Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3(O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:24])[O:4][N:3]=1.N1C=CC=CC=1.O=S(Cl)[Cl:33]>C1COCC1>[Cl:33][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:24])[CH:8]=2)[NH:12][C:11]1=[O:16]
Reactant: O=S(Cl)Cl
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccccc1)C(=O)N2
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(Cl)(c1ccccc1)C(=O)N2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 5-(3,5-dimethylisoxazol-4-yl)-3-hydroxy-3-phenylindolin-2-one (30 g, 0.094 mol) in THF (300 mL) was added pyridine (40 mL) followed by SOCl2 (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h and quenched by the addition of saturated ammonium chloride solution (50 mL). The organic layer was washed with saturated ammonium chloride (2×50 mL). The combined aqueous layers were extracted with CH2Cl2 (200 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford target compound (25 g, 79%). 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 7.37-7.53 (m, 6H), 7.08 (d, J=8.0 Hz, 1H), 2.30 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38](I)[C:37]=1[C:43]1[N:47]([CH3:48])[N:46]=[N:45][N:44]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([F:35])[C:37]=2[C:43]2[N:47]([CH3:48])[N:46]=[N:45][N:44]=2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cn1nnnc1-c1c(F)cccc1I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccc(F)c5-c5nnnn5C)ccc(F)c43)ccc21
Temperature: 100 °C
Reaction time: 12 h

Procedure:
In a microwave vial methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (100 mg), 5-(2-fluoro-6-iodophenyl)-1-methyl-1H-tetrazole (78 mg), K3PO4 (136 mg) are suspended in 1,4-dioxane (3 mL) and purged for 10 minutes with argon. [1,3-Bis(2,6-di-3-pentylphenyl)inidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (8.5 mg) is added, the vial is sealed and the mixture is stirred at 100° C. for 12 hours. After cooling to room temperature the solvents are evaporated and the product thus obtained is used directly in the next step.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:14]([S:15][CH3:16])=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].O.Cl>CO>[CH3:3][O:4][C:5]1[C:14]([S:15][CH3:16])=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc(C(F)(F)F)c(SC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(C(=O)O)ccc(C(F)(F)F)c1SC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
16 ml of 20 percent strength aqueous sodium hydroxide solution were added to 16.0 g (57.1 mmol) of methyl 2-methoxy-3-methylthio-4-(trifluoromethyl)benzoate in 160 ml of methanol, and the mixture was stirred at RT for 4 h. For work-up, the mixture was freed from the solvent and the residue was taken up in a little water. The mixture was cooled in an ice bath and then acidified with dilute hydrochloric acid. The mixture was stirred at RT for 5 min, and the contents was then filtered. This gave 15.3 g of 2-methoxy-3-methylthio-4-(trifluoromethyl)benzoic acid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=1)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[N:18]1([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH2:1]([NH:8][C:9]([C:11]1[N:12]=[N:13][C:14]([N:21]2[CH2:22][CH2:23][N:18]([C:24](=[O:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:33])[F:34])[CH2:19][CH2:20]2)=[CH:15][CH:16]=1)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: CCCCCCCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid heptylamide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethyl-phenyl)methanone, the title compound was obtained as a white powder (41% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.85, 7.72, 7.58, 7.34, 6.98, 4.03, 3.94-3.64, 3.47-3.28, 1.58, 1.32-1.25, 0.84. 13C NMR (75 MHz, CDCl3) δ 167.6, 162.9, 160.0, 145.5, 134.3, 132.4, 129.5, 126.9, 126.3, 125.4, 121.8, 112.6, 46.4, 44.5, 41.3, 39.4, 31.7, 29.6, 29.0, 26.9, 22.6, 14.1. MS (ES+) m/z 478.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([O:14][C:15](=[O:17])[CH3:16])[N:8]([C:11](=[O:13])[CH3:12])[C:9]=1[CH3:10])=[O:4].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([O:14][C:15](=[O:17])[CH3:16])[N:8]([C:11](=[O:13])[CH3:12])[C:9]=1[CH2:10][Br:18])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1nc(OC(C)=O)n(C(C)=O)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(OC(C)=O)n(C(C)=O)c1CBr
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of 4b (9.0 g, 38 mmol) in 300 mL of CCl4 was added N-bromosuccinimide (7.1 g, 40 mmol) and benzoyl peroxide (80 mg). The solution was refluxed for 4 h and then cooled down to rt. Succinimide was then removed through filtration and the filtrate was concentrated to provide 2-acetoxy-1-acetyl-5-bromomethyl-1H-imidazole-4-carboxylic acid methyl ester 4c (12 g, 95%). MS (ESI+) (M+1)=318.9, 320.9.
Reaction SMILES: [Na+:1].[NH2:2][C:3]1[C:12]2[C:11]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]([S:17]([O-:20])(=[O:19])=[O:18])=[CH:5][CH:4]=1.[Na+].[OH-].[Na+].[N+:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([O-:26])=[O:25].Cl>O.CCOCC>[Na+:1].[Na+:1].[N+:24]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([NH:2][C:3]2[C:12]3[C:11]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]([S:17]([O-:20])(=[O:19])=[O:18])=[CH:5][CH:4]=2)=[O:32])=[CH:34][CH:35]=1)([O-:26])=[O:25]
Reactant: Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 25.0 g portion of 4-amino-1,5-naphthalenedisulfonic acid sodium salt is suspended in 100 ml of water and 80 ml of 1N sodium hydroxide is added, then 31.0 g of p-nitrobenzoylchloride is added all at once. The mixture is shaken for about 15 minutes and another 80 ml of 1N sodium hydroxide is added with additional shaking. The latter addition of sodium hydroxide and shaking is repeated three more times with the incorporation of 50 ml of water and 25 ml of ether. The final solution remains basic after about 30 minutes of shaking and is then acidified with 20 ml of concentrated hydrochloric acid (which is indicated by a deep blue color to Congo Red test paper). The solution is then diluted to one liter with water and is then extracted with 500 ml of ether. The emulsified ether phase is removed by vacuum siphoning. The ether extraction is repeated 8 additional times with 250 ml portions of ether. The aqueous phase is neutralized with 5N sodium hydroxide and the insoluble fraction is removed by filtration and is washed with 100 ml of 80% ethyl alcohol followed by 100 ml of absolute ethyl alcohol. The washes are combined with the filtrate obtained above and the combined solution is evaporated in vacuo at 55°-60° C. to about 500 ml. The solution is cooled to room temperature and the resultant crystalline material is collected by filtration and is washed consecutively with two 100 ml portions of 90% ethyl alcohol, 100 ml of absolute ethyl alcohol and two 100 ml portions of ether. The product of the example is then oven dried at 120° C. overnight.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH2:13]([NH2:16])[CH2:14][CH3:15]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH2:13][CH2:14][CH3:15])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: CCCN
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Solvent: ClCCl
Product: CCCNS(=O)(=O)c1ccc(Br)c(F)c1
Yield: 90.2 %

