Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@@H:17]([O:38][Si](C(C)(C)C)(C)C)[CH2:18][C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([NH:8][C@H:9]([C@@H:17]([OH:38])[CH2:18][C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH2:20][C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccncc1)NC(=O)OCc1cccnc1)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccncc1)NC(=O)OCc1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.4 %

Procedure:
A solution of 74.5 mg (0.117 mmol) of (2S,3S,5S)-2-(Boc-amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1-phenyl-6-(4-pyridinyl)-3-(tert-butyldimethylsilyloxy)-hexane in 4 ml of tetrahydrofuran was treated with 102 μl of 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. After being stirred at ambient temperature for 24 h, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography using 10% methanol in dichloromethane to provide 51.4 mg (84%) of the desired compound as a white solid. 1H NMR (CDCl3) δ1.37 (s, 9H), 1.65 (t, 2H), 2.82-3.01 (m, 5H), 3.70 (m, 2H), 4.03 (m, 1H), 4.78 (d, 1H), 5.03 (s, 2H), 5.18 (br d, 1H), 7.06 (d, 2H), 7.16-7.31 (m, 6H), 7.61 (d, 1H), 8.44 (d, 2H), 8.57 (s, 2H). Mass spectrum: (M+H)+ =521.
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:46][CH2:47][CH2:48][CH3:49]>CN(C)C=O.O>[CH2:46]([O:38][C:35]1[CH:36]=[CH:37][C:32]([CH:2]([OH:1])[CH:3]([NH:18][C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=23)=[O:20])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=2)=[CH:33][CH:34]=1)[CH2:47][CH2:48][CH3:49]
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and 1-iodobutane (417 mg, 2.27 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the objective substance (298 mg, 67%).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16].C(N(CC)CC)C.[O-]S([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(Cl)Cl.CO>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH:20][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1)[CH3:16]
Reactant: O=Cc1ccc(-n2cncn2)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNCc1ccc(-n2cncn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3.5 g (20 mmol) of 4-[1,2,4] triazol-1-yl-benzaldehyde and 4.19 g (30 mmol) of glycine ethyl ester hydrochloride in 100 ml of CH2Cl2, 4.18 ml (30 mmol) of triethyl amine and excess of MgSO4 (14 g) are successively added at r.t. After being stirred for 18 h at r.t., the reaction mixture is filtered through celite and concentrated under reduced pressure. The residue is diluted with AcOEt and filtered again. The filtrate is concentrated under reduced pressure to give the crude imine. To a solution of the crude imine in 12 ml of MeOH, 0.756 mg (20 mmol) of NaBH4 is added at −10° C. After being stirred for 1 h, the reaction is quenched with sat. NH4Cl and the reaction mixture is extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: n-Hexane: AcOEt=1:10) to give the title compound. 1H-NMR (400 MHz, CDCl3): 1.29 (t, 3H, J=7.04 Hz), 1.90 (brs, 1H), 3.43 (s, 2H), 3.88 (s, 2H), 4.21 (q, 2H, J=7.04 Hz), 7.49 (d, 2H, J=8.56 Hz), 7.64 (d, 2H, J=8.56 Hz), 8.10 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:28])[CH2:16][C:17](=O)[CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:29]([NH2:32])(=O)[CH3:30].C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1(C)C(C)=CC=CC=1.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[C:15](=[O:28])[CH:16]=[C:17]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[N:32]=[C:29]2[CH3:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC(N)=O
Reactant: O=C(COc1cccc(F)c1)CC(=O)Nc1ccc(N2CCOCC2)c(F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1nc(COc2cccc(F)c2)cc(=O)n1-c1ccc(N2CCOCC2)c(F)c1
Temperature: 165 °C
Reaction time: 24 h
Yield: 16.6 %

