Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:16])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[C:12]1([CH3:15])[CH:13]=[CH:14][C:9]([NH:8][CH2:7][C:6]([OH:16])=[O:5])=[CH:10][CH:11]=1
Reactant: Cc1ccc(NCC(=O)OC(C)(C)C)cc1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NCC(=O)O)cc1
Reaction time: 96 h
Yield: 54.5 %

Procedure:
A solution of crude p-tolylamino-acetic acid tert-butyl ester (200 mmol) in DCM (600 mL) was cooled to 0° C. and treated with TFA (150 mL). The reaction mixture was allowed to reach RT and stirred for 4 d. Water (200 mL) was added, the layers were separated and the aqueous layer was extracted with DCM (4×200 mL). The aqueous layer was adjusted to pH 8 by addition of saturated NaHCO3 solution and extracted with ethyl acetate (4×200 mL). The combined organic layers were dried with Na2SO4 and the solvents were removed in vacuo to give the crude acid (18 g) which was used in the next step without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]#[N:11])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Br:12]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:12][C:3]1[C:4]2[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=2[S:1][CH:2]=1
Reactant: N#Cc1ccc2ccsc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(Br)csc2c1
Temperature: 25 °C

Procedure:
To a solution of 1-benzothiophene-6-carbonitrile (2.13 g, 13.4 mmol) in dry DMF (20 mL) at −10° C. was added freshly recrystallised N-bromosuccinimide (2.38 g, 13.4 mmol). The solution was allowed to warm to room temperature and stirred over the weekend. The mixture was diluted with water and extracted into diethyl ether, and the organic extract washed with water, then brine. The extracts were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica, eluting with ethyl acetate/hexane (1:9), to yield the title compound as a white solid.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9][S:10][CH3:11])(=O)=O.[S:20]([O-:23])([O-:22])=[O:21].[Na+:24].[Na+]>CCO.O>[C:16]([O:15][C:13]([NH:12][C@@H:7]([CH2:8][CH2:9][S:10][CH3:11])[CH2:6][S:20]([O-:23])(=[O:22])=[O:21])=[O:14])([CH3:17])([CH3:18])[CH3:19].[Na+:24]
Reactant: CSCC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSCC[C@@H](CS(=O)(=O)[O-])NC(=O)OC(C)(C)C
Yield: 33.3 %

Procedure:
(S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butyl methanesulfonate (1.1 g, 3.51 mmol, 1.0 eq) was dissolved in EtOH (10 mL) and water (8.0 mL). Sodium sulfite (2.21 g, 5.0 eq) was added. The mixture was heated to reflux for 16 hours, and concentrated. The residue was purified by reversed phase column (Diaion HP-20) using distilled water (200 ml) first, then 10% CH3CN in water and finally 20% CH3CN in water to give sodium (S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butane-1-sulfonate (376 mg, 37%). 1H NMR (DMSO-d6, 300 MHz) d 6.75 (d, 1H, NH), 3.50 (br s, 1H, BocNHCH), 2.3-2.5 (m, 4H, SCH2 and OSCH2, overlapped with DMSO solvent peak), 2.0 (s, 3H, SCH3), 1.8 (m, 1H, NHCHCH2CH2S), 1.6 (m, 1H, NHCHCH2CH2S), 1.35 (s, 9H, OC(CH3)3). LC-MS: 2.03 min; MS (ESI−) m/z 298 (M-Na)+, 198 (M-Na-Boc)+.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[C@@H:14]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][O:16][CH2:17][C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.ClC1C=C(C=CC=1)C(OO)=[O:32].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O-:32][N+:6]1[C:7]2[C:2](=[CH:1][CH:10]=[CH:9][CH:8]=2)[C:3]2[N:13]3[C@@H:14]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:15][O:16][CH2:17][C:12]3=[N:11][C:4]=2[CH:5]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1COCc2nc3cnc4ccccc4c3n21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1COCc2nc3c[n+]([O-])c4ccccc4c3n21
Reaction time: 2 h
Yield: 99.6 %

