Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:11]([N:14]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CC(O)=O.[Fe]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([S:11]([N:14]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:12])=[O:13])=[CH:3][C:2]=1[OH:1]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc([N+](=O)[O-])c(O)c2)cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(N)c(O)c2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 3-hydroxy-N-(4-methoxybenzyl)-4-nitro-N-(thiazol-2-yl)benzenesulfonamide (9 g, 21.3 mmol) in AcOH (70 ml) was added Fe-powder (5.98 g, 106.0 mmol, Qualigens) and the resulting suspension was stirred at 70° C. for 2 h. The mixture was cooled to 25° C. The organic compound was extracted with EtOAc, washed with saturated aqueous solution of NaHCO3, dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel chromatography using a gradient of 0-50% EtOAc in hexanes as eluent to afford 5.5 g of 4-amino-3-hydroxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (INTERMEDIATE AD) as off white solid in 66.2% yield. 1H-NMR (400 MHz, DMSO): δ 9.82 (s, 1H), 7.37 (s, 1H), 7.29 (m, 1H), 7.21-7.25 (m, 2H), 7.08-7.09 (dd, 1H), 7.06 (s, 1H), 6.84 (d, J=8.8 Hz, 2H), 6.62 (d, J=8.4 Hz, 1H), 5.67 (s, 2H), 4.91 (s, 2H), 3.70 (s, 3H); m/z (ESI, positive ion) 392.1 (M+H).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([CH:40]([F:42])[F:41])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:42][CH:40]([F:41])[C:35]1[CH:34]=[C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])[CH:38]=[CH:37][C:36]=1[F:39]
Reactant: CN(C[C@@H](N)c1ccc(F)c(C(F)F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(C(F)F)c1

Procedure:
Compound 51 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-difluoromethyl-4-fluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [391 (M+H)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]([F:24])([F:23])[F:22])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=3)[NH2:17])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[N:26]([O-])=O.[Na+].[Sn](Cl)Cl.[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]([F:22])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([NH:17][NH2:26])[CH:18]=[CH:19][CH:20]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: NNc1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
In 1,4-dioxane (4 mL), 3-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]aniline (1.0 g) was dissolved, and thereto was added a concentrated hydrochloric acid (7 mL) at room temperature. After stirring at the same temperature for 20 minutes, this solution was cooled to 0° C., and thereto was added a solution of sodium nitrite (184 mg) in water (4 mL), and the mixture was stirred at the same temperature for 15 minutes. To this reaction solution was added dropwise a solution of tin(II) chloride (1.11 g) in a concentrated hydrochloric acid (2 ml). The reaction mixture was neutralized with 2N sodium hydroxide. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude 3-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenylhydrazine (1.0 g).
Reaction SMILES: [CH2:1]([S:8]([NH2:11])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]([C:16](Cl)=[O:17])=[O:15]>>[CH2:1]([S:8]([NH:11][C:16](=[O:17])[C:14]([O:13][CH3:12])=[O:15])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(=O)Cl
Reactant: NS(=O)(=O)Cc1ccccc1
Product: COC(=O)C(=O)NS(=O)(=O)Cc1ccccc1

Procedure:
A mixture of benzylsulfonamide (16.7 g, 0.0975 mole) and methyloxalylchloride (38 ml, 0.41 mol) was heated at 100°-120° C. for 2 hours. Upon evaporation, there was obtained the title compound, 20.6 g, mp 119°-124° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH2:17][N:16]2[C:28](OC(C)(C)C)=[O:29])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:75]([O:79][C:80]([NH:82][C:83](C)([CH3:87])[C:84](O)=O)=[O:81])([CH3:78])([CH3:77])[CH3:76]>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH2:17][N:16]2[C:28](=[O:29])[C:83]([NH:82][C:80](=[O:81])[O:79][C:75]([CH3:76])([CH3:78])[CH3:77])([CH3:87])[CH3:84])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O[Si](C)(C)C(C)(C)C)c1

