Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:44](=[O:46])[CH3:45])=[N:41][CH:42]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC#N.O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:37]5[CH:38]=[CH:39][C:40]([NH:43][C:44](=[O:46])[CH3:45])=[N:41][CH:42]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 120 °C
Yield: 14.9 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (416 mg, 1.0 mmol), N-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-acetamide (314 mg, 1.2 mmol), Cs2CO3 (650 mg, 2.0 mmol), Pd(dppf)Cl2 (73 mg, 0.10 mmol) and CH3CN—H2O (1:1, 4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 120° C. for 20 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to 247 (77 mg, yield: 15%). 1HNMR (DMSO-d6, 400 MHz): δ10.62 (s, 1H), 8.88 (s, 1H), 8.27 (s, 1H), 8.15 (s, 2H), 7.42 (t, J=0.8 Hz, 1H), 7.89-7.81 (m, 3H), 7.47 (t, J=8.8 Hz, 2H), 7.15 (s, 1H), 4.27 (s, 2H), 3.17 (s, 2H), 2.08 (s, 3H). ESI-MS: m/z=517 [M+H+]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:9]([OH:13])(=[O:12])[CH:10]=O.S(=O)(=O)(O)O.[OH-].[K+]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:10]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1
Reactant: O=CC(=O)O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 81.8 %

Procedure:
Fluorobenzene (13.6 g, 0.142 mol) and glyoxylic acid monohydrate (2.35 g, 0.0255 mol) were dissolved in warm acetic acid (30.0 mL). The mixture was cooled in an ice/water bath and concentrated sulfuric acid (20.0 mL) was added dropwise over 0.5 h. The resulting thick red suspension was stirred at 80° C. for 12 h and then cooled to room temperature. Water (300 mL) was added and the pH was adjusted to 3 with potassium hydroxide pellets and 10% KOH solution. The aqueous solution was extracted with ethyl acetate (3×100 mL) and the combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate, filtered and concentrated in vacuo to give the desired product (5.18 g, 82%) as a red solid, which was used in the subsequent step without further purification: 1H NMR (400 MHz, CD3OD) δ 9.45 (br s, 1H), 7.31–7.25 (m, 4H), 7.06–7.0 (m, 4H), 5.01 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[OH:5].[Cl:11][C:12]1[C:19]([F:20])=[CH:18][C:15]([C:16]#[N:17])=[C:14](F)[CH:13]=1>>[Cl:11][C:12]1[C:19]([F:20])=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:5][C@@H:4]([C:6]2[CH:10]=[CH:9][S:8][CH:7]=2)[CH2:3][CH2:2][Cl:1])[CH:13]=1
Reactant: O[C@H](CCCl)c1ccsc1
Reactant: N#Cc1cc(F)c(Cl)cc1F
Product: N#Cc1cc(F)c(Cl)cc1O[C@H](CCCl)c1ccsc1

