Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[O:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH2:13]1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([C:20]1[CH:19]=[CH:18][C:17]2[O:12][CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)=[O:5]
Reactant: O=C(Cl)c1cc(I)ccc1Br
Reactant: c1ccc2c(c1)OCCO2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)OCCO2)c1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a stirred solution of 2-bromo-5-iodo-benzoyl chloride (26.4 g, 76.56 mmol) in dichloromethane (250 mL) was added benzo(1,4)-dioxane (10.41 g, 76.26 mmol) at 0° C. To this reaction mixture, AlCl3 (40.78 g, 305.47 mmol) was added in portions. After stirring overnight at room temperature, the reaction mixture was poured into crushed ice. The resulting mixture was extracted with dichloromethane (500 mL×2). The dichloromethane layers were combined and washed with water (200 mL), saturated aqueous sodium bicarbonate solution (200 mL×2), and brine (200 mL), then dried over sodium sulfate and concentrated. The solid product was triturated with hexanes, and the triturated product was dried under vacuum to furnish (2-bromo-5-iodo-phenyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone (30 g).
Reaction SMILES: I[C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)[C:7]([NH2:9])=[N:8][C:4]=2[CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:28][O:27][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][CH2:18][C:19]1[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[CH2:10][N:6]1[C:5]2[CH:29]=[CH:30][C:2]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:3][C:4]=2[N:8]=[C:7]1[NH2:9]
Reactant: CN1CCNCC1
Reactant: COc1ccc(COc2ccc(Cn3c(N)nc4cc(I)ccc43)cc2OC)cn1
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(N5CCN(C)CC5)ccc43)cc2OC)cn1

Procedure:
1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-amine was prepared from 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-2-amine and 1-methylpiperazine according to the procedure described for the synthesis of Example 3-13: 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=2.0 Hz, 1H), 7.67 (dd, J=8.5, 3.0 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.79-6.75 (m, 2H), 6.72 (s, 1H), 6.67 (d, J=8.5 Hz, 1H), 5.03 (s, 2H), 5.02 (s, 2H), 3.94 (s, 3H), 3.77 (s, 3H), 3.22-3.17 (m, 4H), 2.65-2.59 (m, 4H), 2.37 (s, 3H) ppm; (M+1)=489.
Reaction SMILES: [CH2:1]([N:3]([CH2:62][CH3:63])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:61])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][C:53](=[O:60])[N:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2].[CH3:64][C:65]1[CH:70]=[CH:69][C:68]([S:71](Cl)(=[O:73])=[O:72])=[CH:67][CH:66]=1.S(Cl)(Cl)(=O)=O>>[CH2:62]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:61])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][C:53](=[O:60])[N:54]3[CH2:59][CH2:58][N:57]([S:71]([C:68]4[CH:69]=[CH:70][C:65]([CH3:64])=[CH:66][CH:67]=4)(=[O:73])=[O:72])[CH2:56][CH2:55]3)[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:63]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)N3CCNCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O=S(=O)(Cl)Cl
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)N3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared from 262b according to the procedure described in Example 290 using 4-methylbenzene-1-sulfonyl chloride as the sulfonyl chloride. MS (ES, m/z) 1031.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]([NH2:28])[CH3:27]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][NH:28][CH2:26][CH3:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCN
