Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[CH2:10]([O:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22](=O)[CH:23]=[CH:24][NH:25]2)=[CH:20][C:19]=1[C:29]([O:31]C1C=CC=CC=1)=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:38]([NH2:40])[CH3:39]>O.C(OCC)(=O)C>[CH2:38]([NH:40][C:29]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:18]=1[O:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:25]=[CH:24][CH:23]=[C:22]2[Cl:3])=[O:31])[CH3:39]
Reactant: CCN
Reactant: O=C(Oc1ccccc1)c1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCNC(=O)c1cc2c(Cl)ccnc2cc1OCc1ccccc1
Yield: 34 %

Procedure:
After adding thionyl chloride (10 ml) and a catalytic amount of dimethylformamide to phenyl 7-benzyloxy-4-oxo-1,4-dihydro-6-quinolinecarboxylate (2.32 g, 6.25 mmol), the mixture was heated to reflux for 2 hours while stirring. The reaction solution was concentrated under reduced pressure and azeotropically distilled twice with toluene, the residue was dissolved in a dimethylformamide (10 ml) and triethylamine (5 ml) mixed solvent, 2M ethylamine (tetrahydrofuran solution) (6.25 ml, 12.5 mmol) was gradually added thereto while cooling in an ice water bath, and the mixture was stirred at room temperature for 3 hours. The reaction solution was distributed between ethyl acetate and water, and then the organic layer was washed with ammonia water, water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off, after which ethyl acetate and then diethyl ether were added for crystallization and the crystals were filtered out and blow-dried to obtain the title compound (723 mg, 2.12 mmol, 34%) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)Cl.O>[Br:19][CH2:20][C:21]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:22]
Reactant: COc1ccc(N)cc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)CBr)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared via a modification of the literature procedure (Vloon, W. J.; Kruk, C.; Pandit, U. K.; Hofs, H. P.; McVie, J. G. J Med. Chem. 1987, 30,20-4.). To a solution of 4-methoxyaniline (4.93 g, 40.0 mmol) in methylene chloride (200 mL) was added diisopropylethylamine (7.66 mL, 44.0 mmol). The resulting mixture was cooled to -20° C., and bromoacetyl bromide (3.82 mL, 44.0 mmol) was added slowly. The reaction mixture was warmed to room temperature over 20 minutes and stirred additional 30 minutes. The reaction mixture was diluted with water (100 mL), stirred for 30 minutes and the organic layer was separated. The organic layer was washed with water (2×100 mL), brine (100 mL), dried over magnesium sulfate and concentrated in vacuo to afford a beige solid (9.68 g) which was recrystallized from ethyl acetate to provide bromo-N-(4'-methoxyphenyl) acetanide as a white crystal (6.31 g, 65%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11]>>[N:4]1[CH:3]=[C:2]([CH2:11][CH2:10][CH2:9][CH2:8][OH:12])[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncnc1
Reactant: C#CCCO
Product: OCCCCc1cncnc1

Procedure:
5-bromopyrimidine and 3-butyn-1-ol was reacted as above, to give 5-pyrimidinebutanol as a colorless oil, bp 175°-180° C. (0.3 mm). Analysis Calculated for C8H12N2O: C, 63.13; H, 7.95; N, 18.41. Found: C, 62.83; H, 7.98; N, 18.63.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[C:13](O)=[O:14])=[O:6])#[N:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>CO>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][OH:14])=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CO
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CO
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
