Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]1[C:18]([N:20]1[CH2:24][CH2:23][S:22][CH2:21]1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH3:26][N:27](C=O)C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:26]#[N:27])[CH2:10][C@H:9]1[C:18]([N:20]1[CH2:24][CH2:23][S:22][CH2:21]1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCSC1
Reactant: CN(C)C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@H]1C(=O)N1CCSC1
Temperature: 50 °C

Procedure:
To a solution of Example 17B (16.55 g, 44 mmol) in dry DMF (100 mL) under nitrogen was added tetrabutylammonium cyanide (50 g, 200 mmol). The mixture was heated to 50° C. for 60 hours and then poured into cold water and extracted with ethyl acetate (3×250 mL). The combined organic layers were dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography with 50% ethyl acetate/50% hexane to provide the titled compound (12 g). MS (ESI) m/e 312 (M+H)+, 310 (M−H)−; 1H NMR (400 MHz, CD3OD) δ ppm 1.44 (m, 9 H) 2.10 (m, 1 H) 2.79 (m, 1 H) 3.05 (m, 1 H) 3.17 (m, 1 H) 3.33 (m, 1 H) 3.57 (dd, 1 H) 3.83 (m, 2 H) 3.96 (m, 1 H) 4.48 (m, 1 H) 4.65 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.[C:16]([O-])(=O)C.[Na+].Cl.C[O:23][NH2:24]>C(O)C>[CH3:16][O:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][C:12](=[N:24][OH:23])[CH2:11][CH2:10]1
Reactant: CC(=O)[O-]
Reactant: CON
Reactant: O=C1CCC(c2ccc(O)cc2O)CC1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(O)ccc1C1CCC(=NO)CC1
Yield: 46.8 %

Procedure:
To a round bottomed flask, equipped with magnetic stirrer was added 4-(2,4-dihydroxyphenyl)cyclohexanone (21 mg, 0.10 mmol), anhydrous ethanol (3 ml), sodium acetate (16 mg, 0.20 mmol) and O-methylhydroxylamine hydrochloride (9 mg, 0.22 mmol). The reaction mixture was heated under reflux for 6 hr, then partitioned between ethyl acetate (10 ml) and water (10 ml). The organic layer was dried over anhydrous calcium sulphate, filtered and evaporated in vacuo furnishing a colourless oil. Purification via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 1:1, v/v), afforded the title compound as a white solid (11 mg, 47%). δH(CD3OD) 1.43-1.63 (2H, m), 1.81-1.92 (2H, m), 1.93-2.20 (2H, m), 2.24 (1H, dt), 2.38-2.44 (1H, m), 3.07 (1H, tt), 3.78 (3H, s), 6.20-6.23 (1H, m), 6.26 (1H, d), 6.85 (1H, d); m/z (ES−) 234.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+]([O-])=O)[CH:3]=1.[Cl-].[Li+].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:19]C(Cl)C>CN1CCCC1=O>[Cl:19][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CC(Cl)Cl
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
4.55 parts of 4-chloro-2-nitrobenzonitrile, 0.42 parts of lithium chloride, 1.11 parts of anhydrous aluminum chloride and 15 parts of N-methyl-2-pyrrolidone were reacted at 180° C. for 3 hours after the pattern of EXAMPLE B1. The reaction solution was added with 100 parts of dichloroethane, agitated for 30 minutes and filtered. Dichloroethane was distilled off from the filtrate and the residue was added with water to precipitate the crude crystals. The crude crystals were recrystallized by using a water-methanol mixed solvent to obtain 3.4 parts of 2,4-dichlorobenzonitrile with purity of 99%. Yield: 79.2%.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](OCC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl.O>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH2:16][OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2c(Cl)cccc2-n2cnc(CO)c2[C@@H]2CCN12

Procedure:
