Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]([C:12]2[C:17]([NH2:18])=[CH:16][N:15]=[C:14]3[CH:19]([O:22]C(=O)C)[CH2:20][CH2:21][C:13]=23)[CH2:7][C@H:6]1[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=O)C.[CH2:34]([O:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([C:44]2[N:49]=[C:48]([C:50](O)=[O:51])[CH:47]=[CH:46][C:45]=2[F:53])=[C:39]([F:54])[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.[OH-].[Na+].CO>[CH2:34]([O:36][C:37]1[CH:38]=[C:39]([F:54])[C:40]([C:44]2[N:49]=[C:48]([C:50]([NH:18][C:17]3[C:12]([N:8]4[CH2:9][C@H:10]([CH3:11])[C@@H:5]([OH:4])[C@H:6]([NH:26][C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])[CH2:7]4)=[C:13]4[CH2:21][CH2:20][CH:19]([OH:22])[C:14]4=[N:15][CH:16]=3)=[O:51])[CH:47]=[CH:46][C:45]=2[F:53])=[C:41]([F:43])[CH:42]=1)[CH3:35]
Reactant: CCOc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)[C@@H](OC(C)=O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C3)CCC4O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (3R,4R,5S)-1-[7-(acetyloxy)-3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-4-yl acetate (12.4 mg, 0.027 mmol), 6-(4-ethoxy-2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (8.0 mg, 0.027 mmol), HATU (37 mg, 0.098 mmol) in DMF (0.1 mL) and DIPEA (26 mg, 0.20 mmol) was stirred at room temperature for 16 h. The reaction mixture was diluted with 1 M NaOH solution (0.5 mL) and MeOH (0.5 mL). The reaction mixture was stirred at room temperature for 1 h. After concentration under reduced pressure, the aqueous layer was extracted with DCM three times. The combined organic layers were dried, filtered and concentrated under vacuum to give the crude product, which was purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder. LCMS calc. for C33H39F3N5O6 (M+H)+: m/z=658.3. Found: 658.3.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([CH3:16])[CH:8]=1.[CH3:18][C:19]1[C:20]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1>>[O:17]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:30]2[CH2:31][CH2:32][N:27]([C:20]3[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=3)[CH2:28][CH2:29]2)=[O:13])=[C:9]([CH3:16])[CH:8]=1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Product: Cc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2nc(C)c(C)cc2C)CC1
Yield: 59 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylbenzoic acid (128 mg) described in Preparation Example 29 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (103 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Example 87, the title compound (131 mg) was obtained.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[O:15]=[C:16]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:19]=[C:18]([C:27]([OH:29])=O)[NH:17]1.[CH3:30][C:31]1[O:35][C:34](=[O:36])[O:33][C:32]=1[CH2:37][O:38][C:39](=[O:60])[C@H:40]([OH:59])[CH2:41][N:42]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[C:55]([Cl:57])[CH:54]=[CH:53][C:52]=2[F:58])=[CH:47][CH:46]=1)[NH2:43].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:30][C:31]1[O:35][C:34](=[O:36])[O:33][C:32]=1[CH2:37][O:38][C:39](=[O:60])[C@H:40]([OH:59])[CH2:41][N:42]([CH2:44][C:45]1[CH:46]=[CH:47][C:48]([C:51]2[CH:56]=[C:55]([Cl:57])[CH:54]=[CH:53][C:52]=2[F:58])=[CH:49][CH:50]=1)[NH:43][C:27]([C:18]1[NH:17][C:16](=[O:15])[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:19]=1)=[O:29]
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: O=C(O)c1nn(-c2ccccc2)c(=O)[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1nn(-c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 31.8 %

