Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH3:1][C:2]1[CH:9]=[C:8]([O:10][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[C:7]([CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Cc1cc(C=O)c(C)cc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(C)cc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
To a stirring solution of 2,5-dimethyl-4-hydroxy-benzaldehyde (0.43 g, 2.86 mmol) in DMF (8 mL) at room temperature was added imidazole (0.43 g, 6.29 mmol) and chloro-triisopropyl-silane (0.74 mL, 3.43 mmol). The mixture was stirred at room temperature for 16 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (15:75) to afford 2,5-dimethyl-4-triisopropylsilanyloxy-benzaldehyde as a colorless oil (0.7 g, 80%): 1H NMR (300 MHz, DMSO-d6): δ 10.07 (s, 1 H), 7.65 (s, 1 H), 6.69 (s, 1 H), 2.55 (s, 3 H), 2.21 (s, 3 H), 1.35 (m, 3 H), 1.10 (d, J=6.9 Hz, 18 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=5% ethyl acetate in hexanes; Rf=0.68.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3[CH:14]=[C:15]([O:20][CH3:21])[C:16]([NH2:19])=[N:17][CH:18]=3)[N:12]=2)=[CH:4][CH:3]=1.[Br:22]Br>C(Cl)(Cl)Cl>[Br:22][C:10]1[O:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:12][C:11]=1[C:13]1[CH:14]=[C:15]([O:20][CH3:21])[C:16]([NH2:19])=[N:17][CH:18]=1
Reactant: BrBr
Reactant: COc1cc(-c2coc(-c3ccc(F)cc3)n2)cnc1N
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2nc(-c3ccc(F)cc3)oc2Br)cnc1N
Yield: 74.1 %

Procedure:
To a solution of 5-(2-(4-fluorophenyl)oxazol-4-yl)-3-methoxypyridin-2-amine (145 mg, 0.5 mmol) in chloroform (20 mL) at 0° C. was added a pre-cooled solution of bromine (40 μL, 0.7 mmol) in CHCl3 (5 mL). The reaction mixture was stirred for <5 min, concentrated in vacuo, and the resulting residue was azeotroped with CHCl3 (2×). Purification by flash chromatography (SiO2, 100:0-95:5 DCM-MeOH) provided 135 mg of 5-(5-bromo-2-(4-fluorophenyl)oxazol-4-yl)-3-methoxypyridin-2-amine as a yellow solid: LCMS (m/z): 365.8 (MH+), tR=0.83 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]2[N:11]=[C:12]([N+:14]([O-])=O)[CH:13]=[C:7]2[CH2:6]1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]2[N:11]=[C:12]([NH2:14])[CH:13]=[C:7]2[CH2:6]1
Reactant: [H][H]
Reactant: COCCN1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: COCCN1CCn2nc(N)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a solution of 296d (1.7 g, 7.5 mmol) in ethanol (50 mL) was added Pd/C (10%, 800 mg). The reaction was charged with hydrogen gas (via balloon) and stirred at room temperature for 2 h. After reaction was complete, the mixture was filtered through a plug of CELITE®. The filtrate was concentrated reduced pressure to afford 296e as a yellow solid (1.2 g, 82%), which was used directly without further purification. MS-ESI: [M+H]+ 197.3
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:21])([CH3:20])[C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([Li])CCC.IC>C1COCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:21])([CH3:20])[C:8]1[N:9]=[C:10]([CH3:22])[N:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cn(-c2ccc(F)cc2)cn1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1nc(C(C)(C)O[SiH2]C(C)(C)C)cn1-c1ccc(F)cc1
Temperature: -25 °C
Reaction time: 0.17 h

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-1H-imidazole (18.2 g, 59.2 mmol) was dissolved in 600 mL dry THF and cooled to −78° C. n-Butyl lithium (55.5 mL, 1.6M in hexane, 88.8 mmol) was added dropwise. The reaction mixture was warmed up to −25° C., kept at −25° C. for 10 min and then cooled again to −78° C. Iodomethane (7.4 mL, 11.9 mmol) was added dropwise. The reaction mixture was slowly warmed up to RT and stirred at RT overnight. The solvent was evaporated. The residue was taken up in 300 mL water and extracted three times with ethyl acetate (200 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel (cyclohexane/ethyl acetate 50:50→20:80 gradient) and the desired compound was obtained as an orange oil (14.7 g, 77%), MS: m/e=321.1 (M+H+).
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]([C:13]2[CH2:20][S:19][CH:18]3[N:15]([C:16](=[O:30])[CH:17]3[NH:21][C:22](=[O:29])[CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[C:14]=2[C:31]([O:33]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:32])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)=O>[NH:1]([C:8]1[S:9][C:10]([C:13]2[CH2:20][S:19][CH:18]3[N:15]([C:16](=[O:30])[CH:17]3[NH:21][C:22](=[O:29])[CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[C:14]=2[C:31]([OH:33])=[O:32])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4ccccc4)s3)CSC12
Solvent: O=CO
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(c3cnc(Nc4ccccc4)s3)CSC12
Yield: 59.3 %

