Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[Mg].Br[C:14]1[CH:22]=[CH:21][C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1>C1COCC1>[O:18]1[C:17]2[CH:21]=[CH:22][C:14]([C:7]3([OH:10])[CH2:6][CH2:5][C:4]4([O:3][CH2:2][CH2:1][O:11]4)[CH2:9][CH2:8]3)=[CH:15][C:16]=2[O:20][CH2:19]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal (31.2 g, 0.2 mole) in 100 ml dry THF was added to a -60° C. solution of the Grignard reagent prepared from magnesium metal (7.2 g, 0.3 mole) and 5-bromo-1,3-benzodioxole (60.3 g, 0.3 mole). The mixture was allowed to warm to 25° C. and quenched with saturated NH4Cl and extracted with ether. The extracts were dried with Na2SO4 and the solvent removed in vacuo. The residue was crystallized from isopropyl ether to give the product (47.5 g, 85%, m.p: 103°-104° C.).
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[CH:10]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.CCCCCC>[C:2]([N:6]([C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:7][C:16]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:17])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)C1CCCCC1)C(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of t-butylhydrazine hydrochloride (2.0 g, 0.016M) in toluene (30 ml) was added 50% sodium hydroxide (1.3 g, 0.016M). After 15 minutes, the mixture was cooled to 5° C. and cyclohexanecarbonylchloride (2.4 g, 0.016 M) and 50% sodium hydroxide (1.3 g, 0.016M) were added separately and simultaneously so as to maintain the reaction temperature below 10° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 1 hr. The mixture was diluted with hexane and the solid product isolated by filtration. This product (1.5 g, 0.008M) was dissolved in a stirred mixture of toluene (30 ml) and cooled on ice. To this mixture was added benzoylchloride (1.1 g, 0.008 M) and 50% sodium hydroxide (0.6 g, 0.008M) simultaneously. After addition, the mixture was stirred for 1/2 hr., diluted with hexane and the solid product, N'-t-butyl-N-cyclohexylcarbonyl-N'-benzoylhydrazine, isolated by filtration.
Reaction SMILES: Cl[Sn]Cl.[CH2:4]([C:12]1[N:13]([CH2:24][CH3:25])[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([N+:21]([O-])=O)=[CH:16][CH:15]=2)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[CH2:4]([C:12]1[N:13]([CH2:24][CH3:25])[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([NH2:21])=[CH:16][CH:15]=2)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCn1c(CCc2ccccc2)cc2cc([N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(CCc2ccccc2)cc2cc(N)ccc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
SnCl2 (1.2 g, 6.3 mmol) was added to a solution of 2-phenethyl-1-ethyl-5-nitro-1H-indole (0.17 g, 0.57 mmol) in THF (50 ml). The mixture was kept under stirring at 70° C. overnight. After cooling, the mixture was poured in H2O, neutralized with NaHCO3, and extracted with ethyl acetate (3×50 ml). After evaporation of the solvent under reduced pressure, the solid was purified on a chromatographic column using CHCl3 as eluent to give 2-phenethyl-1-ethyl-1H-indol-5-amine.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]([O-:10])=[O:9])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:17]#[C:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+].[N:26]([O-])=O.[Na+].[ClH:30]>C(OCC)C.O>[Cl:30][C:17]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:26][N:1]=[C:2]2[N:6]([CH2:7][C:8]([OH:10])=[O:9])[N:5]=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:3]=12
Reactant: Nc1c(C#Cc2ccccc2)c(-c2ccccc2)nn1CC(=O)[O-]
Reactant: Cl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of sodium 2-(5-amino-3-phenyl-4-(phenylethynyl)-1H-pyrazol-1-yl)acetate (2 g, 6.0 mmol) in diethylether (10 mL) and concentrated HCl (50 mL) was cooled at −15° C. before sodium nitrite (0.62 g, 8.0 mmol) in water (5 mL) was added dropwise. The solution was allowed to warm up to room temperature and left stirring for further 18 h. The reaction mixture was carefully quenched with an aqueous solution of Na2CO3 at 10° C., until pH basic, and then extracted EtOAc, backwashed with water then brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, gradient 2 to 10% diethylether/CH2Cl2) yielding Compound 47 as a yellow foam (580 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([NH2:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[N:17]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:15]=[CH:14][C:12]4[N:13]=[C:27]([C:26]5[CH:29]=[CH:30][C:23]([N:17]6[CH2:22][CH2:21][O:20][CH2:19][CH2:18]6)=[CH:24][CH:25]=5)[NH:16][C:11]=4[CH:10]=3)=[CH:3][C:2]=2[N:1]=[C:27]1[C:26]1[CH:25]=[CH:24][C:23]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:30][CH:29]=1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Product: c1cc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2cc1-c1ccc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1