Procedure:
tert-Butyl (11S)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-ylmethylcarbamate (1.62 g, 4.58 mmol) was dissolved in 40 mL of CH2Cl2 and treated with 3-chloroperoxybenzoic acid (MCPBA) (1.23 g, 77% maximum purity). After stirring for 2 hours, the reaction mixture was treated with 40 mL of 2% Na2CO3 solution and 40 mL of CH2Cl2 and the layers were separated. The aqueous layer was then extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with 10 mL of brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl [(11S)-5-oxido-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]methylcarbamate (1.69 g) as a crusty, off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15].O>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(Br)CBr
Reactant: Nc1cccc(F)c1C(=O)O
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1cccc(F)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
To a solution of 2-amino-6-fluorobenzoic acid (8.0 g, 0.052 mol) in anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) at 0° C. in a 250 mL 3-necked flask fitted with a constant additional funnel was added, dropwise, bromoacetyl bromide (10.4 g, 100 mol%) while keeping the internal temperature between 0° C. and 2° C. After the addition was completed (~30 min), the reaction mixture was stirred at rt overnight. Water (100 mL) was added, and the light crystalline compound which precipitated was filtered, washed sequentially with 5% HBr and water, and then dried in a vacuum oven at 40°-45° C., affording 9.5 g (67%) of the title compound: mp 168.9°-170.3° C.; 1H NMR (DMSO-d6) δ13.80 (bs, 1H, OH), 10.60 (s, 1H, NH), 7.69 (d, 1H, J=8.4), 7.54 (dt, 1H, J=8.4, J=10.4), 7.13-7.08 (m, 1H), 4.16 (s, 2H); 13C NMR (DMSO-d6) δ165.22 (d, J=32.4, C=O), 160.18 (d, J=251), 137.83, 132.69 (d, J=10.0), 118.58, 118.20, 112.18 (d, J=22.9), 30.04; MS (EI, m/z) 275 (M+). HRMS (EI) calcd for C9H7NO3FBr 274.9593, found 274.9595. Anal. Calcd for C9H7NO3FBr: C, 39.16; H, 2.56; N, 5.08. Found: C, 38.96; H, 2.48; N, 5.07.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:3]OS(C)(=O)=O.[I-:17].[Na+]>>[I:17][CH2:3][C:2]([CH3:16])([CH3:1])[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C)(COS(C)(=O)=O)CN1CCCCC1
Reactant: [I-]
Agent: [Na+]
Product: CC(C)(CI)CN1CCCCC1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
In analogy to the procedure described for example 6D, methanesulfonic acid 2,2-dimethyl-3-piperidin-1-yl-propyl ester and sodium iodide stirred at 95° C. for 3 h gave the title compound as brown oil. MS: 282.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[OH:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].CC(C)([O-])C.[K+]>C(C(C)=O)C>[Br:13][CH2:14][CH2:15][CH2:16][O:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=1[Cl:11]
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Reactant: BrCCCBr
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cc(Cl)c(OCCCBr)c(Cl)c1
Yield: 94.8 %

Procedure:
A mixture of 4.16 g of 2,6-dichloro-4-nitrophenol, 40.4 g of 1,3-dibromopropane, 2.76 g of potassium carbonate and 2.46 g of potassium t-butoxide was heated under reflux for 4 hours in 50 ml of methyl ethyl ketone. The reaction mixture was allowed to cool down and insoluble matters were filtered off. The filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform. The thus-prepared chloroform solution was washed with water, and the chloroform was then distilled off. The residue was purified by chromatography on a silica gel column (eluent: chloroform/hexane=4/1, by volume) to obtain 6.24 g of 1-bromo-3-(2,6-dichloro-4-nitrophenyloxy)propane. This compound was employed in the next reaction without any further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:33][C@H:32]([CH2:34][O:35]C(=O)C3C=CC=CC=3)[C@@H:22]([O:23]C(=O)C3C=CC=CC=3)[C@H:12]2[O:13]C(=O)C2C=CC=CC=2)=[C:4]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([I:52])[CH:47]=2)[N:3]=1.N.CO>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([OH:23])[C@H:12]2[OH:13])=[C:4]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([I:52])[CH:47]=2)[N:3]=1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(NCc4cccc(I)c4)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCc4cccc(I)c4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 66.5 h
Yield: 93.8 %

