Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[O:20]=[C:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:22][C:23](OCC)=[O:24]>C1C=CC=CC=1>[N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:23](=[O:24])[CH2:22][C:21](=[O:20])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CC(C)C(c1ccc(N)c([N+](=O)[O-])c1)n1ccnc1
Solvent: c1ccccc1
Product: CC(C)C(c1ccc(NC(=O)CC(=O)c2ccccc2)c([N+](=O)[O-])c1)n1ccnc1
Yield: 44.8 %

Procedure:
A solution of 10 parts of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrobenzenamine, 20 parts of ethyl β-oxobenzenepropanoate and 174 parts of benzene was stirred for 36 hours at reflux temperature. After cooling, the reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 7 parts (44.8%) of N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrophenyl]-β-oxobenzenepropanamide; mp. 106° C. (interm. 96).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:12][CH2:13][CH2:14][C:15]2([NH:25]C(=O)C(F)(F)F)[CH2:24][CH2:23][C:18]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:17][CH2:16]2)[CH3:11])=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH:12][CH2:13][CH2:14][C:15]2([NH2:25])[CH2:16][CH2:17][C:18]3([O:19][CH2:20][CH2:21][O:22]3)[CH2:23][CH2:24]2)[CH3:11])=[CH:6][CH:5]=1
Reactant: C[C@H](NCCC1(NC(=O)C(F)(F)F)CCC2(CC1)OCCO2)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NCCC1(N)CCC2(CC1)OCCO2)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
A mixture of 4 M aqueous NaOH solution (6 mL), N-(8-{2-[(S)-1-(4-chloro-phenyl)-ethylamino]-ethyl}-1,4-dioxa-spiro[4.5]dec-8-yl)-2,2,2-trifluoro-acetamide (2.10 g), and methanol (10 mL) is stirred at 50° C. for 24 h. After cooling to room temperature, most of the methanol is evaporated and the residue is extracted with ethyl acetate. The combined extract is washed with brine, dried (MgSO4), and concentrated to give the title compound. Yield: 98% of theory; LC (method 8): tR=0.78 min; Mass spectrum (ESI+): m/z=339/341 (Cl) [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]([O:7][CH3:8])=[CH2:6])=[CH2:4].CC(O[Na])=O.C(=O)=O.CC(C)=O.[Se:21](Cl)Cl>CCCCCC>[CH3:1][O:2][C:3]1[C:5]([O:7][CH3:8])=[CH:6][Se:21][CH:4]=1
Reactant: C=C(OC)C(=C)OC
Reactant: Cl[Se]Cl
Agent: CC(=O)O[Na]
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COc1c[se]cc1OC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a well stirred solution of 2,3-dimethoxy-1,3-butadiene (1.47 g, 12.9 mmol, (11)) and CH3COONa (2.64 g, 32.25 mmol) in dry hexane (80 mL) at −78° C. (dry ice/acetone bath), under an inert atmosphere, was added a solution of freshly prepared SeCl2 in hexane over a period of 15 min The resulting yellowish solution was further stirred for 1 h at −78° C. and then removed from the cooling bath and the reaction mixture was brought to room temperature over a period of 2 h and further stirred for 5 h. The reaction mixture was filtered through neutral alumina and washed with hexane. The residue was concentrated to give brown yellow oil. The crude product was purified by flash column chromatography on TLC grade silica gel (Hexane: Ethyl acetate −95:5) to provide DMOS (0.85 g, 35%, (12)) as a white crystalline solid. mp. 43-45° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CC(O)=O.O>CCO>[N:26]1([CH2:32][CH2:33][NH:34][C:3]([C:5]2[N:6]=[C:7]([C:24]#[N:25])[C:8]3[C:9](=[O:23])[N:10]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:11]=[CH:12][C:13]=3[C:14]=2[OH:15])=[O:4])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCCN1CCOCC1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1nc(C(=O)NCCN2CCOCC2)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 55.4 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.075 mmol) and 2-morpholin-4-yl-ethylamine (0.034 mL, 0.26 mmol) in EtOH (2 mL) was refluxed for 16 h. After the mixture was cooled to r.t., AcOH (0.1 mL) and water (5 mL) were added. The resulting mixture was extracted with EtOAc, and the organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (0-10% MeOH/CH2Cl2) to give 18 mg of the title compound. MS: (+) m/z 434.34 (M+1).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[NH2:10][CH2:11][C@@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[OH:15])[OH:13].[C:22](=[O:25])([O-])[O-].[K+].[K+]>O>[N:1]1[C:8]([NH:10][CH2:11][C@@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[OH:15])[OH:13])=[N:7][C:5]([NH:10][CH2:11][C@@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[OH:15])[OH:13])=[N:4][C:2]=1[NH:10][CH2:11][C@@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:22][OH:25])[OH:19])[OH:17])[OH:15])[OH:13]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CNc1nc(NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)nc(NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)n1

