Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.6 %

Procedure:
To 10 mL of a methylene chloride solution containing 280 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 150 mg of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde, 0.05 mL of acetic acid was added, and stirred at room temperature for 1.5 hours. To the reaction mixture, 280 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=5:1] to give 233 mg of 7-methoxy-1-(2-(4-((3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:30]([OH:32])=[O:31])=[C:19]([C:20]3[NH:21][C:22](=[O:29])[C:23]([CH:26]([CH3:28])[CH3:27])([CH3:25])[N:24]=3)[C:14]=2[N:13]=[C:12]1[CH3:33])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC.CO>[CH2:4]([N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:30]([O:32][CH3:3])=[O:31])=[C:19]([C:20]3[NH:21][C:22](=[O:29])[C:23]([CH:26]([CH3:28])[CH3:27])([CH3:25])[N:24]=3)[C:14]=2[N:13]=[C:12]1[CH3:33])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=[N+]=[N-]
Reactant: Cc1nc2c(C3=NC(C)(C(C)C)C(=O)N3)c(C(=O)O)ccc2n1Cc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1ccc2c(nc(C)n2Cc2ccccc2)c1C1=NC(C)(C(C)C)C(=O)N1
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
A solution of diazomethane in ether is added to a suspension of 1-benzyl-4-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-2-methyl-5-benzimidazolecarboxylic acid (1.15 g, 2.84 mmol) in methanol until the yellow color persists The reaction is stirred for 5 minutes, quenched with 2 drops of acetic acid and concentrated in vacuo. The resultant residue is purified by HPLC (silica gel, ethyl acetate eluent) to give the title product as a white powder (0.480 g, 40.3%), mp 194°-196° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].O.O.[OH-].[Li+].Cl>O1CCOCC1.CO>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)O)CC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
To a solution of 4-benzylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (1.772 g, 5.315 mmol) in dioxane (24 ml), methanol (12 ml), and water (12 ml) at room temperature was added lithium hydroxide monohydrate (4.460 g, 106.292 mmol). After stirring at 50° C. for 2 days the solution was acidified to pH 6 using 2M HCl and the resulting white precipitate extracted with diethyl ether (2×100 ml). The organic phases were combined, dried over sodium sulphate and concentrated to dryness to give the acid as a white solid (1.477 g, 87%). LC/MS (LCT): Rt 7.37 [M+H]+ 319.
Reaction SMILES: O.C(=O)(O)[O-:3].[Na+].[C:7]([O:12][CH2:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])Cl)(=[O:11])[C:8]([CH3:10])=[CH2:9]>C(OCC)C>[C:7]([O:12][CH2:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[OH:3])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: O=C([O-])O
Reactant: C=C(C)C(=O)OCCC[Si](C)(C)Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: C=C(C)C(=O)OCCC[Si](C)(C)O

Procedure:
After 60 mL of water, 60 ml of diethyl ether, and 7 g (83 mmol) of sodium bicarbonate had been placed into a four-necked flask, the temperature was lowered to 0° C. Next, 15 g (68 mmol) of 3-methacryloxypropyldimethylchlorosilane were added dropwise into the resulting mixture, which was being agitated, via a dropping funnel. After the reaction had been completed, the ether layer was separated and then washed with water once. After the ether had subsequently been distilled and removed at room temperature and reduced pressure, 3-methacryloxypropyldimethylsilanol (hereafter, "MPOH") was obtained. The structure of said compound was verified by gas chromatographic analysis (GLC) and nuclear magnetic resonance analysis (NMR).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:21][N:22]=[C:23]=[O:24].CCCC[Sn](O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC>O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][O:17][C:23](=[O:24])[NH:22][CH3:21])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CN=C=O
Reactant: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CNC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
In dry tetrahydrofuran (6 ml)was dissolved 0.300 g (0.91 mmol)of [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methanol (Compound I-8)and 0.48 ml (8.15 mmol) of methylisocyanate. To this solution was added 0.04 ml of bis(tributyltin)oxide, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was fractionated by silica gel chromatography (acetone:methylene chloride=1:4), and recrystallized from isopropyl ether to obtain 0.345 g of (Compound I-43)(yield 98%). mp 112-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:25][O:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][CH3:25])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COc1ccccc1N
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: CCOCC
Product: COc1ccccc1Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Temperature: 175 °C

