Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[N:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:25][O:26][CH2:27][CH2:28][OH:29].Cl.C([O-])(O)=O.[Na+]>CO.O>[OH:29][CH2:28][CH2:27][O:26]/[N:25]=[C:21](/[C:18]1[CH:19]=[N:20][C:15]2[N:16]([C:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[CH:13][N:14]=2)[N:17]=1)\[CH3:22]
Reactant: CC(=O)c1cnc2ncc(Cc3ccc4ncccc4c3)n2n1
Reactant: NOCCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C/C(=N\OCCO)c1cnc2ncc(Cc3ccc4ncccc4c3)n2n1
Yield: 74.3 %

Procedure:
A solution of 1-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)ethanone (40 mg, 0.13 mmol), 2-(aminooxy)ethanol hydrochloride (30 mg, 0.26 mmol) and HCl (4 N in 1,4-dioxane, 0.1 mL) in methanol (5 mL) was stirred at room temperature for 48 h. The reaction mixture was neutralized with saturated aqueous NaHCO3 solution and diluted with water, extracted with dichloromethane, dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography in silica gel eluting with a ethyl acetate/methanol gradient to afford 35 mg (74%) of the title compound as yellow solid. 1H-NMR (400 MHz, d6-DMSO) δ ppm 8.94 (s, 1H), 8.84 (d, 1H), 8.28 (d, 1H), 7.97-7.91 (m, 3H), 7.77 (d, 1H), 7.49 (dd, 1H), 4.77 (t, 1H), 4.56 (s, 2H), 4.30-4.27 (m, 2H), 3.71-3.70 (m, 2H), 2.25 (s, 3H). LCMS (method B): [MH]+=363, tR=2.08 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([C:42]([O:44][CH3:45])=[O:43])[S:40][CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:37]3[CH:38]=[C:39]([C:42]([O:44][CH3:45])=[O:43])[S:40][CH:41]=3)=[N:8][N:9]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Reactant: COc1ccc(Cn2nc(OS(=O)(=O)C(F)(F)F)c3c(OC)nccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2nn(Cc3ccc(OC)cc3)c3ccnc(OC)c23)cs1
Temperature: 100 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of 4-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (157 mg) obtained in Step C of Example 94 in DME (4 mL) were added methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (121 mg) and 2M aqueous sodium carbonate solution (0.940 mL), and then tetrakis(triphenylphosphine)palladium(0) (42.8 mg) was added thereto under nitrogen atmosphere. The reaction mixture was stirred overnight under nitrogen atmosphere at 100° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (77.9 mg).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[C:20]([Br:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)=[N:8]2)=[C:4]([NH2:22])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:33][CH2:34][CH2:35][C:36]#[CH:37])(=O)=O>CN(C=O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[C:20]([Br:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)[N:8]2[CH2:37][CH2:36][CH2:35][C:34]#[CH:33])=[C:4]([NH2:22])[N:3]=1
Reactant: Nc1nc(F)nc2nc(Cc3cc4c(cc3Br)OCO4)[nH]c12
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc3c(cc2Br)OCO3)nc2c(N)nc(F)nc21