Procedure:
According to general procedure C, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and propylamine (0.30 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-3-fluoro-N-propylbenzenesulfonamide (0.39 g, 90%) was provided after purification. HRMS: calcd for C9H11BrFNO2S, 294.96779; found (EI, M+.), 294.9684. HPLC purity 100.0% at 210-370 nm, 10.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)O)[CH2:10][CH2:9]1.[CH3:23][S:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2>ClCCl>[CH:8]1([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:31]2[C:30]3[C:34](=[C:26]([CH2:25][S:24][CH3:23])[CH:27]=[CH:28][CH:29]=3)[NH:33][CH:32]=2)[CH2:10][CH2:9]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc(C(F)(F)F)cc1)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.76 ml (9.82 mmol) of trifluoroacetic acid was added to 1.77 g (8.19 mmol) of the compound from Example 149A and 1.45 g (8.19 mmol) of the compound from Example 8A in 91 ml of dichloromethane, and the mixture was stirred at RT for 2 h. It was concentrated and the residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 98/2) and preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 890 mg (29% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:29]=[CH:28][C:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][OH:15])=[CH:4][CH:3]=3)=[CH:26][CH:25]=2)[CH2:22][CH2:23]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CO
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CO)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][CH:18]([CH3:20])[CH3:19])[CH2:13][C@H:12]1[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH3-][C:36]#N.[Na+]>CO.O>[CH2:1]([O:8][C:9](=[O:32])[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([CH:18]([CH3:20])[CH3:19])[CH3:36])[CH2:13][C@H:12]1[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: CC(C)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CS(=O)(=O)c2ccc(Br)cc2)C1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CS(=O)(=O)c2ccc(Br)cc2)C1
Reaction time: 0.17 h
Yield: 94.4 %