Procedure:
A mixture of N-(3-fluoro-4-morpholinophenyl)-4-(3-fluorophenoxy)-3-oxobutanamide (510 mg, 1.31 mmol), acetamide (154 mg, 2.61 mmol) and titanium tetraisopropanolate (3.2 mL) in xylene (10 mL) was stirred at 165° C. for 24 h. The mixture was cooled to rt and 60 mL of toluene and 60 mL of saturated NH4Cl aqueous solution were added. The resulting mixture was stirred at rt overnight. The mixture was then filtered and the filtrate was extracted with DCM (20 mL×4). The combined organic phases were washed with brine (30 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (0.09 g, 17%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][C:13]3=[O:16])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=[O:30])[C:23]=1[Cl:31].O>C1COCC1>[C:17]([C:4]1[CH:3]=[C:2]([NH:1][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[C:23]=2[Cl:31])=[O:30])[N:6]([C:7]2[CH:15]=[C:14]3[C:10](=[CH:9][CH:8]=2)[CH2:11][CH2:12][C:13]3=[O:16])[N:5]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3c(c2)C(=O)CC3)n1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3c(c2)C(=O)CC3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of the 6-(5-amino-3-t-butyl-pyrazol-1-yl)indan-1-one (1.5 g, 5.6 mmol) in THF (30 mL) was added a solution of 1,2-dichloro-3-isocyanato-benzene (1.2 g, 6.4 mmol) in THF (5.0 mL) at 0° C. under N2. The resulting mixture was stirred at RT overnight then poured into H2O. The mixture was extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated and purified via column chromatography to afford 1-[5-t-butyl-2-(3-oxo-indan-5-yl)-2H-pyrazol-3-yl]-3-(2,3-dichlorophenyl)urea as a solid (1.1 g, 43% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.22 (s, 1H), 8.68 (s, 1H), 7.94 (t, J=5.1 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.69-7.65 (m, 2H), 7.24 (d, J=4.8 Hz, 2H), 6.34 (s, 1H), 3.14-3.05 (m, 2H), 2.78-2.66 (m, 2H), 1.22 (s, 9H); MS (ESI) m/z: 457 (M+H+).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[N:21][C:22]4[N:23]([N:25]=[CH:26][C:27]=4[CH2:28][CH3:29])[CH:24]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[I-].[Li+]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[N:21][C:22]4[N:23]([N:25]=[CH:26][C:27]=4[CH2:28][CH3:29])[CH:24]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4c(CC)cnn4c3)sc2c1-c1ccc(Cl)cc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCc1cnn2cc(-c3nc4cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c5ccc(Cl)cc5)c4s3)cnc12
Temperature: 170 °C

Procedure:
A mixture of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(3-ethylpyrazolo[1,5-a]pyrimidin-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (24.9 mg, 0.044 mmol) and lithium iodide (200 mg) in pyridine (0.5 mL) was heated in microwave at 170° C. for 1 h. Reaction mixture was diluted with ethyl acetate, washed with 5% acetic acid solution, brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 30% MeOH/CH2Cl2). Lyophilization gave desired product. LCMS-ESI+: calc'd for C28H28ClN4O3S: 535.2. (M+H+); Found: 535.2 (M+H+). 1H NMR (400 MHz, CDCl3) δ 9.22 (dd, J=2.8, 1.6 Hz, 1H), 8.95 (dd, J=2.8, 1.6 Hz, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.58-7.37 (m, 3H), 5.31 (s, 1H), 2.86 (q, J=7.6 Hz, 2H), 2.58 (s, 3H), 1.34 (dd, J=7.8, 7.3 Hz, 3H), 0.99 (s, 9H).
Reaction SMILES: [Br:1]Br.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].O>CN(C=O)C>[Br:1][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:3][C:4]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: BrBr
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2ccccc2c1Br
Reaction time: 0.5 h

Procedure:
A solution of bromine (2.72 ml) in DMF was added dropwise over 10 mins to a solution of ethyl indole-2-carboxylate in DMF. The reaction was stirred for 30 mins, then poured into water to precipitate a pale yellow solid which was filtered off and recrystallized from ethyl acetate to give the desired starting material as white needles (10.2 g, 72%), mp 150-151°; NMR δ (CDCl3) 1.44 (t, 3H), 4.45 (q, 2H), 7.22 (m, 11H), 7.38 (m, 2H), 7.66 (d, 1H), 9.27 (bs, 1H); M/z (−) 268 (M+), 266, 196, 194.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH3:11][NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16]>>[OH:17][CH:14]([CH2:15][OH:16])[CH2:13][N:12]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])[CH3:11]
Reactant: CNCC(O)CO
Reactant: N#Cc1cccc(CBr)c1
Product: CN(Cc1cccc(C#N)c1)CC(O)CO

