Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C(N(CC)CC)C>C(O)C>[CH2:2]([O:4][C:5]([CH2:6][NH:7][CH2:11][CH2:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[O:8])[CH3:3]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNCC(=O)OCC
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 66.6 %

Procedure:
150 g of glycine ethyl ester hydrochloride (1.07 mol) was mixed with 1.200 L of ethanol. To this mixture, 110 mL of ethyl acrylate (1.02 mol) was added at an internal temperature of 2 to 25° C. 150 mL of triethylamine (1.08 mol) was then added dropwise at an internal temperature of 20 to 21° C. over 5 minutes. Subsequently, the mixture was stirred at an internal temperature of 23 to 27° C. for 8.5 hours and was allowed to stand overnight. The insoluble material was separated by filtration and the filtrate was evaporated under reduced pressure. 300 mL of ethyl acetate was added to the resulting residue and the insoluble material was separated by filtration and washed with 50 mL of ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure. The resulting residue was distilled under reduced pressure (533 Pa, 130° C.) to give 138 g of the title compound as a colorless oil (67% yield).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[ClH:15].Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:15].[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:26]3[CH2:25][CH2:24][N:23]([CH2:22][C:21]4[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:19]([O:18][CH3:17])[CH:20]=4)[CH2:28][CH2:27]3)=[O:14])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CN2CCN(C(=O)c3ccc4c(c3)CCCC4=O)CC2)cc(OC)c1OC
Yield: 75.1 %

Procedure:
Using 1-oxo-1,2,3,4-tetrahydro-6-naphthoic acid [Itoh et al., Chem. Pharm. Bull., 32, 130 (1984)] (0.8 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (2.25 g), triethylamine (1.7 g), N,N-dimethylformamide (10 ml) and diethyl phosphorocyanidate (1.6 ml), an amidation as that described in Example 6 is carried out. The product is purified by silica gel column chromatography (hexane:acetone=1:1), and converted to the hydrochloride in a mixture of ethanol, ethyl acetate and ethyl ether to give 1-(1-oxo-1,2,3,4-tetrahydro-6-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (1.5 g) as colorless crystals, m.p. 210°-215° C. (decomp.).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>CO>[CH2:3]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][OH:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCc1ccccc1CO
Reaction time: 0.5 h

Procedure:
0.57 g of sodium borohydride is added in portions, over a period of 15 minutes, to a stirred solution of 9.3 g of 2-nonylbenzaldehyde in 150 ml of methanol. After stirring for a further 30 minutes, the reaction mixture is concentrated by evaporation under reduced pressure and the residue is taken up in ether. The organic phase is washed with ice-cooled 0.2N hydrochloric acid and with water, dried over sodium sulphate and concentrated by evaporation in vacuo. Chromatographic purification of the residue on silica gel with mixtures of petroleum ether with an increasing amount of ether yields 2-nonylbenzyl alcohol in the form of a pale yellow oil.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1>O1CCCC1>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)Nc1ccc2ccc(Cl)nc2n1
Temperature: 60 °C
Yield: 33.9 %

Procedure:
Phenyl isocyanate (15.5 g) is added to a solution of 2-amino-7-chloro-1,8-naphthyridine (17.9 g) in anhydrous tetrahydrofuran (600 cc) and the mixture is heated for 15 hours at approximately 60° C. After cooling the mixture, the crystallized solid is separated by filtration, washed with ethyl ether (3×50 cc) and air-dried. A crude product (25.2 g), m.p. 270° C., is obtained. This product (15 g) is purified under the following conditions: the product is dissolved in a mixture of dimethylformamide (200 cc) and acetonitrile (125 cc). After cooling for 5 hours at 20° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×50 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-N'-phenylurea (10.1 g), m.p. 276° C., is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1.C[O-].C([Sn+](CCCC)CCCC)CCC.C([O:33][C:34]([CH3:36])=[CH2:35])(=O)C.[F-].[K+]>C1(C)C=CC=CC=1>[F:14][C:4]1[CH:3]=[C:2]([CH2:35][C:34](=[O:33])[CH3:36])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C(C)OC(C)=O
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Agent: CCCC[Sn+](CCCC)CCCC
Agent: C[O-]
Agent: [F-]
Solvent: Cc1ccccc1
Product: CC(=O)Cc1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15.0 g of 4-bromo-2-fluorobiphenyl, 25.8 ml of tributyltin methoxide, 8.96 g of isopropenyl acetate and 0.47 g of dichlorobis{tri(o-tolyl)phosphine}palladium, were dissolved in 100 ml of toluene and refluxed under heating for 2 hours. The reaction solution was left to cool to room temperature, and a saturated potassium fluoride aqueous solution was added, followed by stirring for one hour. Then the solution was subjected to celite filtration and washed with ethyl acetate. The filtrate and the washing liquid were put together. Then, the organic layer was separated and washed with a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1→5/1), followed by treatment with methylene chloride-hexane, to obtain 10.6 g of the above identified compound as yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][O:10][CH3:11])=[CH:4][CH:3]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][CH:24]1[CH2:26][O:25]1>>[OH:25][CH:24]([CH2:23][O:22][C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1)[CH2:26][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: c1ccc2cc(OCC3CO3)ccc2c1
Reactant: COC=Cc1ccc(Br)cc1
Product: COC=Cc1ccc(CC(O)COc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.8 %