Procedure:
A solution of tert-butyl 2-(3-{[tert-butyl(dimethyl)silyl]oxy }phenyl)-4-(5-chloro-2-fluorophenyl)-2,5dihydro-1H-pyrrole-1-carboxylate (3-2, 276 mg, 0.683 mmol, 1 equiv), triethylamine (277 mg, 2.73 mmol, 4 equiv), PYBOP (711 mg, 1.37 mmol, 2 equiv) and 2-[(tert-butoxycarbonyl)amino]-2-methylpropanoic acid (278 mg, 1.37 mmol, 2 equiv) in in DMP (10 mL) was warmed at 60° C. for 18 h. The solution was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography. Elution with 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes gave tert-butyl 2-[2-(3{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-(5-chloro-2-fluorophenyl)-2,5-dihydro-1H-pyrrol-1yl]-1,1-dimethyl-2-oxoethylcarbamate (3-3) as a pale yellow gum. LRMS n/z (M+H) 588.9 found, 589.0 required.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([C:18]2[N:27](COCC[Si](C)(C)C)[C:26](=[O:36])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[CH3:43])[CH:24]=3)[N:19]=2)[CH:17]=1)=[O:12])[CH3:9]>>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([C:18]2[NH:27][C:26](=[O:36])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[CH3:43])[CH:24]=3)[N:19]=2)[CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(-c4ccccc4C)cc3c(=O)n2COCC[Si](C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2nc3ccc(-c4ccccc4C)cc3c(=O)[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
A solution of HCl in dioxane (4M, 0.872 mL, 3.48 mmol) was added to 1-[4-oxo-6-o-tolyl-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (88.0 mg, 0.174 mmol). The reaction mixture was stirred at 23° C. After 18 h, the reaction mixture was concentrated under reduced pressure. Et2O was added (5 mL) and the resulting precipitate was collected by filtration and washed well with Et2O to afford the titled compound (52.0 mg, 80%). MS (ESI): mass calcd. for C21H18N4O3, 374.1; m/z found 375.2 [M+H]+. 1H NMR (600 MHz, CDCl3): 9.05 (s, 1H), 8.35 (s, 1H), 8.02 (s, 1H), 7.86 (d, J=6.6 Hz, 1H), 7.78 (s, 1H), 7.37-7.28 (m, 4H), 4.31 (q, J=7.1 Hz, 2H), 2.28 (s, 3H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C[Li]>CCOCC>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1CCc2ccccc21
Agent: [Li]C
Solvent: CCOCC
Product: C1=Cc2ccccc2C1

Procedure:
Starting indanones J may be synthesized from commercially available 1-indanone F, shown by the following reaction sequence, by initial formation of the tosyl hydrazone (H2NNHTs, 1:1 eq./EtOH, 100° until solubilized) followed by methyllithium-induced elimination (3 eq./Et2O, 25°, 2.5 hours) to give indene G. Hydroboration-oxidation of G using standard conditions affords 1,2-oxygen transposition product H. Dess-Martin periodinane oxidation affords desired indanone J. Indanone J is converted in good yield to corresponding compounds of the invention as described hereinbefore. ##STR7##
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.C(N(CC)CC)C.[Cl:18][CH:19]([Cl:23])[C:20](Cl)=[O:21].O>C(Cl)Cl>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:20](=[O:21])[CH:19]([Cl:23])[Cl:18])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)C(Cl)Cl)n[nH]1
Yield: 67 %