(1R,2R)-2-{[(Cyanomethyl)amino]carbonyl}cyclohexanecarboxylic acid (97 mg, 0.46 mmol) in a 25 mL round bottom flask was fitted with a rubber septum and the flask was flushed with nitrogen. After adding tetrahydrofuran (1 mL), the reaction mixture was cooled to −78° C. and 4-methylmorpholine (51 μL, 0.47 mmol) and isobutyl chloroformate (51 μL, 0.46 mmol) were added. After 5 min, the reaction mixture was warmed quickly to 0° C. for 30 minutes. After recooling to −78° C., sodium borohydride (45 mg, 1.2 mmol) and methanol (1 mL) were added. After 5 min., the reaction mixture was allowed to warm to ambient temperature over 2 h. After quenching with 1 mL saturated aqueous ammonium chloride, the reaction mixture was partitioned between saturated aqueous sodium chloride solution and ethyl acetate. The organic layer was separated, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. Toluene (5 mL) was added and stirring was carried out overnight. The solution was decanted and the residue was dried to give (1R,2R)-N-(cyanomethyl)-2-(hydroxymethyl)cyclohexanecarboxamide as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-])=O)=[C:8]([NH:11][C:12](=O)[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[N:4]([CH2:25][C:26]#[C:27][CH2:28][CH3:29])[C:3]1=[O:30].Cl[Sn]Cl.O>C1COCC1.Cl>[CH3:1][C:2]1([CH3:31])[C:10]2[CH:9]=[C:8]3[NH:11][C:12]([CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:22][C:7]3=[CH:6][C:5]=2[N:4]([CH2:25][C:26]#[C:27][CH2:28][CH3:29])[C:3]1=[O:30]
Reactant: CCC#CCN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccccc3)c([N+](=O)[O-])cc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Product: CCC#CCN1C(=O)C(C)(C)c2cc3[nH]c(CCc4ccccc4)nc3cc21
Temperature: 40 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a solution of N-(3,3-dimethyl-6-nitro-2-oxo-1-pent-2-ynyl-2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionamide (50 mg) in THF (0.5 ml) is added a solution of SnCl2.H2O (107 mg; 476 μmol) in hydrochloric acid (1 M; 2 ml) at RT. The mixture is stirred 2 h at RT and subsequent 2 h at 40° C. The reaction mixture is adjusted to pH 12 and extracted with CH2Cl2 (3×15 ml). The combined organic layer is dried over MgSO4 and concentrated in vacuo. The desired compound (19 mg) is obtained by flash chromatography on silica gel eluting with CH2Cl2/MeOH (99:1).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.[CH:17]1([C:20]2[N:21]=[C:22]3[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]3[C:31]=2[CH3:32])[CH2:19][CH2:18]1.C(Cl)Cl.CO>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][N:11]([C:25]3[CH:26]=[CH:27][C:22]4[N:23]([C:31]([CH3:32])=[C:20]([CH:17]5[CH2:19][CH2:18]5)[N:21]=4)[CH:24]=3)[C:10](=[O:14])[CH:9]=2)=[CH:15][CH:16]=1
Reactant: Cc1c(C2CC2)nc2ccc(B(O)O)cn12
Reactant: O=c1cc(OCc2ccc(Cl)cc2)nc[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(C2CC2)nc2ccc(-n3cnc(OCc4ccc(Cl)cc4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.8 %

Procedure:
To a mixture of 6-((4-chlorobenzyl)oxy)pyrimidin-4(3H)-one (150 mg), (2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)boronic acid (275 mg), DCM (15 ml) and MeOH (15 ml) were added copper acetate (346 mg) and pyridine (0.5 ml), and the resulting reaction mixture was stirred at room temperature for 16 h. The solids were then filtered through Celite, and the filtrate was poured into 1 M HCl. The mixture was extracted with DCM, and the combined DCM layer was washed successively with saturated NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (15 mg) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:33]2[C:28]([CH:29]=[N:30][C:31](OS(C(F)(F)F)(=O)=O)=[N:32]2)=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:31]2[N:30]=[CH:29][C:28]3=[CH:27][CH:26]=[C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][CH3:17])[N:33]3[N:32]=2)=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16]
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Reactant: CN1CCCC1COc1cc(N)ccc1Cl
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(Cl)c(OCC4CCCN4C)c3)nn12

Procedure:
Prepared by following a procedure analagous to Example 1220c by using 4-Chloro-3-(1-methyl-pyrrolidin-2-ylmethoxy)-phenylamine and Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester. 1H-NMR (DMSO) 69.7 (br s, 1H), 9.6 (s, 1H), 8.9 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.5 (m, 2H), 7.35 (d, J=9.1 Hz, 1H), 7.28 (d, J=9.2 Hz 1H), 7.2 (d, J=8.3 Hz, 1H), 7.1 (t, 1H), 7 (s, 2H), 3.97 (d, 1H), 3.85 (m, 2H), 3.77 (s, 3H), 3.6 (m, 1H), 3.1 (m, 1H), 3 (s, 3H), 2.2 (m, 1H), 2.0 (m, 1H), 1.9 (m, 1H), 1.65 (m, 1H); LC/MS (ESI+): 464 (M+H).