Procedure:
Compound 286 was prepared according to the procedure similar to that described in Scheme III from 3,3′-diaminobenzidine and 4-morpholinylbenzaldehyde. [M+H]+ calcd for C34H32N6O2: 557.26; found: 557.58.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[C:39]([CH2:40][N:41]2[CH2:61][CH2:60][C:44]3([O:49][CH2:48][CH2:47][N:46]([C:50]([C:52]4[N:53]=[C:54]([CH:57]([CH3:59])[CH3:58])[S:55][CH:56]=4)=[O:51])[CH2:45]3)[CH2:43][CH2:42]2)=[CH:38][CH:37]=[CH:36][C:27]=1[CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33](O)=[O:34].[CH3:62][O:63][CH:64]([O:72][CH3:73])[CH2:65][NH:66][CH2:67][C:68]([F:71])([F:70])[F:69].C(N(CC)CC)C>CN(C=O)C>[CH3:73][O:72][CH:64]([O:63][CH3:62])[CH2:65][N:66]([CH2:67][C:68]([F:69])([F:70])[F:71])[C:33](=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28][C:27]1[CH:36]=[CH:37][CH:38]=[C:39]([CH2:40][N:41]2[CH2:42][CH2:43][C:44]3([O:49][CH2:48][CH2:47][N:46]([C:50]([C:52]4[N:53]=[C:54]([CH:57]([CH3:59])[CH3:58])[S:55][CH:56]=4)=[O:51])[CH2:45]3)[CH2:60][CH2:61]2)[C:26]=1[F:25]
Reactant: COC(CNCC(F)(F)F)OC
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4F)CC3)C2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(CN(CC(F)(F)F)C(=O)CCOCCc1cccc(CN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1F)OC
Temperature: 20 °C
Reaction time: 72 h

Procedure:
HATU (0.30 g) was added in one portion to a cooled solution (ice bath) of 3-(2-fluoro-3-((4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoic acid [Example 7, step d] (0.32 g) and N-(2,2-dimethoxyethyl)-2,2,2-trifluoroethanamine [Amine 14] (0.17 g) and triethylamine (0.25 mL) in DMF (7 mL). The mixture was stirred at 20° C. for 3 days, then partitioned between ethyl acetate and brine. The organic phase was washed with brine (×2), dried, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, using 5% methanol in ethyl acetate with 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 0.15 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH:22]=O.N1CCCCC1>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:14]1[NH:15][C:16]2[C:21]([C:13]=1[CH3:12])=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: Cc1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1ccc2c(c1)C(=Cc1[nH]c3ccccc3c1C)C(=O)N2
Temperature: 90 °C
Yield: 71 %

Procedure:
A mixture of 5-methyl-2-oxindole (59 mg), 3-methylindole-2-carbaldehyde (56 mg) and piperidine (30 mg) in ethanol (1 mL) was heated in a sealed tube at 90° C. for overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven for overnight to give 72 mg (74% yield) of 5-methyl-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one.
Reaction SMILES: N1[C:5](=O)[CH2:4][CH2:3][C@H:2]1[C:7](O)=O.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[Br-:20].[Li+]>C(O)C.CC(C)=O.C(N(CC)CC)C>[Br:20][CH2:7][C:2]#[C:3][CH2:4][CH2:5][CH2:7][CH2:2][CH2:3][CH3:4]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [Li+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCCCC#CCBr