Procedure:
The title compound was prepared following the general procedure 10, starting from 3-(bromomethyl)benzonitrile and 3-(methylamino)-1,2-propanediol. It was isolated as a colorless oil (920 mg, 82%). LC/MS (Method B): 221.1 (M+H)+.
Reaction SMILES: BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(O)OCC)=CC=3OC)N=2)=CC=1.[Br:39][C:40]1[N:45]=[C:44]([C:46](=[O:49])[NH:47][CH3:48])[C:43]([NH:50][C:51]2[C:56]([C:57]([F:60])([F:59])[F:58])=[CH:55][N:54]=[C:53]([NH:61][C:62]3[CH:76]=[CH:75][C:65]([CH2:66][P:67](=[O:74])([O:71]CC)[O:68][CH2:69][CH3:70])=[C:64]([Cl:77])[C:63]=3[O:78][CH3:79])[N:52]=2)=[CH:42][CH:41]=1>>[Br:39][C:40]1[N:45]=[C:44]([C:46](=[O:49])[NH:47][CH3:48])[C:43]([NH:50][C:51]2[C:56]([C:57]([F:59])([F:58])[F:60])=[CH:55][N:54]=[C:53]([NH:61][C:62]3[CH:76]=[CH:75][C:65]([CH2:66][P:67](=[O:71])([OH:74])[O:68][CH2:69][CH3:70])=[C:64]([Cl:77])[C:63]=3[O:78][CH3:79])[N:52]=2)=[CH:42][CH:41]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1Cl)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1Cl

Procedure:
Prepared analogously to Compound 38C with diethyl (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-chloro-3-methoxybenzyl)phosphonate (Compound 54C). MS (ESI): m/z 653.03/655.02 [M+H]+. UPLC: tR=0.98 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [OH:1][C:2]([CH3:17])([C:6]([NH:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[O:7])[C:3]([OH:5])=O.[NH2:18][C@@H:19]1[C:25](=[O:26])[NH:24][C:23]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:22]=2[O:21][C@@H:20]1[CH:32]1[CH2:34][CH2:33]1>>[CH:32]1([C@@H:20]2[C@H:19]([NH:18][C:3](=[O:5])[C:2]([OH:1])([CH3:17])[C:6]([NH:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[O:7])[C:25](=[O:26])[NH:24][C:23]3[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:22]=3[O:21]2)[CH2:34][CH2:33]1
Reactant: N[C@@H]1C(=O)Nc2cc(F)ccc2O[C@@H]1C1CC1
Reactant: CC(O)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: CC(O)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2cc(F)ccc2O[C@@H]1C1CC1

Procedure:
N-((6R,7S)-6-Cyclopropyl-2-fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-2-hydroxy-2-methyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide was obtained as mixture of epimers according to the procedures described for example 2b using racemic 2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid and (6R,7S)-7-amino-6-cyclopropyl-2-fluoro-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one. The epimers were separated by chromatography on Chiralpak AD using isopropanol/heptane 15:85 to yield (−)-N-((6R,7S)-6-cyclopropyl-2-fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-2-hydroxy-2-methyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide, entity A, MS m/e (%): 484.5 (M+H+, 100), as first eluting fraction, and (−)-N-((6R,7S)-6-cyclopropyl-2-fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-2-hydroxy-2-methyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide, entity B, as second eluting fraction, MS m/e (%): 484.5 (M+H+, 100).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C:20]2[C:21]([O:26][C:27]3[CH:35]=[CH:34][C:30]4=[N:31][S:32][N:33]=[C:29]4[CH:28]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[C:12]([F:36])[CH:11]=1)[CH3:8])(C)(C)C.C(OC(=O)C(OC1C=CC(CNC(C2C(OC3C=CC4=NON=C4C=3)=NC=CC=2)=O)=C(F)C=1)C)(C)(C)C>>[N:31]1[S:32][N:33]=[C:29]2[CH:28]=[C:27]([O:26][C:21]3[C:20]([C:18]([NH:17][CH2:16][C:13]4[CH:14]=[CH:15][C:10]([O:9][CH:7]([CH3:8])[C:6]([OH:37])=[O:5])=[CH:11][C:12]=4[F:36])=[O:19])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:35]=[CH:34][C:30]=12
Reactant: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nsnc3c2)c(F)c1)C(=O)OC(C)(C)C
Agent: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nonc3c2)c(F)c1)C(=O)OC(C)(C)C
Product: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nsnc3c2)c(F)c1)C(=O)O