Reaction SMILES: COC1C=C2C(=C(N)C=1)N=CC=C2.[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2.[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36](Cl)(=[O:38])=[O:37])([O-:29])=[O:28]>>[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:23]([NH:26][S:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N+:27]([O-:29])=[O:28])(=[O:37])=[O:38])=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2
Reactant: COc1ccc(N)c2ncccc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: COc1cc(N)c2ncccc2c1
Product: COc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c2ncccc12
Yield: 64 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-methoxyquinolin-8-amine (Intermediate 67) (350 mg, 2.01 mmol) and 2-nitrobenzenesulfonyl chloride (533 mg, 2.41 mmol) gave the title compound (460 mg, 64%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=C)=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:29])([F:28])[F:27])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:34]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=[O:34])=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:28])([F:27])[F:29])([CH3:3])[CH3:2]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)c(C(F)(F)F)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 33 %

Procedure:
To 3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 14B, 0.18 g, 0.451 mmol) in THF (2 mL) was added N-methylmorpholine-N-oxide (50% in water) (0.093 mL, 0.451 mmol) followed by osmium tetroxide (0.071 mL, 9.01 μmol) in one portion at room temperature. The contents were stirred at room temperature for 14 h. LCMS indicated formation of a major peak corresponding to the diol intermediate. Sodium periodate (0.145 g, 0.676 mmol) dissolved in 2 mL of water was added in one portion at room temperature. The milky heterogeneous solution was stirred at room temperature for 45 min. The reaction mixture was concentrated and partitioned between ethyl acetate (15 mL) and water (10 mL). The ethyl acetate layer was dried over sodium sulfate, concentrated and purified by silica gel column chromatography (hexane/ethyl acetate) to yield 3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.06 g, 0.149 mmol, 33.2% yield) as a white solid. LC/MS M+1=402.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([OH:8])[CH:7]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]([F:10])([F:11])[F:12])[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([OH:8])[CH:7]=1
Reactant: Oc1cc(F)cc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)cc(F)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
5-Fluoro-3-(trifluoromethyl)phenol (1.27 g) was dissolved in acetic acid (3 ml) and water (1.5 ml), and nitric acid (3.0 ml) was added thereto. The reaction mixture was stirred at 50° C. for 30 minutes. After cooling, water was added to the reaction mixture, and the mixture was extracted with ether. The extract was washed with an aqueous saturated sodium bicarbonate solution and water, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (developing solution:ethyl acetate-hexane=1:3) to obtain the title compound as oil (0.33 g, 21%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]3[CH2:11][CH2:12][NH:13][CH2:14][CH:5]3[C:4]=2[CH:3]=1.[CH2:15](Br)[CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:17][CH2:16][CH2:15][N:13]1[CH2:12][CH2:11][CH:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[CH:5]2[CH2:14]1
Reactant: OCCBr
Reactant: Cc1ccc2c(c1)C1CNCCC1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc2c(c1)C1CN(CCO)CCC1N2
Reaction time: 16 h

Procedure:
A mixture of 8-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (10.0 g), ethylene bromohydrin (8.0 g) and potassium carbonate (14.6 g) in methyl ethyl ketone (80 ml) is refluxed with stirring for 16 hours. The insoluble materials are filtered off and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in a dilute hydrochloric acid. The dilute hydrochloric acid layer is separated, washed with benzene, made alkaline with aqueous sodium hydroxide and then extracted with benzene. The benzene layer is dried over anhydrous sodium sulfate and concentrated to give a crude product as an oily substance. The crude product is treated in the same manner as described in Example 1 (1) to give the dihydrochloride of the titled compound (7.8 g), m.p. 182° -185°C (recrystallized from aqueous ethanol).
