Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:7][C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2.[CH3:13]I>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH3:13][O:12][C:6]1[CH:5]=[CH:4][C:3]2[C:2](=[O:1])[CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=1
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(n1)CCCC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.3 %

Procedure:
A mixture of compound 5 (8.2 g, 50 mmol) prepared as described in Example 1, methyl iodide (15.7 mL, 250 mmol), and silver carbonate (8.3 g, 30 mmol) in 150 mL of chloroform was stirred in a flask at room temperature for 48 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo, and purified by column chromatography (elution with hexanes-ethyl acetate 3:1) to give compound 8 (7.2 g, 81%) as a light yellow solid, mp 101-102° C. 1H NMR (CDCl3): δ 2.15 (quin, J=6.4 Hz, 2H), 2.62 (t, J=6.6 Hz, 2H), 3.01 (t, J=6.2 Hz, 2H), 3.99 (s, 3H), 6.65 (d, J=8.7 Hz, 1H), 8.15 (d, J=8.7 Hz, 1H); 13C NMR (CDCl3): δ 22.01, 32.49, 38.20, 53.89, 109.83, 122.73, 137.62, 163.89, 166.11, 197.08. FABMS: m/e 178 (M+1, 100), 154 (16), 137 (16). Analysis: Calcd. for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.94; H, 6.36; N, 7.91.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[NH:14][C:15]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39].CO>CN(C)C1C=CN=CC=1.ClCCl>[C:38]([O:30][C:5]1[C:6]([CH2:27][CH2:28][CH3:29])=[C:7]([CH:25]=[CH:26][C:4]=1[C:1](=[O:3])[CH3:2])[O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[NH:14][C:15]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:40])[CH3:39]
Reactant: CCCc1c(OCCCSc2nc3ccc(C(=O)O)cc3[nH]2)ccc(C(C)=O)c1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCCc1c(OCCCSc2nc3ccc(C(=O)O)cc3[nH]2)ccc(C(C)=O)c1OC(C)=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 58.2 %

Procedure:
A mixture of 2-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio]benzimidazole-5-carboxylic acid (1.50 g), triethylamine (4 ml), acetic anhydride (4 ml) and 4-dimethylaminopyridine (100 mg) in dichloromethane (50 ml) was stirred at 0 ° C. and then at room temperature for 5 hours. Methanol (4 ml) was added to the mixture, further stirred for an additional 30 minutes and then the mixture was evaporated. The residue was washed with water, dissolved in ethanol, and concentrated to dryness. The residue was purified by silica gel column chromatography, eluting with dichloromethane-ethyl acetate-methanol (10:2:1), and recrystallized from n-hexane-chloroform to give the title compound (970 mg, 58.2%) as yellow crystals, mp 85-87 ° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.[C:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)([CH3:17])=[CH2:16]>Cl.NC1C=CC=CC=1>[OH:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)([CH3:17])[CH3:16])=[CH:19][CH:20]=1
Reactant: Nc1ccccc1
Reactant: C=C(C)c1ccc(O)cc1
Agent: Cl
Solvent: Oc1ccccc1
Product: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Reaction time: 3 h
Yield: 87 %

Procedure:
Aniline (18.6 g) and 34.4 g of the same mixture of alkenylphenols and phenol as used in Example 7 were stirred at 150° C. (2 moles of aniline per mole of the p-isopropenyl phenol monomeric unit). Then, 0.0065 g of aniline hydrochloride (0.0005 mole of catalyst per mole of the p-isopropenyl phenol monomeric unit) was added as a catalyst, and the reaction was performed for 3 hours. After the reaction, the reaction mixture was analyzed by gas chromatography. It was found that 19.7 g (yield 87%) of 2-(4'-hydroxyphenyl)-2-(4'-aminophenyl)-propane and 0.24 g of bisphenol A were formed.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:29])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:33]=[C:34]([B:38]([OH:40])[OH:39])[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:29])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:31][C:32]2[CH:33]=[C:34]([B:38]([OH:40])[OH:39])[CH:35]=[CH:36][CH:37]=2)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OB(O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(C[C@@H](c1ccc(OCc2cccc(B(O)O)c2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 48 h
Yield: 17.7 %