Procedure:
EDC (127 mg, 660 μmol) and HOBt (89 mg, 660 μmol) were added to a solution of 5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carboxylic acid (150 mg, 330 μmol) and (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester (68 mg, 330 μmol) in DMF (10 mL). DIPEA (86 mg, 660 μmol) was added, and the resulting mixture was stirred for 5 hours at room temperature. The mixture was then washed with saturated aqueous NaCl (2×30 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=1:1) to yield the title compound as a white solid (67 mg). LC-MS: 638.2 [M+H]+. 1H-NMR (400 MHz, DMSO-d6): δ 2.13 (s, 3H), 3.31-3.16 (m, 2H), 4.18-4.21 (q, 2H), 4.35 (br, 1H), 4.98-5.01 (m, 2H), 5.54 (br, 1H), 7.26-7.90 (m, 12H), 9.98 (s, 1H), 12.74 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10](=S)[NH:9]2)[CH:7]=1.[NH3:20].CO>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10](=[NH:20])[NH:9]2)[CH:7]=1
Reactant: CC1(c2cc(Br)ccc2F)NC(=S)COCC1(F)F
Reactant: N
Solvent: CO
Product: CC1(c2cc(Br)ccc2F)NC(=N)COCC1(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepane-3-thione (1.0 g, 2.83 mmol) and 10% NH3/MeOH (25 mL) was stirred in a sealed tube at rt for 24 h. Reaction mixture was concentrated and purified by column chromatography on silica gel with 5% MeOH, 2% NH3 in chloroform to furnish the title compound as a pale brown gum. Yield=1.1 g ( ). LCMS: RtH8=0.146 [M+H]+=337.0, 339.0,
Reaction SMILES: CO.C1COCC1.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[CH:39]=[CH:38][C:17]([C:18]([NH:20]/[C:21](/[C:32]([NH:34][CH2:35][CH2:36][OH:37])=[O:33])=[CH:22]\[C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.C(OCC)(=O)C>C(#N)C.O.[C].[Pd]>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[CH:39]=[CH:38][C:17]([C:18]([NH:20][CH:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH3:31])=[CH:25][CH:24]=3)[C:32]([NH:34][CH2:35][CH2:36][OH:37])=[O:33])=[O:19])=[CH:16][CH:15]=2)[CH2:9][CH2:10]1
Reactant: O=C(NCCO)/C(=C/c1ccc(C2CC2)cc1)NC(=O)c1ccc(OCCC2CC2)cc1
Agent: [Pd]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1ccc(CC(NC(=O)c2ccc(OCCC3CC3)cc2)C(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a methanol:THF (2:1, V/V, 6 mL) solution of 4-(2-cyclopropylethoxy)-N-((Z)-2-(4-cyclopropylphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (215 mg, 0.495 mmol) prepared in Example (1 (1d) was added 10% palladium-carbon (wet, 100 mg). The mixture was stirred under a hydrogen atmosphere (rubber balloon) at room temperature for 2 hours. To the reaction solution was added ethyl acetate (10 mL), and the mixture was filtered. The solvent was evaporated, and the residue was purified by thin layer chromatography for separation (ethyl acetate, developed once) to give a white solid. This solid was suspended in acetonitrile:water (1:1, V/V, 4 mL), and the insoluble substance was collected by filtration, washed with water, and dried under reduced pressure to give 104 mg of the title compound (white powder, yield: 48%).
Reaction SMILES: O1C2C=CC=CC=2OB1.[Br:10][C:11]1[C:12]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[Br:10][C:11]1[C:12]([N:27]2[CH2:28][C:29]([F:32])([F:31])[CH2:30]2)=[C:13]([C@H:19]([OH:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CC(F)(F)C2)c1Br
Agent: B1Oc2ccccc2O1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Product: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CC(F)(F)C2)c1Br
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 51.4 %

Procedure:
The 0.33 mL of benzo[d][1,3,2]dioxaborole (166 mg, 1.38 mmol) was added to a nitrogen purged solution of isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (360 mg, 0.920 mmol) and 0.28 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (77 mg, 0.28 mmol) in toluene (10 mL) at −60° C. and allowed to warm to −15° C. before being placed in the freezer overnight. The reaction was quenched with 1M Na2CO3 (5 mL), diluted with EtOAc, and stirred for 20 min. The organic layer was washed with brine and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (5-60% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate 186 mg (51%). 1H NMR (500 MHz, DMSO-d6) δ 5.24 (s, 1H), 4.97-4.94 (m, 1H), 4.74-4.71 (m, 2H), 4.54-4.51 (m, 2H), 2.50 (s, 3H), 2.33 (s, 3H), 1.19 (d, J=5.9 Hz, 3H), 1.13 (d, J=5.9 Hz, 3H). LCMS (M+H)=395.1.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]2[O:9][C:10](=[O:12])[CH3:11])[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[Cl:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[O:42][CH2:43][CH3:44])[CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[Cl:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[O:42][CH2:43][CH3:44])[CH2:37][NH:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]2[O:9][C:10](=[O:12])[CH3:11])[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(N)nc3ccccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOc1ccc(C=O)cc1OCCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(CNc2nc3ccccc3n2[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)cc1OCCCCl
Temperature: 70 °C
Reaction time: 20 h
Yield: 77.6 %