A suspension of 13.3 g (40 mmol) of ethyl (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate in 85 ml of tetrahydrofuran is heated to 50° and a suspension of 1.06 g (48.7 mmol) of lithium borohydride in 15 ml of tetrahydrofuran is then added dropwise to the solution obtained. The white suspension is subsequently heated to boiling under reflux for 70 minutes. The mixture is cooled to 20° and 54 ml of a solution consisting of 27 ml of conc. hydrochloric acid and 27 ml of water is added dropwise thereto. The tetrahydrofuran is distilled off in vacuo and the aqueous residue is made alkaline with 25 percent ammonia. The mixture is left to crystallize in an ice-bath for 1 hour, the precipitated material is filtered off under suction, rinsed with water and dried at 80° in a high vacuum. There is obtained (S)-8-chloro-12,12 a-dihydro-1-(hydroxymethyl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of decomposition point 256°-258°.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:40]([CH3:42])[CH3:41])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([O:17][CH2:18][C:19](=[O:39])[C:20]1[CH:21]=[CH:22][C:23]2[C:32]3[CH:31]=[C:30]4[CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:29]4=[CH:28][C:27]=3[O:26][CH2:25][C:24]=2[CH:38]=1)=[O:16])=[O:8])=[O:4].[Br-:43].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CO.Cl>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:40]([CH3:42])[CH3:41])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([O:17][CH2:18][C:19]([C:20]1[CH:21]=[CH:22][C:23]2[C:32]3[CH:31]=[C:30]4[CH2:33][CH2:34][CH:35]([Br:43])[C:36](=[O:37])[C:29]4=[CH:28][C:27]=3[O:26][CH2:25][C:24]=2[CH:38]=1)=[O:39])=[O:16])=[O:8])=[O:4]
Reactant: [Br-]
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O)C(C)C
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S,5S)-2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate (400 mg, 0.61 mmol) was dissolved in a solution of DCM (15 mL) and MeOH (6 mL), then treated with pyridinium tribromide (409 mg, 1.28 mmol). At 2 h, an additional portion of pyridinium tribromide (40 mg) was added. After stirring at RT for another 20 min, the reaction mixture was diluted with DCM and 10% HCl, and extracted with DCM. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure and the crude material was carried on without further purification.
Reaction SMILES: O[CH:2]([CH3:13])[CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1.[CH3:14]I.C(=O)([O-])[O-].[Na+].[Na+].[N-:22]=[N+:23]=[N-:24].[Na+]>CC(N(C)C)=O.N1C=CC=CC=1.CS(C)=O>[N:22]([CH:2]([CH3:13])[CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([O:12][CH3:14])=[O:11])=[CH:7][CH:6]=1)=[N+:23]=[N-:24]
Reactant: CI
Reactant: CC(O)CCc1ccc(C(=O)O)s1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: COC(=O)c1ccc(CCC(C)N=[N+]=[N-])s1

Procedure:
4-(5-Acetyl-2-thienyl)-2-butanone (Tetrahedron 35, 1979, 329) was reacted with ethylene glycol, triethyl orthoformate and p-toluenesulphonic acid in methylene chloride to give methyl 5-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-2-thienyl ketone. Oxidation with sodium hypobromite and subsequent hydrolysis gave 5-(3-oxobutyl)-2-thiophene carboxylic acid. With sodium borohydride there was obtained therefrom 5-(3-hydroxybutyl)-2-thiophenecarboxylic acid which was converted in dimethylacetamide with methyl iodide and sodium carbonate into the methyl ester. Treatment with p-toluenesulphochloride in pyridine and reaction with sodium azide in dimethyl sulphoxide gave methyl 5-(3-azidobutyl)-2-thiophenecarboxylate from which there was obtained by saponification the corresponding acid. The acid was treated with thionyl chloride to give the acid chloride from which there was obtained with concentrated ammonia in ether 5-(3-azidobutyl)-2-thiophenecarboxamide. Reduction of the azido group with triphenylphosphine and subsequent hydrolysis gave (R,S)-5-(3-aminobutyl)-2-thiophenecarboxamide of melting point 65°-75°. UV: ε256 =7780; ε275 =9900.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[C:8]=1[Cl:19])(=O)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[Cl:19][C:8]1[C:9]2[C:14](=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: COc1ccc2c(Cl)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2Cl)cc1