Procedure:
Using the product of step (d) (322 mg, 1.84 mmol), 4-chloro-2,5-difluorobenzonitrile (320 mg, 1.84 mmol) and the procedure described in Example 72(c), the title compound was prepared (540 mg, 89%).
Reaction SMILES: [CH3:1]N1C2C(=CC=C(N)C=2)CC1.[N+:12]([C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][NH:21]2)=[CH:17][CH:16]=1)([O-:14])=[O:13].CI.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:23]=2)[CH2:19][CH2:20]1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: CN1CCc2ccc(N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
1-Methyl-2,3-dihydro-1H-indol-6-ylamine. 6-Nitroindoline (2 mmol) was combined with methyl iodide (2.2 mmol), n-Bu4I (7.4 mg, 0.020 mmol), and K2CO3 (350 mg, 2.5 mmol) in acetone (10 mL). The mixture was stirred at 25° C. for 16 h. The mixture was partitioned between CH2Cl2 and satd. aq. NaHCO3 (20 mL), and the organic layer was dried and concentrated. Purification by silica gel chromatography provided 1-methyl-6-nitroindoline (300 mg, 84%). To a solution of 1-methyl-6-nitroindoline (194 mg, 1.15 mmol) in MeOH (2 mL) was added FeCl3.6H2O (3 mg), Me2NNH2 (0.80 mL, 11 mmol), and charcoal (25 mg). The mixture was heated at reflux for 4 h. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to provide the desired compound in quantitative yield. Step B. (1-Benzyl-piperidin-4-yl)-(1-methyl-2,3-dihydro-1H-indol-6-yl)-amine. The product from Step A (161 mg, 1.1 mmol) was converted to the desired compound as in Example 2, Step B. Step C. The title compound (80 mg, 35%) was prepared as in Example 2, Step C. 1H NMR (500 MHz, CDCl3): 7.63 (d, J=15.5 Hz, 1H), 7.30-7.25 (m, 10H), 7.02 (d, J=7.4 Hz, 1H), 6.38-6.36 (d, J=8.8 Hz, 1H), 6.25 (d, J=15.5 Hz, 1H), 6.14 (s, 1H), 4.73-4.68 (m, 1H), 3.46-3.34 (m, 4H), 3.02-2.86 (m, 4H), 2.73 (s, 3H), 2.17-2.12 (m, 2H), 1.86-1.77 (m, 2H), 1.61-1.51 (m, 2H). MS: exact mass calculated for C30H33N3O, 451.26; m/z found, 452.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:10]=2[CH3:26])[CH:7]=1.[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>O.O1CCOCC1.CCCCCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:11]1[C:10]([CH3:26])=[C:9]([NH:8][C:6]2[CH:7]=[C:2]([C:35]3[CH:36]=[CH:37][S:33][CH:34]=3)[CH:3]=[CH:4][C:5]=2[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(Br)ccc1N1CCOCC1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(-c2ccsc2)ccc1N1CCOCC1
Temperature: 130 °C

Procedure:
A mixture of dichlorobis(triphenylphosphine)palladium(II) (13 mg, 18 μmol), N-(5-bromo-2-morpholinophenyl)-2-(2-fluorophenyl)-3-methylquinolin-4-amine (88 mg, 179 μmol), thiophen-3-ylboronic acid (34 mg, 268 μmol) and sodium carbonate (57 mg, 536 μmol) in water (0.25 mL) and 1,4-dioxane (1.00 mL) was purged with nitrogen then heated in a microwave vessel to 130° C. for 60 min, after which time TLC indicated no starting material remained and LC-MS indicated only desired product present. The reaction was partitioned between water and EtOAc (30 mL ea). The organic separation was stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a brown film. The desired product was isolated by chromatography on silica gel eluting isocratically with 33% EtOAc in hexane to afford a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (2H, dd, J=15.3, 8.2 Hz), 7.79 (1H, s), 7.71 (1H, dd, J=7.0, 7.0 Hz), 7.45-7.63 (5H, m), 7.32-7.45 (2H, m), 7.12-7.29 (3H, m), 6.69 (1H, d, J=1.6 Hz), 3.59 (4H, br. s.), 2.91 (4H, br. s.), 2.06 (3H, d, J=1.6 Hz). Mass Spectrum (ESI) m/e=496.1 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.Br[Zn][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:23]([C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)=[N:7][C:6]=2[CH:5]=[C:4]([OH:19])[CH:3]=1)[CH2:24][CH2:25][CH3:26]
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Reactant: CCCC[Zn]Br
Product: CCCCc1cc(O)cc2nc(-c3ccc(O)cc3)oc12

