:64])=[CH:28][CH:29]=1)[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(/C(C)=C/CO)cc3)cc2)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(/C(C)=C/COc4ccc(C[C@H](OCC)C(=O)OCC)cc4)cc3)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.6 %

Procedure:
Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (0.50 g, 1.89 mmol) was added at 0–5° C. to a stirred solution of tributylphosphine (0.37 mL, 1.89 mmol), (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.32 g, 1.32 mmol) and (E)(E)(S) 2-ethoxy-3-(4-{3-[4′-{3-hydroxy-1-methyl-propenyl)-biphenyl-4-yl]-but-2-enyloxy}-phenyl)-propionic acid ethyl ester (0.65 g, 1.26 mmol) in dry THF (15 ml). The mixture was warmed to room temperature, and stirred for 18 h. The resulting mixture was diluted with water and ethyl acetate, the aqueous layer collected and further extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (MgSO4) and evaporated to give 580 mg (63%) of the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5](N(C(C)C)CC)(C)C.[CH3:14][O:15][C:16](=[O:31])[C@H:17]([CH2:29][OH:30])[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(O)C>[CH2:14]([O:15][C:16](=[O:31])[C@H:17]([CH2:29][OH:30])[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH3:5]
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 16 h

Procedure:
Thionyl chloride (5.25 mL, 72 mmol, 3.6 equiv.) is added dropwise to a 0° C. solution of absolute ethyl alcohol (20 ml). Diisopropyl ethylamine (3.45 ml, 19. mmol, 1 equiv.) was added and then 4.8 g of N-CBZ-L-serine methyl ester was added as a solid. Stirring is continued for 16 hours at room temperature. The ethanol and thionyl chloride are then removed by rotary evaporation and the residue is dissolved in ethyl acetate (200 mil). The organic phase is washed with 1N hydrochloric acid (50 ml) and saturated sodium bicarbonate (50 ml) and brine (20 ml). The organic layer is dried with magnesium sulfate. Rotary evaporation of the product gives an oil which is chromatographed on silica gel with hexane/ethyl acetate (3:1) to give N-CBZ-L-serine ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>ClCCl>[C:13]([Si:10]([O:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([F:1])[CH:3]=1)([CH3:12])[CH3:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(O)cc(F)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1cc(F)cc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
To a solution of 3-fluoro-5-methylphenol (19.7 g, 156 mmol) and tert-butyldimethylsilyl chloride (25.9 g, 172 mmol) in dichloromethane (250 mL) was added imidazole (12.7 g, 187 mmol) at 0° C., and the mixture was stirred at room temperature for 2 h. The mixture was washed with water and brine and dried on anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (98:2 hexane/ethyl acetate) to give tert-butyl(3-fluoro-5-methylphenoxy)dimethylsilane (38.6 g, 100%).
Reaction SMILES: C12CC(CC1)C([C:8](=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1)N2.C1(CS(Cl)(=O)=O)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:24][O:23][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[O:25])[CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22]
Reactant: COc1cc(CCCCC(=O)C2NC3CCC2C3)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(Cl)CC1CCCCC1
Solvent: ClCCl
Product: COc1cc(CCCCC=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 85 mg (0.24 mmol) of 1-(2-aza-bicyclo[2.2.1]hept-3-yl)-5-(3,4,5-trimethoxy-phenyl)-pentan-1-one (mixture of exo and endo isomers), 70 mg (0.36 mmol) of cyclohexyl-methanesulfonyl chloride (J.Org.Chem. 1951; 16 621-624) and 58 mg (0.48 mmol) of 4-dimethylaminopyridine in 10 ml of methylene chloride was stirred at room temperature for 14 hours. The reaction mixture was washed with 1N hydrochloric acid (HCl), dried (Na2SO4), and evaporated. The residue was chromatographed on 20 g of silica using 3:1 hexanes:ethyl acetate as the elutant. Appropriate fractions were combined to yield 4 mg of 1-(2-cyclohexylmethanesulfonyl-2-aza-bicyclo[2.2.1]-exo-hept-3-yl)-5-(3,4,5-trimethoxy-phenyl)-pentan-1-one (Rf=0.5). 1H NMR: (CDCl3) δ 6.40 (s, 2 H), 4.05 (m, 2 H), 3.80 (s, 6 H), 3.75 (s, 3 H), 2.90 (m, 2 H), 2.62 (s, 1 H), 2.50 (m, 4 H), 2.10 (m, 1 H), 1.90 (m, 4 H), 1.60 (m, 15 H), 1.20 (m, 1 H) ) and 10 mg of 1-(2-Cyclohexylmethanesulfonyl-2-aza-bicyclo[2.2.1]-endo-hept-3-yl)-5-(3,4,5-trimethoxy-phenyl)-pentan-1-one (Rf=0.4)13C NMR: (CDCl3) δ 6.40 (s, 2 H),4.50 (s, 1 H), 4.20 (s, 1 H), 3.90 (s, 6 H), 3.86 (s, 3 H),2.8-3.1 (m, 3 H), 2.5 (m, 4 H), 1.8-2.0 (m, 4 H), 1.4-1.8 (m, 15 H), 1.1 (m, 2 H)).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)[CH2:23][OH:24])=[CH:18][CH:17]=1)(C)(C)C.[C:40](N1C=CN=C1)(N1C=CN=C1)=[O:41].CCN(CC)CC.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:23][O:24][C:40](=[O:41])[N:25]2[C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)=[CH:18][CH:17]=1
Reactant: COc1cc(NC(CO)c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)cc(OC)c1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(N2C(=O)OCC2c2ccc(C(=O)Nc3ccccc3N)cc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.5 %

