Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](O)(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(Cl)(=O)OCC.[CH3:38][N:39]([CH3:50])[CH2:40][CH2:41][NH:42][C:43]1[C:44]([NH2:49])=[CH:45][CH:46]=[CH:47][CH:48]=1>C(Cl)(Cl)Cl>[CH2:9]([C:8]1[N:42]([CH2:41][CH2:40][N:39]([CH3:50])[CH3:38])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[N:49]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CN(C)CCNc1ccccc1N
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCCCCc1nc2ccccc2n1CCN(C)C
Reaction time: 1.5 h
Yield: 65.8 %

Procedure:
Triethylamine (2.25 ml) was added to a suspension containing n-docosanoic acid (4.930 g) in chloroform (50 ml), and then ethyl chlorocarbonate (1.52 ml) was added thereto while being cooled with ice. After being stirred for 1.5 hours, a solution containing N-[2-(dimethylamino)ethyl]-1,2-benzenediamine (2.593 g) in chloroform (13 ml). After being stirred for 2.5 hours while being cooled with ice, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (12.1 ml) was added to a solution containing the residue (8.644 g) in ethanol (87 ml). After being stirred for 2.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (6.90 g) was purified by silica gel column chromatography (silica gel 150 g, chloroform:methanol=60:1-30:1), thereby yielding the entitled compound (4.604 g) as pale yellow solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])O.[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[C:16]([C:22]#[N:23])[N:15]=1.O>C(#N)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:16]([C:22]#[N:23])[N:15]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1nc(Cl)ccc1CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1nc(Cl)ccc1COc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
A solution (10 ml) of 1.50 g (5.70 mmol) of the resulting N-oxide substance in phosphorus oxychloride was stirred at 80° C. for 1 hour. The reaction solution was concentrated in vacuo, a saturated aqueous solution of sodium hydrogen carbonate was added to the residue followed by extracting with chloroform and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous saline solution. After drying and concentrating, the resulting residue was purified by a silica gel column chromatography (hexane:ethyl acetate=2:1) to give 625 mg (yield: 58%) of 2-chloro-5-chloromethyl-6-cyanopyridine as a white solid. Phenol (30 mg; 0.32 mmol) and 44 mg (0.32 mmol) of sodium hydrogen carbonate were added to a solution (5 ml) of 50 mg (0.27 mmol) of 2-chloro-5-chloromethyl-6-cyanopyridine in acetonitrile followed by stirring at room temperature for 8 hours and 30 minutes. Water was added to the reaction solution followed by extracting with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, dried and concentrated in vacuo and the resulting residue was purified by a thin-layer column chromatography (hexane:ethyl acetate=6:1) to give 61 mg (yield: 93%) of 2-chloro-6-cyano-5-phenoxymethylpyridine as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[N:27]=[C:26]([N:28]([CH3:30])[CH3:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C(N(CC)CC)C>CC(O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:9][CH2:10][C@@H:11]([CH2:14][NH:15][C:18]2[N:27]=[C:26]([N:28]([CH3:30])[CH3:29])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CN)CC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CN(C)c1nc(NC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nc2ccccc12
Temperature: 170 °C
Yield: 64.1 %

Procedure:
A mixture of cis-(4-aminomethyl-cyclohexyl)-carbamic acid tert-butyl ester (1.14 g, 5 mmol), (2-chloro-quinazoline-4-yl)-dimethyl-amine obtained in step B of example 1 (1.035 g, 5 mmol), and triethylamine (1.5 mL, 11 mmol) in 2-propanol (2.5 mL) was heated at 170° C. for 35 min using a Smith Microwave Synthesizer. The mixture was concentrated and the residue was purified by column chromatography (silica gel, CH2Cl2 to 10% 2 M NH3/MeOH in CH2Cl2) to give cis-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.28 g, 80%) as a white solid.