Procedure:
The title compound was prepared by reacting 1-chloro-6-methoxy-2-naphthyl trifluoromethanesulfonate (0.95 g, 2.79 mmol) with 4-methoxyphenyl boronic acid (0.59 g, 3.9 mmol) according to method A to yield 0.71 g (85%) of a white solid: mp 126-128° C.; 1H NMR (CDCl3): δ 3.88 (3H, s), 3.95 (3H, s), 7.01 (2H, d, J=8.60 Hz), 7.16 (1H, d, J=2.49 Hz), 7.27 (1H, dd, J=1.97 Hz, J=8.99 Hz), 7.41 (1H, d, J=8.45 Hz), 7.46 (2H, d, J=8.61 Hz), 7.68 (1H, d, J=8.48 Hz), 8.28 (1H, d, J=9.27 Hz); MS (ESI) m/z 299/301 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH:12][CH:11]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
A mixture of methyl 4-bromobutyrate (1.5 g, 8.29 mmol), 4-chlorophenol (1.17 g, 9.11 mmol), potassium carbonate (2.86 g, 20.7 mmol), and anhydrous N,N-dimethylformamide (5 mL) was added to a 25 mL RBF with a magnetic stirring bar. The mixture was allowed to stir at room temperature for 16 hours. Progress of the reaction was monitored by analytical HPLC with UV detection (Rt=6.5 min). The mixture was added to stirring ice/water (150 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with saturated aqueous NaCl (2×30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using a gradient elution of 0-100% ethyl acetate in hexanes to afford the title compound as a clear oil (1.45 g, 76% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2].[I:17]I>C(Cl)(Cl)Cl>[I-:17].[CH2:1]([C:3]1[C:16]2[C:7](=[S+:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: II
Reactant: CCc1cccc2c1Nc1ccccc1S2
Solvent: ClC(Cl)Cl
Product: CCc1cccc2[s+]c3ccccc3nc12
Product: [I-]
Temperature: 5 °C
Reaction time: 8 h

Procedure:
1-Ethylphenothiazine (664 mg, 2.84 mmol) was dissolved in CHCl3 (50 mL) and cooled to 5° C. The solution was stirred as a solution of I2 (2.16 g, 8.51 mmol) dissolved in CHCl3 (10 mL) was added dropwise. The mixture was stirred at 5° C. overnight and allowed to warm to RT. The solvent was evaporated to dryness. The residue was stirred in Et2O and was filtered off and washed with Et2O until the filtrate was colorless. The dark solid was dried under vacuum and used without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([C:17]2[NH:18][C:19]([CH3:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])=[O:16])[C@H:10]([CH2:25][O:26]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][O-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([C:17]2[NH:18][C:19]([CH3:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])=[O:16])[C@H:10]([CH2:25][O:26][CH3:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2NC(=O)c2[nH]c(C)c(Cl)c2Cl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Cis-tert-butyl-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-({[(4-methylphenyl)sulfonyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 72; 325 mg) was dissolved in 5 ml of a 30 wt % MeOH solution containing NaOMe and an additional 5 ml of dry MeOH. The homogeneous reaction was stirred at room temperature for 2 days. Upon reacting, solids began to precipitate from solution. The reaction was concentrated to a solid residue, re-dissolved in EtOAc and washed with saturated NH4Cl (2×10 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The residual material was purified by flash column chromatography eluting with (1:1 EtOAc/hexanes) to give the title compound (192 mg). MS (ES)(MH+): 420 for C19H27Cl2N3O4.