Procedure:
184 mg of cyanuric chloride, 543.5 mg of D-glucamine and 450 mg of potassium carbonate were stirred at room temperature in 10 ml of water for three days. The thus-obtained crude product was thereupon chromatographed on LiChroprep RP-18 silica gel with water and subsequently with water containing an increasing amount of methanol. The relevant fractions were lyophilized; N,N',N"-(1,3,5-triazine-2,4,6-triyl)-tris-(1-amino-1-desoxy-D-glucitol) was thus obtained as a colorless powder, MS: m/z 619.2 ([M+H]+).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[S-:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Na+]>C(O)C.C(OCC)(=O)C.CCCCCC>[CH:26]1([NH:25][C:23]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:17]=3)[C:7]=2[CH2:6][S:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:24])[CH2:28][CH2:27]1
Reactant: [S-]c1ccccc1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)methyl methanesulfonate (310 mg, 0.761 mmol) obtained in Example 126a), potassium carbonate (52.6 mg, 0.380 mmol, 0.5 eq.) and sodium thiophenoxide (168 mg, 1.14 mmol, 1.5 eq.) were dissolved in ethanol (6.0 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (30 ml) and hexane (2 ml), washed twice with 2% aqueous sodium carbonate solution and with saturated brine, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (290 mg, 0.688 mmol, 90.4%).
Reaction SMILES: [C:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br)=[C:6]([CH2:18][CH3:19])[CH:5]=1)(=[O:3])[CH3:2].N1C=[CH:23][N:22]=[N:21]1.C(=O)([O-])[O-].[K+].[K+].O.[CH3:32][N:33](C)C=O>>[CH2:18]([C:6]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:22]2[CH:23]=[N:33][CH:32]=[N:21]2)=[CH:15][C:16]([OH:17])=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)[CH3:19]
Reactant: CN(C)C=O
Reactant: c1c[nH]nn1
Reactant: CCc1cc(C(C)=O)c(O)cc1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1cc(C(C)=O)c(O)cc1OCCCCCn1cncn1
Temperature: 85 °C