Reaction SMILES: [C:1]([C@@:9]1([OH:37])[C@@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:16]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:15]([CH2:35][OH:36])[O:14][C@H:10]1[S:11][CH2:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>ClCCl>[C:44]([O:36][CH2:35][C@H:15]1[O:14][C@@H:10]([S:11][CH2:12][CH3:13])[C@:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([OH:37])[C@@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: CCS[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OC(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS[C@@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OC(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Ethyl 2,3-O-dibenzoyl-4-O-benzyl-1-thio-β-D-glucohexopyranoside (200 mg, 0.38 mmol) was dissolved in an ice-cooled mixture of pyridine and acetic anhydride (1:1, 6 Å). The mixture was stirred and attained at room temperature overnight. The mixture was diluted with dichloromethane, washed with satd. aq. sodium hydrogen carbonate and water and dried over sodium sulphate. The solvents were removed under reduced pressure and the residue was subjected to flash chromatography on silica gel (toluene-acetonitrile 6:1) to yield 204 mg, 93% of ethyl 6-O-acetyl-2,3-O-dibenzoyl-4-O-benzyl-1-thio-β-D-glucohexopyranoside.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17][OH:18])=[C:14]([CH3:19])[C:13]=2[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=[O:18])=[C:14]([CH3:19])[C:13]=2[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(CO)oc2ccc(OCc3ccccc3)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Cc1c(C=O)oc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Yield: 96.4 %

Procedure:
To a solution (30 mL) of [5-(benzyloxy)-3-methyl-1-benzofuran-2-yl]methanol (2.8 g) synthesized in the above-mentioned (2) in toluene was added manganese dioxide (5 g), and the mixture was heated under reflux with a Dean-Stark trap for 1 hr. The reaction mixture was allowed to cool to room temperature, catalyst was filtered through celite. The filtrate was concentrated under reduced pressure to give the title object compound (2.68 g, 94%) as a colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([C:22]([CH3:32])([CH3:31])[CH2:23][C:24]2([C:27]([F:30])([F:29])[F:28])[CH2:26][O:25]2)[C:16]2[O:20][CH2:19][CH2:18][C:17]=2[CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:22]([CH3:32])([CH3:31])[CH2:23][C:24]([CH2:26][N:1]2[C:9]3[C:4](=[N:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)([OH:25])[C:27]([F:28])([F:29])[F:30])[C:16]2[O:20][CH2:19][CH2:18][C:17]=2[CH:21]=1
Reactant: c1cnc2cc[nH]c2c1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cc(Cl)cc2c1OCC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(CC(O)(Cn1ccc2ncccc21)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
A solution of 1H-pyrrolo[3,2-b]pyridine (33.0 mg, 0.279 mmol) in 4 mL of DMF was treated with NaH (60% in mineral oil, 16.8 mg, 0.419 mmol) at room temperature. After 30 minutes, 5-chloro-7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-2,3-dihydrobenzofuran (188 mg, 0.558 mmol) was added and the resulting mixture was stirred overnight. The reaction was then diluted with 5 mL of ethyl acetate and quenched with 5 mL of saturated ammonium chloride solution. The aqueous layer was extracted with 5 mL of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diethyl ether to afford 55.0 mg (45% yield) of the title product as white solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:36][CH:35]([OH:37])[CH2:34]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:36][CH:35]([OH:37])[CH2:34]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CC(O)C4)c4ccc(OC(F)F)cc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCCN4CC(O)C4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(3-hydroxyazetidin-1-yl)propyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (43 