Reaction SMILES: [BH4-].[Na+].C(O[C:11]([NH:13][CH:14]([CH2:19][N:20]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:27]2[C:22]([N:23]([CH3:38])[C:24](=[O:37])[N:25]([CH3:36])[C:26]2=[O:35])=[CH:21]1)[C:15](OC)=[O:16])=O)C1C=CC=CC=1.[Cl-:39].[Li+].[CH2:41]1[CH2:45][O:44][CH2:43][CH2:42]1>CCO>[Cl:39][C:45]1[O:44][C:43]([C@H:11]2[C:21]3=[C:22]4[C:27](=[C:28]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:20]3[CH2:19][C@H:14]([CH2:15][OH:16])[NH:13]2)[C:26](=[O:35])[N:25]([CH3:36])[C:24](=[O:37])[N:23]4[CH3:38])=[CH:42][CH:41]=1
Reactant: [Cl-]
Reactant: C1CCOC1
Reactant: COC(=O)C(Cn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)[C@H](c1ccc(Cl)o1)N[C@@H](CO)C3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium borohydride (0.234 g, 6.20 mmol) was added to a solution of methyl 2-(((benzyloxy)carbonyl)amino)-3-(1,3-dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)propanoate (1.52 g, 3.10 mmol) and lithium chloride (0.263 g, 6.20 mmol) in THF (79 ml) and EtOH (39.7 ml) at 0° C. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated NaHCO3(aq) (20 mL), diluted with water (50 ml) and extracted with DCM (3×150 ml). The combined organic extracts were diluted with MeOH (50 ml), dried over sodium sulfate, passed through a hydrophobic frit and evaporated under vacuum to afford the title compound and was a by-product. The resulting mixture was taken forward to the next step without further purification.
Reaction SMILES: Cl[P:2]1[S:6][CH2:5][CH2:4][O:3]1.[CH:7]([NH:10][CH:11]([CH3:13])[CH3:12])([CH3:9])[CH3:8]>CCCCC>[CH:7]([N:10]([P:2]1[S:6][CH2:5][CH2:4][O:3]1)[CH:11]([CH3:13])[CH3:12])([CH3:9])[CH3:8]
Reactant: ClP1OCCS1
Reactant: CC(C)NC(C)C
Solvent: CCCCC
Product: CC(C)N(C(C)C)P1OCCS1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 1 (0.2 mol) is dissolved in n-pentane (300 mL) and diisopropylamine (0.4 mol) is added dropwise. The reaction mixture is stirred at room temperature for 30 minutes, after which diisopropylamine hydrochloride is filtered off, solvent is evaporated under reduced pressure and crude product is purified by vacuum distillation. Product 2 is obtained as the fraction boiling at 70° C./0.1 mm Hg and is characterized by 31P NMR and mass spectroscopy.
Reaction SMILES: C(OC1C=C(C=[CH:17][CH:18]=1)C(OC)=O)C1C=CC=CC=1.[S:19]([OH:23])(=[O:22])(=[O:21])[CH3:20].S(O)(=O)(=O)C.[NH2:29][NH:30][C:31]([NH2:33])=[NH:32].N>>[S:19]([OH:23])(=[O:22])(=[O:21])[CH3:20].[NH2:33][C:31]1[N:30]=[N:29][CH:17]=[CH:18][N:32]=1
Reactant: N=C(N)NN
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1
Agent: CS(=O)(=O)O
Agent: N
Product: Nc1nccnn1

Procedure:
Prepared by reacting acenaphthenequinone (3) with aminoguanidine bismesylate for 24 hrs using the above procedure except that the basification step with ammonia was omitted. The title compound was obtained as bright yellow prisms in 83.2%, mpt=264-266° (froth)
Reaction SMILES: O.[NH2:2][NH2:3].[P:4]([O-:11])([O:8]CC)[O:5][CH2:6][CH3:7]>O>[CH2:6]([O:5][P:4]([O-:11])[O-:8])[CH3:7].[NH3+:2][NH2:3].[NH3+:2][NH2:3]
Reactant: NN
Reactant: CCOP([O-])OCC
Solvent: O
Product: CCOP([O-])[O-]
Product: N[NH3+]
Reaction time: 2 h

Procedure:
0.2 mol of hydrazine hydrate is run, whilst stirring, into 0.2 mol of diethyl phosphite. During the addition, the mixture is heterogeneous and its temperature rises to 70° C. Ten minutes after the end of the addition, the mixture becomes homogeneous. The mixture is stirred for two hours, and the alcohol and water are then driven off in vacuo at 80° C. A clear oil remains.