Procedure:
Pentadeca-2,5,8-triyn-1-ol tetrahydropyranyl ether can be prepared by coupling propargyl alcohol tetrahydropyranyl ether with n-hexyl bromide in the presence of lithium amide, to produce 2-nonyn-1-ol tetrahydropyranyl ether, then hydrolysing of the tetrahydropyranyloxy function with Pyr/PTS in ethanol solution followed by esterification of the hydroxy compound with methanesulfonyl chloride in the presence of triethylamine. The mesylate is then reacted with lithium bromide in acetone solution to produce 1-bromo-2-nonyne. Finally the latter compound is coupled with hexa-2,5-diyn-1-ol-tetrahydropyranyl ether in the presence of ethylmagnesium bromide and cuprous chloride. The sequence of reaction conditions are essentially the same as those described hereinafter in detail.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:25])[C:10](=[O:24])[N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)(=O)C.[Cl:38]C(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)([O-])O.[Na+]>[ClH:38].[CH2:26]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:25])[C:10]([N:11]2[CH2:12][CH2:13][CH:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:24])[CH:5]=[CH:6][CH:7]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1cccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)c1
Reactant: O=Cc1ccccc1
Reactant: CC(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cl
Product: O=C(Nc1cccc(NCc2ccccc2)c1)C(=O)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.9 %

Procedure:
To a stirred solution of 0.51 g (1.5 mmol) of N-(3-aminophenyl)-2-(4-benzyl-piperidin-1-yl)-oxo-acetamide (Example 11), 0.15 ml (1.5 mmol) of benzaldehyde, 0.18 ml (3 mmol) of acetic acid in 15 ml of dichloroethane 0.48 g (2.25 mmol) of sodium triacetoxyborohydride (Aldrich) is added in small portions below 20° C., and the reaction mixture is stirred at room temperature for 2 hours. Then 30 ml of 8% sodium hydrogencarbonate solution is added to the mixture, the organic layer is separated and the water phase is extracted three times with 30 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated and the residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and ethyl acetate:hexane=1:2 as eluent. The product is treated with 2.5 N hydrochloric acid in ethyl acetate solution to yield 0.25 g (36%) of the title compound. Melting Point: 190-207° C. (dec.) (ethyl acetate)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11](I)[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(OCC)(=O)C>[CH2:11]([O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)[CH3:12]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOc1cccc(C(C)=O)c1
Temperature: 70 °C
Reaction time: 9 h

Procedure:
3′-Hydroxyacetophenone (200 mg) was dissolved in acetonitrile (4 ml). After adding ethyl iodide (0.2 ml) and potassium carbonate (347 mg), the mixture was stirred at 70° C. for 9 hours. After 9 hours, water and ethyl acetate were added to the reaction mixture followed by separation. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated. The crude product thus obtained was purified by silica gel chromatography (n-hexane:ethyl acetate=8:1) to thereby give 204 mg of 3′-ethoxyacetophenone. The procedure employed for the synthesis of F-12 was repeated, but replacing the 3′-methoxyacetophenone by 3′-ethoxyacetophenone to thereby give (±)-N-(1-(3-ethoxyphenyl)ethyl)-2-(2′,5′-dichlorophenylthio)ethylamine (F-63). MS m/z: 369 (M+).
Reaction SMILES: N#N.[Br:3][C:4]1[CH:5]=[N:6][N:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:9][C:8]=12.CCN(C(C)C)C(C)C.Cl[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:32]([O:31][C:29]([N:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:11]=[CH:12][N:7]3[N:6]=[CH:5][C:4]([Br:3])=[C:8]3[N:9]=2)[CH2:14][CH2:15]1)=[O:30])([CH3:34])[CH3:33]
Reactant: Brc1cnn2ccc(N3CCNCC3)nc12
Reactant: CC(C)OC(=O)Cl
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 0 °C