mg, 66.8 μmol) in dichloromethane (4.00 mL) was added TFA (740 mg, 0.5 mL, 6.49 mmol, Eq: 97.2), the reaction mixture turned orange and was stirred at 25° C. for 18 h, mixture concentrated and the residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 1 h, then evaporated to a yellow foam, which was dissolved in dichloromethane (with few drops of MeOH) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 10% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane and cyclohexane added to allow solid formation, off-white solid was separated by decantation and dried under high vacuum to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(3-hydroxyazetidin-1-yl)propyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (21 mg, 40.9 μmol, 61.2%). MS (M+H)+=514; 1H NMR (DMSO-d6) δ: 9.06 (s, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 7.81-7.91 (m, 2H), 7.39 (d, J=8.7 Hz, 1H), 7.19 (t, J=74.4 Hz, 1H), 5.23 (d, J=6.4 Hz, 1H), 4.53 (t, J=6.6 Hz, 2H), 4.07-4.25 (m, 1H), 3.50 (t, J=6.4 Hz, 2H), 2.62 (t, J=6.8 Hz, 2H), 2.35 (t, J=6.8 Hz, 2H), 1.78-2.01 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=CC=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14]C(C3SC(C(OC)=O)=CN=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:31]O.O1CCOCC1.[OH-].[Na+]>O>[CH:3]1[C:2]2[C:1](=[CH:25][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]=1[S:7]([N:10]1[CH2:11][CH2:12][NH:31][CH2:14][CH2:15]1)(=[O:8])=[O:9]
Reactant: NO
Reactant: COC(=O)c1cnc(C2CCN(S(=O)(=O)c3ccc(-c4ccccc4)cc3)CC2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 2-[1-(1,1′-biphenyl-4-ylsulfonyl)piperidin-4-yl]-1,3-thiazole-5-carboxylate 25.3 (9 mg), 50% hydroxylamine in water (0.05 mL), and dioxane (1 mL) were cooled in ice-water. To the reaction was added 1N sodium hydroxide (0.053 mL) followed by removal of the cooling bath. After stirring overnight, the reaction was neutralized with 1 N hydrochloric acid (0.053 mL) and the solvent evaporated. The residue was purified by preparative hplc to give Example 25 as a floculant white solid (3.5 mg). 1H NMR (DMSO) δ: 2.75 (m, 2H), 2.15 (m, 2H), 2.5 (m, 2H), 3.1 (m, 1H), 3.75 (m, 2H), 7.45-7.55 (m, 3H), 7.72-7.96 (m, 6H), 8.08 (s, 1H), 11.3 (s, 1H); m/e=444 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH:13]([OH:29])[CH2:14][NH:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[C:21]([OH:28])[CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>O1CCOCC1.[Pd]>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][NH:15][CH2:14][CH:13]([OH:29])[C:12]2[CH:30]=[CH:31][C:9]([OH:8])=[CH:10][CH:11]=2)=[CH:20][C:21]=1[OH:28])(=[O:27])[NH2:26]
Reactant: [H][H]
Reactant: NC(=O)c1ccc(OCCNCC(O)c2ccc(OCc3ccccc3)cc2)cc1O
Agent: [Pd]
Solvent: C1COCCO1
Product: NC(=O)c1ccc(OCCNCC(O)c2ccc(O)cc2)cc1O

Procedure:
A solution of 8.7 g of 4-benzyloxy-α-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-ethyl]-aminomethyl]-benzyl alcohol in 100 ml of dioxan is hydrogenated under normal conditions with the addition of 2 g of palladium-on-charcoal catalyst (5%) until 1 equivalent of hydrogen has been taken up. The product which has precipitated is brought into solution after adding 200 ml of methanol, by warming, the catalyst is filtered off and the filtrate is evaporated. Recrystallisation of the residue from isopropanol yields crystalline α-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-ethyl]-aminomethyl]-4-hydroxybenzyl alcohol with a melting point of 181°-182°.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C@H:15]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[C@@H:16]3[CH2:26][N:27]=[N+]=[N-])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[C].[Pd]>[NH2:27][CH2:26][C@@H:16]1[C@@H:15]([NH:14][C:10]2[N:9]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=[CH:12][N:11]=2)[CH2:19][CH2:18][N:17]1[CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: [N-]=[N+]=NC[C@@H]1[C@@H](Nc2nccc(N3CCCCCC3)n2)CCN1C1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: NC[C@@H]1[C@@H](Nc2nccc(N3CCCCCC3)n2)CCN1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