Procedure:
By the method of example 48, 1-bromo-4-(2-methoxyethenyl)benzene (2.13 g) is lithiated and reacted with (2-naphthyloxymethyl)oxirane (2.0 g). The reaction mixture is allowed to warm to room temperature and stirred for 48 hr before quenching with saturated ammonium chloride. The product is extracted with ether, and the extract is dried and concentrated to leave 1-(2-hydroxy-3-(2-naphthyloxy)propyl)-4-(2-methoxyethenyl)benzene as a yellow oil (1.93 g). By the methods of example 1, this is converted into the title compound, which is obtained as a colorless solid, mp 175°-178° after recrystallization from hexane-ethyl acetate. This material is racemic at the propyl carbinol carbon, but substitution of a chiral form of the starting oxirane provides the title compound in chiral form.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl>[CH2:23]([O:22][C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CN1CCN(c2cccc3ccc(NC(=O)OCc4ccccc4)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.225 g, 0.933 mmol), benzyl chloroformate (0.147 mL, 1.03 mmol), and potassium carbonate (0.142 g, 1.03 mmol) were combined in a two phase mixture of methylene chloride (10 mL) and water (3 mL) and the mixture was stirred at room temperature overnight. Benzyl chloroformate (0.147 mL, 1.03 mmol) was added and the reaction was stirred 5 hours more. The reaction was diluted with methylene chloride and the phases were separated. The organic layer was washed with brine, dried over calcium sulfate and concentrated to a brown oil which was flash chromatographed on silica gel (1×4 inches). Gradient elution with ethyl acetate/hexane of from 50% to 100% followed by gradient ethanol/ethyl acetate elution of from 5% to 10% gave 0.29 g of a brown foam. This residue was recrystallized from ethyl acetate to give 0.095 g (27%) of the title product in two crops; mp 143°-144° C. Analysis calculated for C23H25N3O2 : C, 73.58; H, 6.71; N, 11.19. Found: C, 73.46; H, 6.71; N, 11.05.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[C:24]1(=[O:34])[O:29][C:27](=[O:28])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:23][O:22][C:10]1[CH:9]=[CH:8][C:7]2[CH2:20][C@H:19]3[N:2]([CH3:1])[CH2:3][CH2:4][C@:5]45[C:6]=2[C:11]=1[O:12][C@H:13]4[C:14](=[O:15])[CH2:16][CH2:17][C@@:18]35[O:21][C:24](=[O:34])[C:25]1[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:27]([OH:29])=[O:28]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(OC(=O)c5ccccc5C(=O)O)[C@@H](C2)N(C)CC[C@]314
Reaction time: 24 h
Yield: 35 %

Procedure:
A solution comprised of oxycodone free base, 1-1, (63 mg, 0.2 mmol), phthalic anhydride (1.185 g, 8.0 mmol) and DMAP (24 mg, 0.2 mmol) in 10 mL of pyridine was stirred in an oil bath at 50–55° C. for 24 h and concentrated under reduced pressure. The residue was subjected to silica gel flash chromatography with a 5%–20% methanol in dichloromethane gradient. The fraction containing 2-1 was collected and concentrated under reduced pressure. HPLC indicated that the fraction was 60% pure. The concentrated fraction was subjected to another silica gel flash chromatography using a gradient of 0–20% methanol in dichloromethane as eluent to yield a fraction containing 32 mg (35% yield) of 96% pure (HPLC) 2-1, which was further purified by HPLC. The 1H and 13C NMR spectra verified the structure of 2-1 as a hydrogen phthalate ester of the 14-hydroxyl group of oxycodone. (The absence of an 1H resonance in the region of 5.5–6 ppm for a C7 vinylic proton, and the presence of a 13C resonance at 207.5 ppm for the C6 carbonyl group excluded the presence of an enol ester linkage in 2-1.)
Reaction SMILES: [C:1]([C:3]1[CH:40]=[CH:39][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4C(OC(C)(C)C)=O)=[O:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)=O)N(COCC[Si](C)(C)C)C=2C=1)#N.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl-].[NH4+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CCOC(C)=O>[CH3:22][O:21][C:20]1[CH:19]=[C:18]([CH3:23])[C:17]2[NH:16][CH:15]=[CH:14][C:13]=2[C:12]=1[C:10]([C:8]1[NH:7][C:6]2[CH:39]=[CH:40][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)=[O:11]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=O)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=O)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C)c2[nH]ccc2c1C(=O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 65 °C