Reaction SMILES: C(OC(=O)[N:10]([CH2:15][CH:16]=[CH2:17])[CH2:11][CH:12]=[N:13]O)C1C=CC=CC=1.[CH2:19](OC(=O)N(CC=C)CC=O)[C:20]1[CH:25]=CC=C[CH:21]=1.Cl.NO.O.O.O.[C:42]([O-:45])(=[O:44])C.[Na+]>C(#N)C.O>[C:20]([O:45][C:42]([N:13]1[CH2:17][CH:16]2[CH:12]1[CH2:11][NH:10][CH2:15]2)=[O:44])([CH3:25])([CH3:21])[CH3:19]
Reactant: C=CCN(CC=NO)C(=O)OCc1ccccc1
Reactant: C=CCN(CC=O)C(=O)OCc1ccccc1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CNCC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Allyl-(2-hydroxyimino-ethyl)-carbamic acid benzyl ester. To a 1 L round-bottomed flask, were added allyl-(2-oxo-ethyl)-carbamic acid benzyl ester (45.2 g, 193.8 mmol) and hydroxylamine hydrochloride (17.5 g, 251.9 mmol) in acetonitrile (260 mL). To the resulting mixture was added a solution of sodium acetate trihydrate (29.5 g, 217 mmol) in H2O (130 mL). The reaction mixture was stirred at room temperature under nitrogen(g) overnight. The mixture was concentrated under reduced pressure and the resulting residue was extracted with ethyl acetate (2×130 mL). The combined organics were washed with brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (46.5 g, 97%). 1H-NMR (CDCl3, 400 MHz): 7.32 (m, 5H), 6.72 (m, 1H), 5.77 (bs, 1H), 5.16 (m, 4H), 4.19 (m, 1H), 3.95 (m, 3H). MS (electrospray): exact mass calculated for C13H16N2O3, 248.12; m/z found, 249.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][C:17](=[O:19])[NH:16][C:15](=[O:20])[CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCO>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:14][C:15](=[O:20])[NH:16][C:17](=[O:19])[CH2:18]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CC(=O)NC(=O)C2)cc1C1=CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CC(=O)NC(=O)C3)cc2C2=CCCCC2)n1
Yield: 10 %

Procedure:
A solution of 70.0 mg (0.131 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2,6-dioxo-piperidin-4-yl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with EtOH (2 drops) and TFA (3 mL) at RT for 1.5 h. Solvents were removed in vacuo. Purification of the residue by reverse phase high pressure liquid chromatography (RP-HPLC) (C18) with 10-80% CH3CN in 0.1% TFA/H2O over 30 min afforded 5.3 mg (8%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.18 (d, 1H, J=8.4 Hz), 8.01 (s, 1H), 7.24 (dd, 1H, J=8.4, 2.4 Hz), 7.15 (d, 1H, J=2.4 Hz), 5.85-5.78 (m, 1H), 3.48-3.38 (m, 1H), 2.90-2.71 (m, 4H), 2.32-2.22 (m, 4H), 1.90-1.73 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C22H21N5O3, 404.2 (M+H). found 404.0.