Procedure:
A solution of 2-Fluoro-8-(6-bromo-benzo[1,3]dioxol-5-ylmethyl)adenine (20 mg, 55 mol), Cs2CO3 (18 mg, 55 mol) and pent-4-ynyl tosylate (17 mg, 72 mol) in anhydrous DMF (138 L) was stirred at 60° C. for 2 h. Following solvent removal, the product (13 mg, 54.7%) was collected through silica gel column purification (EtOAc:hexanes:CHCl3:i-PrOH at 10:20:20:1). 1H NMR (400 MHz, CDCl3) 7.05 (s, 1H), 6.60 (s, 1H), 6.15 (bs, 2H), 5.96 (s, 2H), 4.28 (s, 2H), 4.13 (t, J=7.5 Hz, 2H), 2.25-2.21 (m, 2H), 2.00 (t, J=2.6 Hz, 1H), 1.98-1.92 (m, 2H); 13C NMR (100 MHz, CDCl3) 157.6, 156.0, 152.6, 150.2, 147.5, 127.6, 116.4, 114.1, 112.5, 109.5, 101.6, 81.9, 69.5, 41.9, 33.7, 27.8, 15.5; MS m/z 432.0 (M+H)+. HPLC: (a) 99.0% (60% water-40% acetonitrile); (b) 98.5% (35% to 55% acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21][CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].CN(C)C=[O:34].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[Cl:1][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:34])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]1=[O:14]
Reactant: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCSC4)cc1
Reactant: CN(C)C=O
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)C4)cc1
Temperature: -7 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A mixture of 1-{[3-chloro-4-(4-methoxyphenyl)-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione (239.6 g) and dimethylformamide (1.8 L) was cooled to −7° C. and vanadium (IV) oxyacetylacetone (691 mg) was added thereto. 30% Hydrogen peroxide (59.2 g) was added dropwise and the mixture was stirred at 2° C. or lower for 8 hours. 0.5N Sodium thiosulfate (100 ml) and water (3 L) were added dropwise at 5 to 7° C. and the mixture was stirred at 15 to 20° C. for 1 hour. Crystals deposited were filtered off to obtain the titled compound (242 g, 97.5%). 1H-NMR (CDCl3) δ: 2.13-2.20 (1H, m), 2.54-2.73 (2H, m), 3.02-3.09 (1H, m), 3.90 (3H, s), 4.00 (1H, d, J=16.9 Hz), 4.10 (1H, d, J=16.9 Hz), 5.00 (1H, d, J=17.2 Hz), 5.06 (1H, d, J=17.2 Hz), 7.01 (2H, d, J=8.1 Hz), 7.16 (2H, d, J=8.1 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Reactant: FC(F)(F)c1cccc(CBr)c1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2cccc(C(F)(F)F)c2)cc1
Yield: 53.2 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 3-trifluoromethyl-benzyl bromide (145 mg, 0.6 mmol) to afford the title product (120 mg, 55% yield); LCMS; 100% APCI+, Calcd: 451.49. Found m/z: 452.27 (M+1). 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.09 (m, 4H), 3.26-3.44 (m, 2H), 3.69-3.91 (m, 1H), 4.02-4.18 (m 2H), 5.05 (s, 2H), 6.88 (s, 4H), 7.49 (t, J=7.6 Hz, 1H), 7.57-7.62 (m, 2H), 7.70 (s, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].N(C(OCC)=O)=NC(OCC)=O.[OH:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44]O>C(Cl)Cl.O1CCCC1>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:44][C:43]1[CH:42]=[C:41]([OH:40])[CH:48]=[CH:47][CH:46]=1
Reactant: Oc1ccccc1Cl
Reactant: OCc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Oc1cccc(COc2ccccc2Cl)c1
Reaction time: 1 h
Yield: 50.9 %