Procedure:
A mixture of 0.113 g (0.29 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.50 g (4.10 mmol) of 2-methoxyaniline was heated, with stirring, in a 175° C. oil bath. The resulting solution was heated for 5 minutes and cooled to room temperature. Ether (2 mL) was added. The crystals that developed were filtered and washed with 1 mL of ether; wt 0.070 g. The solid was purified to remove dark colors by silica gel chromatography, eluting with chloroform. Recrystallization from ether gave pure product; wt 0.029 g; mp 200°-201° C.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C([Li])CCC.[CH3:15][C:16]([CH3:18])=[O:17]>C1(C)C=CC=CC=1>[Br:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([C:16]([OH:17])([CH3:18])[CH3:15])=[N:3][CH:4]=1
Reactant: Fc1cc(Br)cnc1Br
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(O)c1ncc(Br)cc1F
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To 2,5-dibromo-3-fluoropyridine in toluene at −78° C. was added n-butyllithium drop wise. The resulting solution was stirred at −78° C. for 1.5 hours. Then at −78° C., added acetone drop wise to the reaction mixture and continue to stir reaction at −78° C. for 2 hours at which point LC-MS and TLC indicated the reaction was complete. The reaction was warmed to 0° C. and quenched with saturated ammonium chloride solution (aq.) and then diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to afford crude product. Gradient column chromatography on silica eluting with 0 to 30% EtOAc/hexanes gave the desired product (1.04 g).
Reaction SMILES: [Si]([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)(C)(C)C.[C:10](Cl)(Cl)=[O:11].C1(C)C=CC=CC=1.[C:21]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].N1C=CC=CC=1>C(Cl)Cl>[C:24]([O:23][C:21]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][C:10]([C:5]2[S:6][CH:7]=[CH:8][N:9]=2)=[O:11])=[CH:33][CH:34]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: O=C(Cl)Cl
Reactant: C[Si](C)(C)c1nccs1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccc(OC(=O)c2nccs2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To a solution of 2-TMS-thiazole (2.25 mL, 14.1 mmol) in DCM (5 mL) at 0° C. was slowly added a solution of phosgene in toluene (20%, 7.45 mL, 14.1 mmol) over 15 Min. After stirring for 2 h at RT, the resulting solution was slowly added via syringe to a solution of N-BOC-4-hydroxyaniline (4.39 g, 21.2 mmol) and pyridine (2.3 mL, 28.2 mmol) in DCM (100 mL) at 0° C. After stirring for 20 h at RT, the reaction mixture was quenched by addition of sat. NaHCO3 (100 mL), EtOAc (150 mL) was added, and the phases were separated. The aqueous phase was extracted with EtOAc (2×75 mL), and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (10-50% EtOAc in hexanes) afforded the product as a green solid (518 mg, 12%). 1H-NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H) 8.29 (d, J=3.0 Hz, 1H), 8.22 (d, J=3.0 Hz, 1H), 7.53 (d, J=8.9 Hz, 2H), 7.23 (d, J=6.9 Hz, 2H), 1.48 (s, 9H) LC/MS (10-99%) M/Z: M+1 obs=321.1; tR=2.94 min.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][C:3]=1[N+:8]([O-:10])=[O:9].C([Sn](CCCC)(CCCC)[C:16]1[S:17][CH:18]=[CH:19][N:20]=1)CCC.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[Br:7][C:6]1[C:2]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[C:3]([N+:8]([O-:10])=[O:9])[S:4][CH:5]=1
Reactant: O=[N+]([O-])c1scc(Br)c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1scc(Br)c1-c1nccs1
Temperature: 130 °C
Yield: 85.9 %

Procedure:
A mixture of 3,4-dibromo-2-nitrothiophene (242 mg, 0.85 mmol), 2-(tributylstannyl)thiazole (315 mg, 0.84 mmol), Pd(Ph3P)4 catalyst (194 mg, 0.17 mmol) and dioxane (0.9 mL) was heated in the microwave to 130° C. for 25 min. The reaction mixture was diluted with EtOAc and filtered to remove solids. The remaining organic solution was washed with saturated, aqueous solutions of sodium bicarbonate and salt before drying over sodium sulfate. The organic was concentrated under reduced pressure to give a dark oil. The crude product was purified by column chromatography (30% EtOAc/hexanes) to give 2-(4-bromo-2-nitrothiophen-3-yl)thiazole (210 mg). LCMS m/z of 289.1/291.1 with a retention time of 2.043 min on the [1] method.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](=[O:39])[CH2:10][C@@:11]1([C:26]2[S:27][C:28]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][CH:32]=3)=[CH:29][CH:30]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH2:13][CH2:12]1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>CO.C(Cl)(Cl)Cl>[OH:7][NH:8][C:9](=[O:39])[CH2:10][C@@:11]1([C:26]2[S:27][C:28]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][CH:32]=3)=[CH:29][CH:30]=2)[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][N:14]([S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH2:13][CH2:12]1
Reactant: CCCS(=O)(=O)N1CC[C@](CC(=O)NOC2CCCCO2)(c2ccc(-c3ccc(CC)cc3)s2)S(=O)(=O)CC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCS(=O)(=O)N1CC[C@](CC(=O)NO)(c2ccc(-c3ccc(CC)cc3)s2)S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.1 %