Procedure:
A mixture of 2-chloro-N6 -(3-iodobenzyl)-9-[2,3,5-tri-O-benzoyl-β-D-ribofuranosyl]-adenine (760 mg, 0.916 mmol) and NH3 /MeOH (15 ml) was stirred for 66.5 h at room temperature. After the reaction mixture was concentrated to dryness, the residue was purified on a silica gel column chromatography (CHCl3 --MeOH, 20:1) to yield 2-chloro-N6 -(3-iodobenzyl)-9-[β-D-ribofuranosyl]-adenine (445 mg, 94%) as a foam. 1H NMR (DMSO-d6) d 3.55 (m, 1H, H-5'a), 3.65 (m, 1H, H-5'b), 3.94 (d, J=3.6 Hz, 1H, H-4'), 4.12 (m, 1H, H-3'), 4.51 (q, J=5.5 Hz, 1H, H-2'), 4.60 (br d, J=5.7 Hz, 2H, CH2), 5.04 (pseudo t, J=5.7 and 5.5 Hz, 1H, exchangeable with D2O, 5'-OH), 5.19 (d, J=4.9 Hz, 1H, exchangeable with D2O, OH), 5.47 (d, J=6.0 Hz, 1H, exchangeable with D2O, OH), 5.83 (d, J=5.5 Hz, 1H, H-1'), 7.13 (pseudo t, J=7.9 and 7.6 Hz, 1H, H-5"), 7.36 (d, J=7.5 Hz, 1H, H-4" or -6"), 7.60 (d, J=7.9 Hz, 1H, H-4" or -6"), 7.74 (s, 1H, H-2"), 8.43 (s, 1H, H-8), 8.94 (br t, J=6.0 Hz, 1H, exchangeable with D2O, NH,).
Reaction SMILES: C([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([OH:27])=[O:26])[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([OH:27])=[O:26])[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H](CCC1CCCCC1)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCC2CCCCC2)C(=O)O)COc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
In 1 ml of ethanol is dissolved 0.2 g of 3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid obtained in Example 54, and 3 ml of 1N sodium hydroxide solution is added to the solution. After stirring at room temperature for 2 hours, the solution is acidified slightly with 1N hydrochloric acid. The deposited crystals are collected by filtration, washed with water, dried and recrystallized from ethanol to give 0.14 g of 3(S)-[1(S)-carboxy-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid as colorless crystals, melting at 202°-205° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:12])=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:13](O)(=O)C.OS(O)(=O)=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[OH-].[NH4+]>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:12][C:5]1[N:4]=[N:3][C:2]([Cl:1])=[C:7]([C:8]([F:9])([F:10])[F:11])[C:6]=1[CH3:13]
Reactant: CC(=O)O
Reactant: FC(F)(F)c1cc(Cl)nnc1Cl
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: Cc1c(Cl)nnc(Cl)c1C(F)(F)F
Temperature: 50 °C
Yield: 87 %