Procedure:
At 0° C. to 616 mg (2.35 mmol) of triphenylphosphine and 400 μL (3.84 mmol) of 2-chlorophenol in 20 mL of methylene chloride was added 370 mL (2.35 mmol) of diethyl azodicarboxylate followed by dropwise addition of a solution of 233 mg (1.9 mmol) 3-hydroxybenzyl alcohol in 2 mL of tetrahydrofuran. The reaction mixture was stirred at 0° C. to ambient temperature for 1 h. The reaction mixture was quenched with water, extracted into diethyl ether, dried (MgSO4), and purified by flash chromatography (methylene chloride/hexane (2:1 to 4:1)) to provided 227 mg (44% yield) of the title compound as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.39 (dd, 1 H, J=1.6, 7.8 Hz), 7.25 (t, 1 H), 7.15-7.21 (m, 1 H), 6.88 -7.01 (m, 4 H), 6.79 (dd, 1 H, J=2.5, 8.1 Hz), 5.12 (s, 2 H), and 4.97 (s, 1 H).
Reaction SMILES: [C:1]1([C:7]([NH:20][CH2:21][C:22]2[N:23]([CH2:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:24]=[CH:25][N:26]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][O:35][CH:36]([O:40][CH3:41])N(C)C>>[CH3:34][O:35][CH:36]([O:40][CH3:41])[N:31]1[CH2:32][CH2:33][CH:28]([CH2:27][N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH2:21][NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:29][CH2:30]1
Reactant: COC(OC)N(C)C
Reactant: c1ccc(C(NCc2nccn2CC2CCNCC2)(c2ccccc2)c2ccccc2)cc1
Product: COC(OC)N1CCC(Cn2ccnc2CNC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[(2-triphenylmethylaminomethyl-1H-imidazol-1-yl)methyl]piperidine (1.45 g, 0.0033M) and dimethylformamide dimethylacetal wass heated at 100° C. for 8 hrs. After this period, the reaction was stripped to dryness to give 4-[(2-triphenylmethylaminomethyl-1H-imidazol-1-yl)methyl]-piperidine carboxaldehyde dimethylacetal. The solution of the piperidinecarboxaldehydedimethylacetal in methylene chloride (5 ml) was added to the mixture of 6-aminopenicillanic acid (0.57 g, 0.0026M) and diisopropylethylamine (0.45 ml) in methylene chloride (5 ml) at 0° C. and stirred at room temperature for 3 hrs. The solvent was removed and the residue was stirred for 2 hrs in water (20 ml) which was maintained at pH 3 with 1NHCl. The mixture was filtered and the filtrate was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[[4-[[2-(aminomethyl)-1H-imidazol-1-yl]methyl]-1-piperidinyl] methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (0.27 g, 24% yield).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([CH2:17][C:18]3[NH:19][C:20]([C:36]4[S:37][CH:38]=[CH:39][N:40]=4)=[N:21][C@@H:22]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[Cl:35])[C:23]=3[C:24]([O:26][CH3:27])=[O:25])[CH:10]([CH2:11][O:12][CH2:13]2)[CH2:9]1)=O)(C)(C)C.[C:41](O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:27][O:26][C:24]([C:23]1[C@H:22]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[Cl:35])[N:21]=[C:20]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)[NH:19][C:18]=1[CH2:17][N:16]1[CH:14]2[CH2:15][N:8]([C:6](=[O:5])[CH3:41])[CH2:9][CH:10]1[CH2:11][O:12][CH2:13]2)=[O:25]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)C1=C(CN2C3COCC2CN(C(=O)OC(C)(C)C)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1=C(CN2C3COCC2CN(C(C)=O)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 9-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester (280 mg, 0.47 mmol) in CH2Cl2 (10 mL) was added TFA (2 mL) dropwise in ice-bath. The mixture was stirred at room temperature for 16 hours. The mixture was neutralized with a saturated aqueous sodium bicarbonate solution and then extracted with CH2Cl2 (20 mL×2). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL×2), and then dried over anhydrous sodium sulfate and then concentrated in vacuo to afford (R)-6-(7-acetyl-3-oxa-7,9-diaza-bicyclo[3.3.1]non-9-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound AC) as light yellow oil (230 mg, 98%) which was used for next step without further purification. MS: calc'd (MH+) 492, measured (MH+) 492.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[I:10].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O>[N:11]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[I:10])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1ccc(CBr)c(I)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(F)cc1I
Temperature: 50 °C
Yield: 99.8 %

Procedure:
A solution of 1-(bromomethyl)-4-fluoro-2-iodobenzene (M. Protiva et al., Collect. Czech. Chem. Comm., 44, 1979, 2108–2123) (17.9 g, 56.8 mmol) in N,N-dimethylformamide (35 ml) was treated with sodium azide (5.0 g, 76.7 mmol) and the resulting mixture was heated to 50° C. for 4 h. The cooled mixture was filtered, the filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (elution hexane) to give 15.7 g (97% yield) of the title azide as a clear oil. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 4.53 (2H, s, CH2), 7.32 (1H, m, aromatic), 7.54 (1H, dd, J=6 Hz and J=8.6 Hz, aromatic), 7.83 (1H, dd, J=3 Hz and J=8 Hz, aromatic).
Reaction SMILES: CS([C:4]1[NH:5][CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=O.[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH2:22]>CO>[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:4]1[NH:5][CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CS(=O)c1[nH]ccc1[N+](=O)[O-]
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CO
Product: Cc1[nH]cnc1CSCCNc1[nH]ccc1[N+](=O)[O-]
Yield: 34.1 %