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[(S)-7-(5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-4-propanesulfonyl-1,4-thiazepin-7-yl]acetamide (3.51 g) in methanol (8 ml) and chloroform (8 ml) was added toluenesulfonic acid monohydrate (112 mg). The resulting mixture was stirred for 4 hours at room temperature. The solvent was evaporated off to give a pale yellow solid. Silica gel column chromatography (eluent: methanol in chloroform from 0 to 4%) afforded N-hydroxy-2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-4-propanesulfonyl-1,4-thiazepin-7-yl]acetamide (2.41 mg) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41])(OCC)=O>O.C(#N)C>[C:32]1(=[O:41])[N:2]([CH:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]12
Reactant: CCOc1cc(C(N)CC(=O)OC)ccc1OC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOc1cc(C(CC(=O)OC)N2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a stirred solution of methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (0.87 g, 3.0 mmol) and sodium carbonate (0.32 g, 3.0 mmol) in a mixture of water (10 mL) and acetonitrile (10 mL) was added N-carbethoxyphthalimide (0.68 g, 3.0 mmol). The resulting solution was stirred for 3 hours at room temperature. The acetonitrile was removed in vacuo. To the resulting mixture was added ether (5 mL) and the mixture was stirred at room temperature overnight allowing the ether to evaporate. The resulting white solid was filtered. The solid was washed with water, air dried, and dried in vacuo (60° C.,<1 mm) to afford 1.0 g (87%) of methyl 3-phthalimido-3-(3-ethoxy-4-methoxyphenyl)propionate as a white solid: mp 86-87° C.; 1H NMR (CDCl3)δ 7.86-7.63 (m, 4H), 7.16-7.05 (m, 2H), 6.88-6.76 (m, 1H), 5.77 (dd, J=5.9, 10 Hz, 1H), 4.11 (q, J=7 Hz, 2H), 3.84 (s, 3H), 3.77 (dd, J=10, 6.7 Hz, 1H), 3.63 (s, 3H), 3.25 (dd, J=5.9, 16.5 Hz, 1H), 1.45 (t, J=7 Hz, 3H); 13C NMR (CDCl3)δ 171.0, 168.0, 149.0, 148.2, 133.9, 131.7, 130.9, 123.2, 120.2, 112.5, 111.1, 64.3, 55.8, 51.8, 50.7, 35.8, 14.6; HPLC (Waters Nova-Pak C18 column, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 45/55, acetonitrile/0.1% aqueous phosphoric acid 6 min, 100%, Anal. Calcd. for C21H21NO6. Theoretical: C, 65.79; H, 5.52; N, 3.65. Found: C, 65.71; H, 5.70; N, 3.63.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:13]2[C:8](=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pt]=O>[C:1]([O:4][CH:5]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OC1CCc2c1cccc2[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: CC(=O)OC1CCc2c(N)cccc21
Reaction time: 16 h
Yield: 97.6 %

Procedure:
A solution of 10.0 g (0.045 mole) of 4-nitro-1-indanyl acetate in 200 mL of ethanol was mixed with 0.1 g of platinum oxide in 20 mL of ethanol, and the mixture was contacted with hydrogen in a Parr hydrogenator. Upon complete uptake of hydrogen, the reaction mixture was allowed to stand for 16 hours. The platinum oxide was removed by filtration through diatomaceous earth, and the filter cake was washed with ethanol. The ethanol washings were combined with the filtrate, and the whole was concentrated under reduced pressure to give 8.4 g of 4-amino-1-indanyl acetate as an oil.
Reaction SMILES: [CH2:1]([C:8]1[C:13]2[CH2:14][O:15][CH2:16][C:12]=2[C:11]([OH:17])=[C:10]([CH3:18])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[Cl:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25]>>[ClH:20].[ClH:20].[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][CH2:21][O:17][C:11]1[C:12]2[CH2:16][O:15][CH2:14][C:13]=2[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:10]=1[CH3:18]
Reactant: Cc1nc(Cc2ccccc2)c2c(c1O)COC2
Reactant: CN(C)CCCCl
Agent: [Na]
Product: Cc1nc(Cc2ccccc2)c2c(c1OCCCN(C)C)COC2
Product: Cl
Yield: 106.8 %

Procedure:
12.1 g (50 millimoles) of 4-benzyl-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-ol are converted to the sodium salt as described in Example I (a) and are reacted with 9.2 g (75 millimoles) of N-(3-chloropropyl)-N,N-dimethylamine. Working up as described in Example I gives 16.0 g of 4-benzyl-6-methyl-1,3-dihydro-furo[3,4-c]pyridin-7-yl 3-dimethylaminopropyl ether bishydrochloride, which is recrystallized from isopropanol-ethanol; melting point 202°-204° C. % N: calculated 7.0, found 7.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[C:15]([O:19][C:20](=[O:26])[N:21]([CH2:23][CH2:24][NH2:25])[CH3:22])([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:25][CH2:24][CH2:23][N:21]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:26])[CH3:22])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NCCN(C)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Yield: 103.7 %