Procedure:
The title compound was prepared in substantially the same manner as described in Example 35, from 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole, and bromo(butyl)zinc. The desired product was obtained as a white solid, m.p. 125–127° C.; MS m/e 282 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13](F)=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:20]([CH3:22])[CH3:21])=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O>[N:23]([C:13]1[CH:12]=[C:11]2[C:16]([C:17](=[O:18])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]([CH:20]([CH3:22])[CH3:21])[O:10]2)=[CH:15][CH:14]=1)=[N+:24]=[N-:25]
Reactant: CC(C)c1oc2cc(F)ccc2c(=O)c1-c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1oc2cc(N=[N+]=[N-])ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
To a solution of 3-(4-chlorophenyl)-7-fluoro-2-isopropyl-chromen-4-one (4.0 g, 12.7 mmol) in dry dimethylformamide (120 ml) is added sodium azide at room temperature. The reaction mixture is heated at 90° C. for 16 h, cooled to room temperature and partitioned between ethyl acetate and water. The organic phase is washed with water and brine, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography on silica gel using iso-hexane:ethyl acetate (10:1) as the eluent, followed by recrystallisation from iso-hexane, gives the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][S:8][C:5]2=[CH:6][N:7]=1.C(=[NH:24])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[S:8]1[C:5]2=[CH:6][N:7]=[C:2]([NH2:24])[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: Clc1cc2ccsc2cn1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cc2ccsc2cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A mixture of 5-chlorothieno[2,3-c]pyridine (685 mg, 4.00 mmol), benzophenone imine (1.03 mL, 6.00 mmol), sodium tert-butoxide (595 mg, 6.00 mmol), Xantphos (358 mg, 0.600 mmol), tris(dibenzylideneacetone)dipalladium(0) (185 mg, 0.200 mmol) and toluene (40 mL) was heated at 120° C. under a nitrogen atmosphere for 3 h. After cooling, the reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic fractions were washed with water (30 mL) and brine (30 mL), dried over MgSO4, and concentrated in vacuo. The residue was dissolved in THF (80 mL) and treated with aqueous 2 N hydrochloric acid (8.0 mL, 16 mmol). After 1 h at RT, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×30 mL). The extracts were washed with water (2×30 mL) and brine (30 mL). The aqueous layer was treated with aqueous NaOH until the pH was >9 and then extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, and concentrated in vacuo. The resultant solid was purified by ISCO chromatography (50% to 100% EtOAc:heptane) to afford 420 mg (70%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1 H), 7.59 (d, J=5.6 Hz, 1 H), 7.12 (d, J=5.6 Hz, 1 H), 6.88 (d, J=1.2 Hz, 1 H), 4.36 (br s, 2 H); MS (ESI): 151.03 [M+H]+; HPLC tR=0.43 min (TOF: polar—3 min).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]([CH3:50])([O:19][N:20]=[C:21]([C:25]1[N:26]=[C:27]([NH:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:28][CH:29]=1)[C:22](O)=[O:23])[CH3:18])=[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.[NH2:51][CH:52]1[C:77](=[O:78])[N:54]2[C:55]([C:61]([O:63][CH:64]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[O:62])=[C:56]([CH2:59][Cl:60])[CH2:57][S:58][C@H:53]12.CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[Cl:60][CH2:59][C:56]1[CH2:57][S:58][C@@H:53]2[CH:52]([NH:51][C:22](=[O:23])[C:21](=[N:20][O:19][C:17]([C:15]([O:14][CH:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:16])([CH3:50])[CH3:18])[C:25]3[N:26]=[C:27]([NH:30][C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[S:28][CH:29]=3)[C:77](=[O:78])[N:54]2[C:55]=1[C:61]([O:63][CH:64]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)=[O:62]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CC(C)(ON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 81.4 %