Procedure:
A mixture of tert-butyl 4-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (62 mg, 0.11 mmol) was dissolved in THF (1.1 mL) and then TBAF (1.1 mL, 1.1 mmol) was added and the reaction was heated at 65° C. for 17 hours. The mixture was then cooled to room temperature and treated with 10 mL of a saturated aq. solution of ammonium chloride and then diluted with EtOAc. The organic layer was separated and washed with water (3×100 mL). The organic extract was dried over magnesium sulfate and concentrated. The resulting residue was dissolved in MeOH (4 mL), cesium carbonate (48.9 mg, 0.15 mmol) was added and the reaction was heated at 60° C. for 1 h. The reaction was cooled to room temperature, a saturated aq. solution of ammonium chloride was added, followed by EtOAc. The organic layer was separated, washed with water and the organic extracts combined, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.73 (br. s., 1H) 11.33 (br. s., 1H) 8.29 (br. s.) 8.07 (br. s.) 7.60-7.90 (m, 2H) 7.45 (t, J=2.78 Hz, 1H) 6.89 (s, 1H) 6.42 (br. s., 1H) 3.56 (s, 3H) 2.54-2.63 (m, 3H). HRMS calcd. for C19H14N4O2 (M+H)+ 331.119. found 331.1202.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[S:26]1[CH2:30][CH2:29][C:28](=O)[CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:28]3[CH2:29][CH2:30][S:26][CH2:27]3)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Reactant: O=C1CCSC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCN(C3CCSC3)CC2)nc1
Temperature: 50 °C
Reaction time: 96 h
Yield: 77.3 %

Procedure:
A solution of 5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-acetic acid was treated with excess tetrahydrothiophen-3-one (1.07 mL, 12.5 mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 96 h, the mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-2 M ammonia in methanol afforded 0.43 g (77%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](C=C[CH:9]=[C:10]2[CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.C[O:20]C1C=CC2OC=C(CON)C=2C=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:20][CH:9]=[C:10]([CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17])[C:11]=2[CH:12]=1
Reactant: COc1ccc2cccc(CONC(C)=O)c2c1
Reactant: COc1ccc2occ(CON)c2c1
Product: COc1ccc2occ(CONC(C)=O)c2c1

Procedure:
By carrying out the procedure in the same manner as for the synthesis of the compound of Example 1, but replacing O-[(7-methoxynaphth-1-yl)methyl]hydroxylamine with O-[(5-methoxybenzofuran-3-yl)methyl]hydroxylamine (preparation 9), the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[C@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:27]2[C:23](=[O:33])[C:24]3[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:26]2=[O:28])[C@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(O)c2ccc(F)c(Cl)c2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](C(c2ccc(F)c(Cl)c2)N2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
To a solution of 69a/69b (364.3 mg, 1.105 mmol) in THF (5.5 mL, 0.2 M) under nitrogen was added phthalimide (178.8 mg, 1.215 mmol) and PPh3 (376.7 mg, 1.436 mmol). The reaction was cooled to 0° C. and diethyl azodicarboxylate (654.0 μL, 1.436 mmol) was added dropwise via syringe. The reaction was allowed to warm to RT and stirred for 16 h. The reaction was concentrated to dryness by rotovap, diluted to 30 mL with EtOAc and washed with water (2×30 mL) and brine (1×30 mL). The organics were isolated, dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with a hexanes/acetone gradient (5 to 70% acetone) to afford 212 mg (42%) of 71a/71b as a clear oil containing approximately a 1:1 mixture of diastereomers.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].[Cl:18][C:19]1[C:24]2[NH:25][C:26]([CH3:28])=[N:27][C:23]=2[CH:22]=[C:21]([O:29][C:30]2[CH:35]=[C:34](Cl)[N:33]=[CH:32][N:31]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:18][C:19]1[C:24]2[NH:25][C:26]([CH3:28])=[N:27][C:23]=2[CH:22]=[C:21]([O:29][C:30]2[N:31]=[CH:32][N:33]=[C:34]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:35]=2)[CH:20]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1nc2cc(Oc3cc(Cl)ncn3)cc(Cl)c2[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2cc(Oc3cc(N4CCC5(CC4)OC(=O)Nc4ncccc45)ncn3)cc(Cl)c2[nH]1