Procedure:
The above derivative (118ba) (1.96 g) was dissolved in MeOH (15 ml) prior to the addition of 37% formaldehyde in water (1.41 ml). After 10 min, NaBH3CN (708 mg) was added. After 2 h, the reaction was concentrated. EtOAc was added and the organic layer was washed with H2O, brine, dried, filtered, and concentrated to give [(1S,2R,4R)-2-(4-Bromo-benzenesulfonylmethyl)-4-(isopropyl-methyl-amino)-cyclohexyl]-carbamic acid benzyl ester (1.9 g), MS found: (M+H)+=539.3.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1CCCC1.[F:20][C:21]1[CH:22]=[CH:23][C:24](O)=[C:25]([C:27](=[O:29])[CH3:28])[CH:26]=1>CO>[F:20][C:21]1[CH:26]=[C:25]2[C:24](=[CH:23][CH:22]=1)[O:1][C:2]1([CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH2:28][C:27]2=[O:29]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(F)ccc1O2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 66.8 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (12.1 g, 60.9 mmol) in pyrrolidine (7.3 mL, 87.2 mmol) and anhydrous methanol (16.5 mL) was added 1-(5-fluoro-2-hydroxy-phenyl)ethanone (9.3 g, 60.7 mmol). The reaction mixture was stirred at 80° C. for 2.5 hours. The methanol was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate (150 mL), washed with 1 N HCl (1×150 mL) and brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a yellow oil. The oil was diluted with hexanes (400 mL) and was heated at 60° C. until in solution. Once dissolved, the solution was allowed to cool to 25° C. The crystals were collected via vacuum filtration, rinsed with hexanes to obtain tert-butyl 6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (13.6 g, 67%) as a light yellow solid. ESI-MS m/z calc. 335.2, found 336.7 (M+1)+. Retention time 1.85 minutes (3 min run).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:32]1[C:33]2[C:38]([C:39]([Br:46])=[C:40]3[C:45]=1[CH:44]=[CH:43][CH:42]=[CH:41]3)=[CH:37][CH:36]=[CH:35][CH:34]=2.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[Br:46][C:39]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([C:20]2[CH:21]=[C:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH:17]=[CH:18][CH:19]=2)=[C:45]2[C:40]=1[CH:41]=[CH:42][CH:43]=[CH:44]2
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: CC1(C)OB(c2cccc(-c3nc4ccccc4n3-c3ccccc3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1c2ccccc2c(-c2cccc(-c3nc4ccccc4n3-c3ccccc3)c2)c2ccccc12
Temperature: 85 °C
Yield: 75.1 %

Procedure:
Compound 5 (see WO 2007046658 A1, US 20070205412 A1 and WO 2007086695 A1, which are incorporated by reference herein for their relevant teachings) was prepared as follows: a mixture of Compound 2 (5.270 g, 13.30 mmol), 9,10-dibromoanthracene (13.41 g, 39.90 mmol), tetrakis(triphenylphosphine)palladium(0) (0.922 g, 0.798 mmol), Na2CO3 (9.539 g, 90.00 mmol), H2O (90 mL) and tetrahydrofuran (THF) (150 mL) was degassed with argon for 1.5 h. while stirring. The reaction mixture was then maintained under argon at 85° C. while stirring for 46 h. Upon completion, the reaction was cooled to RT and poured over dichloromethane (about 500 mL). The soluble organics were then washed with H2O and brine, dried over MgSO4, filter and concentrated in vacuo. The crude product was purified via flash chromatography (SiO2, 100% dichloromethane) to provide Compound 5 (5.25 g, 75%) as a light yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][CH:17]1[CH2:19][CH2:18]1>CN(C=O)C.C(OCC)(=O)C>[CH:17]1([CH2:16][O:8][C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][N:6]=2)[CH2:19][CH2:18]1
Reactant: BrCC1CC1
Reactant: Oc1ccc(I)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Ic1ccc(OCC2CC2)nc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 32.9 %

Procedure:
To a solution of 5-iodopyridin-2-ol (5.32 g, 24.0 mmol) in DMF (50 mL) were added cesium carbonate (23.4 g, 72.0 mmol) and (bromomethyl)cyclopropane (4.67 mL, 48.2 mmol), and the mixture was stirred at 60° C. for 15 min. The reaction mixture was diluted with ethyl acetate, and the mixture was washed three times with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:4) to give the title compound (2.17 g, yield 32%) as an oil.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH2:32]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O)[CH3:33]>COCCOC>[CH2:32]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH3:33]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: CCOc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOc1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 29.1 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-ethoxyphenylboronic acid (31 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate in hexanes gradient to afford the product as a white solid (16 mg, 29%). MS m/e 451.23 (M+H+)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH2:23]([O:33][C:34]([NH:36][C:37]1[CH:42]=[CH:41][N:40]([CH2:43][C:44](O)=[O:45])[C:39](=[O:47])[N:38]=1)=[O:35])[C:24]1[CH:32]=[CH:31][C:30]2[O:29][CH2:28][O:27][C:26]=2[CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:44](=[O:45])[CH2:43][N:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]([O:33][CH2:23][C:24]2[CH:32]=[CH:31][C:30]3[O:29][CH2:28][O:27][C:26]=3[CH:25]=2)=[O:35])=[N:38][C:39]1=[O:47])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: O=C(O)Cn1ccc(NC(=O)OCc2ccc3c(c2)OCO3)nc1=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1ccc(NC(=O)OCc2ccc3c(c2)OCO3)nc1=O
Yield: 85.9 %