Reaction SMILES: B(Br)(Br)[Br:2].Cl.Cl.C[O:8][C:9]1[C:10]([CH3:41])=[C:11]([CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35]C)=[C:31]([O:37]C)[C:30]=2[CH2:39][CH3:40])[CH:12]=[CH:13][C:14]=1[O:15]C.CO>ClCCl>[BrH:2].[BrH:2].[OH:8][C:9]1[C:10]([CH3:41])=[C:11]([CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][C:29]2[C:30]([CH2:39][CH3:40])=[C:31]([OH:37])[C:32]([OH:35])=[CH:33][CH:34]=2)[CH:12]=[CH:13][C:14]=1[OH:15]
Reactant: CCc1c(CCNCCCCCCNCCc2ccc(OC)c(OC)c2C)ccc(OC)c1OC
Reactant: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Br
Product: CCc1c(CCNCCCCCCNCCc2ccc(O)c(O)c2C)ccc(O)c1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of boron tribromide (1.2 ml) in dichloromethane (10 ml) was added dropwise under nitrogen to a stirred, cooled solution of the product from Stage (i) (1.2 g) in dry dichloromethane (100 ml) at 0°. The mixture was stirred at room temperature for 5 h and methanol was then added. The mixture was evaporated in vacuo to give a solid which was recrystallised from methanol/ethyl acetate to give the title compound as a white powder (1 g), m.p. 178°-180°.
Reaction SMILES: C1C=CN=CC=1.F.[Si:8]([O:15][C@@H:16]([CH2:42][CH2:43][O:44][Si](C(C)(C)C)(C)C)[C@H:17]([CH3:41])/[CH:18]=[CH:19]/[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>N1C=CC=CC=1.C1COCC1>[Si:8]([O:15][C@H:16]([C@H:17]([CH3:41])/[CH:18]=[CH:19]/[CH2:20][O:21][C:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:42][CH2:43][OH:44])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: C[C@H](/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C[C@H](/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](CCO)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
HF-pyridine in pyridine (40 mL, prepared by slow addition of 12 mL pyridine to 3 mL HF-pyridine complex followed by dilution with 25 mL THF) was added to a solution of TBS ether 12 (4.46 g, 7.07 mmol) in THF (10 mL). The mixture was stirred overnight at room temperature and quenched with sat'd NaHCO3 (100 mL). The aqueous layer was separated and extracted with Et2O (3×50 mL). The combined organic layers were washed with sat'd CUSO4 (3×50 mL), dried over MgSO4, and concentrated. Flash column chromatography (EtOAc/hexane 1:4) afforded 3.26 g (89%) of alcohol 13 as a colorless oil: IR (CHCl3) 3407, 2955, 2928, 2856, 1490, 1471, 1448, 1254, 1058, 1031, 836, 773, 705 cm−1; 1H NMR (300 MHz, CDCl3) ε7.57 (m, 6H), 7.37 (m, 9H), 5.78 (dd, J=15.6, 6.5 Hz, 1H), 5.73 (dt, J=15.5, 4.8 Hz, 1H), 3.91 (m, 1H), 3.82 (d, J=5.9 Hz, 2H), 3.69 (d, J=4.4 Hz, 2H), 2.51 (m, 1H), 2.22 (br, 1H), 1.77 (m, 2H), 1.13 (d, J=6.8 Hz, 3H), 1.03 (s, 9H), 0.21 (s, 3H), 0.19 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 144.2, 134.1, 128.6, 127.7, 127.1, 126.9, 86.8, 74.3, 64.9, 60.4, 42.0, 34.8, 25.9, 18.0, 14.5, −4.4, −4.6; LRMS (ESI) 539.2 [M+Na]+, 243.2; HRMS (ESI) calcd for C33H44O3Si1Na 539.2957 [M+Na]+, found 539.2976; [α]20D−2.8 (c 2.0, CHCl3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]2[CH2:22][O:21]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH3:17].[CH2:23]([NH:30][CH2:22][C@@H:20]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[OH:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: O=c1ccc2c([C@@H]3CO3)ccc(OCc3ccccc3)c2[nH]1