Procedure:
90 mg (0.35 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 110 mg (0.37 mmol) 7-chloro-5-(6-chloropyrimidin-4-yloxy)-2-methyl-1H-benzo[d]imidazole and 0.14 mL (0.81 mmol) DIPEA in 2.0 mL DMF were stirred for 3 h at RT and 4 h at 40° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]3([CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)[CH2:17][CH2:16]1)=[O:14])[CH:9]=[CH:8]2.C([O-])(O)=O.[Na+].[CH3:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([CH3:46])[C:39]=1[S:47](Cl)(=[O:49])=[O:48]>C1COCC1.O.C1COCC1.O>[CH3:45][O:44][C:42]1[CH:43]=[C:38]([CH3:37])[C:39]([S:47]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]3[C:11]=2[N:10]([CH2:12][C:13](=[O:14])[N:15]2[CH2:20][CH2:19][C:18]4([CH2:21][CH2:22][N:23]([C:26]5[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=5)[CH2:24][CH2:25]4)[CH2:17][CH2:16]2)[CH:9]=[CH:8]3)(=[O:48])=[O:49])=[C:40]([CH3:46])[CH:41]=1
Reactant: NCc1cccc2ccn(CC(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)c12
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)NCc2cccc3ccn(CC(=O)N4CCC5(CC4)CCN(c4ccncc4)CC5)c23)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
A mixture of 2-(7-(aminomethyl)-1H-indol-1-yl)-1-(9-(pyridin-4-yl)-3,9-diazaspiro-[5.5]undecan-3-yl)ethanone (220 mg, 0.53 mmol, 1.0 equiv.) and NaHCO3 (134 mg, 1.59 mmol, 3.0 equiv.) in THF-water(1:1, 20 ml) was added at 0° C. to a solution of 2,6-dimethyl-4-methoxyphenylsulfonyl chloride (136 mg, 0.58 mmol, 1.1 equiv.) in THF (5 ml), and the mixture was stirred for 16 h at RT. The reaction mixture was diluted with water (15 ml) and extracted with ethyl acetate (3×30 ml). The combined organic phases were washed with sat. NaCl solution (40 ml) and dried over Na2SO4. The solvent was removed under vacuum and the crude product was purified by column chromatography (silica gel; 6-8% MeOH/DCM), and the desired product was thus obtained in the form of a white solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][NH:10][OH:11].[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([N:23]=[C:24]=[O:25])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21].O>C(Cl)(Cl)Cl>[OH:11][N:10]([CH3:9])[C:24]([NH:23][C:16]1[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:14]([C:13]([F:26])([F:27])[F:12])[CH:15]=1)=[O:25]
Reactant: O=C=Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CNO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(O)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
24 ml of triethylamine were added over 5 minutes to a stirred mixture of 15 g of N-methylhydroxylamine hydrochloride in 100 ml of chloroform cooled to 0° C and then 37.5g of 3-trifluoromethyl-4-nitrophenyl isocyanate were added at 20° to 25° C. The mixture was stirred at 20° C for 16 hours and was then poured into water. The mixture was vacuum filtered and the recovered crystals were dried under reduced pressure. The raw product was taken up in hot isopropyl ether and the solution was treated with activated carbon and was evaporated to dryness under reduced pressure to obtain 20 g of N-hydroxy-N-methyl-N'-(3'-trifluoromethyl-4'-nitrophenyl)-urea melting at 129°-130° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]2=[O:16])=[CH:6][CH:5]=1)(O)=[O:2].C(Cl)(=O)C([Cl:20])=O>C1C=CC=CC=1>[C:14]1(=[O:15])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([Cl:20])=[O:2])=[CH:5][CH:6]=2)[C:11](=[O:16])[CH:12]=[CH:13]1
Reactant: O=C(O)c1ccc(N2C(=O)C=CC2=O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(N2C(=O)C=CC2=O)cc1

Procedure:
Para-maleimidobenzoyl chloride was prepared in accordance with the procedure described by Adams et al. in J. Am. Chem. Soc., 42, 599 (1920). The N-(para-carboxyphenyl) maleimide (15 g) was suspended in about 80 ml of benzene with stirring. To this mixture was added 15 ml (a 2.5:1 molar excess) of oxalyl chloride, whereupon some gas was evolved. The mixture was then heated slowly to reflux and maintained at reflux for two hours. Excess oxalyl chloride was removed by distillation. The reaction mixture was then cooled and the yellow product recovered by suction filtration. The resultant product was washed with hexane and dried under vacuum at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C:9]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][S:11][C:10]=3[CH2:14][OH:15].Cl.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26]Cl>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C:9]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][S:11][C:10]=3[CH2:14][O:15][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23]
Reactant: CN(C)CCCl
Reactant: OCc1scc2c1-c1ccccc1Oc1ccc(Cl)cc1-2
Agent: Cl
Product: CN(C)CCOCc1scc2c1-c1ccccc1Oc1ccc(Cl)cc1-2

Procedure:
Starting from the alcohol 13 (0.29 mmole) and 2-dimethylaminoethylchloride-hydrochloride (2.9 mmoles), an oily product was obtained.