Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]3)[CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(=C(c1ccccc1)c1ccccc1)C1CCNCC1
Reactant: ClCCCCCCCCCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C(=C(c1ccccc1)c1ccccc1)C1CCN(CCCCCCCCCCC2CCCNC2)CC1

Procedure:
The title compound was prepared in a manner similar to that employed for the compound of Example 23 starting with 6.59 g of 4-(2,2-diphenylethenyl)piperidine, 6.4 g of 3-(10-chlorodecyl)pyridine, 3.75 g of sodium iodide, 2.65 g of anhydrous sodium carbonate, and 40 mL of dimethylformamide. The mixture was heated at 75° for 18 hours and the solvent was evaporated. The residue was partitioned between 1N sodium hydroxide and ethyl acetate and the organic layer was removed, dried over sodium sulfate, decolorized with charcoal, filtered, and evaporated to give 10.4 g (86%) of product as a colorless oil. Crystallization from hexane provided the pure 3-[10-[4-(2,2-Diphenylethenyl)-1-piperidinyl]decyl]pyridine, mp 63°-65° C. Analysis Calculated for C34H44N2 : C, 84.95; H, 9.23; N, 5.83. Found: C. 85.21; H 9.27; N, 5.84. The fumaric acid salt was obtained from acetone, mp 134°-136° C. Analysis Calculated for C34H44N2.C4H4O4 : C, 76.48; H, 8.11; N, 4.69. Found: C, 76.53; H, 8.17; N, 4.88.
Reaction SMILES: [CH3:1][CH:2]1[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:20])[NH:4][CH2:3]1.[OH-].[Na+]>C1COCC1.C(O)C>[CH3:1][CH:2]1[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:20])[NH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)C(C)CNC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1CNC(=O)c2cc3ccc(C(=O)O)cc3n21
Temperature: 75 °C
Yield: 76.3 %

Procedure:
To a suspension of ethyl 4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylate (3.2 g, 11.8 mmol) in THF:ethanol (1:1, 50 mL) is added 1N NaOH solution (43 mL, 43 mmol). The reaction mixture is heated at 75° C. for 18 h. The solvents are removed and the residue is dissolved in water. The aqueous solution is washed with ether and acidified to pH 4 using 3N HCl solution. The resulting white solid is filtered and rinsed more ether to afford the title compound (2.2 g, 76%).
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]([C@@H:19]1[CH:23]=[CH:22][CH2:21][O:20]1)[CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(=[O:4])=[O:3].C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=[O:29].[Na+].[Na+].FC(F)(F)C(C)=O.C(=O)(O)[O-].[Na+].OOS([O-])=O.[K+]>C(#N)C.O>[CH3:1][S:2]([O:5][C@H:6]([C@H:19]1[O:20][CH2:21][C@H:22]2[C@@H:23]1[O:29]2)[CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(=[O:3])=[O:4]
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Reactant: CS(=O)(=O)O[C@@H](CNC(=O)OCc1ccccc1)[C@@H]1C=CCO1
Agent: CC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])OO
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)O[C@@H](CNC(=O)OCc1ccccc1)[C@H]1OC[C@@H]2O[C@H]12
Reaction time: 0.5 h