Procedure:
To a solution of 293 (200 mg, 0.372 mmol) in toluene (5 mL) and THF (1 mL) was added 1,1′-carbonyldiimidazole (72 mg, 0.45 mmol) followed by Et3N (156 μL, 1.12 mmol) and the mixture was stirred at room temperature for 5 h then at 90° C. for 48 h. The reaction mixture was diluted with AcOEt, a solution of sat. NH4Cl was added and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (DCM/AcOEt: 80/20) to afford the desired compound (120 mg, 0.21 mmol, 57% yield). 1H NMR (DMSO) δ (ppm): 9.37 (s, 1H), 7.98 (d, J=8.1 Hz, 2H), 7.76 (d, J=7.5 Hz, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.25-15 (m, 3H), 6.88 (s, 1H), 6.61 (s, 2H), 5.40 (dd, J=8.7, 6.0 Hz, 1H), 4.79 (t, J=8.7 Hz, 1H), 4.19 (dd, J=8.7, 6.0 1H), 3.75 (s, 3H), 3.72 (s, 6H), 1.47 (s, 9H).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:14][C:13]1[C:12]([O:15][CH3:16])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[Cl:5]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(Cl)c1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
1,2-Dibromoethane (46 mL, 0.54 moles) was added to a mixture of 3-chloro-4-hydroxy-5-methoxybenzaldehyde (10 g, 54 mmoles) and potassium carbonate (37 g, 0.27 moles) in DMF (180 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with saturated sodium chloride (150 mL), dried over MgSO4 and evaporated in vacuo to afford 9.33 g (59%) of 4-(2-bromoethoxy)-3-chloro-5-methoxybenzaldehyde. M.p. 52-54° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:12][CH2:11]2)=[N:8][CH:9]=1
Reactant: COC(=O)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC1CCN(c2ccc(N)cn2)CC1
Reaction time: 4 h
Yield: 85.8 %

Procedure:
A solution of methyl [1-(5-nitropyridin-2-yl)piperidin-4-yl]acetate (710 mg, 2.60 mmol) in EtOH (26 mL) was treated with 10% Pd on charcoal (71 mg), and stirred vigorously under an atmosphere of hydrogen for 4 h. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated to dryness to give the title compound (556 mg, 70%) as an oil; 1H NMR δ 1.12-1.27 (2H, m), 1.67 (2H, d), 1.75-1.89 (1H, m), 2.25 (2H, d), 2.56 (2H, t), 3.33 (2H, s), 3.58 (3H, s), 4.52 (2H, s), 6.61 (1H, d), 6.86-6.93 (1H, m), 7.58 (1H, d); MS m/e MH+ 250.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:23][CH:22]=2)=[O:20])[CH2:7]1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(Oc2ccccc2)cc1

