Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12](C(=O)C)=[C:13]3[C:18]=2[NH:17][C:16](=[O:19])[CH:15]=[CH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([OH:26])(=O)[CH3:24].I([Cl:30])(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>O>[Cl:30][CH2:24][C:23]([N:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=[CH:15][C:16]1=[O:19])=[O:26]
Reactant: CC(=O)O
Reactant: O=I(=O)Cl
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: O
Product: O=C(CCl)n1c(=O)ccc2cccc(OCc3ccccc3)c21
Temperature: 67.5 °C
Reaction time: 0.75 h

Procedure:
A 3 L, 4-necked flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser is charged with 40 g 8-(phenylmethoxy)-5-acetyl-(1H)-quinolin-2-one and 800 mL acetic acid under an atmosphere of nitrogen. To this yellow solution is added 94.93 g benzyl-trimethylammoniumdichloroiodate and 400 mL acetic acid. The resulting suspension is heated under stirring to an internal temperature of 65-70° C. The mixture is stirred at this internal temperature until an in-process control shows complete conversion to 5-chloroacetyll-8-phenylmethoxy-(1H)-quinolin-2-one. Then the mixture is cooled to an internal temperature of 40-45° C. Within 30-60 minutes, 600 mL water is added. The resulting suspension is stirred at room temperature for 30-60 minutes and then filtered. The solid residue is washed with 200 mL water in several portions and then added to 2000 L ethyl acetate in a 3 L, 4-necked flask equipped with a mechanical stirrer, thermometer and refluxing condenser. This mixture is heated to reflux and refluxed for 15 minutes. The mixture is cooled to an internal temperature of 0-2° C. and stirred at this internal temperature for 2 hours. The mixture is filtered and washed with 250 mL water in several portions, and dried overnight in a vacuum drier at 60° C. to give the title compound with a yield of 39.64 g.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[C:27]([CH3:38])[C:26]=1[CH3:39]>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C:8]2[C:7]([CH2:6][O:5][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([CH3:38])[C:26]=3[CH3:39])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: COc1cccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)c1
Product: COc1cccc(-c2nsc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (5-(trifluoromethyl)-3-(3-methoxyphenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.21-7.38 (m, 3H), 6.96-7.04 (m, 2H), 6.72 (d, J=7.8 Hz, 1H), 5.08 (s, 2H), 3.60 (s, 3H), 2.91 (t, J=7.2 Hz, 2H), 2.51 (t, J=7.5 Hz, 2H), 2.23 (s, 3H), 2.067 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H22F3NO4S, 464.1 (M−H). found 464.0.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C1(O)C=CC=CC=1.[Cl:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[C:26]([Cl:38])[C:25]=1O>>[Cl:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[C:26]([Cl:38])[C:25]=1[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(COc2c(Cl)cc(OCc3ccccc3)cc2Cl)CC1