Procedure:
To a solution of mesylate (51) (439 mg, 1.29 mmol) in acetonitrile (7 mL) and aqueous Na2.EDTA (7 mL, 0.4 mmol solution) at 0° C. was added 1,1,1-trifluoroacetone (1.38 mL, 15.4 mmol). To this solution was added in portions a mixture of sodium bicarbonate (0.907 g, 10.8 mmol) and OXONE® (2.45 g, 3.99 mmol) over a period of 80 minutes. The mixture was stirred for 30 minutes then diluted with water (10 mL) and the product extracted into dichloromethane (1×10 mL and 2×20 mL). The combined organic layers were washed with brine (30 mL) then dried (MgSO4), filtered and reduced in vacuo. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 10:90 to 50:50 gave (in order of elution) anti-(52) (271 mg, 59%) and syn-epoxide (71 mg, 15%) as colourless oils. Data for anti-(52); TLC (Rf=0.41, EtOAc:heptane 3:2), analytical HPLC single main peak, Rt=13.556 min., HPLC-MS 358.2 [M+H]+, 380.2 [M+Na]+, 737.3 [2M+Na]+; [□]D12.5−28.8° (c=1.910, CHCl3); δH (500 MHz, CDCl3) 2.99 (3H, s, OSO2CH3), 3.47 and 3.50 (1H total, each brt, J=6.24 Hz, CH2NH), 3.60 and 3.63 (1H total, each brt, 5.63 respectively, CH2NH), 3.86-3.90 (3H, m, OCH2CHCH), 3.98 (1H, d, J=10.27 Hz, OCH2CH), 4.17 (1H, d, J=2.70 Hz, OCHCHOMs), 4.83-4.87 (1H, m, CHOMs), 5.08-5.14 (2H m, CH2Ph), 5.23 (1H, brs, NH), 7.30-7.36 (5H, m, aromatic CH); δC (125 MHz, CDCl3) 38.570 (OSO2CH3), 42.217 (CH2NHCbz), 56.231 and 57.062 (OCH2CHCH), 67.176 (CH2Ph), 68.353 (OCH2CH), 77.063 (OCHCHOMs), 79.435 (CHOMs), 128.209, 128.343 and 128.587 (aromatic CH), 136.089 (Cbz quaternary), 156.528 (Cbz C═O). Data for syn-epoxide; TLC (Rf=0.29, EtOAc:heptane 3:2), analytical HPLC main peak, Rt=13.639 min., HPLC-MS 358.1 [M+H]+, 737.2 [2M+Na]+; [□]D12.5−9.2° (c=3.543, CHCl3); δH (500 MHz, CDCl3) 3.04 (3H, s, OSO2CH3), 3.60-3.80 (2H, m, CH2NH), 3.72 (1H, d, J=10.54 Hz, OCH2CHCH), 3.79 (1H, d, J=2.90 Hz, epoxide CH), 3.96 (1H, d, J=2.84 Hz, epoxide CH), 3.99 (1H, d, J=7.36 Hz, OCHCHOMs) 4.06 (1H, d, J=10.68 Hz, OCH2CHCH), 4.78 (1H, dt, 4.25 Hz, CHOMs), 5.07-5.14 (2H, m, CH2Ph), 5.29 (1H, brs, NH), 7.29-7.37 (5H, m, aromatic CH); δC (125 MHz, CDCl3) 38.234 (OSO2CH3), 42.241 (CH2NHCbz), 55.571 and 56.081 (OCH2CHCH), 67.047 (CH2Ph), 67.852 (OCH2CH), 76.662 (OCHCHOMs), 80.615 (CHOMs), 128.023, 128.195 and 128.531 (aromatic CH), 136.212 (Cbz quaternary), 156.653 (Cbz C═O).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[CH:6][N:5]=[C:4]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]2)[N:3]=1
Reactant: CC(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2ccc(OC)cc2)c(N)n1
Product: COc1ccc(C(=O)c2cnc(NC3CCN(C(C)=O)CC3)nc2N)cc1

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(4-methoxy-phenyl)-methanone (Example 358) and 1-(4-amino-piperidin-1-yl)-ethanone to give 1-[4-[4-amino-5-(4-methoxyl-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid. MS (M+H)+, 370.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][NH:12][CH2:13][CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22](Br)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][N:12]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:13][CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C2=CCCNC2)c1
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cccc(C2=CCCN(CCc3ccccc3)C2)c1