In a solution of the compound 9 (125 mg) in ethanol (4 mL), 10% palladium carbon (wet, 112 mg) was added under an argon atmosphere. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 30 minutes. The reaction mixture was filtered with Celite (trade name) and the filtrate was concentrated and obtained the title compound (116 mg) having the following physical properties.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Li]CCCC.[CH:23](N1CCOCC1)=[O:24].Cl>C1COCC1.O>[CH:23]([C:17]1[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:24]
Reactant: CC(C)(C)C(=O)Nc1ccc2ccccc2n1
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc2ccccc2cc1C=O
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of 2-pivaloylaminoquinoline (5.00 g, 21.92 mmol) in THF (75 mL) at −78° C. was added dropwise BuLi (5.48 mL, 10 M in hexane, 54.80 mmol). After 2 hours at −78° C. the dianion was quenched by the addition of N-formylmorpholine (3.79 g, 37.88 mmol). The reaction mixture was allowed to warm to room temperature and poured into 2M aqueous HCl (20 mL). The pH of the aqueous phase was adjusted to 7.0 by addition of 2M HCl and the aqueous phase was diluted with water (100 mL) and extracted with diethyl ether (2×100 mL). The organic phase was dried (MgSO4) and evaporated to dryness in vacuo. The crude product was recrystallized from petrol ether/ethyl acetate to give 2.92 g (52%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].[CH:36]([S:38]([CH:41]=C)(=[O:40])=[O:39])=[CH2:37]>>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:37][CH2:36][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Reactant: C=CS(=O)(=O)C=C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CCS(C)(=O)=O)CC3)cc1OCC2

Procedure:
Following the procedure for 152, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt was reacted with vinyl sulfone to give 225 as a white solid. 1H NMR δ (ppm) (DMSO-d): 8.27 (1H, d, J=8.29 Hz), 7.86-7.84 (2 H, m), 7.00 (1 H, dd, J=8.37, 1.76 Hz), 6.85 (1 H, d, J=1.70 Hz), 5.88-5.78 (1 H, m), 4.44 (4 H, q, J=5.99 Hz), 3.26 (3 H, m), 3.00 (3 H, s), 2.95 (2 H, d, J=11.00 Hz), 2.68 (2 H, t, J=6.79 Hz), 2.02 (2 H, t, J=11.39 Hz), 1.72 (2 H, d, J=12.62 Hz), 1.57 (2 H, qd, J=12.27, 3.58 Hz), 1.42 (6 H, d, J=6.60 Hz). LCMS: RT=2.68 min, M+H+=485
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[C:5]=2[N:6]=1.[Br-].[C:24]1([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:5]=3[N:6]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)CCOc1cccc2c1CCc1sc(S)nc1-2
Agent: [Br-]
Product: O=C(O)CCOc1cccc2c1CCc1sc(SC(c3ccccc3)c3ccccc3)nc1-2
Yield: 35 %

Procedure:
Using ethyl 3-[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]propionate and diphenylmethane bromide, the procedure of Example 21 was otherwise repeated to synthesize the title compound. Yield 35%.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[N:13]=[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[C:11]([N+:28]([O-:30])=[O:29])=[C:10]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:9]=1.[F:37][CH:38]([F:50])[C:39]1[NH:43][C:42]2[CH:44]=[CH:45][CH:46]=[C:47]([O:48][CH3:49])[C:41]=2[N:40]=1>CN(C=O)C.O>[F:50][CH:38]([F:37])[C:39]1[N:43]([C:8]2[N:13]=[C:12]([NH:14][CH:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]3)[C:11]([N+:28]([O-:30])=[O:29])=[C:10]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[N:9]=2)[C:42]2[CH:44]=[CH:45][CH:46]=[C:47]([O:48][CH3:49])[C:41]=2[N:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)nc(N3CCOCC3)c2[N+](=O)[O-])CC1