Procedure:
As depicted in Scheme 1, an appropriately substituted hydroxy compound, for example, the commercially available tert-butyl 4-(hydroxymethyl)piperidinecarboxylate was coupled with a phenol (A), for example the known compound 2,6-dichloro-4-(phenylmethoxy)phenol, affording the corresponding tert-butyl 4-{[2,6-dichloro-4-(phenylmethoxy)phenoxy]methyl}piperidinecarboxylate (A1). The intermediate (A1) was in turn treated with hydrogen gas under catalytic conditions using, for example, a Parr hydrogenation apparatus, to convert the phenylmethoxy moiety of (A1) to a hydroxy moiety, thereby making the hydroxy moiety available for further reaction. The so-prepared hydroxy derivative (A2) was then reacted with an appropriate haloalkane, for example, 1,1,1,3-tetrachloropropane, under basic conditions, yielding the corresponding dihaloalkene derivative, a compound of formula I, for example, tert-butyl 4-{[4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy]methyl}piperidinecarboxylate. Example 1, set forth below, provides detailed methods to how compounds of formula I shown in Scheme 1 were prepared.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:10](=[S:19])[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].Cl.[Cl:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[CH3:31]>CN(C)C=O.O>[ClH:23].[CH3:31][N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[CH2:24][S:19][C:10]1[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: S=c1[nH]c2ccccc2cc1-c1ccccc1
Reactant: [H][H]
Reactant: CN1CCCCC1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCCCC1CSc1nc2ccccc2cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (0.96 g. of a 50% w/w dispersion in mineral oil) was added to a solution of 3-phenylquinolin-2-thione (2.37 g.) in dimethylformamide (100 ml.) at ambient temperature. When all the hydrogen had evolved, 2-chloromethyl-1-methylpiperidine hydrochloride (1.84 g.) was added and the mixture was stirred at ambient temperature for 16 hr. The mixture was then poured into water (750 ml.) and extracted with ethyl acetate (2×150 ml.). The ethyl acetate extract was washed with water (2×50 ml.) and then dried (MgSO4). The solvent was evaporated and the residue was chromatographed on basic alumina (150 g. Brockmann Grade III), eluted with increasing concentrations of chloroform in petroleum ether. The eluate obtained with 20% v/v chloroform in petroleum ether was evaporated. The residue was dissolved in diethyl ether (50 ml.) and ethereal hydrogen chloride was added until precipitation was complete. The solid was collected by filtration and crystallised from ethanol-diethyl ether to give 2-[(1-methyl-2-piperidylmethylthio]-3-phenylquinoline hydrochloride, m.p. 198°-200°.
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33]([CH:41]=O)[N:32]=1.[C:43]([BH3-])#[N:44].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:44]([CH2:43][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:26][CH:25]=[CH:24][N:23]=3)[CH2:41][C:33]3[N:32]=[CH:31][C:40]4[C:35]([CH:34]=3)=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: [BH3-]C#N
Reactant: O=Cc1cc2ccccc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3cc4ccccc4cn3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (53.9 mg) obtained in Example 47-3 was dissolved in methanol (2.0 ml) and then added with the compound (20.2 mg) obtained in Example 47-1 and sodium cyanoborohydride (12.8 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (10.1 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])([CH2:12][CH2:13]S(C)(=O)=O)[C:8]1=[O:27].[F:35][C:36]1[CH:58]=[CH:57][C:39]([CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[C:50]2([OH:56])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][C:50]([C:42]3[N:41]([CH2:40][C:39]4[CH:57]=[CH:58][C:36]([F:35])=[CH:37][CH:38]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)([OH:56])[CH2:51][CH2:52]2)([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[C:8]1=[O:27]
Reactant: COc1cc(CN2CCC(CCS(C)(=O)=O)(Cc3ccc(F)cc3F)C2=O)cc(OC)c1OC
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Product: COc1cc(CN2CCC(CCN3CCC(O)(c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(Cc3ccc(F)cc3F)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzyl)-3-(2,4-difluoro-phenylmethyl)-3-(2-methanesulfonyl-ethyl)-2-oxo-pyrrolidine and 4-[1-(4-fluoro-benzyl)-1H-benzoimidazol-2-yl]-4-hydroxy-piperidine to give the title compound: Rf=0.38 (silica gel, 20% methanol/ethyl acetate).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2([CH3:17])[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]1)=[O:5])C.C1COCC1.CCO.O[Li].O>O>[CH3:17][C:14]1([C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:13])[CH2:15][CH2:16]1
Reactant: CCOC(=O)C1CCN(C(=O)C2(C)CC2)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC1(C(=O)N2CCC(C(=O)O)CC2)CC1
Reaction time: 1 h
Yield: 86 %

Procedure:
To a stirred solution of 1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester (26.09 g, 0.109 mol) in 500 mL of a mixture of THF, EtOH and H2O) (1/1/1) was added LiOH.H2O) (6.86 g, 0.163 mol). After one hour at RT, the solvent were evaporated and the residue taken up in CH2Cl2 and the organic phase was washed with aqueous HCl 1M. The organic phases were dried over Na2SO4 and evaporated under vacuo to gave 19.8 g (86%) of the title compound as a white solid. ES-MS m/e: 212.1 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([CH2:27][CH3:28])[CH:20]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[NH:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:41][CH2:40][C:39]3[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=3[NH:37][C:36]2=[O:46])[CH2:31][CH2:30]1.C1C[O:50][CH2:49]C1>CN(C=O)C>[CH2:27]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[CH2:25][CH3:26])[CH2:18][C@@H:2]([NH:1][C:49]([N:29]1[CH2:30][CH2:31][CH:32]([N:35]2[CH2:41][CH2:40][C:39]3[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=3[NH:37][C:36]2=[O:46])[CH2:33][CH2:34]1)=[O:50])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)[CH2:7][CH2:6]1)=[O:4])[CH3:28]
Reactant: CCc1ccc(C[C@@H](N)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc1CC
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc1CC
Temperature: 0 °C