Procedure:
A mixture of 0.3 g of 5-(4-acetyl-2-ethyl-5-hydroxyphenoxy)pentyl bromide, 0.06 % of triazole, and 0.13 g of potassium carbonate in dimethylformamide was heated at 80-90° C. for approximately 18 hours. The mixture was poured into acidic water and extracted with ethyl acetate and methylene chloride. The extracts were combined, washed with dilute sodium hydroxide solution, dried over sodium sulfate, and concentrated in vacuo. The residue was twice crystallized from ethyl acetate/hexane to provide the title product having a melting point of 87° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:32]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:32])[CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:15][CH2:16]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 3,5-dichlorobenzyl 4-(2-((tert-butoxycarbonyl)amino)ethyl)piperidine-1-carboxylate (step 1) (3.5 g, 8.11 mmol) in DMF (40 ml) was cooled to 0° C. 60% sodium hydride/oil (0.487 g, 12.17 mmol) was added. The solution was stirred at 0° C. for 15 mins and then was warmed to RT. Iodomethane (0.761 ml, 12.17 mmol) was added and the resulting mixture was stirred at room temperature for 5 hours. The reaction was quenched with ammonium chloride (20 ml). The mixture was diluted with water (200 ml) and extracted with EtOAc (2×200 ml). The organic portion was dried using MgSO4, filtered and concentrated under reduced pressure. The residue was applied to an 80 g silica cartridge in DCM and eluted with 0-100% EtOAc in iso-hexane to afford the title compound;
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21]3[N:22]([C:32]4[N:33]=[CH:34][N:35]=[C:36]([NH2:39])[C:37]=4[N:38]=3)[C@@H:23]3[O:31][C@H:28]([CH2:29][OH:30])[C@@H:26]([OH:27])[C@H:24]3[OH:25])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)=O.CO.[NH3:42]>>[C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21]3[N:22]([C:32]4[N:33]=[CH:34][N:35]=[C:36]([NH2:39])[C:37]=4[N:38]=3)[C@@H:23]3[O:31][C@H:28]([CH2:29][OH:30])[C@@H:26]([OH:27])[C@H:24]3[OH:25])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:2])[NH2:42]
Reactant: N
Reactant: COC(=O)COc1cccc(-c2ccc(CNc3nc4c(N)ncnc4n3[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cc2)c1
Solvent: CO
Product: NC(=O)COc1cccc(-c2ccc(CNc3nc4c(N)ncnc4n3[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
8-(3′-Methoxycarbonylmethoxybiphenyl-4-ylmethyl-amino)adenosine (0.080 g) was dissolved in 2.0 M ammonia methanol solution (3.0 mL), and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (0.080 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:12].[ClH:30]>C(Cl)Cl.CCOCC>[ClH:30].[ClH:30].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][NH:20][CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)Nc3nc4ccccc4s3)c2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1A) (8.5 g, 20.75 mmol) in DCM (80 mL) was added 2N HCl in ether (80 mL). The reaction mixture was stirred at rt overnight and concentrated under reduced pressure to provide the desired product N-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide dihydrochloride (1B): LC/MS(APCI): m/z 309.9 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15]C)[CH:12]=[CH:11][C:10]=1[CH2:17][CH2:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+]>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CCCc2ccc(C(=O)O)cc2)c(OCc2ccccc2)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(CCCc2ccc(O)cc2OCc2ccccc2)cc1
Temperature: 190 °C
Yield: 20.8 %

Procedure:
To a solution of 4-[3-(2-benzyloxy-4-methoxyphenyl)-propyl]benzoic acid (0.75 g) in DMSO (20 ml) was added sodium cyanide (0.5 g). The reaction mixture was heated at 190° C. for 40 hours, cooled, partitioned between 1N aqueous NaOH and diethyl ether. The aqueous layer was separated, acidified to pH1 (conc. HCl) and extracted with ethyl acetate. The organic solution was dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel eluting with diethyl ether, and crystallisation from CH2Cl2 /hexane mixtures to give the title compound (150 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([NH:14][CH3:15])=S)=[N:5][N:4]=[N:3]1.C[I:17].O.[NH2:19][NH2:20]>CO>[IH:17].[NH2:19][NH:20][C:12]([NH:11][CH2:10][CH2:9][CH2:8][S:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)=[N:14][CH3:15]
Reactant: CNC(=S)NCCCSc1nnnn1C
Reactant: CI
Reactant: NN
Solvent: CO
Solvent: O
Product: CN=C(NN)NCCCSc1nnnn1C
Product: I
Yield: 70.3 %