Procedure:
The phenol (7.5) (400 mg, 1.02 mmol) and 3-(bromomethyl)phenylboronic acid (219 mg, 1.02 mmol) were dissolved in DMF (10 mL). Cesium carbonate (664 mg, 2.04 mmol) was added to the mixture, and the slurry was stirred for 48 hours. The reaction was then diluted with water and extracted with EtOAc (2×100 mL). The organic layers were combined and washed with a 1 M lithium chloride solution (1×50 mL) and brine (1×50 mL), and dried over magnesium sulfate. The filtrate was concentrated, and the residue was purified by medium pressure chromatography (silica gel, 30 to 100% EtOAc:hexanes) to give 34.1 (95.0 mg). MS ESI (pos.) m/e: 527.2 (M+H).
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4](=[O:12])[O:3]1.[CH:13]1[CH:18]=[CH:17][C:16]([C@H:19]([NH2:22])[CH2:20]O)=[CH:15][CH:14]=1.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:11][C:8]1[CH:9]=[C:10]2[C:5]([C:4](=[O:12])[N:22]3[CH:19]([C:16]4[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=4)[CH2:20][O:3][CH:2]32)=[CH:6][CH:7]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: Cc1ccc2c(c1)C(O)OC2=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc2c(c1)C1OCC(c3ccccc3)N1C2=O
Temperature: 25 °C

Procedure:
3-hydroxy-5-methyl-3H-isobenzofuran-1-one (4.66 g, 28.39 mmol) and H-phenylglycinol (3.89 g, 28.39 mmol) was taken up in dry toluene and heated to reflux under argon for 12 h. The water generated was collected in a Dean-Stark trap. The reaction mixture was cooled to room temp and poured into 1N HCl and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (4:1 hexane/ethyl acetate) Yield 5.20 g.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[CH2:18][OH:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=2)=[CH:13][C:12]=1[CH2:18][OH:19]
Reactant: O=Cc1ccc(Cl)nc1
Reactant: OCc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(Br)c(CO)c2)nc1
Yield: 68.4 %

Procedure:
Coupling reaction of 6-chloronicotinaldehyde (5.4 g, 38.15 mmol) and 4-bromo-3-(hydroxymethyl)phenol (8.15 g, 38.15 mmol) in the presence of K2CO3 (8.5 g, 1.5 eq) in DMF (100 mL) for 2 h at 100° C. under N2 gave the desired 6-(4-bromo-3-(hydroxymethyl)phenoxy)nicotinaldehyde (8.03 g, 26.1 mmol, yield 68.3%) as a white solid after silica gel column purification (hexane:EtOAc=3:1, v/v).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[C:15]([S-:17])#[N:16].[K+].BrBr>CC(O)=O>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]2[N:13]=[C:15]([NH2:16])[S:17][C:11]=2[CH:12]=1)[CH3:6])[CH3:2]
Reactant: N#C[S-]
Reactant: CCOC(=O)C(C)c1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)C(C)c1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3 (3.13 g, 1 mmol) in CH3COOH (15 ml) was cooled to −5° in iced bath. A mixture KSCN (6.36 g, 4.04 mmol) in CH3COOH (15 ml) added to the flask that contained 4 and CH3COOH at −5° in iced bath. A solution of bromine (0.80 ml) in CH3COOH (10 ml) is added dropwise to a stirred mixture of 4, KSCN and CH3COOH at −5° in iced bath. The reaction mixture is stirred for 1 h at room temperature. The mixture is extracted with ethyl acetate. The extracts are washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (n-Hexane:EtOAc).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:7]([O:9][CH3:10])=[O:8])([O-])=O>[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Zn]
Product: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(N)c1

Procedure:
The title compound was prepared from the methyl 3-nitro-4-((tert-butoxycarbonyl)amino)benzoate (Example A4; 3 mmol) by reduction with zinc according to the general procedure B. Obtained as a yellow solid (71%), MS (EI) 267 [(M+1)+].
Reaction SMILES: [CH3:1][C:2](=[CH2:56])[C:3]([NH:5][C:6]1[N:7]=[C:8]([CH2:53][CH2:54][CH3:55])[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:4].Cl.C(O)C>>[CH3:56][C:2](=[CH2:1])[C:3]([NH:5][C:6]1[N:7]=[C:8]([CH2:53][CH2:54][CH3:55])[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:30][N:31]=[N:32][N:33]=3)=[CH:19][CH:18]=2)[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:4]
Reactant: C=C(C)C(=O)Nc1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1C(=O)OCC
Agent: Cl
Solvent: CCO
Product: C=C(C)C(=O)Nc1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1C(=O)OCC
Temperature: 90 °C
Reaction time: 4 h
Yield: 42.2 %