Procedure:
A mixture of 5 g of 3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine hydrochloride, 100 ml of acetone, 7 g of sodium carbonate and 3.5 ml of phenethyl bromide was refluxed for 16 hours and was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. The elution with a 7-3 cyclohexane-ethyl acetate mixture yielded 6.2 g of 3-(3-methoxyphenyl)-1-phenethyl-1,2,5,6-tetrahydropyridine.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[C:21]1([NH:27]N)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[C:14]1([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccccc1
Yield: 7 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-phenylpyridazin-4(1H)-one (crude 620 mg, 2.30 mmol) in 20 mL of methanol was added phenylhydrazine (996 mg, 9.22 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-phenyl-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (50 mg, yield 7% for two steps) as a yellow solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl.O1CCOCC1.CO>C(Cl)Cl>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C2CCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: C1CC(N2CCCNCC2)C1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To a stirred solution of tert-butyl 4-cyclobutyl-1,4-diazepane-1-carboxylate (6.1 g, 23.98 mmol) in DCM (70 ml) at 20 to 25° C. was added a solution of 4M HCl in dioxane (30 ml, 120 mmol) dropwise. The resulting mixture was stirred at 20 to 25° C. for ca. 2 h. MeOH (6 ml) was added and the resulting mixture stirred at 20 to 25° C. for 1 to 2 days. The solvent was removed in vacuo and the resulting gummy residue slurried in ether (100 ml) for 0.5 h. The solvent was evaporated and the residue slurried in ether/MeOH (10:1, 66 ml). The resulting white solid was collected by filtration, suspended in DCM (150 ml) and treated with 2M NaOH. The aqueous phase was extracted with DCM until complete transfer of product in the organic layer, as monitored by TLC analysis (eluent, DCM/MeOH/conc.NH3 (90:10:1); stain, PMA) was achieved. The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound as orange oil (2.67 g, 73%).
Reaction SMILES: COCC1CC2C(=CC=CC=2)NC1.[CH2:14]([NH:18][C:19](=[O:56])[C@H:20]([CH3:55])[CH2:21][C@H:22]([OH:54])[C@@H:23]([NH:46]C(OC(C)(C)C)=O)[CH2:24][C:25]([CH3:45])([CH3:44])[CH2:26][C:27]([N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH:31]([C:39]([O:41][CH2:42]C)=O)[CH2:30]1)=[O:28])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([NH:18][C:19](=[O:56])[C@H:20]([CH3:55])[CH2:21][C@H:22]([OH:54])[C@@H:23]([NH2:46])[CH2:24][C:25]([CH3:44])([CH3:45])[CH2:26][C:27]([N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH:31]([CH2:39][O:41][CH3:42])[CH2:30]1)=[O:28])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C(=O)OCC)Cc2ccccc21)NC(=O)OC(C)(C)C
Agent: COCC1CNc2ccccc2C1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1CC(COC)Cc2ccccc21

Procedure:
Starting from 300 mg of 3-[N-tert-butoxycarbonyl-4(S)-(3-carboxy-2,2-dimethylpropyloxy-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-methyl-propionic acid (N-butyl)amide and 465 mg of 3(R,S)-methoxymethyl-1,2,3,4-tetrahydroquinoline and subsequent reaction of the (4O,5N-isopropylidene)-5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[3(R,S)-methoxymethyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonyl]-octanoic acid (N-butyl)amide obtained (in a manner analogous to that described in Example 1a); Rf (A)=0.38), by the method described in Example 1), the title compound is obtained as a diastereomer mixture: Rf (S)=0.31; FAB-MS: (M+H)+ =476.
Reaction SMILES: [Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCCCCCCC.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=C(C=O)N=C2)C=CC=CC=1.[NH:56]1[CH:60]=[C:59]([CH:61]=[CH:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[N:58]=[CH:57]1>>[NH:56]1[CH:60]=[C:59]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[N:58]=[CH:57]1
Reactant: CCCCCCCC=Cc1c[nH]cn1
Agent: CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Br-]
Product: CCCCCCCCCc1c[nH]cn1

Procedure:
10 mmol of nonyltriphenylphosphonium bromide, 10 mmol of (1-triphenymethyl-1H-imidazol-4-yl)methanal (see Example 51) are treated as described in Example 51. The product of this reaction ((1H-imidazol-4-yl)-1-nonene) is treated as described in Example 52.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH2:16][CH3:17])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH2:6]1)[CH2:2][CH3:3].Cl.[Br:19]Br.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O.CCCCCC.O>[Br:19][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[O:7][CH2:6][CH:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:15][CH2:16][CH3:17])[CH2:14]2
Reactant: CCCN(CCC)C1COc2ccccc2C1
Reactant: BrBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCN(CCC)C1COc2ccc(Br)cc2C1
Reaction time: 2 h