Procedure:
28 g (41 mmol) of 2-(1-benzhydryloxycarbonyl-1-methylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (syn-isomer) and 17 g (41 mmol) of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-caroxylate, were dissolved in 300 ml of dry methylene chloride, and 15.6 ml (123 mmol) of N,N-dimethylaniline was added thereto. The mixture was cooled to -10° C., and 4 ml (43 mmol) of phosphorus oxychloride was dropwise added thereto. The reaction solution was stirred at room temperature for 2.5 hours, and then concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed sequentially with 1N hydrochloric acid, a 5% sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 36 g (yield: 81%) of benzhydryl 3-chloromethyl-7-[2-(1-benzhydryloxycarbonyl-1-methylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn-isomer).
Reaction SMILES: [CH2:1]([C:3]1[S:43][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=O)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Cl.[NH2:45][O:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].N1C=CC=CC=1.Cl>O.C(Cl)(Cl)Cl.C(O)C>[CH2:1]([C:3]1[S:43][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13](=[N:45][O:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Reactant: CCOC(=O)CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CON=C(Cn1c(=O)c2cc(CC)sc2n(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c1=O)c1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g), ethyl (aminooxy)acetate hydrochloride (0.053 g), pyridine (10 mL) and ethanol (10 mL) was stirred at 100° C. for 16 hr. To the reaction mixture were added chloroform and water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a stereoisomer mixture (0.061 g, 26%).
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:9]2[CH2:10][NH:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:13][C:8]=2[N:7]=1)[CH2:3][CH2:4][CH3:5].[CH2:37]([O:44][C:45]([CH2:47][C:48](O)=[O:49])=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:2]([C:6]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:9]2[CH2:10][N:11]([C:48](=[O:49])[CH2:47][C:45]([O:44][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[O:46])[CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:13][C:8]=2[N:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C(O)CC(=O)OCc1ccccc1
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CNC(C(=O)OC)C2
Agent: Cl
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CN(C(=O)CC(=O)OCc1ccccc1)C(C(=O)OC)C2

Procedure:
Methyl 2-n-butyl-3-{2'-(1H-tetrazol-5-yl)-biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine 6-carboxylate hydrochloride and benzyloxycarbonyl-acetic acid are treated in the same manner as in Example 8-(1) to give methyl 2-n-butyl-5-benzyloxycarbonylacetyl-3 -{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetra-hydroimidazo[4,5-c]pyridine-6-carboxylate.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([OH:17])[CH2:12][CH2:13][CH2:14][C:15]#[CH:16].C(N(CC)CC)C>C(Cl)Cl>[C:4]1([C:3]2[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][OH:17])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ON=C(Cl)c1ccccc1
Reactant: C#CCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCCCc1cc(-c2ccccc2)no1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 51 %

Procedure:
To N-hydroxybenzenecarboximidoyl chloride (622 mg, 4 mmol) in dry DCM (6 ml) was added 5-hexyn-1-ol (431 mg, 4.4 mmol). The mixture was cooled to 0° C. under nitrogen as triethylamine (0.612 ml, 4.4 mmol) was added dropwise over 10 min. Stirred for a further 20 min at 0° C. then at room temperature overnight. The mixture was washed with water and the organic phase evaporated. The product was purified by silica SPE (20 g) eluting with EtOAc-cyclohexane (1:2, then 3:1) to give a white waxy solid (443 mg).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[N:23]([C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[CH2:24][CH:25]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[CH:19]12)=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])C1C=CC=CC=1>CO>[NH2:10][CH:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[N:23]([C:35]3[N:36]=[CH:37][CH:38]=[CH:39][N:40]=3)[CH2:24][CH:25]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[CH:19]12)=[O:17]
Reactant: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2c1ncccn1
Solvent: CO
Product: CC(C)(C)C(N)C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2c1ncccn1
Reaction time: 3 h
Yield: 98.3 %