Procedure:
3-(2-Anilinothiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.9 g) is treated with formic acid (9 cc) by following the procedure described in Reference Example 1, and 3-(2-anilinothiazol-5-yl)-2-carboxy-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.4 g) is obtained in the form of a yellow solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@H:25]3[CH2:29][NH:28][CH2:27][C@H:26]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH:37](OCC)=[O:38]>>[CH:37]([N:28]1[CH2:29][C@H:25]([NH:24][S:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:11]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[C:3]([CH3:2])[CH:12]=3)=[CH:16][CH:17]=2)(=[O:23])=[O:22])[C@H:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1)=[O:38]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CNC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Reactant: CCOC=O
Agent: Cl
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C=O)C[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Yield: 61 %

Procedure:
According to the procedure of Example 17, Step 3, the reaction of 320.4 mg of tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylate hydrochloride with ethyl formate provided 191 mg (61% yield) of tert-butyl cis-1-formyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylate. MS: 526.2(M+H)+
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:20][OH:21].[OH-].[Na+]>CO>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[N:20][OH:21])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=Cc1ccc(OCCCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: ON=Cc1ccc(OCCCc2ccccc2)cc1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
A solution of 750 mg of p-(3-phenylpropoxy)benzaldehyde and 2.3 g of hydroxylamine hydrochloride in 20 ml of methanol was adjusted to pH 8 by addition of 10% sodium hydroxide under cooling. The mixture was stirred for 1 hour and, then, the methanol was evaporated. Water was added to the residue, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated to give 750 mg of p-(3-phenylpropoxy)benzaldehyde oxime. A solution of this compound in 10 ml of tetrahydrofuran was added dropwise to a suspension of 300 mg of lithium aluminum hydride in 6 ml of tetrahydrofuran at -30° C. After 20 minutes of stirring at -30° C., the temperature was raised to room temperature and stirring was continued for 2 hours. The excess lithium aluminum hydride was decomposed with sodium sulfate decahydrate, and the reaction mixture was filtered. The filtrate was diluted with ethyl acetate and washed with 10% hydrochloric acid. The hydrochloric acid layer was made alkaline with solid potassium hydroxide, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed in sequence with water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 260 mg of p-(3-phenylpropoxy)benzylamine.
Reaction SMILES: C([Li])CCC.[CH:6]1[CH:7]=[CH:8][C:9]2[S:14][CH:13]=[CH:12][C:10]=2[CH:11]=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[O:23])[O:19][C:20]=1[CH3:21]>C1COCC1>[S:14]1[C:13]([CH:22]([C:18]2[O:19][C:20]([CH3:21])=[C:16]([CH3:15])[CH:17]=2)[OH:23])=[CH:12][C:10]2[CH:11]=[CH:6][CH:7]=[CH:8][C:9]1=2
Reactant: c1ccc2sccc2c1
Reactant: Cc1cc(C=O)oc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(O)c2cc3ccccc3s2)oc1C
Reaction time: 0.25 h
Yield: 102.2 %

Procedure:
n-Butyl lithium (2.5 N in hexanes, 32.2 mL, 80.5 mmol) was added to a stirred solution of thianaphthene (10.6 g, 78.9 mmol) in THF (290 mL) at −78° C. After 15 min., a solution of 4,5-dimethyl-2-furaldehyde (9.79 g, 78.9 mmol) in THF (10 mL) was added. After additional 1 hour, the reaction mixture was quenched with 10% aqueous ammonium chloride (150 mL) and further diluted with water (150 mL). Aqueous mixture was extracted with dichloromethane. The combined dichloromethane extracts were washed with water, dried with brine and anhydrous Na2SO4, and concentrated to provide the title compound as an yellow oil (20.84 g, 100%): NMR (DMSO-d6); δ 7.89 (d, J=8 Hz, 1H), 7.76 (d, J=8, Hz, 1H), 7.35-7.26 (m, 2H), 7.25 (s, 1H), 6.36 (s, 1H), 6.08 (s, 1H), 5.92 (s, 1H), 2.13 (s, 3H), 1.86 (s, 3H); MS (EI): [M+], 258.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[N:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:14]=1[C:15]([O:17]C)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[N:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:14]=1[C:15]([OH:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Cl)cnc1N1CCCC1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(Cl)cnc1N1CCCC1Cc1ccccc1
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 97.8 %