Procedure:
The free base of 3-(di-n-propylamino)chromane (60 mg, 0.026 mmol) was converted to the hydrochloride with HCl-saturated EtOH. The residue after evaporation of the solvent and excess HCl was dissolved in CH2Cl2 and 4 equivalents of Br2 dissolved in CH2Cl2 were added. The reaction was complete after 2 hours and water was added. The product was found in the organic layer, which was basified with 10% Na2CO3. The organic phase was dried (Na2SO4), filtered and the solvent was evaporated, yielding an oil, which was converted to the hydrochloride with HCl-saturated EtOH. Crystals were formed from EtOAc-Hexane (30 mg) melting at 120° C. GC/MS showed M+ /M+2 at m/e=310.95(10%)/312.95(10%) and the base peak pair at m/e=282.00(100%)/284.00(97%).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23](O)=[O:24])[CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:72][C@@H:73]1[C:76](=[O:77])[NH:75][C@@H:74]1[CH2:78][N:79]1[N:83]=[C:82]([CH2:84][NH:85][C:86](=[O:92])[O:87][C:88]([CH3:91])([CH3:90])[CH3:89])[CH:81]=[N:80]1>C(Cl)Cl.C(Cl)Cl.CN(C=O)C>[C:88]([O:87][C:86]([NH:85][CH2:84][C:82]1[CH:81]=[N:80][N:79]([CH2:78][C@@H:74]2[C@H:73]([NH:72][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([O:14][CH:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:16])[CH2:19][CH2:18]3)/[C:26]3[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[S:29][CH:30]=3)[C:76](=[O:77])[NH:75]2)[N:83]=1)=[O:92])([CH3:91])([CH3:89])[CH3:90]
Reactant: CC(C)(C)OC(=O)NCc1cnn(C[C@H]2NC(=O)[C@H]2N)n1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a solution of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (prepared according to Yamawaki et al. Bioorg. Med. Chem. Lett. 2007, 15, 6716-6732) (1.50 g, 2.79 mmol) in DCM (15 mL) at 0° C. was added DIPEA (1.22 mL, 6.98 mmol) and HATU (1.11 g, 2.93 mmol). After warming to rt, a solution of tert-butyl ((2-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)methyl)carbamate (827 mg, 2.79 mmol) in DCM:DMF (1.7:1, 12.7 mL). After 1 h of stirring it was diluted with DCM and washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-Heptane, 0-90%), to afford the title compound (1.92 g, 84%) as a purple oil. LCMS: Rt=1.08 min, m/z=816.5 (M+1) Method 2m_acidic.
Reaction SMILES: CC(C)([O-])C.[K+].C(C1C=COC=1)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[PH4+].COC=C(C1SC=CC=1COC1C=CC=CC=1)C(OC)=O.[CH2:56]([C:63]1C=CS[C:64]=1[C:68](=[CH:73][O:74][CH3:75])C(OC)=O)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.CCOCC.O>[CH:63](/[C:64]1[CH:68]=[CH:73][O:74][CH:75]=1)=[CH:56]\[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: COC=C(C(=O)OC)c1sccc1Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: COC=C(C(=O)OC)c1sccc1COc1ccccc1
Agent: O=Cc1ccoc1
Solvent: CCOCC
Solvent: O
Product: C(=C/c1ccoc1)\c1ccccc1
Reaction time: 1 h
Yield: 32.1 %

Procedure:
Potassium tert-butoxide (35.7 g) was added in one portion to a stirred suspension of benzyltriphenylphosphonium chloride (41.6 g) in ether (1 liter). After 1 hour, a solution of 3-formylfuran (17.5 g) in ether (60 ml) was added to the resulting orange mixture which was then stirred for 2 hours, poured into water, and extracted with ether. The extracts were washed with water, dried and concentrated to give a solid. Trituration of this solid with ether enabled much of the weakly-soluble triphenylphosphine oxide and excess phosphonium salt to be separated, and the ether-soluble fraction (37.06 g) was chromatographed using ether as eluent to give a mixture of (E)- and (Z)-isomers of 3-styrylfuran (27 g) as a yellow solid. Crystallisation twice from methanol gave (E)-3-styrylfuran (5.12 g), mp 96° C., as a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH:5]=1)([CH3:3])[CH3:2].[Li]CCCC.CN([CH:21]=[O:22])C>C1COCC1>[CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH:21]=[O:22])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)c1coc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1c(C=O)oc2ccccc12
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of 3-isopropylbenzofuran (250 mg, 1.56 mmol) in THF (1 mL) is added nBuLi (2 mL, 2 mmol) drop wise and the reaction is stirred for 30 minutes. DMF (1 mL) was added to the reaction and stirred at room temperature overnight. The solution is placed in an ice bath and carefully quenched with 5% aqueous 110 solution (2 mL), and extracted with ethyl acetate (3×5 mL), dried over sodium sulfate and concentrated. The product was purified on silica with 100% hexanes to yield title compound in as a colorless oil (250 mg, 85%): 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 7.78 (d, 1H, J=9.0 Hz), 7.55 (d, 1H, J=9.0 Hz), 7.32-7.24 (m, 2H), 3.11-3.07 (m, 1H), 1.33-1.31 (2s, 6H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][NH2:12])=[S:10])=[CH:5][CH:4]=1.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=O>CO>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][CH:14]([C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:12][N:11]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)C=O
Reactant: CSc1ccc(C(=S)NN)cc1
Solvent: CO
Product: CSc1ccc(C2=NNC(C(=O)OC(C)(C)C)S2)cc1