Procedure:
To a stirred suspension of Preparative Example 3, C4 (1.0 eq) and AgNO3(0.5 eq.) in H2O (0.15M) was added acetic acid (2.0 eq.). The mixture was heated to 50° C. and then a solution of conc. H2SO4(3.0 eq.) in H2O (0.5M) was added to the mixture. The temperature was then raised to 70° C. and a solution of ammonium persulfate (3.0 eq.) in H2O (0.5M) was added dropwise over 10 min. The reaction mixture was heated at 70-75° C. for a further 30 min. After cooling, the reaction mixture was adjusted to pH=7 with 32% ammonium hydroxide solution, and extracted with Et2O. The extracts were washed with brine, dried (Na2SO4) and the solvent was removed under reduced pressure. Crude product was purified by flash column chromatography on silica gel using 2-10% Et2O/Petroleum ether, the desired D1 as a yellow oil (87% yield). 1H-NMR (300 MHz, CDCl3, 300K) δ 2.66 (3H, s). MS (ES) C6H3Cl2F3N2 requires: 231; 233, found: 232; 234 (M+H)+.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.[CH2:15]([C@@H:22]1[CH2:26][O:25][C:24](=[O:27])[N:23]1[C:28](=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Br[CH2:35][C:36]1[CH:44]=[C:43]2[C:39]([CH:40]=[N:41][N:42]2[CH2:45][CH2:46][CH2:47][O:48][CH3:49])=[CH:38][CH:37]=1.[NH4+].[Cl-]>C1COCC1>[CH2:15]([C@@H:22]1[CH2:26][O:25][C:24](=[O:27])[N:23]1[C:28](=[O:33])[C@H:29]([CH2:35][C:36]1[CH:44]=[C:43]2[C:39]([CH:40]=[N:41][N:42]2[CH2:45][CH2:46][CH2:47][O:48][CH3:49])=[CH:38][CH:37]=1)[CH:30]([CH3:31])[CH3:32])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COCCCn1ncc2ccc(CBr)cc21
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCCn1ncc2ccc(C[C@@H](C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)C(C)C)cc21
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a stirred solution of hexamethyldisilazane (200 mg, 1.24 mmol) in anhydrous THF (2 mL) cooled to −78° C. under N2 was added dropwise 2.5 M n-BuLi (0.5 mL, 1.25 mol) over 30 min. After stirring for an additional 30 min, a solution of (R)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one (313 mg, 1.2 mmol) in THF (2 mL) was added dropwise to the reaction mixture. The mixture was stirred at −78° C. for 2 h and a solution of 6-(bromomethyl)-1-(3-methoxypropyl)-1H-indazole (300 mg, 1.1 mmol) in THF (2 mL) was added. The mixture was allowed to warm from −78° C. to 0° C. over 2 h and stirred at it for 18 h. 10% aq NH4Cl was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel to give (R)-4-benzyl-3-((R)-2-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutanoyl)-oxazolidin-2-one (250 mg, 49%). 1H NMR (400 MHz, CDCl3): 1.09 (m, 6H), 1.96 (m, 1H), 2.09 (m, 3H), 2.61 (m, 1H), 3.12 (m, 2H), 3.22 (m, 2H), 3.29 (s, 3H), 3.89 (m, 1H), 4.02 (m, 1H), 4.35 (m, 1H), 4.40 (m, 1H), 4.59 (m, 1H), 6.75 (m, 2H), 7.07 (m, 3H), 7.13 (m, 1H), 7.26 (m, 1H), 7.33 (m, 1H), 7.61 (m, 1H), 7.91 (m, 1H); MS: 464 (M++1)
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:10]=[CH:9][N:8]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:10]=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nccc(N2CCCCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: ClCc1nccc(N2CCCCC2)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Thionyl chloride (3.01 ml) was added dropwise to a stirred solution of 2-hydroxymethyl-4-piperidinopyrimidine (2.66 g) in chloroform (20 ml) cooled in an ice/salt bath. The mixture was allowed to warm to room temperature and stirred for a further 2.5 hours. The solution was poured onto ice, the pH raised to ca. 8 (NaOH), and extracted with chloroform. The extracts were dried and stripped to give 2-chloromethyl-4-piperidino-pyrimidine (2.92 g) as an unstable oil which was used immediately.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>O.C(Cl)Cl.C(N(CC)CC)C>[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(CC=C)c1nc(NC(=O)c2ccccc2)n2oc(=O)nc2n1
Temperature: 0 °C

Procedure:
7.0 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 250 ml. of methylene chloride and 10 ml. of triethylamine, cooled while stirring to 0° C. and treated with 4.5 ml. of benzoyl chloride in 35 ml. of methylene chloride. The mixture is subsequently stirred at 0° C. for 1 hour, then diluted with water and adjusted to pH 4 with hydrochloric acid. The two phases are separated and the aqueous phase is extracted twice with methylene chloride. The organic extracts are combined, dried over magnesium sulfate and evaporated at 20° C. under reduced pressure. The residue is recrystallized from methylene chloride and diethyl ether, there being obtained pure N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}benzamide having a melting point of 182°-183° C.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10](=[O:13])[CH2:11]I)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[O:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:8][C:6]1[N:7]=[C:2]2[N:21]([CH2:20][CH:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)[CH2:11][C:10](=[O:13])[NH:9][C:3]2=[N:4][CH:5]=1
Reactant: NCC1CCOCC1
Reactant: O=C(CI)Nc1ncc(Br)nc1Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(CC2CCOCC2)c2nc(Br)cnc2N1
Temperature: 40 °C
Yield: 78.6 %