Procedure:
To methyl 2-(2-benzylpyrrolidin-1-yl)-5-chloronicotinate (D74) (75 mg, 0.226 mmol) in a mixture 1,4-dioxane/water (3 ml/1 ml), lithium hydroxide monohydrate (14.3 mg, 0.34 mmol) was added and the resulting mixture was stirred at 150° C. under microwave irradiation for 10 min (2 cycles of 5 min each). Solvents were evaporated in vacuo. The obtained residue was diluted with water/1M HCl (5 ml/15 ml) and extracted with ethyl acetate (3×30 ml). Collected fractions after solvent evaporation afforded the title compound (D100) (70 mg).
Reaction SMILES: [C:1](=O)([O:37]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]([CH2:18][C:19]1[CH:27]=[C:26]([CH3:28])[C:25]2[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:24]=2)[CH:20]=1)[C:4](=[O:17])[N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1.[C:48]1([C:54]2[NH:55][C:56](=[O:65])[N:57]([CH:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)[CH:58]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[O:65]=[C:56]1[NH:55][C:54]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[CH:58][N:57]1[CH:59]1[CH2:60][CH2:61][N:62]([C:1]([O:2][C@H:3]([CH2:18][C:19]2[CH:27]=[C:26]([CH3:28])[C:25]3[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:34])[CH3:36])[N:24]=3)[CH:20]=2)[C:4](=[O:17])[N:5]2[CH2:10][CH2:9][CH:8]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:7][CH2:6]2)=[O:37])[CH2:63][CH2:64]1
Reactant: Cc1cc(C[C@@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: O=c1[nH]c(-c2ccccc2)cn1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3cc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-nitrophenyl carbonate (150 mg, 0.23 mmol) and 4-phenyl-(piperidin-4-yl)-1H-imidazol-2(3H)-one (PCT Int. Appl. 1998, WO 9811128 A1) (82.2 mg, 1.50 equiv) in dimethylformamide (1 mL) was added diisopropylethylamine (79 μL, 0.45 mmol) and stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography to give 74 mg (43%) as a colorless film. Mass spec.: 770.57 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4]([C:5]1[C:13](=[O:21])[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:22])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)c1cccc(C)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(C)cc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.5 %

Procedure:
2-(3-Methylbenzoyl)-3-phenyl acrylic acid ethyl ester (1 g, 3.39 mmol) obtained in Step 2 was dissolved in dichloromethane, and methanesulfonic acid (5.22 g, 54.35 mmol) was added thereto, followed by stirring for 3 hrs at RT. Once the reaction was completed, the mixture was cooled to 0° C., neutralized with sodium bicarbonate, and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 273 mg of the titled compound (yield: 27%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([NH:23][CH:24]1[CH:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][C:26](=[O:37])[CH2:25]1)=O)C=C>>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:9]1[C:10]([NH:23][CH:24]1[CH:28]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:27][C:26](=[O:37])[CH2:25]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 85.9 %

Procedure:
Reaction of N-tert-butoxycarbonylpipecolic acid (460 mg, 2.0 mmol) and N-allyloxycarbonyl-4-amino-5-benzyloxy-2-oxotetrahydrofuran (530 mg, 1.82 mmol) was carried out by a method analogous to that reported by Chapman (Bioorg. & Med. Chem. Lett. 1992, 2, 613-618.) to give 654 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]([N:38]3[CH2:42][CH2:41][C@@H:40]([OH:43])[CH2:39]3)=[N:36][CH:37]=2)O1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:37]=[N:36][C:35]([N:38]6[CH2:42][CH2:41][C@@H:40]([OH:43])[CH2:39]6)=[CH:34][CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC1(C)OB(c2ccc(N3CC[C@@H](O)C3)nc2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(N5CC[C@@H](O)C5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and (R)-1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-pyrrolidin-3-ol (stage 212.1.1) to give the title compound as a white solid. (HPLC: tR 2.03 min (Method A); M+H=456 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.25-8.22 (m, 1H), 8.12 (s, 1H), 8.05-8.01 (m, 1H), 7.87-7.83 (m, 1H), 7.57-7.53 (m, 1H), 7.43-7.41 (m, 1H), 6.55-6.51 (m, 1H), 4.95 (d, 1H), 4.42-4.36 (m, 1H), 3.92 (s, 3H), 3.56 (s, 3H), 3.54-3.43 (m, 3H), 3.37-3.31 (m, 1H), 2.08-1.86 (m, 2H), 1.96 (s, 3H))
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Cl.Cl.[CH:23]12[CH2:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][NH:24]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:23]12[CH2:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][N:24]2[C:3]1[C:2]([F:1])=[CH:15][C:14]2[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]3[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=23
Reactant: C1CC2CNC1CN2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1COc2c(N3CC4CCC3CN4)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 26.8 %