Procedure:
The compound of Formula (5.5.7) was prepared in a manner analogous to that described in Example 3, substituting (+)-2-[4-({[2-(benzo[2,1,3]thiadiazol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid tert-butyl ester for the corresponding (±)-2-[4-({[2-(benzo[2,1,3]oxadiazol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro -phenoxy]-propionic acid tert-butyl ester material.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:45]=[CH:44][CH:43]=[CH:42][C:4]=1[O:5][CH2:6][CH2:7][O:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]1>CN(C)C=O.C1O[C@H]1C.N12CCN(CC1)CC2.Cl>[OH:5][CH:4]([CH3:42])[CH2:3][O:1][CH2:2][C:3]1[CH:45]=[CH:44][CH:43]=[CH:42][C:4]=1[O:5][CH2:6][CH2:7][O:8][CH:9]1[CH:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:19][CH:20]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[CH2:10]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CO)cc1
Agent: C1CN2CCN1CC2
Agent: C[C@H]1CO1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2COCC(C)O)cc1

Procedure:
A solution of 0.34 g of tert-butyl 3-[2-(2-hydroxymethylphenoxy)ethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 10 ml of N,N-dimethylformamide and 0.39 ml of (S)-(−)-propylene oxide (plus 0.3 ml after 2.5 hours, 1.0 ml after 5 hours) and one drop of 1,4-diazabicyclo[2.2.2]octane is stirred at 100° C. over 26 hours. The reaction mixture is cooled, diluted with 1N HCl and extracted with ethyl acetate (2×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.38 (2:1 EtOAc-heptane); Rt=5.88.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:16]=2)=[C:4]([O:17]C)[CH:3]=1.[C:19]([O-])(=O)/C=C/C([O-])=O>>[OH:17][C:4]1[CH:3]=[C:2]([O:1][CH3:19])[CH:7]=[CH:6][C:5]=1[C:8]1[NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[N:16]=1
Reactant: COc1cc(O)ccc1-c1nc2cnccc2[nH]1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Product: COc1ccc(-c2nc3cnccc3[nH]2)c(O)c1

Procedure:
2-(4-Hydroxy-2-methoxyphenyl)imidazo(4,5-c)pyridine, fumarate, m.p. 255°.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[NH:28][CH2:29][CH2:30][CH2:31][NH2:32]>C(O)(C)C>[OH:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:32][CH2:31][CH2:30][CH2:29][NH:28][C:22]2[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=2[CH3:20])=[CH:11][CH:10]=1
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Reactant: Cc1cccc(C)c1NCCCN
Solvent: CC(C)O
Product: Cc1cccc(C)c1NCCCNCC(O)COc1ccc(O)cc1

Procedure:
4.23 g. 4-Benzyloxyphenyl glycidyl ether, 5.9 g. N-(2,6-dimethylphenyl)-1,3-diaminopropane and 5 ml. isopropyl alcohol are stirred for 24 hours at ambient temperature. The reaction mixture is worked up by chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[C:33]([S:34]([CH3:37])(=[O:36])=[O:35])=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:18][CH2:19]OS(C)(=O)=O)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8]1)=[O:6].C(N(CC)CC)C.I.[CH2:46]([O:48][CH2:49][CH2:50][N:51]1[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=2[N:53]=[C:52]1[N:60]1[CH2:66][CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH3:47].CO.ClCCl>C(#N)C.ClCCl>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[C:33]([S:34]([CH3:37])(=[O:35])=[O:36])=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:18][CH2:19][N:63]2[CH2:64][CH2:65][CH2:66][N:60]([C:52]3[N:51]([CH2:50][CH2:49][O:48][CH2:46][CH3:47])[C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=4[N:53]=3)[CH2:61][CH2:62]2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2nnnc2S(C)(=O)=O)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5nnnc5S(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21
Reaction time: 12 h