Reactant: COc1cccc2[nH]c(C(F)F)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c(N2CCOCC2)n1
Reaction time: 60 h
Yield: 89 %

Procedure:
Powdered K2CO3 (1.305 g, 9.44 mmol) was added to a stirred suspension of tert-butyl 4-{[2-chloro-6-(4-morpholinyl)-5-nitro-4-pyrimidinyl]amino}-1-piperidinecarboxylate (U.S. Pat. Appl. Publ. No. 2009/0181963, the disclosure of which is incorporated herein by reference in its entirety) (1.047 g, 2.36 mmol) and 2-difluoromethyl-4-methoxy-1H-benzimidazole (Example 2) (608 mg, 3.07 mmol) in DMF (70 mL) at room temperature, and the mixture was stirred for 2.5 days. The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration and dried. Recrystallization from CH2Cl2/MeOH gave tert-butyl 4-{[2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-5-nitro-4-pyrimidinyl]amino}-1-piperidinecarboxylate (1.27 g, 89%): mp 229-231° C.; 1H NMR (CDCl3) δ 8.64 (d, J=7.7 Hz, 1H), 7.81 (dd, J=8.4, 0.6 Hz, 1H), 7.36 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 4.36 (m, 1H), 4.11 (m, 2H), 4.06 (s, 3H), 3.85 (t, J=4.9 Hz, 4H), 3.65 (t, J=4.6 Hz, 4H), 3.01 (t, J=11.5 Hz, 2H), 2.08 (m, 2H), 1.64-1.51 (m, 2H), 1.48 (s, 9H); Anal. Calcd. for C27H34F2N8O6: C, 53.6; H, 5.7; N, 18.5. Found: C, 53.35; H, 5.7; N, 18.8%.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1)([CH3:9])[C:6](O)=[O:7].[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][CH:15]=1)([CH3:9])[C:6]([NH:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=[O:7]
Reactant: Nc1nccs1
Reactant: CC(Oc1ccc(F)cc1F)(C(=O)O)c1ccc(S(C)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(F)cc1F)(C(=O)Nc1nccs1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a mixture of 2-(2,4-Difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)-propionic acid (0.184 g, 0.52 mmol), 2-aminothiazole (0.59 g, 0.60 mmol) HOBt (0.070 g, 0.52 mmol), and EDCI 0.10 g, 0.52 mmol) in methylene dichloride (10 ml) was added triethyl amine (0.06 g, 0.59 mmol). The resulting mixture was stirred at room temperature for overnight followed by dilution with 10 ml methylene dichloride. The reaction mixture was poured onto water (20 ml), and organic layer separated, washed with water (2×20 ml), brine (20 ml), dried over sodium sulfate and solvent evaporated to get residue which was purified by preparative TLC using 50% ethyl acetate in hexane as mobile phase to give the desired compound (0.12 g). 1H NMR (400 MHz, CDCl3): δ 1.90 (s, 3H), 3.08 (s, 3H), 6.64-6.71 (m, 2H), 6.94 (m, 1H), 7.05 (d, J=3.6 Hz, 1H), 7.51 (d, J=3.6 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 8.01 (d, J=8.4 Hz, 2H), 10.20 (s, 1H); MS (EI) m/z: 439.00 (M+1); mp: 89-90° C.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH:8]3[C:13](=O)[CH:11]([CH2:12][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH2:10][CH2:9]3.Cl.[NH2:16][OH:17]>N1C=CC=CC=1.CCO>[CH:1]1[C:6]2[CH2:7][CH:8]3[C:13](=[N:16][OH:17])[CH:11]([CH2:12][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH2:10][CH2:9]3
Reactant: O=C1C2CCC1Cc1ccccc1C2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1C2CCC1Cc1ccccc1C2

Procedure:
To a solution of 34.3 g of 5,6,7,8,9,10-hexahydro-6,9-methano-benzo[a][8]annulen-11-one (0.184 mol) in 100 mL of pyridine and 100 mL of EtOH was added 29.7 g of hydroxylamine hydrochloride (0.460 mol). The resultant solution was refluxed for 4 hours prior to concentration in vacuo. The residue was partitioned between CH2Cl2 and 10% aqueous citric acid. The aqueous layer was extracted with CH2Cl2 (4×200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford the oxime.