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and ethylamine (2M in THF).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:18][C:19]1[C:24]([C:25]#N)=[C:23]([CH3:27])[CH:22]=[C:21]([CH3:28])[N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.[O:30]1CCCC1>>[CH2:11]([O:18][C:19]1[C:24]([CH:25]=[O:30])=[C:23]([CH3:27])[CH:22]=[C:21]([CH3:28])[N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(C)c(C#N)c(OCc2ccccc2)n1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Product: Cc1cc(C)c(C=O)c(OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 3-cyano-4,6-dimethyl-1H-pyridin-2-one (4.6 g) in dichloromethane (150 mL) were added benzyl bromide (5.6 mL) and silver carbonate (26 g), and the mixture was stirred under shading for 3 hours at 50° C. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=7/1) to give 2-benzyloxy-3-cyano-4,6-dimethylpyridine (7.1 g). To diisobutylaluminum hydride (1.5 mol/L solution in toluene, 8.7 mL) was added a solution of 2-benzyloxy-3-cyano-4,6-dimethylpyridine (2.4 g) in tetrahydrofuran (4.3 mL) at 0° C., and the mixture was stirred for 4 hours at 0° C. The reaction mixture was poured into 1 mol/L hydrochloric acid solution (40 mL), and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=50/1-20/1-10/1) to give 2-benzyloxy-3-formyl-4,6-dimethylpyridine (0.90 g). To a solution of 4-ethylbromobenzene (0.044 g) in tetrahydrofuran (1.2 mL) was added tert-butyllithium (1.5 mol/L solution in hexane, 0.17 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. A solution of 2-benzyloxy-3-formyl-4,6-dimethylpyridine (0.048 g) in tetrahydrofuran (1.3 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes for 0° C. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with diethylether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=5/1) to give 2-benzyloxy-4,6-dimethylpyridin-3-yl-4-ethylphenylmethanol (0.066 g). To a solution of the obtained 2-benzyloxy-4,6-dimethylpyridin-3-yl-4-ethylphenylmethanol (0.061 g) in ethanol (3.5 mL) was added 10% palladium carbon powder (0.037 g), and the mixture was stirred for 12 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloro-methane/methanol=10/1) to give 3-(4-ethylbenzyl)-4,6-dimethyl-1H-pyridin-2-one (0.039 g).
Reaction SMILES: [C:1]([NH:18][C:19]1[CH:31]=[CH:30][N:22]([C@@H:23]2[O:29][C@H:26]([CH2:27][OH:28])[CH2:25][CH2:24]2)[C:21](=[O:32])[N:20]=1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].C[O:41][P:42](OC)([O:44]C)=[O:43]>>[P:42]([O:28][CH2:27][C@H:26]1[O:29][C@@H:23]([N:22]2[CH:30]=[CH:31][C:19]([NH:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:20][C:21]2=[O:32])[CH2:24][CH2:25]1)([OH:44])([OH:43])=[O:41]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1ccn([C@H]2CC[C@@H](CO)O2)c(=O)n1
Reactant: COP(=O)(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)Nc1ccn([C@H]2CC[C@@H](COP(=O)(O)O)O2)c(=O)n1
Temperature: 0 °C

Procedure:
2.7 g (6 mmol) N4 -palmitoyl-2',3'-dideoxycytidine is added gradually to a mixture of 1.09 ml (12 mmol) phosphorylchloride and 20 ml trimethylphosphate that is stirred at 0° C. The batch is stirred for a further 2 hours when cold and then slowly neutralized with 0.5N NaOH during cooling. The precipitate that is formed is centrifuged off, absorbed in chloroform/methanol; 7/3; V/V, filtered over sodium sulphate and freed of solvent in a vacuum. The residue so obtained is crystallized several times from ethanol. When this is done, 2.5 g of N4 -palmitoyl-2',3'-dideoxycytidine-5'-phosphate is obtained and this displays an Rf value of 0.35 on the silica gel plate in the chloroform/methanol; 1/1; V/V system.