Procedure:
Combine 1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoyl)-3-(2-methanesulfonyloxyethyl)-3-phenylpyrrolidine (0.44 g, 0.81 mmol), triethylamine (0.33 g, 3.23 mmol), and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.44 g, 8.1 mmol) in acetonitrile (10 mL). Heat to reflux. After 12 hours, cool the reaction mixture, dilute with dichloromethane, and extract with water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:2]=1.C(OCC)(=O)C>[Pd].C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:2]=1
Reactant: OCCCCC#Cc1cccnc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCCC/C=C\c1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.9 %

Procedure:
6-(3-Pyridyl)-1-hex-5-ynol (0.15 g, 0.86 mmol) was added to a stirred suspension of 10% palladium on charcoal (20 mg) in ethanol. The reaction was stirred at room temperature under hydrogen for 24 h. The mixture was filtered through celite and evaporated to give a clear oil. Column chromatography (flash silica gel; ethyl acetate) gave Z-6-(3-pyridyl)-1-hex-5-enol (70 mg, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH:6]=[O:7].[N+:17]([CH3:20])([O-:19])=[O:18]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH2:20][N+:17]([O-:19])=[O:18])[CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1cc(C=O)ccc1-c1ccccn1
Reactant: C[N+](=O)[O-]
Solvent: C1CCOC1
Product: COc1cc(C(O)C[N+](=O)[O-])ccc1-c1ccccn1

Procedure:
A THF solution of 3-methoxy-4-pyridin-2-ylbenzaldehyde (0.3 g, 1.4 mmol), nitromethane (0.23 mL, 4.2 mmol) and TEA (0.2 mL, 1.4 mmol) was stirred at 55° C. over night, concentrated and purified on silica gel (2:1 hexane-ethyl acetate) to afford a yellow foam.
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH3:8][NH:9][O:10][CH3:11].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:11][O:10][N:9]([CH3:8])[C:1](=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCC(=O)N(C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a mixture of butanoic acid (1.01 g, 0.0115 mol) and N,O-dimethylhydroxylamine hydrochloride (1.12 g, 0.0115 mol) in DCM (50 mL) was added benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (5.6 g, 0.013 mol) and TEA (3.2 mL, 0.023 mol). The mixture was stirred overnight at room temperature. The solution was then washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash column chromatography (ether/hexanes). The solvent was removed (235 mbar/40° C.) to afford the product (1.33 g, 88%). 1H NMR (300 MHz, CDCl3): 3.68 (s, 3H), 3.18 (s, 3H), 2.40 (t, 2H), 1.74-1.59 (m, 2H), 0.96 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[C:16]([O:25][CH3:26])[CH:15]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCOCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[C:16]([O:25][CH3:26])[CH:15]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc(NC(=O)Nc2cccc([N+](=O)[O-])c2)ccc1-c1cnco1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(NC(=O)Nc2cccc(N)c2)ccc1-c1cnco1
Yield: 46.2 %

Procedure:
A solution of 0.7 g (2 mmol) of 49A in 60 ml of dioxane and 30 ml of methanol was hydrogenated at rt and one atmosphere pressure over 0.14 g of 10% Pd/C catalyst. The catalyst was removed by filtration through Celite. The filtrate was evaporated to dryness to yield 0.3 g of 49B as a tan solid. The filter cake was suspended in dioxane—methanol and stirred at 50° C. for 1 hr. The hot solution was again filtered, and the filtrate evaporated to dryness to yield an additional 0.6 g of material. The combined batches were triturated with methylene chloride and the insolubles filtered to give 645 mg (2 mmoles, 100%) of 49B as a light tan powder.