Procedure:
To a rapidly stirred, 0° C., N2 blanketed, solution of 3-bromo-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine (15.8 g, 56.0 mmol) and Hunig's base [7087-68-5] (20.0 mL, 114.8 mmol) in ethyl acetate (280 mL) was steadily added a 1.0M solution of isopropyl chloroformate in toluene (67.0 mL) over the course of 10 minutes. The reaction was allowed to stir and warm to ambient temperature over night at which time it was washed with brine, dried (MgSO4), preloaded onto silica gel, chromatographed (Silica gel, eluted with 100% ethyl acetate) and crystallized from ethyl acetate/heptane to afford 13.2 g of white powder, mp. 78-79° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J=6.32 Hz, 6 H) 3.44-3.54 (m, 4 H) 3.67-3.79 (m, 4 H) 4.82 (spt, J=6.23 Hz, 1 H) 6.77 (d, J=7.83 Hz, 1 H) 7.97 (s, 1 H) 8.69 (d, J=7.83 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) δ ppm 21.94, 42.80, 43.87, 68.17, 77.32, 97.66, 136.47, 143.87, 144.40, 154.29, 155.64. LRMS (ESI) m/z 368.0/370.0 [(M+H)]+, calc'd for C14H18BrN5O2: 368.24.
Reaction SMILES: [CH2:1]([P:3]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[Cl:27])[CH:13]=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29])(=O)[O:4][CH2:5][CH3:6])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32]>>[CH2:1]([P:3]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[Cl:27])[CH:13]=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29])(=[S:32])[O:4][CH2:5][CH3:6])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOP(=O)(CC)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: CCOP(=S)(CC)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of ethyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphinate (4.7 mmol) and phosphorus pentasulfide (1.2 mmol) is heated to 150°-160° under nitrogen for 3-4 hours. After cooling, the residue is purified by prep. TLC to give O-ethyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphinothioate.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(OCC)(=O)C.O>CN(C=O)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Cn2cncn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
4-Nitrobenzylbromide (21.6 g, 0.1 mol) was added to a rapidly stirred suspension of 1,2,4-triazole sodium salt (9.1 g, 0.1 mol) in anhydrous DMF (100 ml) and the mixture stirred at room temperature for 16 h. Ethyl acetate (400 ml) was added followed by water (250 ml) and the layers separated. The organic phase was washed with water (3×250 ml), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate to give the title-product (10.6 g, 52%); m.p. 98°-100° C. δ (360 MHz, CDCl3) 5.47 (2H, s, CH2) 7.40 (2H, d, J=9 Hz, Ar-H), 8.02 (1H, s, Ar-H), 8.18 (1H, s, Ar-H), 8.23 (2H, d, J=9 Hz, Ar-H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:24])[CH3:23])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:25]([O:27]C)=[O:26])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-]>CO.O>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:24])[CH3:23])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:25]([OH:27])=[O:26])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@H](N(C(C)=O)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
Methyl (2S,4S)-1-BOC-4-[acetyl(4,4-dimethylcyclohexyl)amino]pyrrolidine-2-carboxylate (0.98 g, 2.47 mmol) obtained in Step B, was dissolved in MeOH (8 mL) and water (1.6 mL). LiOH (0.18 g, 7.52 mmol) was added thereto at 0˜5° C. After the reaction mixture was stirred at room temperature for 3 hours and concentrated in vacuo, the obtained residue was diluted with water and the solution was extracted with EtOAc. The extracted organic solution was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (0.92 g, 97%).
Reaction SMILES: C1([CH:7]2O[C:15]3[C:10](=[N:11][C:12]([CH:17]=C)=[CH:13][CH:14]=3)[CH2:9][O:8]2)C=CC=CC=1.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([O:28]O)=[O:27])[CH:21]=1.ClC1C=C(C=CC=1)C(O)=[O:35]>C(Cl)Cl>[O:8]1[CH2:7][CH:9]1[C:10]1[N+:11]([O-:35])=[C:12]2[CH2:17][O:27][CH:26]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:20][CH:21]=3)[O:28][C:13]2=[CH:14][CH:15]=1
Reactant: C=Cc1ccc2c(n1)COC(c1ccccc1)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1c(C2CO2)ccc2c1COC(c1ccccc1)O2
Yield: 21 %

Procedure:
In a 4-neck 500 ml., round bottom flask, fitted with a reflux condenser, a mechanical stirrer/magnetic stirring bar and a thermometer, was placed 2-phenyl-6-vinyl-4H-1,3-dioxino[5,4-b]pyridine (8.0 g., 0.033 mole) in methylene chloride (250 ml.). The solution was treated portion wise with m-chloroperbenzoic acid (20.0 g., 0.116 mole). When all of the peracid was added, the solution was heated at reflux overnight. Upon cooling m-chlorobenzoic acid crystallized from the reaction mixture and was filtered off. The filtrate was washed with aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated in vacuo to give the crude product (5.1 g.) which was recrystallized from ethyl acetate to give 6-(1,2-epoxyethyl)-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine N-oxide (1.9 g., 21%), m.p. 180°-181.5° C. (dec.); NMR (CDCl3) delta 7.28 (m, 5H), 6.82 (q, 2H), 5.82 (s, 1H), 5.05 (s, 2H), 4.40 (d of d, 1H), 3.18 (d of d, 1H), 2.97 (d of d, 1H); mass spec (70 eV), m/e 217 (M+), 241 (M-O, CH2), 206, 165, 149, 132, 107, 105, 101, 82, 80, 79, 77.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]2[CH2:25][O:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:26][CH2:27][CH2:28][CH2:29][OH:30].CN1CCCC1=O.Cl>[Cl-].[Na+].O.ClCCl>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]([OH:24])[CH2:25][NH:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C[C@@H]2CO2)ccc1Cl
Reactant: NCCCO
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C[C@@H](O)CNCCCO)ccc1Cl