Reaction SMILES: C[C:2]1[C:3]([I:15])=[C:4]([O:13][CH3:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](O)=[O:8].C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[CH3:14][O:13][C:4]1[C:5]([I:12])=[C:6]([C:10]([I:11])=[CH:2][C:3]=1[I:15])[C:7]([Cl:19])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1c(I)c(C)c(I)c(C(=O)O)c1I
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(I)cc(I)c(C(=O)Cl)c1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 25 mL round-bottom flask equipped with a condenser, methyl 3-methoxy-2,4,6-triiodobenzoic acid (0.250 g) was suspended in 3 mL anhydrous methylene chloride. Oxalyl chloride (0.58 mL) and one drop of DMF was added. The reaction mixture was stirred for 4 h at RT. The solvent and excess oxalyl chloride were removed by rotary evaporation. The desired acyl chloride was dried under vacuum to give a pale yellow solid which was used in the next step without any further purification. Yield 0.272 g (crude ˜100%)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].[CH3:11][C:12]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][CH:15]=1)=O.OS(O)(=O)=O.O>C(O)(=O)C>[C:20]([C:18]1[CH:19]=[C:14]([CH:12]=[CH:11][C:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:7])[CH:15]=[CH:16][CH:17]=1)#[N:21]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC(=O)c1cccc(C#N)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cccc(C=CC(=O)c2cccc(C#N)c2)c1

Procedure:
3-Cyanobenzaldehyde (3.0 g, 23.0 mmol) and 3-cyanoacetophenone (3.34 g, 23.0 mmol) in glacial acetic acid (5 mL) and concentrated H2SO4 (3.66 mL, 69 mmol) was stirred at room temperature for 72 hours. Water (200 mL) was added and the reaction filtered. The precipitate was washed with water (2×200 mL) and dried in vacuo to give 3,3′-dicyanochalcone as an off-white solid. MS (APCI) m/z 258 (M+−1, 100%). 13C NMR (50 MHz, d6-DMSO): δ 111.7, 117.8, 118.0, 123.0, 129.7, 131.6, 132.1, 132.4, 133.3, 133.5, 135.3, 136.1, 137.4, 142.1, 187.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.[C:23](Cl)(=[O:26])[CH2:24][OH:25]>N1C=CC=CC=1>[C:24]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)(=[O:25])[CH2:23][OH:26]
Reactant: O=C1Nc2ccc(O)cc2C1=Cc1ccnc2ccccc12
Reactant: O=C(Cl)CO
Solvent: c1ccncc1
Product: O=C(CO)Oc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Temperature: 0 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a stirred solution of 5-hydroxy-3-(quinol-4-ylmethylene)-2-oxindole (2.883 g, 10 mmol) in pyridine (10 ml) was added gradually glycoloyl chloride (0.945 g, 10 mmol) at 0°-5° C. under cooling. The reaction mixture was stirred for about 4 h at 0°-5° C. and then for 15 h at room temperature. The mixture was poured onto an ice-water mixture, the precipitate filtered off, the residue washed thoroughly with water and then chromatographed on silica gel, using CHCl3 --MeOH mixtures as eluant. Thus pure title compound was obtained in about 60% yield.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([F:35])=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([F:35])=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ncc(-c2nc(-c3ccc(F)c4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
Sodium hydroxide (35 mg) was added to a solution of ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoate (D48) (222 mg) in THF (3 mL) and water (3 mL). The reaction mixture was stirred at 90° C. for 1 hour. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoic acid (E22) (137 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.40 (6H, d), 2.62 (2H, t), 3.07 (2H, t), 5.46 (1H, m), 6.98 (1H, dd), 7.26 (1H, d), 7.91 (1H, dd), 8.72 (1H, d), 9.04 (1H, d), 11.09 (1H, s), 11.71 (1H, br s). δF (DMSO-d6, 376 MHz): −118.7. MS (ES): C21H18ClFN4O4 requires 444; found 445.1 (M+H+).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21](Cl)[N:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:25][C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH:18][CH2:17][CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[CH:24]=1
Reactant: Cc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)nc(Cl)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(NCC2CCNCC2)ncn1
Reaction time: 6 h

Procedure:
A mixture of 4-[(2-chloro-6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (EXAMPLE 57, 0.50 g, 1.33 mmol), Pd/C (10%, 0.05 g) in absolute ethanol (15 mL) was vigorously stirred under 1 atm H2 for 6 h. Filtered and concentrated, the reaction gave 4-[(6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine. M.S.(M+1):207.30