Procedure:
4-[2-(tert-Butoxycarbonyl-methyl-amino)-ethylamino]-3-nitro-benzoic acid methyl ester (1.7 g) was prepared by following General Procedure A starting from 4-chloro-3-nitro-benzoic acid methyl ester (1 g), (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester (1.2 g) and DIEA (1.7 mL) in THF (20 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=O)[C:12]([C:16]#[N:17])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:13]1[C:12]([C:16]#[N:17])=[CH:11][C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Temperature: 100 °C

Procedure:
To 6-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-nitrile (40.75g) was added POCl3 (20 mL). The reaction was heated to 100° C. for 13 hours. After cooling to room temperature the excess POCl3 was removed in vacuo before the residue was dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3 solution. The solution was concentrated and purified via flash chromatography on silica gel with a gradient elution of 30% to 100% CH2Cl2 in hexane affording the title compound. HPLC/MS: 392.9 (M+1), 394.9 (M+3); Rt=4.45 min.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][O:4][N:3]=1.[CH3:13][I:14]>CC(C)=O>[I-:14].[NH2:1][C:2]1[C:6]([C:7]2[CH:8]=[N+:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:5][O:4][N:3]=1
Reactant: CI
Reactant: Nc1nonc1-c1cccnc1
Solvent: CC(C)=O
Product: C[n+]1cccc(-c2nonc2N)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(3-amino-1,2,5-oxadiazol-4-yl)pyridine (870 mg, 5.3 mmol) in acetone (20 ml) was added methyl iodide (990 μl, 16 mmol) and the reaction mixture was stirred overnight at room temperature. The title compound precipitated and was collected by filtration (1.1 g, 69%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C@@:12]34[C:15]5[C:21]6[CH2:22][C@@H:6]2[C@@:7]23[CH2:25][CH2:24][C@:10]([O:26][CH3:27])([C@@H:11]4[O:17][C:16]=5[C:18]([OH:23])=[CH:19][CH:20]=6)[C@@H:9]([CH2:28][O:29][CH2:30][C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:34]=[CH:35][CH:36]=3)[CH2:8]2)[CH2:3][CH2:2]1.BrC1C=C(C=CC=1)CBr.NC1C=CC=CC=1.C([Cl:60])(=O)C.C(O)(C(F)(F)F)=O>>[CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C@@:12]34[C:15]5[C:21]6[CH2:22][C@@H:6]2[C@@:7]23[CH2:25][CH2:24][C@:10]([O:26][CH3:27])([C@@H:11]4[O:17][C:16]=5[C:18]([OH:23])=[CH:19][CH:20]=6)[C@@H:9]([CH2:28][O:29][CH2:30][C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:34]=[CH:35][CH:36]=3)[CH2:8]2)[CH2:2][CH2:3]1.[ClH:60]
Reactant: CC(=O)Cl
Agent: BrCc1cccc(Br)c1
Agent: CO[C@]12CC[C@@]3(C[C@@H]1COCc1cccc(NC(C)=O)c1)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Solvent: O=C(O)C(F)(F)F
Solvent: Nc1ccccc1
Product: Cl

Procedure:
In a similar manner N-(3-((((4R,4aS,6R,7R,7aR,12bS)-3-(cyclopropylmethyl)-9-hydroxy-7-methoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-6-yl)methoxy)methyl)phenyl)acetamide (Compound 72) was prepared from R-101 using 3-bromobenzyl bromide, followed by conversion of the aryl bromide to the aniline, subsequent reaction of the aniline with acetyl chloride and final cleavage of the p-methoxybenzyl group by TFA. Purification by flash column chromatography (silica gel, 0-10% MeOH/DCM) followed by HCl salt formation gave Compound 72 HCl salt as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:19]=3)[O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:43][O:44][CH:45]4[CH2:50][CH2:49][CH2:48][CH2:47][O:46]4)=[O:27])[CH:19]=3)[O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCCC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
TEA (0.259 ml, 1.86 mmol) was added to solution of (±)-(E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid (481 mg, 1.24 mmol) in DCM (15 ml). The mixture was cooled down to 0° C., and EDC (356 mg, 1.86 mmol) and HOBt (251 mg, 1.86 mmol) were added. The mixture was stirred at 0° C. for 2 h, then NH2OTHP (174 mg, 1.49 mmol) was added and the mixture was stirred at RT overnight. The solution was washed with aqueous 5% NaHCO3 solution and brine. The organic layer was then dried over Na2SO4 and evaporated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 98:2) to give (E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (410 mg).