Procedure:
4.2 g (0.03 mole) of 3-amino-5-t-butylpyrazole prepared in Example 1 and 3.1 g of triethylamine were dissolved in 30 ml of methylene chloride, and 4.4 g of dichloroacetyl chloride was added dropwise thereto at about 30° C. The resulting mixture was allowed to stand over night. Thereafter, water was added thereto whereby crystals were precipitated. The crystals were collected by filtration and washed with water to obtain 5.0 g of 5-t-butyl-3-dichloroacetylaminopyrazole.
Reaction SMILES: C(OC([C:12]1[NH:16][C:15]([CH3:17])=[C:14]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]=1[CH3:24])=O)(=O)C1C=CC=CC=1>CC(C)=O.[Pd]>[CH3:17][C:15]1[NH:16][CH:12]=[C:13]([CH3:24])[C:14]=1[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CCc1c(C)[nH]c(C(=O)OC(=O)c2ccccc2)c1C
Agent: [Pd]
Solvent: CC(C)=O
Product: COC(=O)CCc1c(C)c[nH]c1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methyl 5-(benzoyloxy-carbonyl)-2,4-dimethyl-3-pyrrolepropionate (1.55 g, 4.91 mmol) was dissolved in acetone (150 mL) containing 10% palladium/carbon, and the mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction mixture was filtered, the solvent was evaporated under reduced pressure, then the residue was immediately dissolved in trifluoroacetic acid (TFA, 10 mL), and the mixture was stirred at room temperature for 10 minutes under an argon atmosphere. The reaction mixture was added with dichloromethane (30 mL), then washed successively with water and 1 mol/L aqueous sodium hydrogencarbonate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain pale brown oil (1, 0.835 g, 94%).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][CH2:14][CH:15]([OH:32])[CH2:16][N:17]1[C:29]2[CH:28]=[CH:27][C:26]([Br:30])=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Br:31])[CH:22]=2.CCN(CC)CC.C(Cl)Cl.CCOC(C)=O>C(Cl)Cl>[Br:31][C:21]1[CH:20]=[CH:19][C:18]2[N:17]([CH2:16][CH:15]3[O:32][C:2](=[O:4])[NH:13][CH2:14]3)[C:29]3[C:24]([C:23]=2[CH:22]=1)=[CH:25][C:26]([Br:30])=[CH:27][CH:28]=3
Reactant: NCC(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1NCC(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)O1
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 92.2 %

Procedure:
A solution of triphosgene (0.0890 g, 0.300 mmol, 0.35 equiv) in 2 mL anhydrous CH2Cl2 was added dropwise to a solution of 1-amino-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol (0.3413 g, 0.857 mmol) and Et3N (0.1909 g, 1.886 mmol) in 1 mL CH2Cl2 under N2 atmosphere at 4° C. The reaction mixture was stirred for 15 min at 4° C. and then warmed to room temperature and stirred for 1 hour. CH2Cl2 was removed under vacuum. Saturated NH4Cl (5 mL) and 10 mL EtOAc was added to the residue and stirred for 20 min. Then the aqueous layer was separated and the organic layer was washed with water 2×10 mL. The combined aqueous layers were extracted with EtOAc, dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using CH2Cl2/EtOAc to afford 0.1173 g white solid, yield 20.0% over 2 steps.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[N:22]=[N:21][N:20]=2)[CH2:8][C@H:7]1[CH2:39][CH3:40])=[O:5])[CH3:2].[CH3:41][O:42][C:43](=[O:49])[C:44]([CH3:48])([CH3:47])[CH2:45]O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[C:27]([C:35]([F:36])([F:38])[F:37])[CH:26]=3)[N:22]([CH2:45][C:44]([C:43]([O:42][CH3:41])=[O:49])([CH3:48])[CH3:47])[NH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:39][CH3:40])=[O:5])[CH3:2]
Reactant: COC(=O)C(C)(C)CO
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2nnnn2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC2=NNN(CC(C)(C)C(=O)OC)N2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 19 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(tetrazol-5-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (230 mg) is dissolved in tetrahydrofuran (3 ml), and thereto are added 3-hydroxy-2,2-dimethylpropionic acid methyl ester (58 μl), a solution (0.18 ml) of 40% diethyl azodicarboxylate in toluene and triphenylphosphine (121 mg). The mixture is stirred at room temperature for 19 hours, and partitioned by adding water and diethyl ether. The organic layer is washed with saturated brine, then dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[2-(2-methoxycarbonyl-2-methylpropyl)-2H-tetrazol-5-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (243 mg). MS (m/z): 688 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:12]1[C:17]([CH2:18][NH:19][C:20]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([Cl:32])[C:26]=3[Cl:33])[N:23]=[N:22][N:21]=2)=[CH:16][CH:15]=[CH:14][N:13]=1>>[Cl:33][C:26]1[C:27]([Cl:32])=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[N:24]1[C:20]([NH:19][CH2:18][C:17]2[C:12]([C:7]3[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:21][N:22]=[N:23]1
Reactant: OB(O)c1cccnc1F
Reactant: Fc1ccc(-n2nnnc2NCc2cccnc2Cl)c(Cl)c1Cl
Product: Fc1ccc(-n2nnnc2NCc2cccnc2-c2cccnc2F)c(Cl)c1Cl