Procedure:
A solution of 2-methylsulphinyl-3-nitropyrrole (2g, 0.01 mol) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (2g, 0.01 mol) in methanol (50 ml) was refluxed for 7 days and evaporated to dryness. The residue was chromatographed on a silica gel column eluted with ethyl acetate, and the eluate was evaporated to dryness and recrystallised from propan-2-ol to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-3-nitropyrrole (0.96g, 31%) m.p. 161-162°.
Reaction SMILES: Cl[C:2]1([CH2:7][C:8]([Cl:11])(Cl)[Cl:9])[O:5][C:4](=O)[CH2:3]1.Cl.[NH2:13][C:14]([NH2:16])=[NH:15].Cl>>[NH2:16][C:14]1[N:15]=[C:2]([CH:7]=[C:8]([Cl:11])[Cl:9])[CH:3]=[C:4]([OH:5])[N:13]=1
Reactant: O=C1CC(Cl)(CC(Cl)(Cl)Cl)O1
Reactant: N=C(N)N
Agent: Cl
Product: Nc1nc(O)cc(C=C(Cl)Cl)n1
Temperature: 140 °C
Reaction time: 0.75 h

Procedure:
119 Parts of 4-chloro-4-(2,2,2-trichloroethyl)-oxetan-2-one and 95.5 parts of guanidine hydrochloride were charged to a reaction flask and heated in an oil bath at 140° C. for 15 minutes. The solid dissolved and HCl gas was evolved. The oil bath temperature was raised to 160° C. and heating was continued for a further 45 minutes. The heat was removed and the reaction mass was stirred until cool and solidified. The solid was stirred with 250 parts of ethyl acetate and filtered. The filtrate was discarded and the solid dissolved in 1000 parts of hot water, treated with charcoal and filtered. The aqueous solution was cooled and neutralised by the addition of saturated sodium acetate solution. The precipitated solid was filtered and washed with water. This crude product was then dissolved in 550 parts of concentrated hydrochloric acid, diluted with 800 parts of water and stirred with 5 parts of charcoal for 20 minutes. The solution was filtered and the product precipitated by the addition of saturated sodium acetate solution to pH 6. The solid was filtered, washed with water and dried in a vacuum oven at 110° C. to give 2-amino-4-(2,2-dichloro-vinyl)-6-hydroxypyrimidine m.p. 245°-248° C. (decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C@H:17]([CH2:29][OH:30])[CH2:18][CH2:19][N:20]2[CH2:27][CH2:26][C:23]3([CH2:25][CH2:24]3)[C@H:22]([OH:28])[CH2:21]2)[C:13](=[O:31])[C@@H:12]1[CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C@H:17]([CH2:29][O:30][C:36](=[O:37])[NH:35][CH2:33][CH3:34])[CH2:18][CH2:19][N:20]2[CH2:27][CH2:26][C:23]3([CH2:25][CH2:24]3)[C@H:22]([OH:28])[CH2:21]2)[C:13](=[O:31])[C@@H:12]1[CH3:32])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN=C=O
Reactant: C[C@H]1C(=O)N([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)OCc1ccccc1
Solvent: CC#N
Product: CCNC(=O)OC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)OCc2ccccc2)[C@@H](C)C1=O
Temperature: 40 °C
Reaction time: 72 h
Yield: 45.6 %

Procedure:
To a solution of (S)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-hydroxymethyl-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (intermediate 39; 63 mg, 0.14 mmol) in acetonitrile (1 mL) was added ethyl isocyanate (11 mg, 0.14 mmol) at 0° C. The ice bath was removed, then after 16 h another portion of ethyl isocyanate (11 mg, 0.14 mmol) was added, and the reaction mixture was stirred at 40° C. for 72 h. Volatile material was removed by concentration under vacuum, and the residue was chromatographed (SiO2; dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) to afford the title compound (33 mg, 45%). Colorless gum, MS (ISP)=517.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][C:20]2[C:21]([C:25]([NH:27][CH3:28])=[O:26])=[C:22]([CH3:24])[O:23][C:19]=2[CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[O:16][C:17]1[CH:30]=[CH:29][C:20]2[C:21]([C:25]([NH:27][CH3:28])=[O:26])=[C:22]([CH3:24])[O:23][C:19]=2[CH:18]=1
Reactant: CNC(=O)c1c(C)oc2cc(O)ccc12
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)c1c(C)oc2cc(Oc3ncnc4cc(OC)c(OC)cc34)ccc12
Reaction time: 10 h
Yield: 85 %