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([CH3:14])[CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([CH3:14])[CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1
Reactant: CC1CCNc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1CCNc2cc(N)ccc21
Yield: 93.2 %

Procedure:
A solution of 7-nitro-1,2,3,4-tetrahydro-4-methylquinoline (36 mg, 0.172 mmol) in ethyl acetate (3 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (4 mg) at rt for 2 h. Filtration over Celite™ afforded 26 mg (85%) of 7-amino-1,2,3,4-tetrahydro-4-methylquinoline (structure 61A of Scheme XLVIII, where R1-3═H, R4═methyl) that was used without further purification for the next step. The title compound was prepared by General Method 13 (EXAMPLE 147) from 7-amino-1,2,3,4-tetrahydro-4-methylquinoline (26 mg, 0.145 mmol), ZnCl2 (30 mg, 0.218 mmol) and ethyl 4,4,4-trifluoroacetate (21 mL, 0.145 mol) to afford 0.8 mg (2%) of 1,2,3,4-tetrahydro-4-methyl-6-trifluoromethyl-8-pyridono[5,6-g]quinoline (Compound 425). Data for Compound 425: 1H NMR (400 MHz, DMSO-d6) 11.65 (bs, 1H), 7.20 (s, 1H), 6.96 (s, 1H), 6.37 (s, 2H), 3.25 (m, 2H), 2.90 (m, 1H), 1.84 (m, 1H), 1.59 (m, 1H), 1.20 (d, J=6.9, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([C:23]([O:25]C)=[O:24])[C:19]([F:22])([F:21])[F:20])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.O1CCOCC1.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH:18]([C:19]([F:22])([F:21])[F:20])[C:23]([OH:25])=[O:24])=[O:16])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(OC(=O)N1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C(OC(=O)N1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To a stirring solution of 1,1,1-trifluoro-3-methoxy-3-oxopropan-2-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate (6h) (18 mg, 0.036 mmol) in a 1:1 mixture of 1,4-dioxane:water (1 mL) was added NaOH (360 μL, 0.36 mmol, 1.0 N in water). After stirring the reaction mixture overnight at room temperature, the reaction was quenched by the addition of aqueous 1N HCl (5 mL) and extracted with dichloromethane (3×, 25 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by SiO2 preparative TLC (50% EtOAc/hexanes, 1% HCO2H) to give the title compound as a colorless oil (9.1 mg, 52%): 1H NMR (600 MHz (CDCl3) δ 7.42 (d, J=7.32 Hz, 4H), 7.30 (d, J=8.16 Hz, 4H), 5.35 (s, 1H), 4.53 (bs, 1H), 3.78-3.53 (m, 4H), 2.81-2.54 (m, 4H); HRMS m/z calc'd for [M+H]+ C21H19Cl2F3N2O4: 491.0747. found 491.0735.
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([C:23]([NH:25][CH:26]4[CH2:28][CH2:27]4)=[O:24])[CH:17]=3)=[CH:12][CH:11]=2)=[N:7][N:6]=1)=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:1][CH2:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([C:23]([NH:25][CH:26]4[CH2:28][CH2:27]4)=[O:24])[CH:17]=3)=[CH:14][CH:15]=2)=[N:7][N:6]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN=[N+]=[N-])o2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1

Procedure:
4′-[5-(Azidomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 44) (27.8 mg) and palladium on carbon (10% w/w, 5 mg) in ethanol (5 ml) were hydrogenated under 1 Atm. of hydrogen for 2 hours. The reaction was filtered through celite, the filtrate reduced to dryness under vacuum and the residue applied to a bond-elut (silica, 4 g). The column was eluted with chloroform, ether, ethyl acetate, and methanol. The methanol fraction was reduced to dryness under vacuum to give 4′-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2].[I:16]N1C(=O)CCC1=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[I:16])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cc(-c2cccs2)n[nH]1
Solvent: ClCCl
Product: CCOC(=O)c1[nH]nc(-c2cccs2)c1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.0 g (4.5 mmol) of 5-thiophen-2-yl-2H-pyrazole-3-carboxylic acid ethyl ester was dissolved in 15 ml of dichloromethane and 1.01 g (4.5 mmol) of N-iodosuccinimide was added. The resulting solution was stirred at room temperature for 16 h. The solution was washed with aqueous sodium thiosulfate solution. The organic phase was dried with sodium sulfate and filtered. The resulting solution was passed through a short silica gel column, washing with dichloromethane. The solvent was removed under reduced pressure.