Procedure:
To 250 mg of ethyl 4-[N-(2-methylacryloyl)amino]-2-n-propyl-1-[[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate was added 10 mL of 2N-HCl-ethanol (1:1) and the mixture was stirred at an external temperature of 90° C. for 4 hours. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (chloroform-methanol=20:1) and recrystallized from acetonitrile to provide 71 mg of ethyl 4-[N-(2-methylacryloyl)amino]-2-n-propyl-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylate (yield 42%).
Reaction SMILES: [CH:1]([N:4]([CH2:8]C)[CH:5](C)C)(C)C.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:38])[CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[C:28]2[C:29]([NH:33][CH2:34][CH2:35][C:36]#[N:37])=[N:30][O:31][N:32]=2)=[CH:13][CH:12]=1.P(Cl)(Cl)(Cl)=O.[Cl-].[NH4+]>CN(C)C=O>[C:36]([CH2:35][CH2:34][NH:33][C:29]1[C:28]([C:20]2[N:19]([CH2:18][C:17]([C:14]3[CH:13]=[CH:12][C:11]([N:10]=[CH:1][N:4]([CH3:8])[CH3:5])=[CH:16][CH:15]=3)=[O:38])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=2)=[N:32][O:31][N:30]=1)#[N:37]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#CCCNc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(N)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=Nc1ccc(C(=O)Cn2c(-c3nonc3NCCC#N)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 0.05 ml N,N-diisopropylethylamine in 1 mL of N,N-dimethylformamide is slowly added to a solution of 116 mg (0.3 mmol) 3-(4-{1-[2-(4-amino-phenyl)-2-oxo-ethyl]-1H-benzoimidazol-2-yl}-furazan-3-ylamino)-propionitrile and 459 mg (0.3 mmol) phosphorus oxychloride in 3 mL of N,N-dimethylformamide at −10° C. After the addition, the mixture is allowed to warm to room temperature and stirred for three days. Then, saturated aqueous ammoniumchloride solution is added and the reaction mixture is extracted with dichloromethane. A precipitate is formed in the dichloromethane phase. This precipitate is collected by filtration, washed with water and dichloromethane, and dried under reduced pressure. The residue is solved in acetonitrile and the solution is added to a 2 N solution of sodium hydroxide in water at 0° C. The resulting pH value is above 11. The mixture is stirred at room temperature for 1 h. The formed precipitate is collected by filtration, washed with water and acetonitrile, and dried under reduced pressure to provide 89 mg of the desired product.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)[CH2:7][CH3:8].[I:17]I.C(=O)(O)[O-].[Na+]>CCCCCC.O1CCCC1>[CH2:6]([C:9]1[CH:10]=[C:11]([F:16])[C:12]([I:17])=[C:13]([F:15])[CH:14]=1)[CH2:7][CH3:8]
Reactant: CCCc1cc(F)cc(F)c1
Reactant: II
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCc1cc(F)c(I)c(F)c1
Temperature: 25 °C

Procedure:
22 ml of a 1.6N butyllithium solution in hexane were added dropwise during 30 min. to a solution of 5 g of 1-propyl-3,5-difluorobenzene in 50 ml of dry tetrahydrofuran at -70° C. and left to react at -70° C. for 1 hour. Then, a solution of 8.95 g of iodine in 20 ml of dry tetrahydrofuran was added dropwise at -60° within 10 minutes and the mixture was gradually warmed to room temperature within a further 30 minutes. The resulting yellow solution was then treated with 40 ml of a 10 percent aqueous sodium bicarbonate solution and extracted with ether. The ether solution was washed with saturated sodium chloride solution and several times with water, dried over magnesium sulphate, filtered and concentrated. Chromatography of the residue over 200 g of silica gel with hexane gave 1-propyl-3,5-difluoro-4-iodobenzene as a colourless liquid.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([NH2:14])=O)[CH:10]=[CH:11][C:6]=2[O:5][CH:4]([C:15]([Cl:18])([Cl:17])[Cl:16])[NH:3]1.S(Cl)(Cl)=O>>[O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:14])[CH:10]=[CH:11][C:6]=2[O:5][CH:4]([C:15]([Cl:18])([Cl:16])[Cl:17])[NH:3]1
Reactant: NC(=O)c1ccc2c(c1)C(=O)NC(C(Cl)(Cl)Cl)O2
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc2c(c1)C(=O)NC(C(Cl)(Cl)Cl)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,4-Dihydro-4-oxo-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazine-6-carboxamide (prepared as described in Example 10--1.0 g.) and thionyl chloride (20 ml.) were heated together under reflux for 1 hour, cooled to room temperature, and drowned into ice-water (200 ml.). After stirring for 1 hour, the white suspension so formed was filtered off, washed with water, dried at 60° C. and extracted with toluene (3×200 ml.). The toluene extracts were combined, and the solvent was evaporated to give 3,4-dihydro-4-oxo-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazine-6-carbonitrile, m.p. 212°-214° C.
Reaction SMILES: C(#N)C.[CH2:4]([C:6]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[C:17]([CH2:19][O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]([NH:31]C(=O)OC(C)(C)C)=[CH:23][CH:22]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=[N:8][CH:7]=1)[CH3:5].S(=O)(=O)(O)O.N>O>[NH2:31][C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:20][CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:10]3[CH:9]=[N:8][CH:7]=[C:6]([CH2:4][CH3:5])[N:11]=3)[CH:18]=2)=[CH:22][CH:23]=1
Reactant: CCc1cncc(Nc2cc(COc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)ccn2)n1
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: CCc1cncc(Nc2cc(COc3ccc(N)c4ccccc34)ccn2)n1
Temperature: 20 °C
Yield: 75 %