Procedure:
2-Amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1H-benzimidazole (13.7 g) and 3-(3-chloropropoxy)-4-ethoxybenzaldehyde (15.3 g) were suspended in tetrahydrofuran (150 mL), and the mixture was stirred at 70° C. for 20 hours. To the stirred reaction mixture was added sodium triacetoxyborohydride (21.7 g) under ice-cooling, and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/3) to give the title compound (16.8 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][CH2:23]OS(C)(=O)=O)[N:18]=2)[S:5][C:6]=1[C:7](=[O:16])[NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[CH3:29][NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:8][C:7]([C:6]2[S:5][C:4]([C:17]3[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][N:30]([CH3:29])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:18]=3)=[N:3][C:2]=2[CH3:1])=[O:16])[CH:11]=1
Reactant: CNc1ccccc1
Reactant: Cc1nc(-c2ccn(CCOS(C)(=O)=O)n2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(CCN(C)c3ccccc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from methanesulfonic acid 2-(3-{4-methyl-5-[(pyridin-3-ylmethyl)-carbamoyl]-thiazol-2-yl}-pyrazol-1-yl)-ethyl ester and methyl-phenyl amine as describe in Example 77 and isolated as a white solid (0.043 g, 54% yield). 1H NMR (400 MHz, CDCl3) δ 8.63 (bs, 1H), 8.57 (d, J=4 Hz, 1H), 7.73 (d, J=8 Hz, 1H), 7.28-7.34 (m, 1H), 7.29 (d, J=2 Hz, 1H), 7.21-7.26 (m, 2H), 6.77 (d, J=2 Hz, 1H), 6.73 (t, J=8 Hz, 1H), 6.65 (d, J=8 Hz, 2H), 6.06-6.13 (bm, 2H), 4.64 (d, J=4 Hz, 2H), 4.34 (t, J=5 Hz, 2H), 3.83 (t, J=5 Hz, 2H), 2.76 (s, 3H), 2.74 (s, 3H); MS (M+H)+=432.9; Rt=1.28 min; HRMS (M+H)+=433.17.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][NH:17]3)=[C:13]([NH:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(OCC)(=O)C.CO.[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][NH:17]3)=[C:13]([NH:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(Nc2nc(Nc3cccc([N+](=O)[O-])c3)nc3[nH]cnc23)cc1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1ccc(Nc2nc(Nc3cccc(N)c3)nc3[nH]cnc23)cc1
Yield: 39.3 %

Procedure:
214 mg of the product of Example 24 are treated with 95 mg of platinum oxide (PtO2) in a mixture of 2.6 ml of ethyl acetate and 2.6 ml of methanol in the presence of hydrogen, H2. 78 mg of the expected product are thus obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.Cl>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)[CH2:14][CH2:15]2)=[CH:25][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 0.1 %

Procedure:
1-[1-(4-Nitrophenethyl)piperidin-4-yl]indoline (780 g) was dissolved in methanol (7 ml) and conc. hydrochloric acid (0.5 ml) was added dropwise into the resultant solution. Subsequently, the resultant mixture was catalytically reduced under atmospheric pressure in the presence of a palladium catalyst. After filtering off the catalyst, a 1 N aqueous solution of sodium hydroxide was added to the filtrate followed by extraction with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent, the title compound (620 mg) was obtained as an oil.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH:13]3[CH2:14][N:9]([C:10]4[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:11]=4[CH2:12]3)[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+]>C(O)C.O.[Fe]>[CH:1]1([C:4]([N:6]2[CH:13]3[CH2:14][N:9]([C:10]4[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:11]=4[CH2:12]3)[CH2:8][CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(C1CC1)N1CCN2CC1Cc1ccc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)N1CCN(C(=O)C3CC3)C(C2)C1
Reaction time: 4 h
Yield: 64 %