Procedure:
4.1 g (10.61 mmol) of (R)-2-amino-3-(3,4-diethyl-phenyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-propan-1-one, dissolved in 50 mL of THF, were slowly added dropwise to the ice-cooled mixture of 150 mL of THF and 1.9 g (11.2 mmol) of CDT. Then the mixture was stirred for 30 min in the ice bath and for a further 45 min at RT before the solution of 2.7 g (11.0 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one in 20 mL of DMF was added and the mixture was refluxed for 4 h. The reaction mixture was evaporated down under reduced pressure, the residue was combined with Na2CO3 solution and exhaustively extracted with EtOAc. The combined organic extracts were washed with water, dried over Na2SO4, evaporated down and purified over aluminium oxide. The product was obtained as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH3:23])=[C:14]([CH2:24][OH:25])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28]I>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH3:23])=[C:14]([CH2:24][O:25][CH3:28])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CCc1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [H-]
Agent: [Na+]
Product: CCc1nc2c(cc1COC)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 1, intermediate d) from (4R,9aR)-6-ethyl-7-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and methyl iodide.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](Br)[CH:18]=[CH2:19].[C:21](#N)C>>[CH3:21][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:17][CH:18]=[CH2:19]
Reactant: c1ccc(C2=NCCc3ccccc32)cc1
Reactant: C=CCBr
Reactant: CC#N
Product: C=CCN1CCc2ccccc2C1(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-phenyl-3,4-dihydroisoquinoline (1.0 g) and allyl bromide (0.44 ml) in acetonitrile (10 ml) was refluxed for 2 hours. After cooling it to room temperature, the solvent was evaporated in vacuo and then the residue was stirred in diethyl ether (15 ml) at room temperature. To the mixture was added 3M diethyl ether solution of methylmagnesium bromide (2.0 ml). After 1 hour, the mixture was poured into aqueous ammonium chloride solution. The organic layer was washed with water, sodium chloride aqueous solution and dried over magnesium sulfate, and evaporated in vacuo to give 1-methyl-1-phenyl-2-allyl-1,2,3,4-tetrahydroisoquinoline (0.7 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:16])C(O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](=[O:20])([O-])[O-:18].[K+].[K+].Cl[CH2:24][C:25]([N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])=[O:26]>CN(C=O)C.O>[CH2:28]([N:27]([CH2:31][CH2:32][CH3:33])[C:25]([CH2:24][O:18][C:17](=[O:20])[CH2:16][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:26])[CH2:29][CH3:30]
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCN(CCC)C(=O)CCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCC)C(=O)COC(=O)CCNC(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a solution of benzyloxycarbonylamino-propionic acid (22.3 g, 99.9 mmol) in DMF (150 ml) was added potassium carbonate (19.3 g, 139.9 mmol). 2-Chloro-N,N-dipropyl-acetamide (17.7 g, 99.9 mmol) was added over 30 min, and the reaction mixture was heated to 60° C. and stirred for 2.5 h. The reaction mixture was allowed to cool to RT and diluted with water (500 ml) and extracted with isopropyl acetate (total 500 ml). The combined organic phases were washed with water (3×200 ml) to afford a solution of 3-benzyloxycarbonylamino-propionic acid dipropylcarbamoylmethyl ester in isopropyl acetate which was not isolated further. LC-MS; 365.2 [M+H]+ Method (i)
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:12]1[CH:13]=[C:14]2[C@@:26]3([CH2:30][O:29][C:28]([NH2:31])=[N:27]3)[C:25]3[C:20](=[N:21][CH:22]=[C:23]([CH2:32][O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:24]=3)[O:19][C:15]2=[CH:16][C:17]=1[F:18].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.CCOC(C)=O>[C:34]([O:33][CH2:32][C:23]1[CH:24]=[C:25]2[C@:26]3([CH2:30][O:29][C:28]([NH2:31])=[N:27]3)[C:14]3[C:15](=[CH:16][C:17]([F:18])=[C:12]([C:7]4[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=4)[CH:13]=3)[O:19][C:20]2=[N:21][CH:22]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)OCc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)c(F)cc1O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OCc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3F)c(F)cc1O2
Temperature: 100 °C
Yield: 41.8 %