Procedure:
Example 33 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-isocyanato-4-phenoxybenzene (24.6 μl) to give the title compound (0.0171 g). LC-MS (System A): Rt 2.62 mins, Mass Spectrum m/z 486 [MH+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH:12]=2)=[CH:4][C:3]=1[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C>CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][C:14]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:16])[CH:12]=2)=[CH:4][C:3]=1[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1
Reactant: Nc1ncc(-c2cnn(CC(=O)O)c2)cc1-c1nc2ccccc2s1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ncc(-c2cnn(CC(=O)N3CCOCC3)c2)cc1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of [4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-acetic acid (5.00 mg, 0.0142 mmol), morpholine (10.0 mg, 0.11 mmol), TBTU (9.14 mg, 0.0284 mmol), DIPEA (0.02 mL, 0.1 mmol) and DMF (2 mL, 0.03 mol) was stirred at rt for 10 min. The solution was transferred to a separatory funnel, diluted with EtOAc and washed 3× with water. The organic layer was concentrated in vacuo and loaded onto a prep TLC plate, eluting with 5% MeOH/DCM. The band containing the pure product was filtered off using 1:1 MeOH/DCM, and the filtrate was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=3.60-3.64 (m, 4H), 3.72 (dt, J=12.8, 4.7 Hz, 4H), 5.17 (s, 2H), 7.40-7.45 (m, 1H), 7.48-7.54 (m, 1H), 7.85 (s, 1H), 7.94-7.98 (m, 2H), 8.02 (d, J=7.8 Hz, 1H), 8.16 (d, J=2.3 Hz, 1H), 8.30 (d, J=2.3 Hz, 1H). MS (ES+): m/z=421.12 (100) [MH+]. HPLC: tR=2.79 min (ZQ3, polar—5 min).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:13]2[N:14]=[C:15](O)[C:16]3[CH:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].P(Cl)(Cl)([Cl:26])=O>C(N(CC)C1C=CC=CC=1)C>[Cl:26][C:15]1[N:14]=[C:13]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:2][CH:3]=2)[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccc(OC(F)(F)F)c(F)c2)cc2ncccc12
Solvent: CCN(CC)c1ccccc1
Product: FC(F)(F)Oc1ccc(-c2cc3ncccc3c(Cl)n2)cc1

Procedure:
200 mg 7-(3-fluoro-4-trifluormethoxy-phenyl)-[1,6]-naphthyridine-5-ol (5.1) and 10 μL N,N-diethylaniline were stirred into 4 mL phosphorus oxychloride overnight at 120° C. The reaction mixture was evaporated down, followed by co-evapoartion with toluene (×3) and the residue purified via silica gel chromatography (ethyl acetate→dichloromethane/methanol 4:1).
Reaction SMILES: CN(C=O)C.[CH2:6]([C:10]1[N:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]#[N:46])=[CH:35][CH:34]=2)[C:13]2[C:14](=[O:30])[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:16]=[CH:17][C:12]=2[N:11]=1)[CH2:7][CH2:8][CH3:9].[Cl-].C([NH+](CC)CC)C.[N-:55]=[N+:56]=[N-:57].[Na+]>O.C(OCC)(=O)C>[CH2:6]([C:10]1[N:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[NH:57][N:56]=[N:55][N:46]=3)=[CH:35][CH:34]=2)[C:13]2[C:14](=[O:30])[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:16]=[CH:17][C:12]=2[N:11]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1nc2ccn(Cc3ccccc3C(=O)OCC)c(=O)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc2ccn(Cc3ccccc3C(=O)OCC)c(=O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of 1450 ml of DMF, 219.7 g of 2-butyl-3-(2'-cyano-biphenyl-4-ylmethyl)-4,5-dihydro-4-oxo-5-(o-ethoxycarbonyl-benzyl)-3H-imidazo[4,5-c]pyridine, 166.5 g of triethylammonium chloride and 78.6 g of sodium azide is heated to 120° for 22 hours. After cooling, the mixture is worked up conventionally with ethyl acetate and water, the crude product is purified several times by suspending it in ethanol and filtering, and 2-butyl-4,5-dihydro-4-oxo-3-[2'-(tetrazol-5-yl)-biphenyl-4-ylmethyl]-5-(o-ethoxycarbonyl-benzyl)-3H-imidazo[4,5-c]-pyridine is obtained; m.p. 203°-204°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([CH3:19])([C:14]([O:16]CC)=[O:15])[O:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([CH3:19])([C:14]([OH:16])=[O:15])[O:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C1(C)CC(c2cc(Cl)cc(Cl)c2)=NO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C(=O)O)CC(c2cc(Cl)cc(Cl)c2)=NO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.00 g (16.55 mmol) of ethyl 3-(3,5-dichlorophenyl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxylate were dissolved in 50 ml of ethanol, and 24.82 ml of 1N NaOH were then added. After 1 h of stirring at RT, the solvent was removed, 100 ml of water were added and the aqueous phase was adjusted to pH 2 by addition of 2N HCl. The product formed was obtained by extraction with 100 ml of ethyl acetate, drying the organic phase over Na2SO4, filtration and concentration.