Procedure:
1-[3-(1-Methyl-1,2,3,4-tetrazol-5-yl)thiopropyl]-3-methylthiourea (8 g) is dissolved in methanol (80 ml). To the mixture is added methyl iodide (5.7 g) and the mixture is refluxed for 5 hours. To the reaction mixture is further added hydrazine hydrate (2.4 g) and the mixture is refluxed for 2 hours. After the solvent is distilled off, the resulting crystalline product is recrystallized from ethanol to give 1-amino-2-methyl-3-[3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiopropyl]guanidine hydroiodide (8.5 g), colorless prisms, m.p. 105°-108° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2F)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[ClH:19]>CN(C)C=O.C1C=CC=CC=1.CCOCC>[ClH:19].[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:8]2)[CH2:4][CH2:3]1
Reactant: CN1CCC(O)(Cc2ccccc2F)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CN1CCC2(CC1)Cc1ccccc1O2
Temperature: 120 °C
Reaction time: 84 h

Procedure:
12.5 g of 1-methyl-4-(2-fluorobenzyl)-4-piperidinol dissolved in 50 ml of dimethylformamide and 20 ml of benzene are added to a stirred suspension at 120° C. of 2.3 g of a 57% oil dispersion of sodium hydride in 110 ml of dimethylformamide and 20 ml of benzene. The reaction mixture is stirred at 120° C. for 84 hours and then successively permitted to cool to ambient temperature, poured into 800 ml of ice-water and extracted with ether. The combined ether extracts were dried before the ether evaporated leaving a light yellow oil. The oil is dissolved in ether and converted to its hydrochloride salt with ethereal hydrogen chloride. The salt is recrystallized twice from an ethanol-ether mixture to provide the product, 2,3-dihydro-1'-methylspiro[benzofuran-2,4'-piperidine]hydrochloride, mp 248°-250° C.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]2.Br[CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>CC#N>[C:13]([O:12][C:10]([N:3]1[CH2:2][CH:1]2[CH2:9][CH:5]([CH2:6][N:7]([CH2:18][CH2:19][O:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:8]2)[CH2:4]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Reactant: N#Cc1ccc(OCCBr)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CCOc3ccc(C#N)cc3)C2)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
tert-Butyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (3.62 g; 16 mmol; see Example F above) was added to added to a stirred solution of 4-(2-bromoethoxy)benzonitrile (3.62g; 16 mmol; see Example 67(a) above) and TEA (3.34 mL; 24 mmol) in MeCN (70 mL) and the reaction mixture was stirred at 60° C. overnight and then stored at room temperature for 48 h. The solids were filtered off, washed with IPA (2×100 mL) and the filtrate concentrated. The residue was partitioned between DCM and NaHCO3 (sat.), the organic layer was separated, dried (MgSO4) and concentrated. The oily residue was subjected to column chromatography (DCM:MeOH; 25:1) to give the title compound in a 72% yield.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.O[N:35]=[C:36]([NH2:45])[CH:37]([OH:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.NC(=NO)C1CCN(C(OC(C)(C)C)=O)CC1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[O:18][N:45]=[C:36]([CH:37]([OH:44])[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:35]=2)[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC(=NO)C(O)c1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC(C(N)=NO)CC1
Product: CON=C1C[C@@H](c2nc(C(O)c3ccccc3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 59, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and (2RS)-N′,2-dihydroxy-2-phenylethanimidamide (an Intermediate 7), the title compound was obtained in 75% purity by HPLC. MS(ESI+): m/z=469.3.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[CH2:23][NH2:24]>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:24][C:23]([C:22]3[CH:25]=[CH:26][C:27]([N+:28]([O-:30])=[O:29])=[C:20]([CH3:19])[CH:21]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: Cc1cc(CN)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(OC)cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])c(C)c2)[nH]c1-c1ccc(OC)cc1
Yield: 22.5 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methoxyphenyl)-3-oxopropionate (121.6 g) and 3-methyl-4-nitrobenzylamine (105.4 g) were reacted in the same manner as in Starting Material Synthetic Example 1. After the reaction, the solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography to give ethyl 5-(4-methoxyphenyl)-2-(3-methyl-4-nitrophenyl)imidazole-4-carboxylate (41.5 g), melting point 187-191° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:22](=[N:25]O)[CH2:23][CH3:24])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:6]=2[N:7]=1>CO.[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([CH:22]([NH2:25])[CH2:23][CH3:24])[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([C:13]3[C:14]([CH3:21])=[CH:15][C:16]([CH3:20])=[CH:17][C:18]=3[CH3:19])[C:6]=2[N:7]=1
Reactant: CCC(=NO)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Agent: [Pd]
Solvent: CO
Product: CCC(N)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C