Procedure:
N-(3,5-Dibromopyrazin-2-yl)-2-iodoacetamide (See Example 5.B) (8.0 g, 19.01 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (2.63 g, 22.81 mmol) and diisopropylethylamine (6.64 mL, 38.0 mmol) were placed in a 250 mL round bottom flask, suspended in acetonitrile (80.0 mL) and heated to 40° C. for 16 h. The resulting white precipitate was filtered, washed with acetonitrile followed by hexanes and dried under vacuum to afford the title compound (4.89 g, 14.95 mmol, 79% yield). MS (ESI) m/z 327.4 [M]+, 329.5 [M+2]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12].[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:17]=1[C:18](Cl)=[O:19]>C(Cl)Cl>[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:17]=1[C:18]([NH:12][CH2:11][CH:10]([O:13][CH3:14])[O:9][CH3:8])=[O:19]
Reactant: COC(CN)OC
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(CNC(=O)c1cc([N+](=O)[O-])ccc1Cl)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
Thionyl chloride (14 mL, 192 mmol) was added-dropwise to a solution of 2-chloro-5-nitrobenzoic acid (10 g, 49.6 mmol) in chloroform (150 mL) at 0° C. The mixture was heated to reflux for 4 h then cooled to r.t., concentrated in vacuo and dried under high vacuum to yield 2-chloro-5-nitrobenzoyl chloride (10 g, 91.7%) as a solid. Under nitrogen, triethylamine (19 mL, 136 mmol) was added slowly to a solution of aminoacetaldehyde dimethyl acetal (5.43 mL, 50.0 mmol) in dry DCM (20 mL) at 0° C. 2-Chloro-5-nitrobenzoyl chloride (10 g, 45.5 mmol) was slurried in dry DCM (30 mL) and added over a period of 30 minutes. The mixture was allowed to warm to r.t. and stirred overnight then partitioned between water and DCM. The organic phase was washed with saturated sodium bicarbonate solution, water and brine then dried over sodium sulfate and concentrated. The crude product was triturated with petroleum ether then diethyl ether and finally purified by column chromatography on silica gel (60-120 mesh) eluting with ethyl acetate/petroleum ether (2% to 40% gradient) to afford 2-chloro-N-(2,2-dimethoxy-ethyl)-5-nitro benzamide (8.3 g, 63%) as a yellow solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=1.[Cl-].[Na+]>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([Cl:1])[C:13]([NH2:16])=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=1
Reactant: CC(C)(C)c1cc(Br)ccc1N
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Br)cc(Cl)c1N
Temperature: 70 °C
Yield: 98.7 %

Procedure:
6.4 g (48 mmol) of N-chlorosuccinimide are added to a solution of 10 g (44 mmol) of 4-bromo-2-tert-butylphenylamine (example 1a) in 150 ml of DMF. The medium is heated at 70° C. for 2 hours. It is then poured into a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The organic phases are combined and washed with water and then dried over sodium sulphate. The residue is chromatographed on silica gel (90/10 heptane/ethyl acetate). 11.4 g of 4-bromo-2-tert-butyl-6-chlorophenylamine are obtained in the form of an orange oil (yield=99%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[C:12]([O-])([O-])=O.[K+].[K+].CI.CN(C=O)C>CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ncccc1O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1ncccc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.1 %

Procedure:
In a 50 mL round-bottom flask fitted with magnetic stirrer were placed 3-hydroxypyridine-2-carboxylic acid methyl ester (3.5 g, 22.80 mmol), K2CO3 (3.46 g, 25.0 mmol), MeI (4.87 g, 34.3 mmol) and DMF (20 mL). The reaction mixture was stirred for 18 h at rt under nitrogen. The reaction mixture was diluted with EtOAc (30 mL) and water (10 mL). The organic layer was separated and aqueous layer was extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by column chromatography using 30% EtOAc in hexane to give 2.1 g of 3-methoxypyridine-2-carboxylic acid methyl ester (54%).
Reaction SMILES: N[C:2]1[C:10]2[N:9]=[N:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.N([O-])=O.[Na+].[ClH:21]>O>[Cl:21][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: Nc1cccc2c1nnn2C1CCCCC1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cccc2c1nnn2C1CCCCC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of the 4-amino-1-cyclohexylbenzotriazole (11.4 g, 0.054 mol) in 75 ml of concentrated hydrochloric acid and 75 ml of water at 5°, was slowly added 4.1 g of sodium nitrite (0.059 mol) in 15 ml of water. On completion of the addition, the reaction mixture was allowed to stir an additional 1/2 hour at 0°-5°. Next the solution was added slowly to an excess of freshly prepared cuprous chloride in 120 ml of concentrated hydrochloric acid also at 0°-5°. On completion of the addition, the reaction came to room temperature over a 21/2 hour period. Then one liter of water was added to the reaction mixture and the crude product which precipitated was collected by filtration, washed with water and air-dried. This material was purified by column chromatography to yield 6.2 g of product, m.p. 141°-144°.