Procedure:
Iron powder (104 g.) was added to a warm (50° C.) solution of 4-cyclopropanecarbonyl-9-nitro-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (75 g.) in ethanol (600 ml.) and water (300 ml.). The mixture was heated to reflux, then a solution of concentrated hydrochloric acid (45 ml.), ethanol (90 ml.) and water (90 ml.) was added dropwise. Stirring was continued for four hours after the addition was complete. The mixture was allowed to cool somewhat, then sodium bicarbonate (75 g.) was cautiously added, and the mixture was filtered. The filtrate was concentrated nearly to dryness, and the residue was partitioned between water and chloroform. The chloroform layer was washed with brine, dried, treated with charcoal and stripped of chloroform. Two recrystallizations of the tan foam residue from methanol afforded 4-cyclopropanecarbonyl-9-amino-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (43 g., m.r. 105°-107° C.), the compound of Formula II wherein Q' is cyclopropanecarbonyl. The product appeared to be a methanol solvate. Recrystallization of part of a similarly prepared product from ethyl acetate afforded product free of solvent (m.r. 142°-144° C.).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[C:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:3]=1.[N:18]([CH:21]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)[CH3:22])=[N+]=[N-].C(C1C=CC(C#N)=CC=1)(=O)C.C1([Se][Se]C2C=CC=CC=2)C=CC=CC=1.C(P(CCCC)CCCC)CCC>C(#N)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:18][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH3:22])=[O:9])=[C:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:3]=1
Reactant: CC(N=[N+]=[N-])c1ccc(C#N)cc1
Reactant: O=C(O)c1sc(Cl)cc1Cc1cccc(Cl)c1
Agent: CC(=O)c1ccc(C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: c1ccc([Se][Se]c2ccccc2)cc1
Solvent: CC#N
Product: CC(NC(=O)c1sc(Cl)cc1Cc1cccc(Cl)c1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 5-chloro-3-(3-chlorobenzyl)thiopbene-2-carboxylic acid from Example 1, Step 6 (230 mg, 0.801 mmol), 4-(1-azidoethyl)benzonitrile (146 mg, 0.848 mmol) [prepared according to Thompson et al. J. Org. Chem. 1993, 58, 5886, after reduction of commercially available 4-acetylbenzonitrile] and diphenyl diselenide (549 mg, 1.76 mmol) in acetonitrile at r.t. under N2 was added tributylphosphine (217 μL, 0.881 mmol, 1.1 eq) dropwise (suspension dissolved, slightly exothermic) and the mixture was stirred at r.t. for 6 h, quenched with saturated NaHCO3 and extracted with ether. The crude was purified by Combi Flash chromatography system (10-40% EtOAc/hexane) to give the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[S:16][C:17]([CH3:20])=[N:18][N:19]=2)[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]2[N:32]([CH3:33])[C:31](=[O:34])[O:30][CH2:29][CH2:28][C:27]=2[CH:35]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[S:16][C:17]([CH3:20])=[N:18][N:19]=2)=[N:7][C:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]3[N:32]([CH3:33])[C:31](=[O:34])[O:30][CH2:29][CH2:28][C:27]=3[CH:35]=2)=[N:3][CH:4]=1
Reactant: Cc1nnc(-c2ccccc2Nc2nc(Cl)ncc2Cl)s1
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Product: Cc1nnc(-c2ccccc2Nc2nc(Nc3ccc4c(c3)CCOC(=O)N4C)ncc2Cl)s1