Procedure:
Hydrogenation of 1-[-2,5,6-Trimethyl-7-(2,4,6-trimethyl phenyl )-7H-pyrrolo[2,3-d]-pyrim-idin-4-yl]-propan-1-one oxime with 10% Pd/C in MeOH using the general procedure described in Example 29 resulted in the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[Cl:20])[NH:16][CH2:15][CH2:14]2>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[Cl:20])[N:16]([C:8](=[O:9])[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:15][CH2:14]2
Reactant: Clc1cc2c(cc1Cl)NCC2
Reactant: O=C=Nc1cccnc1
Product: O=C(Nc1cccnc1)N1CCc2cc(Cl)c(Cl)cc21

Procedure:
The title compound was prepared as in the method of (Example 2) from 3-pyridylisocyanate and 5,6-dichloroindoline (D39) to give (E20) (1.27 g, 65%) m.p. 236°-238° C.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN1CCOCC1.[C:29](Cl)(=[O:34])[O:30][C:31]([CH3:33])=[CH2:32]>C1COCC1>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:29](=[O:34])[O:30][C:31]([CH3:33])=[CH2:32])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=C(C)OC(=O)Cl
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=C(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Yield: 94.5 %

Procedure:
To a solution of 6-(4-nitronaphthalen-1-yloxy)pyrimidin-4-amine (89 mg, 0.315 mmol) and NMM (45 μl, 0.410 mmol) in THF (2.0 mL) at 0° C. was added, dropwise, a solution of prop-1-en-2-yl carbonochloridate (45 μl, 0.410 mmol) in THF (1.0 mL) and the reaction mixture warmed to RT for 15 hr and then partitioned between EtOAc (20 mL) and water (5.0 mL). The aq layer was separated and extracted with EtOAc and the combined organic layers were dried (MgSO4) and then evaporated in vacuo to afford the title compound as a yellow oil (109 mg, 87%); Rt 2.54 min (Method 2); m/z 367 (M+H)+ (ES+). This material was used directly in the next step (below) without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][NH2:12]>C(Cl)Cl>[CH3:11][NH:12][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Solvent: ClCCl
Product: CNc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C

Procedure:
A solution of 2-bromo-5-nitro-pyridine (4 g, 19.7 mmol) and methylamine (2 M in THF, 15 mL, 30 mmol) in methylene chloride (40 mL) was heated at 50 degrees overnight. After cooling to room temperature, the reaction mixture was concentrated to give methyl-(5-nitro-pyridin-2-yl)-amine that was used in the following step without purification. Acetic anhydride (9.3 mL, 98.5 mmol) was added to the solution of methyl-(5-nitro-pyridin-2-yl)-amine (3.01 g, 19.7 mmol), pyridine (24 mL, 197 mmol), and a catalytic amount of 4-dimethylamino-pyridine (DMAP) in methylene chloride (40 mL). The resulted mixture was heated at 90 degrees for overnight. After the reaction was complete, solvent was removed, and then ethyl acetate was added. The ethyl acetate solution was extracted three times with water. Organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 50% ethyl acetate in hexane for 20 min) gave N-methyl-N-(5-nitro-pyridin-2-yl)-acetamide.