Reaction SMILES: [F:1][C:2]1([F:26])[C:9]2([OH:13])[C:10]([F:12])([F:11])[C:5]3(F)[C:6]([F:21])([F:20])[C:7]([OH:19])([C:16]([F:18])([F:17])[C:3]1([OH:25])[C:4]3([F:24])[F:23])[C:8]2([F:15])[F:14].[OH:27]C12CC3(O)CC(O)(CC(O)(C3)C1)C2>>[OH:25][C:3]12[C:16]([F:17])([F:18])[C:7]3([OH:19])[C:6]([F:20])([F:21])[C:5]([OH:27])([C:10]([F:11])([F:12])[C:9]([OH:13])([C:8]3([F:14])[F:15])[C:2]1([F:26])[F:1])[C:4]2([F:23])[F:24]
Reactant: OC12CC3(O)CC(O)(C1)CC(O)(C2)C3
Reactant: OC12C(F)(F)C3(O)C(F)(F)C(O)(C1(F)F)C(F)(F)C(F)(C2(F)F)C3(F)F
Product: OC12C(F)(F)C3(O)C(F)(F)C(O)(C1(F)F)C(F)(F)C(O)(C2(F)F)C3(F)F

Procedure:
By changing 1,3,5-trihydroxyadamantane in Example 9 to 1,3,5,7-tetrahydroxyadamantane, reactions are carried out in the same manner as in Examples 9-1 to 9-3 to obtain 1,3,5,7-tetrahydroxy(perfluoroadamantane).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([NH:21][CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:11]=3[C:12](=[O:14])[CH:13]=2)=[CH:4][C:3]=1[F:28].S(=O)(=O)(O)[OH:30].O>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([OH:30])([CH3:26])[CH3:27])[C:11]=3[C:12](=[O:14])[CH:13]=2)=[CH:4][C:3]=1[F:28]
Reactant: CC(C)=CCCNc1c(F)cc(F)c2oc(-c3ccc(N)c(F)c3)cc(=O)c12
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CC(C)(O)CCCNc1c(F)cc(F)c2oc(-c3ccc(N)c(F)c3)cc(=O)c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
16 mg (0.041 mmol) of Compound 137 obtained in Example 137 was dissolved in 3 mL of ethanol, 3 mL of 50% sulfuric acid was added and the mixture was stirred at 100° C. for 1 hour. The reaction solution was cooled on ice, water was added and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with an aqueous saturated solution of sodium bicarbonate, once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 14 mg of Compound 138 (yield: 84%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH:34]([CH2:37][OH:38])[CH2:35][OH:36]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:33][CH:34]([CH2:37][OH:38])[CH2:35][OH:36])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: NC(CO)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NC(CO)CO)c(Nc2ccc(I)cc2F)cc1=O
Yield: 34 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in anhydrous THF/DMF (5:1) and treated with 2-amino-1,3-propandiol as for example 34. After workup, the residue was further purified by flash chromatography on silica gel (5% MeOH/CH2Cl2—10% MeOH/CH2Cl2 gradient elution) to give 4-(2-fluoro-4-iodoanilino)-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (34%) as a white solid; m.p. (EtOAc/Hexane) 93-98° C. (glue-liquid). 1H NMR [400 MHz, CH3OD] δ 8.22 (s, 1H), 7.61 (dd, J=9.9, 1.8 Hz, 1H), 7.58-7.54 (m, 1H), 7.21 (t, J=8.4, 1H), 5.78 (d, J=1.1 Hz, 1H), 4.12 (p, J=5.6 Hz, 1H), 3.72 (ddd, J=15.1, 11.2, 5.6 Hz, 4H), 3.51 (s, 3H). HRMS (FAB+) calcd for C16H18FIN3O4 462.0326 (M+), found 462.0323. HPLC 89.9% (254 nm).