Procedure:
The title compound was prepared by combining (2,5-dichloro-pyrimidin-4-yl)-[2-(5-methyl-[1,3,4]thiadiazol-2-yl)-phenyl]-amine (Example N?, 75 mg, 0.22 mmol) and 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (Example N?, 47 mg, 0.24 mmol) in an analogous manner described in Example 356c. The title product was isolated as described in Example 1477b as a white powder (32 mg, 26%) and had the following properties: m.p: 174-177° C.; LC/MS (m/e): 494 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 10.75 (s, 1H), 9.40 (s, 1H), 8.40-5.06 (series of m, 2H), 8.04 (d, J=7.0, 1H), 7.75-7.30 (series of m, 4H), 7.10 (d, J=8.6, 1H), 4.30 (t, J=6.3, 2H), 3.23 (s, 3H), 2.37 (s, 3H), 2.60 (m, 2H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([CH:24]=[CH:25][CH:26]=[O:27])=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[OH:27][CH:26](/[CH:25]=[CH:24]/[C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:29][CH:28]=1)[C:3]#[C:2][C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])=[O:4]
Reactant: COc1ccc(C=CC=O)cc1
Reactant: C#CC(=O)OCCOCCOC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCOCCOC(=O)C#CC(O)/C=C/c1ccc(OC)cc1
Reaction time: 0.08 h

Procedure:
A solution of 1.75 g (10.2 mmol) of 2-(2-methoxyethoxy)ethyl propiolate in 20 ml of tetrahydrofuran was treated at -78° under argon with 7 ml of n-butyllithium solution (1.6M in hexane). The mixture was stirred at -78° for 5 minutes and then a solution of 1.65 g (10.2 mmol) of 4-methoxycinnamaldehyde in 25 ml of tetrahydrofuran was added within 10 minutes. The reaction mixture was stirred at -78° for 5 minutes and then treated with 50 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed with water, dried over sodium sulphate, filtered and concentrated. Flash chromatography of the residue on 120 g of silica gel (elution agent methylene chloride/ether 4:1) yielded 2-(2-methoxyethoxy)ethyl (E)-4-hydroxy-6-(4-methoxyphenyl)-5-hexen-2-ynoate as a yellow oil.
Reaction SMILES: [C:1]1([B:7]([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:10]([O-])([OH:12])=[O:11]>C(OC(=O)C)(=O)C>[N+:10]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[B:7]([OH:9])[OH:8])([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: OB(O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccccc1B(O)O
Temperature: 25 °C
Yield: 15 %

Procedure:
A solution of phenyl boronic acid (5.0 g, 41 mmol) in acetic anhydride (50 mL) at −15° C. was treated with nitric acid (2.5 mL) dropwise over 30 minutes maintaining a temperature below −10° C. The reaction was allowed to warm to room temperature overnight, then poured onto ice. The resulting solution was concentrated to 25 mL and water (50 mL) was added. The mixture was again concentrated. This procedure was repeated five times. The solid that developed was filtered and dried. The crude product was purified by flash chromatography (SiO2, 2% EtOH/CH2Cl2) to afford the desired product (1.0 g, 15%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[H-].[Na+].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.O>CN(C)C=O>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:5]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](=[O:4])[C:2]([F:14])([F:15])[F:1]
Reactant: O=C(NCCc1ccccc1)C(F)(F)F
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N(CCCCCCBr)CCc1ccccc1)C(F)(F)F
Yield: 63.1 %

Procedure:
2,2,2-Trifluoro-N-(2-phenylethyl)acetamide (21.7 g., 0.1 mole) in dry dimethylformamide (100 ml) was added dropwise with stirring and under nitrogen to sodium hydride (2.4 g., 0.1 mole, ether washed) in dry dimethylformamide (150 ml). Stirring was continued until a clear solution was obtained and 1,6-dibromohexane (73.2 g., 0.3 moles) was added. The solution was heated at 60° for 3 hr then poured into water and extracted with ether. The extracts were washed well with water and dried and evaporated. Excess dibromohexane was recovered by distillation (b.p. 60°-70°/0.1 mmHg) and the residue was separated on a silica gel column using ether-light petroleum (1:2) as eluant. The major fraction was evaporated to give the title compound as a pale yellow oil (24 g). A sample was distilled to give a colourless viscous liquid, b.p. 146°-152°/0.05 mmHg, (with slight decomposition).