Procedure:
A mixture of carbamate 29 (140 mg, 0.25 mmol) and 10% Pd-on-carbon (wet, 100 mg, 0.09 mmol) in MeOH (20 mL) was stirred vigorously under 1 atm H2. After 3 h, the catalyst was removed by filtration with an Acrodisc® 0.45 μm nylon membrane syringe filter and the solvent was removed in vacuo to afford 106 mg (100%) of 30 as a white solid which was used without further purification. Mass spectrum, m/z [431.8] (M+H)+.
Reaction SMILES: CS[C:3]1[S:4][CH2:5][CH2:6][N:7]=1.C(O)(=O)C.[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16](/[CH:20]=[CH:21]/[S:22]([N:25]2[CH2:41][CH2:40][C:28]3([C:32](=[O:33])[NH:31][C:30]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[N:29]3)[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[C:15]([CH3:42])[CH:14]=1>CCO.C(OCC)(=O)C>[CH:34]1([C:30]2[NH:31][C:32](=[O:33])[C:28]3([CH2:27][CH2:26][N:25]([S:22](/[CH:21]=[CH:20]/[C:16]4[C:17]([CH3:19])=[CH:18][C:13]([NH:12][C:3]5[S:4][CH2:5][CH2:6][N:7]=5)=[CH:14][C:15]=4[CH3:42])(=[O:23])=[O:24])[CH2:41][CH2:40]3)[N:29]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CSC1=NCCS1
Reactant: Cc1cc(N)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(NC2=NCCS2)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
2-(Methylthio)-2-thiazoline (19 μL, 0.17 mmol) and acetic acid (1.2 ml) were added to a solution of 8-[(E)-2-(4-amino-2,6-dimethyl-phenyl)vinyl]sulfonyl-3-cyclohexyl-2,4,8-triazaspiro[4.5]dec-3-en-1-one (74 mg, 0.16 mmol) in EtOH (2.5 ml) at room temperature, and the mixture was heated with stirring at 80° C. for 16 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was then sequentially washed with water and saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 2-cyclohexyl-8-{(E)-2-[4-(4,5-dihydro-thiazol-2-ylamino)-2,6-dimethyl-phenyl]-ethenesulfonyl}-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (46.1 mg, 52%).
Reaction SMILES: [OH:1][C:2]1[N:3]=[N:4][C:5]([OH:8])=[CH:6][CH:7]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br>>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][N:3]1[C:2](=[O:1])[CH:7]=[CH:6][C:5](=[O:8])[NH:4]1
Reactant: BrCCCCBr
Reactant: Oc1ccc(O)nn1
Product: O=c1ccc(=O)n(CCCCBr)[nH]1

Procedure:
By the method of Example 1, 3,6-dihydroxypyridazine is reacted with 1,4-dibromobutane to yield the title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[I:14]I.C(O)(=O)C.S(=O)(=O)(O)O>C(OC(C)C)(=O)C.O>[I:14][C:11]1[S:10][C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:13][CH:12]=1
Reactant: Fc1ccc(Cc2cccs2)cc1
Reactant: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)C
Product: Fc1ccc(Cc2ccc(I)s2)cc1
Temperature: 40 °C

Procedure:
A mixture of 2-(4-fluorophenylmethyl)thiophene (15 g, 78 mmol), prepared as in step 1, HIO3 (2.8 g, 16 mmol), I2 (7.9 g, 1.2 mmol), acetic acid (36 mL), concentrated sulfuric acid (1.2 mL), and H2O (9 mL) was heated at 40° C. for 2 hours at which point all starting material was consumed by GC analysis. The reaction mixture was cooled to ambient temperature and H2O (150 mL) and isopropyl acetate (150 mL) were added. The aqueous layer was separated, neutralized with saturated aqueous K2CO3, and extracted with isopropyl acetate (100 mL). The organic layers were combined and washed with H2O (100 mL), saturated aqueous NaHCO3 (2×100 mL), and saturated aqueous Na2S2O3 (2×100 mL). The organic phase was then treated with activated carbon, dried over MgSO4, filtered, and concentrated in vacuo to give a quantitative yield of 2-iodo-5-(4-fluorophenylmethyl)thiophene as a solution in isopropyl acetate, which is used without further purification.