Procedure:
The title compound (2.89 g, 86%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [4-N-(piperonyloxycarbonyl)-cytosin-1-yl]-acetic acid (1.74 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 10.65 (s, 1H), 8.80 (brs, 0.6H), 8.68 (brs, 0.4H), 8.19(d, 1H), 8.11 (d, 1H), 7.81 (d, 0.6H), 7.75 (d, 0.4H), 7.62–7.54 (m, 2H), 6.92 (t, 1H), 6.90 (s, 1H), 6.82 (s, 2H), 5.93 (s, 2H), 5.00 (s, 2H), 4.72 (s, 1.2H), 4.54 (s, 0.8H), 4.26 (s, 0.8H), 4.01 (q, 0.8H), 4.00 (s, 1.2H), 4.96 (q, 1.2H), 3.51 (t, 1.2H), 3.35˜3.30 (m, 2H), 3.13 (t, 0.8H), 1.12 (t, 1.2H), 1.06 (t, 1.8H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1>[CH:10]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:7]=2)[C:8]#[N:9])[CH2:12][CH2:11]1
Reactant: OB(O)C1CC1
Reactant: N#Cc1cncc(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cncc(C2CC2)c1
Yield: 58.9 %

Procedure:
To a solution of 3-bromo-5-cyanopyridine (1 g, 5.3 mmol) in tetrahydrofuran was added cyclopropyl boronic acid (0.5 g, 5.6 mmol) and potassium phosphate (1.08 g, 15.9 mmol). The resulting solution was degassed with nitrogen for 10 minutes and then palladium (II) acetate and S-phos were added. The reaction mixture was refluxed for 16 h. The reaction mixture was diluted with water, extracted with ethyl acetate and concentrated under reduced pressure. The crude material was purified via column chromatography to afford 5-cyclopropylnicotinonitrile (0.45 g, 58%). MS (ES+) (M+H) 145.1774.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[N:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]([O:20][CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29]C(=O)O)[CH2:25][CH2:24]1)=[CH:13]2>ClCCl>[CH3:8][O:9][C:10]1[N:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]([O:20][CH2:21][CH2:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([NH2:29])[CH2:27][CH2:28]1)=[CH:13]2
Reactant: COc1ccc2ncc(OCC[C@H]3CC[C@H](NC(=O)O)CC3)cc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(OCC[C@H]3CC[C@H](N)CC3)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (6.33 mL, 82.2 mmol, 20 eq) is added at room temperature to a stirred solution of {trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexyl}-carbamic acid tort-butyl ester (1.65 g, 4.11 mmol, 1.0 eq) in dichloromethane (100 mL). After 2 hours stirring at room temperature, the reaction mixture is partitioned between saturated sodium hydrogen carbonate aqueous solution and dichloromethane and the pH value is about 10. The combined organic layers are dried over sodium sulfate and concentrated to afford trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexylamine as a yellow solid (1.24 g, 95% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Sn](Cl)(Cl)(Cl)Cl.[N:14]1([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[CH:18]=[CH:17][CH:16]=[CH:15]1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:15]1[N:14]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[CH:18]=[CH:17][CH:16]=1)=[O:7]
Reactant: O=C(Cl)c1cccs1
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(c1cccs1)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-thiophenecarbonylchloride (10.7 ml) in 500 ml of dry DCM was treated at -10° C. with tin tetrachloride (11.7 ml) and stirred for 30 minutes. 2-(1H-pyrrol-1-yl)-1H-isoindole-1,3(2H)dione (21.2 g) was then added in small portions over a period of 30 minutes at -10° C. After the addition was completed, the reaction mixture was stirred for an additional 30 minutes at -10° C. and subsequently poured into 500 ml of ice water. The precipitate was dissolved by addition of about 1000 ml of DCM and the separated aqueous layer extracted again with DCM. The combined organic layers were washed twice with 2N hydrochloric acid and with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, DCM/ethyl acetate 99:1) and the desired fractions were concentrated. The residue was recrystallized from DCM/ethyl ether affording the product as crystals (17.9 g), m.p. 165°-166° C.