Procedure:
The title compound was prepared from 2-fluoropyridine-3-boronic acid and the product of Example 285B using General Procedure 6. MS (ESI+) m/z 434.2 (M+H)+; Rt=1.87 min. 1H-NMR (400 MHz, DMSO-d6) δ 5.56 (s, 2H), 7.46 (m, 2H), 7.55 (m, 2H), 7.73 (dd, J=1.5 Hz, J=7.9 Hz, 1H), 7.98 (ddd, J=2.0 Hz, J=7.4 Hz, J=9.6 Hz, 1H), 8.31 (d, J=4.8 Hz, 1H), 8.68 (dd, J=1.6 Hz, J=4.7 Hz, 1H), 8.99 (s, 1H).
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([F:20])[CH:14]=2)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26]([C:28]1([CH2:41][CH:42]=O)[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)=O)C.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][C:28]2([C:26](=[O:25])[N:19]([C:16]3[CH:17]=[CH:18][C:13]([CH:10]4[CH2:11][CH2:12][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:22])[CH3:21])[CH2:8][CH2:9]4)=[CH:14][C:15]=3[F:20])[CH2:42][CH2:41]2)[CH2:29][CH2:30]1)=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(c2ccc(N)c(F)c2)CC1
Reactant: CCOC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)cc1F)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-2-fluoro-phenylamine (520 mg, 1.7 mmol, 1 equiv) was dissolved in DCE (15 mL). To this solution was transferred a solution of 4-(2-oxo-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (598 mg, 2.07 mmol, 1 equiv.) in DCE (5 mL). To this clear solution was then added acetic acid (372 mg, 6.21 mmol, 3 equiv) in DCM (2 mL), followed by addition of powder NaBH(OAc)3 (1.31 g, 6.2 mmol, 3 equiv.) in one portion under N2 at rt. The yellowish milky solution was stirred at rt overnight. The reaction was diluted with DCM (10 mL) and quenched with 10 mL of aqueous NaHCO3. The two layers were separated, and the aqueous layer was extracted with DCM (10 mL×2). The combined DCM extracts were washed with sodium bicarbonate (10 mL), brine (15 mL), dried (anhydrous potassium carbonate), filtered, and concentrated to obtain the title compound as a liquid and was used in next step without further purification.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][CH2:16][CH2:17][N:18]([CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=4)[CH2:25][CH2:24]3)[CH2:19][CH3:20])OCC[O:11]2)=[CH:6][CH:5]=1.Cl.C(=O)(O)[O-].[Na+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CO>[ClH:36].[ClH:1].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:11])[CH2:15][CH2:16][CH2:17][N:18]([CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[CH2:27][CH2:28]2)[CH2:19][CH3:20])=[CH:6][CH:5]=1
Reactant: CCN(CCCC1(c2ccc(F)cc2)OCCO1)CCN1CCC(Oc2cccc(Cl)c2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C([O-])O
Solvent: CO
Product: CCN(CCCC(=O)c1ccc(F)cc1)CCN1CCC(Oc2cccc(Cl)c2)CC1
Temperature: 25 °C