Procedure:
To a solution of 4-chloro-6,7-dimethoxyquinazoline (1 equiv.) in 2 ml CH3CN were added 6-hydroxy-N,2-dimethylbenzofuran-3-carboxamide (1 equiv.) and K2CO3 (1.5 equiv.). The mixture was refluxed under stirring for 10 hr. After the solvent was evaporated, the residue was washed with water, dried over MgSO4, filtered, concentrated, and purified by column chromatography to give the title compound in a yield of 85%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>>[N+:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][C:17](=[O:18])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C:9]3=[O:14])=[CH:4][C:3]=2[F:15])=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(N2CCOCC2=O)cc1F
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1

Procedure:
72.1 Using general method G, 4-(4-amino-3-fluoro-phenyl)-morpholin-3-one (prepared according to WO 2003045912) was activated with 4-nitrophenyl chloroformate to give [2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester. White solid.
Reaction SMILES: [CH3:1][C:2]([CH3:31])=[C:3]([N:8]1[C@H:11](SC)[C@@H:10]([CH:14]([O:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[CH3:15])[C:9]1=[O:30])[C:4]([O:6][CH3:7])=[O:5].[Cl:32]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:32][CH:11]1[N:8]([C:3](=[C:2]([CH3:31])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])[C:9](=[O:30])[C@@H:10]1[CH:14]([O:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])[CH3:15]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1SC
Reactant: ClCl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C1Cl
Temperature: 0 °C

Procedure:
To a solution of a mixture (1:3) of methyl 3-methyl-2-[(3S,4R)-4-methylthio-3-{(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-but-2-enoate (1.30 g) in dichloromethane (13 ml) was added a solution of chlorine (211 mg) in carbon tetrachloride (2.2 ml) at -78° C. The solution was allowed to warm to 0° C. during 45 minutes and concentrated. The residue was dissolved in ethyl acetate (30 ml) and washed with a chilled aqueous sodium bicarbonate (2.5 g), water, and brine. Drying over magnesium sulfate and evaporation left an oil (1.30 g), which showed two spots on silica gel thin layer chromatography (1:1 hexane/ethyl acetate). The residue was chromatographed on silica gel (40 g) eluting with 10-30% ethyl acetate in hexane to afford firstly a mixture (5:6:4) of methyl 2-[(3S)-4-chloro-3-{1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbutenoate [a mixture (5:6:4) of (1S,4R) isomer, (1R, 4R) isomer and (1R, 4S) isomer] (550 mg).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].Br[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17](OC)=[CH:16][CH:15]=1)=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[CH2:13]([O:12][C:10]([CH2:9][S:4][CH2:3][C@@H:2]([C:5]([OH:7])=[O:6])[NH2:1])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@H](CS)C(=O)O
Reactant: COc1ccc(COC(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H](CSCC(=O)OCc1ccccc1)C(=O)O

Procedure:
D-cysteine is S-alkyl substituted with p-methoxybenzyl bromoacetate in presence of sodium carbonate in a THF-water medium. The S-benzyloxycarbonylmethylcysteine thus obtained is N-acylated with (R)-3-tetradecanoyloxytetradecanoic acid chloride, and the S-alkyl-N-acyl-D-cysteine derivative is then coupled with (2R)-5-amino-2-[(R)-3-hydroxytetradecanoylamino]pentan-1-ol amine {obtained by hydrogenolysis of the (2R)-5-amino-2-[(R)-3-benzyloxy-tetradecanoyl-amino]pentan-1-ol, see 4.1.1.} in presence of IIDQ. The thus obtained product is selectively O-acylated in its primary position with the ester derived from reacting HOBt with 7-(p-methoxybenzyloxy-carbonylamino)heptanoic acid. The two p-methoxybenzyl groups are then removed by treating the ester with aqueous trifluoroacetic acid. C59H112N4O10S. MM 1069.64.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]1([C:12](Cl)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(OCC)(=O)C>[C:12]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Reaction time: 20 h
Yield: 41.3 %

Procedure:
To a stirred solution of 23.5 g (0.35 mole) of imidazole in 425 mL of ethyl acetate was added 48.0 g (0.32 mole) of triphenylmethyl chloride. The mixture was stirred for 20 hours and then 500 mL of water was added. After being stirred for an additional 2 hours, the mixture was filtered. The ethyl acetate layer was separated, dried (MgSO4) and concentrated. Recrystallization of the residue from xylene gave 41 g of white crystals, mp 222°-225° C..