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.F[C:7](F)(F)[C:8](O)=O.ICI.[F:16][C:17]([F:35])([F:34])[C:18]([N:20]1[CH2:26][C:25](=[CH2:27])[C:24]2[CH:28]=[CH:29][C:30]([O:32]C)=[CH:31][C:23]=2[CH2:22][CH2:21]1)=[O:19]>ClCCl>[F:34][C:17]([F:35])([F:16])[C:18]([N:20]1[CH2:26][CH:25]([CH:27]2[CH2:8][CH2:7]2)[C:24]2[CH:28]=[CH:29][C:30]([O:32][CH2:4][CH3:5])=[CH:31][C:23]=2[CH2:22][CH2:21]1)=[O:19]
Reactant: C=C1CN(C(=O)C(F)(F)F)CCc2cc(OC)ccc21
Reactant: CC[Zn]CC
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ICI
Product: CCOc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C1CC1
Reaction time: 0.25 h

Procedure:
A solution of diethyl zinc (1 mL, 1M in hexanes) in dichloromethane (1 mL) at 0 C was treated with trifluoroacetic acid in dichloromethane (0.5 mL) and the mixture stirred for 15 min. Diiodomethane (0.280 g, 1.0 mmol) in dichloromethane (0.5 mL) was then added and stirred for 15 minutes. N-Trifluoroacetyl-7-methoxy-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine (0.075 g, 0.26 mmol) in dichloromethane (1 mL) was added and the mixture stirred for 30 minutes at 0 C and then for 2 hours at 20 C. The product mixture was quenched with aqueous saturated NH4Cl (5 mL), extracted twice with CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3 (10 mL), washed with H2O (10 mL), and concentrated. Flash chromatography (7% EtOAc in hexanes, silica) resulted in 0.050 g of a white solid. MS calculated for C15H16F3NO2+H: 300, observed: 300.
Reaction SMILES: ClC1C=CC(C(O[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O)=CC=1.[Cl:19][C:20]1[C:21]([CH3:33])=[C:22]([CH:31]=[CH2:32])[C:23]([O:29][CH3:30])=[C:24]([C:26](=[O:28])[CH3:27])[CH:25]=1.C(=O)([O-:36])N>O.C(#N)C.[Os](=O)(=O)(=O)=O>[C:26]([C:24]1[C:23]([O:29][CH3:30])=[C:22]([CH:31]([OH:36])[CH2:32][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:21]([CH3:33])=[C:20]([Cl:19])[CH:25]=1)(=[O:28])[CH3:27]
Reactant: NC(=O)[O-]
Reactant: CC(C)(C)OC(=O)NOC(=O)c1ccc(Cl)cc1
Reactant: C=Cc1c(C)c(Cl)cc(C(C)=O)c1OC
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC#N
Product: COc1c(C(C)=O)cc(Cl)c(C)c1C(O)CNC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
0.2 M Osmium tetraoxide in water (1 mL) was added to a solution of tert-butyl [(4-chlorobenzoyl)oxy]carbamate (2.0 g, 7.2 mmol) (Ref Lawrence Harris, J. Org. Chem., 2011, 76, 358-372) in acetonitrile (22 mL) and stirred for 10 minutes. 1-(5-Chloro-2-methoxy-4-methyl-3-vinylphenyl)ethanone (1.1 g, 4.8 mmol) as a solution in acetonitrile (22 mL) was added to the carbamate solution followed by the addition of water (5 mL). The reaction was stirred for 3 hours at room temperature. The reaction was quenched with saturated 10 M dipotassium disulfite in water (25 mL) and stirred for 5 minutes. Water was added to the reaction and the mixture was extracted with ethyl acetate. The organic extracts were washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate and evaporated under reduced pressure. Purification on silica gel using ethyl acetate in hexane (0-100%) gave the desired compound as a racemic mixture, 1.2 g, 69%. LCMS calculated for C17H24ClNO5Na (M+Na)+: m/z=380.1; found: 380.1. 1H NMR (500 MHz, DMSO-d6): δ 7.48 (s, 1 H), 6.80 (m, 1 H), 5.50 (br s, 1 H), 5.20 (br s, 1 H), 3.83 (s, 3 H), 3.32 (m, 1 H), 3.22 (m, 1 H), 2.59 (s, 3 H), 2.55 (s, 3 H), 1.32 (s, 9 H).