Procedure:
A solution of pd(Ph3P)4 (0.019 g, 0.017 mmol), 2-fluoropyridin-3-ylboronic acid (0.047 g, 0.34 mmol), (S)-7-bromo-3-(tert-butoxymethyl)-8-fluoro-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.073 g, 0.17 mmol), and potassium carbonate (0.12 g, 0.84 mmol) in 1 mL dioxane, was treated with 0.4 mL water and was heated to 100° C. overnight. The reaction mixture was diluted with EtOAc, dried over MgSO4, and concentrated. Purification of the crude residue by column chromatography [0-100% (9:1 DCM:MeOH)/DCM] gave (4′S)-3-(tert-butoxymethyl)-8-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.032 g, 0.071 mmol, 42.3% yield). [M+H]+=453.0
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([OH:29])[CH:23]=[CH:22]2.O>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH:23]=[CH:22]2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc(Oc3ccc([N+](=O)[O-])cc3)ccc2c1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 6-methoxy-2-naphthol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100 mL), extracted with EtOAc (2×50 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(6-methoxy-naphthalen-2-yloxy)-1-nitrobenzene. The crude product was used for further transformation.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Cl:25][CH2:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[N:31]=1)=[O:28]>CC#N>[Cl-:25].[CH3:36][C:32]1[N:31]=[C:30]([NH:29][C:27]([CH2:26][N+:1]23[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]2)[C@@H:3]([O:9][C:10]([C:12]2([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:2]3)=[O:28])[CH:35]=[CH:34][N:33]=1
Reactant: Cc1nccc(NC(=O)CCl)n1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: Cc1nccc(NC(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)C2(c4ccccc4)CCCCCC2)C3)n1
Product: [Cl-]
Yield: 37 %

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e, 0.29 mmol) and 2-chloro-N-(2-methyl-pyrimidin-4-yl)-acetamide (Example 58a) (0.35 mmol) in MeCN (2.0 mL) were stirred together at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue purified by silica gel chromatography eluting with 0-10% MeOH/dichloromethane to give the title compound as a white solid (55 mg).
Reaction SMILES: Cl.[CH2:2]([O:4]N)[CH3:3].[OH-].[Na+].O1CCOCC1.[Cl:14][C:15]1[CH:16]=[C:17]([C:22]2([C:41]([F:44])([F:43])[F:42])[O:26][N:25]=[C:24]([C:27]3[CH:39]=[CH:38][C:30]([C:31]([N:33]=[CH:34][N:35](C)C)=[O:32])=[C:29]([CH3:40])[CH:28]=3)[CH2:23]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1>O.C(O)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([C:22]2([C:41]([F:44])([F:43])[F:42])[O:26][N:25]=[C:24]([C:27]3[CH:39]=[CH:38][C:30]([C:31]([NH:33][CH:34]=[N:35][O:4][CH2:2][CH3:3])=[O:32])=[C:29]([CH3:40])[CH:28]=3)[CH2:23]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: CCON
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N=CN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: CCON=CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Yield: 68.6 %

Procedure:
in a solution of 0.25 g of ethoxyamine hydrochloride in 4 mL of water and 8 mL of acetic acid, a solution of 0.20 g of sodium hydroxide in 4 mL of water was added, and then 5 mL of 1,4-dioxane solution of 0.62 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-N-(dimethylaminomethylidene)-2-methyl benzamide synthesized in Synthetic Example 30 was added dropwise at room temperature with stirring. After the completion of the addition dropwise, it was continued to stir at the same temperature further for 2 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, 50 mL of ethyl acetate was added in the residue, and washed with water. The organic phase was dehydrated with and dried over saturated sodium chloride and then anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (2:3) to obtain 0.44 g of the aimed product as white crystal.
Reaction SMILES: Cl.N[OH:3].[C:4]([C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[C:11]([C:21]([N:23]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:24]2[CH2:29][C@@H:28]([C:30]3[N:31]=NN[N:34]=3)[CH2:27][N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:25]2)=[O:22])=[CH:10][N:9]=1)([CH3:7])([CH3:6])[CH3:5].C1[CH2:50][O:49]CC1>CO.C(N(CC)CC)C.O>[C:4]([C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[C:11]([C:21]([N:23]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:24]2[CH2:29][C@@H:28]([C:30]3[NH:31][C:50](=[O:49])[O:3][N:34]=3)[CH2:27][N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:25]2)=[O:22])=[CH:10][N:9]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](c2nn[nH]n2)CN(C(=O)OC(C)(C)C)C1
Reactant: C1CCOC1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](c2noc(=O)[nH]2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (35 mg) was dissolved in THF (3 ml)-methanol (3 ml), triethylamine (0.07 ml) was added, and the mixture was stirred at room temperature for 1 hr. A solution of tert-butyl (3S*,5R*)-3-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-(2H-tetrazol-5-yl)piperidine-1-carboxylate (120 mg) in THF (3 ml) was further added, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, and diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 ml). 1,1′-Carbonylbis(1H-imidazole) (72 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.066 ml) were added and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with 0.5 M hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography. The fraction eluted with ethyl acetate-hexane (10:95) to ethyl acetate was concentrated under reduced pressure to give the object compound (26.1 mg).