Procedure:
Acetonitrile (200 mL) was added to tert-butyl (4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)carbamate (Intermediate D (protected)) (10.5 g) and the heterogeneous mixture was stirred at 20° C. Sulfuric acid (4.5 eq, 5.5 mL) was added over 2 h at 20° C. The heterogeneous mixture was stirred for an additional 2 h at 20° C. Aqueous ammonia (10 eq, 17 mL) was added to the reaction mixture over 15 min and the temperature was kept at 20° C. by cooling. Water (33.4 mL) was added to the heterogeneous mixture over 5 min at 20° C. After stirring for 30 min at 20° C., the mixture was cooled to 5° C. and stirred for an additional 2 h at 5° C. The precipitate was filtered and washed with water (33.4 mL) and 2-propanol (18 mL). The product was dried at 50° C. in vacuo for 24 h to give N-(4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)-6-ethylpyrazin-2-amine (6.2 g, 75%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:28]=[C:29]1[O:33][C:31](=[O:32])[CH2:30]1>C1(C)C=CC=CC=1>[O:33]=[C:29]([CH3:28])[CH2:30][C:31]([O:20][CH:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:32]
Reactant: C=C1CC(=O)O1
Reactant: OC(COCc1ccccc1)COCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OC(COCc1ccccc1)COCc1ccccc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
1.00 g (3.67 mmol) 1,3-dibenzyloxy-2-propanol is dissolved in 10 ml toluene, 3.72 mg (0.04 mmol) triethylamine are added, and the mixture is stirred at 90° C. 401 mg (4.77 mmol) diketene are added, and stirring is continued for 1 h. The mixture is cooled to room temperature, diluted with ice-water and extracted with toluene. The organic layer is dried over magnesium sulfate and evaporated to dryness. The crude product is purified by column chromatography on silica gel (eluent: cyclohexane/ethylacetate 2:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[N:10]=[N:9][C:8]([C:11]2[S:15][C:14](Br)=[N:13][CH:12]=2)=[N:7]1)[CH3:2].[O:18]1[C:22]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[N:10]=[N:9][C:8]([C:11]2[S:15][C:14]([N:25]3[CH2:26][CH2:27][C:22]4([O:21][CH2:20][CH2:19][O:18]4)[CH2:23][CH2:24]3)=[N:13][CH:12]=2)=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1nnc(-c2cnc(Br)s2)n1
Reactant: C1CC2(CCN1)OCCO2
Product: CCOC(=O)Cn1nnc(-c2cnc(N3CCC4(CC3)OCCO4)s2)n1

Procedure:
The title compound was prepared in a similar manner as that described for Example 13 (step 1) from Intermediate 2 and 1,4-dioxa-8-azaspiro[4.5]decane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].S(Cl)([Cl:19])(=O)=O>C(OCC)C>[Cl:19][CH:9]([C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1F
Yield: 97.2 %

Procedure:
Using ethyl 3-(2-fluorophenyl)-3-oxopropanoate (1.0 g, 4.75 mmol), sulfuryl chloride (771 mg, 5.7 mmol) and diethyl ether (50 mL) as starting materials and in the same manner as in Example 20(i), the title compound (1.13 g, 97%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].C(#N)C>C(OC)(C)(C)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C@@:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19]
Reactant: COc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21
Solvent: COC(C)(C)C
Solvent: CC#N
Product: COc1cc2c(cc1C)[C@]1(CO2)C(=O)Nc2ccccc21