Procedure:
A solution of 0.56 g (2.0 mmol) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, 0.41 g (2.2 mmol) of 2,5-diazabicyclo[2.2.2]octane dihydrochloride, 0.90 ml (6.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 25 ml of acetonitrile was heated under reflux for 18 hours. The solution was evaporated to dryness and the residue was triturated with methanol and filtered to give 0.20 g of the title compound, 260°-265° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:33])[C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[CH2:14][CH2:13]2)[C:11](=[O:34])[NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35]I>>[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:33])[C:19]3[CH:20]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=3)[CH2:14][CH2:13]2)[C:11](=[O:34])[N:10]([CH3:35])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2Cc1ccccc1
Product: CN1CN(Cc2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=500.3 (M+H+), was prepared in accordance with the general method of example 71 from 1-benzyl-8-(3,5-bis-trifluoromethyl-benzoyl)-1,3,8-triaza-spiro[4.5]decan-4-one and methyliodide.
Reaction SMILES: [ClH:1].Cl.[C@H:3]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([CH3:44])[C:41]([CH3:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CC[CH2:4]1.Cl.Cl.Cl.NC1CCN(C[C@@H]([N:58]2[CH2:63][CH2:62][CH:61]([OH:64])[CH2:60][CH2:59]2)C)CC1>>[ClH:1].[ClH:1].[OH:64][CH:61]1[CH2:62][CH2:63][N:58]([C@@H:3]([CH3:4])[CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([CH3:44])[C:41]([CH3:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:59][CH2:60]1
Reactant: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)c2cc1C
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Agent: Cl
Product: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CCC(O)CC6)CC5)cc34)c2cc1C

Procedure:
This compound is synthesized from 4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (127, see example 104) and amine 50 analogously to the method described in example 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[NH:4][C:3]1=[O:12].Cl[CH2:15][CH2:16][O:17]C1CCCCO1>>[OH:17][CH2:16][CH2:15][N:4]1[C:5]2[C:10](=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=2)[C:2]([CH3:13])([CH3:1])[C:3]1=[O:12]
Reactant: ClCCOC1CCCCO1
Reactant: Cc1ccc2c(c1)C(C)(C)C(=O)N2
Product: Cc1ccc2c(c1)C(C)(C)C(=O)N2CCO

Procedure:
Prepared from 3,3,5-trimethyl-1,3-dihydro-2H-indol-2-one (prepared by the method of Endler and Becker; Organic Syntheses Coll. vol. 4 page 657) and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described above.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:28])[CH:22]=2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:29][C@H:30]([CH3:52])[CH2:31][O:32]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC)C=CC=CC=1>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:28])[CH:22]=2)(=[O:19])=[O:20])[CH:14]=[C:13]([O:29][C@H:30]([CH3:52])[CH2:31][OH:32])[N:12]=1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccc(=O)n(C)c2)nc(SCc2cccc(F)c2F)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: COc1ccccc1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)c2ccc(=O)n(C)c2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-methyl-2-(triphenylmethoxy)ethoxy]-4-pyrimidinyl]-1,6-dihydro-1-methyl-6-oxo-3-pyridinesulfonamide (the product from step ii) (0.16 g) in MeOH (10 mL) was added p-toluenesulfonic acid (50 mg) and anisole (0.22 g). The reaction was then stirred at room temperature for 18 h. The reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The aqueous layer was then further extracted with EtOAc (2×100 mL). Combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by reverse phase HPLC using TFA (0.2%)/MeCN to give a white solid. Yield: 9 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Sn](Cl)Cl.C(O)C.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:16][C:13]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([CH:12]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)c(C(=O)c2ccccc2)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-5-nitrobenzophenone (1.3 g,5.0 mmol), tin(II) chloride (4.5 g, 20 mmol), and ethanol (20 ml) were mixed and heated at 70° C. for 1 h. After cooling to room temperature, to the reaction mixture were added ice, EtOAc and aqueous NaHCO3 and it was stirred for 30 min. The organic layer was washed with brine and dried over MgSO4. Filtration and evaporation afforded 5-amino-2-Chlorobenzophenone. 1H NMR, 7.85(m,2H), 7.30-7.66 (m,3H7.20 (d,1H,J=8.8 Hz), 6.60-6.80 (m,2H). MS calcd 231.1; MS (M+1) 232.0.