Procedure:
The product of step d) (3.0 g) was stirred at room temperature under nitrogen with t-butyl glyoxylate (2.0 g) in methanol (100 ml) for 18 hours. The mixture was evaporated and the residue purified by flash chromatography (ether/petroleum ether 1:3) to afford the sub-title compound (3.9 g) as a pale yellow solid. mp 71°-72°.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH2:22][C:23](=[N:25][C:26]1[S:27][CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][OH:38])[N:32]=2)[N:30]=1)[NH2:24].C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.O1CCCC1>[NH2:24][C:23](=[N:25][C:26]1[S:27][CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=[O:38])[N:32]=2)[N:30]=1)[NH2:22]
Reactant: NC(N)=Nc1nc(-c2cccc(CO)n2)cs1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(N)=Nc1nc(-c2cccc(C=O)n2)cs1
Reaction time: 5 h
Yield: 18.4 %

Procedure:
A solution of pyridinium dichromate (3.2 g) in N,N-dimethylformamide (10 ml) was added dropwise to a solution of 2-(diaminomethyleneamino)-4-(6-hydroxymethylpyridin-2-yl)thiazole (1.7 g) in N,N-dimethylformamide (17 ml) at -10~-5° C. and the mixture was stirred for 5 hours at the same temperature. The reaction mixture was added to a mixture of ethyl acetate, tetrahydrofuran and water and the mixture was adjusted to pH 10 with potassium carbonate. The separated organic layer was washed with brine, and dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (9:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 2-(diaminomethyleneamino)-4-(6-formylpyridin-2-yl)thiazole (0.31 g).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:37]=1[CH2:38]Br.N1CCOCC1>CN(C=O)C.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:22]=[N:21][N:20]([CH2:38][C:37]4[C:40]([F:44])=[CH:41][CH:42]=[CH:43][C:36]=4[Cl:35])[CH:19]=3)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCc1cn[nH]c1)c(=O)n2CCCCC
Reactant: Fc1cccc(Cl)c1CBr
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: CN(C)C=O
Solvent: C1COCCN1
Product: CCCCCn1c(=O)n(CCCc2cnn(Cc3c(F)cccc3Cl)c2)c(=O)c2[nH]c(Cl)nc21
Temperature: 45 °C
Yield: 74.9 %

Procedure:
8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (61 mg, 0.15 mmol) in dry DMF (2 ml) was stirred with sodium carbonate (64 mg, 0.6 mmol) and 2-chloro-6-fluorobenzyl bromide (134 mg, 0.6 mmol) and heated at 45° C. for 18 h under nitrogen. After cooling to rt the mixture was degassed by evacuating and readmitting nitrogen, and stirred with tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.303 mmol) and morpholine (0.13 ml) for 5.5 h. The mixture was partitioned between EtOAc and 2M HCl, the organic phase separated and evaporated and the residue purified by aminopropyl SPE (5 g, washing with THF-MeOH (1:1) then neat MeOH and finally eluting with DCM-MeOH (1:1) containing 5% AcOH) to give the title compound (57 mg) as a solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([CH3:12])[NH:7][C:6]=2[C:5]([N+:13]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([CH3:12])[NH:7][C:6]=2[C:5]([NH2:13])=[CH:4][CH:3]=1
Reactant: C[C@H]1COc2c(F)ccc([N+](=O)[O-])c2N1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H]1COc2c(F)ccc(N)c2N1
Reaction time: 16 h
Yield: 102.1 %

Procedure:
A suspension of (S)-8-fluoro-3-methyl-5-nitro-3,4-dihydro-2H-benzo[1,4]oxazine (183 mg, 0.86 mmol) and 10% Pd/C (37 mg) in EtOAc (12 mL) and IMS (1.2 mL) was stirred under a H2 balloon for 16 h. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (160 mg, quant.). 1H NMR (CDCl3, 300 MHz): δ 6.35 (1H, dd, J=10.8, 8.6 Hz), 6.14 (1H, dd, J=8.6, 4.6 Hz), 4.19 (1H, dd, J=10.5, 2.9 Hz), 3.64 (1H, dd, J=10.5, 8.4 Hz), 3.43 (1H, dqd, J=8.4, 6.5, 2.9 Hz), 3.10 (3H, br s), 1.17 (3H, d, J=6.5 Hz)