Procedure:
6-Methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (2.16 g, 0.10 g per run) was resolved on a semi-prep chiral IA column with 10% acetonitrile in tert-butyl methylether. (R)-6-methoxy-5-methyl-2H-spiro[benzofuran-3,3′-indolin]-2′-one was isolated as a crystalline colorless solid (0.81 g, 75% recovery): ee>99% (analytical chiralpak IA, 1:1 acetonitrile/tert-butyl methylether); mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ10.57 (s, 1H), 7.23 (ddd, J=7.6, 7.6, 1.3 Hz, 1H), 7.07 (d, J=6.8 Hz, 1H), 6.99-6.89 (m, 1H), 6.61 (s, 1H), 6.45 (s, 1H), 4.81-4.74 (m, 1H), 4.64 (d, J=9.2 Hz, 1H), 3.77 (s, 1H), 1.95 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ179.2, 160.4, 158.9, 142.2, 133.4, 129.1, 124.4, 124.2, 122.7, 120.3, 118.4, 110.2, 94.3, 80.1, 58.0, 56.0, 16.0; MS (ES+) m/z 282.1 (M+1).
Reaction SMILES: CC([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:25][C@H:24]([CH2:26][N:27]=[N+]=[N-])[O:23][C:22]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:10][CH2:9]1)=[O:7])(C)C>[Pd].CO>[C:14]1([CH2:11][O:5][C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:19]([F:20])=[CH:18][C:17]([N:21]4[CH2:25][C@H:24]([CH2:26][NH:27][C:24](=[O:23])[CH3:25])[O:23][C:22]4=[O:30])=[CH:16][C:15]=3[F:31])[CH2:10][CH2:9]2)=[O:7])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(F)cc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(C3CCN(C(=O)OCc4ccccc4)CC3)c(F)c2)C(=O)O1
Reaction time: 18 h

Procedure:
A mixture of (R)-(−)-4-[4-[5-(azidomethyl)-2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester ((EXAMPLE 35, Step 6, 1.51 g) and 10% palladium on carbon (367 mg) in methanol (35 mL) is stirred under a hydrogen atmosphere (balloon) for 18 hours, the catalyst is removed by filtration through Celite and the filtrate is concentrated under reduced pressure to give the 5-aminomethyl-2-oxazolidinone intermediate (Rf=0.10 by TLC, methanol/chloroform, 5/95). A solution of this intermediate (1.28 g) and pyridine (2.51 mL) in dry methylene chloride (31 mL) at 0° C. under N2 is treated with acetic anhydride (1.47 mL), and the resulting solution is allowed to warm to ambient temperature with stirring over 1.5 hours. The mixture is then diluted with methylene chloride (15 mL), washed with water (10 mL), saturated aqueous sodium bicarbonate (2×10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (70-230 mesh, 150 g), eluting with a gradient of methanol/methylene chloride (1/99-4/96). Pooling and concentration of those fractions with an Rf=0.31 by TLC (methanol/chloroform, 5/95), trituration with diethyl ether and filtration gives the title compound, NMR (CDCl13, 400 MHz) 7.06, 6.56, 4.78, 4.22, 4.00, 3.74, 3.65, 3.05, 2.75, 2.02, 1.96, 1.64, 1.47δ.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:8](NCCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(C1C=CC=CC=1)C1C=CC=CC=1)C2)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[Cl-].[NH2:47][CH:48]([CH3:75])[CH2:49][N+:50]12[CH2:57][CH2:56][CH:53]([CH2:54][CH2:55]1)[C@@H:52]([O:58][C:59](=[O:74])[C:60]([OH:73])([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH2:51]2>>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:8]([NH:47][CH:48]([CH3:75])[CH2:49][N+:50]12[CH2:57][CH2:56][CH:53]([CH2:54][CH2:55]1)[C@@H:52]([O:58][C:59](=[O:74])[C:60]([OH:73])([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[CH2:51]2)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(NCCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2)c1ccccc1
Reactant: CC(N)C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Agent: [Cl-]
Product: CC(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2)NC(=O)c1ccccc1

Procedure:
This compound is prepared analogously to (R)-1-(3-benzoylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octane trifluoroacetate [Example 2] but by replacing (R)-1-(3-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane chloride hydrochloride [Example 1(ii)] with (R)-1-((R/S)-2-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azoniabicyclo[2.2.2]octane chloride hydrochloride.