Product: N
Product: O=c1ccc2c([C@@H](O)CNCc3ccccc3)ccc(OCc3ccccc3)c2[nH]1
Temperature: 150 °C

Procedure:
8-(Benzyloxy)-5-[(2R)-oxiran-2-yl]quinolin-2(1H)-one (0.102 g) (WO 9525104), was dissolved in benzylamine (0.5 ml) and heated in a microwave oven for 15 min at 150° C. Excess benzylamine was removed by evaporation on a rotary evaporator and the residue was purified on a silica SPE cartridge using methanol-dichloromethane-0.880 ammonia mixtures, to give the title compound (106 mg) LCMS RT=2.30 min
Reaction SMILES: Cl.CC(C)CNCC1CCCC1N.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH2:22][NH:23][C:24]([C:26]1[C:27](=[O:56])[C:28]([O:48]CC2C=CC=CC=2)=[C:29]2[C:45](=[O:46])[N:33]3[CH:34]4[CH2:44][CH2:43][CH2:42][CH:35]4[CH2:36][N:37]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH:32]3[CH2:31][N:30]2[CH:47]=1)=[O:25]>[Pd]>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH2:22][NH:23][C:24]([C:26]1[C:27](=[O:56])[C:28]([OH:48])=[C:29]2[C:45](=[O:46])[N:33]3[CH:34]4[CH2:44][CH2:43][CH2:42][CH:35]4[CH2:36][N:37]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH:32]3[CH2:31][N:30]2[CH:47]=1)=[O:25]
Reactant: CC(C)CN1CC2CCCC2N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3CC12
Agent: [Pd]
Agent: CC(C)CNCC1CCCC1N
Agent: Cl
Product: CC(C)CN1CC2CCCC2N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3CC12

Procedure:
In a manner similar to that described in example Z-35, from racemic-(1S,2S)-2-{[(2-methylpropyl)amino]methyl}cyclopentanamine hydrochloride 105 mg, 0.434 mmol) and 16a (56 mg, 0.119 mmol) was prepared racemic-(3aS,5aS,13aS)—N-[(2,4-difluorophenyl)methyl]-5-(2-methylpropyl)-10,12-dioxo-11-[(phenylmethyl)oxy]-2,3,3a,4,5,5a,6,10,12,13a-decahydro-1H-cyclopenta[e]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (52 mg, 74%). This material was deprotected in a second step similar to the procedure described in example Z-37. Thus, from racemic-(3aS,5aS,13aS)—N-[(2,4-difluorophenyl)methyl]-5-(2-methylpropyl)-10,12-dioxo-11-[(phenylmethyl)oxy]-2,3,3a,4,5,5a,6,10,12,13a-decahydro-1H-cyclopenta[e]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (48 mg, 0.081 mmol) and 10% Pd/C (catalytic amount), the title compound was prepared as a white solid after purification by HPLC (30 mg, 75%). 1H NMR (CDCl3) 12.59 (s, 1H), 10.42 (s, 1H), 828 (s, 1H), 7.34 (m, 1H), 6.79 (m, 2H), 4.83 (s, 1H), 4.63-4.58 (m, 3H), 4.29 (m, 1H), 4.14 (m, 1H), 2.91 (m, 1H), 2.46-2.32 (m, 3H), 2.15-2.09 (m, 2H), 1.85-1.61 (m, 5H), 1.39 (m, 1H), 0.88 (m, 6H); ES+ MS: 501 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]#[N:18])[CH:12]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O.C(OCC)(=O)C>[C:17]([C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][OH:8])[CH:16]=[CH:15][N:14]=1)#[N:18]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccnc(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(CCO)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