Procedure:
A solution of 5.68 g (10.1 mmol) of 1-{2-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-ethylamino}ethyl}-4-(3-chlorophenoxy)piperidine dihydrochloride, 150 ml of methanol and 70 ml of 3N HCl was heated at reflux for 4 hours under nitrogen and allowed to cool to room temperature. The mixture was neutralized with saturated sodium bicarbonate after which the methanol was evaporated. The residual aqueous solution was made basic with saturated sodium carbonate, extracted twice with ether and dried over potassium carbonate. Evaporation of the solvent provided an oil. The yield of the dihydrochloride was 5.20 g (99%). Recrystallization from ethanol provided 4.16 g (80%) of analytically pure material.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[N:7]=[C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=5)=[CH:16][C:15]4=[O:29])=[CH:10][N:9]3[C:30]=2[CH2:31][OH:32])[CH2:5][CH2:4]1.I[CH3:34]>C1COCC1>[CH:3]1([C:6]2[N:7]=[C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=5)=[CH:16][C:15]4=[O:29])=[CH:10][N:9]3[C:30]=2[CH2:31][O:32][CH3:34])[CH2:4][CH2:5]1
Reactant: O=c1cc(OCc2ccc(F)cc2)ccn1-c1ccc2nc(C3CC3)c(CO)n2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of NaH (40% oil dispersion, 22 mg) in THF (9 ml) was added a solution of 1-(2-cyclopropyl-3-(hydroxymethyl)imidazo[1,2-a]pyridin-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (100 mg) in THF (1 ml) at 0° C., and then the mixture was allowed to warm to room temperature and stirred for 30 min. Iodomethane (22 pa) in THF (0.5 ml) was added, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice-water and extracted with DCM. The combined DCM layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) followed by recrystallization from DCM/hexane to give the title compound (40 mg) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[NH:8][CH:7]=[N:6][C:5]=1[C:9](=[O:14])[NH:10][CH2:11][CH:12]=[CH2:13])([O-])=O>[Cl-].[Cl-].[Ti+2]>[NH2:1][C:4]1[NH:8][CH:7]=[N:6][C:5]=1[C:9](=[O:14])[NH:10][CH2:11][CH:12]=[CH2:13]
Reactant: C=CCNC(=O)c1nc[nH]c1[N+](=O)[O-]
Agent: [Ti+2]
Agent: [Cl-]
Product: C=CCNC(=O)c1nc[nH]c1N

Procedure:
The 5-amino-4-allylcarbamoylimidazole was prepared from 5-nitro-4- allylcarbamoylimidazole (m.p. 218°-220C.) by reduction by means of titanous chloride.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]=2[O:11][CH2:10]1)=O)(C)(C)C.C(OCC)(=O)C.[ClH:38]>>[ClH:38].[NH2:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]=2[O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reaction time: 3 h

Procedure:
To 7.6 g of benzyl 3(S)-tert-butoxycarbonylamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate is added 30 ml of hydrogen chloride-ethyl acetate solution (5N) and the mixture stands for 3 hours at room temperature. The mixture is concentrated under reduced pressure and the resulting residue is crystallized from a mixture of ethyl acetate and ether to give 6.2 g of benzyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate hydrochloride as a colorless crystalline powder, melting at 169°-172° C.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.CCO>[OH-].[Na+].O>[CH:6]1([CH2:5][C@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@@H:3]2[CH2:2][O:20]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CO1
Reaction time: 1 h
Yield: 93.9 %

Procedure:
tert-Butyl (2S,3R)-4-chloro-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (1 g, 3.28 mmol) was dissolved in a solution of 0.7 N NaOH in EtOH (5.6 mL, 3.95 mmol, 1.2 eq). After stirring for 1 h, the mixture was concentrated to give the residue, which was dissolved in water, extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl (S)-2-cyclohexyl-1-((R)-oxiran-2-yl)ethylcarbamate (0.83 g, 95%). 1H NMR: 0.85 (m, 1H), 0.99 (m, 1H), 1.12-1.32 (m, 3H), 1.41 (m, 3H), 1.45 (s, 9H), 1.58 (m, 4H), 1.88 (m, 1H), 2.59 (m, 1H), 2.73 (m, 1H), 2.98 (m, 1H), 4.04 (m, 1H), 4.32 (m, 1H). MS (E/Z): 270 (M+H+).