Procedure:
2-Chloro-5-[(2R)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 5c) (133 mg), 3-amino-1-propanol (3 mL) and 1-methyl-2-pyrrolidinone (5 mL) were heated together at 80° C. in a sealed tube for 22 hours, cooled and poured into brine (50 mL), extracted into ethyl acetate (3×50 mL), washed with brine (3×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. This was purified by Waters' MCX resin and then by column chromatography eluting with 9:1:0.1 dichloromethane/methanol/ammonia. This was further purified by reverse phase HPLC (gradient 25–95% acetonitrile in 0.2% aqueous trifluoroacetic acid on Xterra™ column). The oil obtained was dissolved in dichloromethane (5 mL) and 1M ethereal hydrogen chloride (4 mL) was added. The mixture was concentrated to give the titled compound as a solid (60 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][NH:6][C:7](=[O:18])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=1[O:16][CH3:17].[CH2:20](O)[CH2:21][CH2:22]C.C1(C)C=CC=CC=1>CCCCO.CCCCO.CCCCO.CCCCO.[Ti].CO.C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3](=[O:19])[CH2:4][O:5][NH:6][C:7](=[O:18])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=1[O:16][CH3:17])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCO
Reactant: COC(=O)CONC(=O)c1c(Cl)ccc(Cl)c1OC
Agent: [Ti]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCOC(=O)CONC(=O)c1c(Cl)ccc(Cl)c1OC
Temperature: 85 °C

Procedure:
To 161.8 g. of methyl[(3,6-dichloro-2-methoxybenzoyl) aminooxy]acetate was added 80 g. of n-butyl alcohol, 600 ml. of toluene, and 9.5 g. of titanium n-butoxide. The mixture was stirred and heated to 85° C. for 2 hours to drive off a methanol/toluene mixture. The heat was then maintained at 95°-100° C. to distill off n-butanol/toluene. The reaction mixture was cooled to 40° C. and 150 ml. of 1 M. HCl added. The mixture was then washed with 1 M. HCl, water, then saturated NaHCO3 solution, and then dried over MgOS4, filtered, and evaporated in vacuo to yield the title product as a white solid, m.p. 68°-71° C.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([Br:21])[C:19]=1[OH:20])[C:13](=[N:15]O)[NH2:14]>N1C=CC=CC=1>[Br:9][C:10]1[CH:11]=[C:12]([C:13]2[N:15]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:8][N:14]=2)[CH:17]=[C:18]([Br:21])[C:19]=1[OH:20]
Reactant: NC(=NO)c1cc(Br)c(O)c(Br)c1
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2cc(Br)c(O)c(Br)c2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
Ethyl 2-chloro-2-oxoacetate (12.3 g, 82 mmol) was added dropwise to a stirred solution of 3,5-dibromo-N′,4-dihydroxybenzimidamide (25.5 g, 82 mmol) in pyridine (120 mL) and the mixture was stirred at room temperature for 1 hour and then at 60° C. for 2 hours. The resulting suspension was poured onto water (1.5 L) and extracted with ethyl acetate (2×400 mL). The combined extracts were washed with saturated sodium chloride, dried (MgSO4) and evaporated in vacuo to give an oily solid that was purified by flash chromatography to give a colourless powder. Crystallisation from toluene (400 mL) gave the title compound (14.7 g, 46%) as colourless crystals. 1H NMR δ (ppm) (DMSO-d6): 1.14 (3 H, t), 4.49 (2 H, q), 8.14 (2 H, s), 10.93 (1 H, br s).