4-[2-(tert-Butyldimethylsilyloxy)ethyl]-2-cyanopyridine (12.8 g, 48.8 mmol) and a solution of tetrabutylammonium fluoride (1 M in THF, 73 mL, 73 mmol) were charged to a round bottom flask and stirred at room temperature overnight. The mixture was diluted with water and ethyl acetate. The layers were separated and the water layer extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (SiO2, 50:1 CH2Cl2: methanol) to provide 2-cyano-4-(2-hydroxyethyl)pyridine (4.4 g, 61%) as an off white solid.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[C:16](=[O:18])=[O:17]>CCOCC.CCCCCC>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:16]([OH:18])=[O:17])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C=O
Reactant: c1ccc2c(c1)CCCO2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(O)c1cccc2c1OCCC2
Temperature: 0 °C

Procedure:
At RT a solution of chroman (17.7 mmol) in ether (15 mL) is added over 10 min to a solution of n-BuLi (19.5 mmol) in a mixture of hexane (12.2 mL) and ether (15 mL). The mixture is stirred at reflux for 150 min, allowed to reach RT and poured into a mixture of dry ice and ether. Ice water is added and the layers are separated. The aq. layer is made acidic and extracted with a mixture of ether and EtOAc. The combined organic layers are washed with water, dried over Na2SO4 and concentrated in vacuo to give a crude product which is purified by CC (heptane/EtOAc 9/1 to EtOAc). LC-MS: tR=0.76 min; [M+CH3CN+H]+=220.1.
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]1[C:6](=[O:26])[N:7]([CH2:20][C:21]([O:23]CC)=[O:22])[CH:8]=[CH:9][C:10]=1[S:11](=[O:19])(=[O:18])[NH:12][CH2:13][CH:14]1[CH2:17][CH2:16][CH2:15]1.Cl>O.CO.C1COCC1>[NH2:4][C:5]1[C:6](=[O:26])[N:7]([CH2:20][C:21]([OH:23])=[O:22])[CH:8]=[CH:9][C:10]=1[S:11](=[O:18])(=[O:19])[NH:12][CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)Cn1ccc(S(=O)(=O)NCC2CCC2)c(N)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(S(=O)(=O)NCC2CCC2)ccn(CC(=O)O)c1=O
Reaction time: 2 h

Procedure:
Lithium hydroxide hydrate (40 mg, 0.952 mmol) was added to a stirred solution of 3-amino-4-(N-cyclobutylmethylsulfamoyl)-1-ethoxycarbonylmethyl-2-pyridinone (170 mg, 0.476 mmol) in 1:3:3 water/methanol/THF (14 mL). After 2 h, the reaction was acidified with 1M HCl and the mixture was partitioned between chloroform and brine. The organic layer was dried (Na2SO4) and evaporated to give the title compound as a solid;
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[OH-:8].[Na+].C1C=CC(S(O)(=O)=[N:17]O)=CC=1>C(O)C>[NH2:17][CH:2]([CH3:1])[CH2:6][CH2:5][CH2:4][C:3]([OH:7])=[O:8]
Reactant: [OH-]
Reactant: O=S(O)(=NO)c1ccccc1
Reactant: CC1CCCC1=O
Agent: [Na+]
Solvent: CCO
Product: CC(N)CCCC(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
5-Aminohexanoic Acid was prepared by combining 0.5 g 2-methylcyclopentanone and 9.5 ml 2 N NaOH in sufficient ethanol to give a homogeneous solution. The mixture was cooled to 0° C., 0.9 g of benzene sulfohydroxamic acid (C6H5SO2NHOH) was added, and the mixture stored overnight in the refrigerator. Thereafter the mixture was concentrated in vacuo and extracted with ether. The post-extraction residue is brought to between pH 5-6 with 2 N HCl extracted with chloroform to give an oil bp. 70°-80° C. (4 mm), 7-8% yield. This product N-hydroxy-6-methyl-2-piperidone, is reduced with hydrogen over 10% palladium-charcoal to a lactam, 6-methyl-2-piperidone (mp. 79°-80° C.). The lactam is hydrolyzed with aqueous Ba(OH)2 to yield 5-amino-hexanoic acid. ##STR7##