Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.CO.C(Cl)(Cl)Cl.CO.O>C(N)(C)C.CO>[Cl:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:14])[N:3]([C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17])[C:2]([NH:3][CH:4]([CH3:9])[CH3:5])=[C:10]2[CH:11]=[O:12]
Reactant: O=Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Solvent: CC(C)N
Solvent: O
Solvent: CO
Product: CC(C)Nc1c(C=O)c2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
2,5,6-Trichloro-3-formyl-1-(β-D-ribofuranosyl)indole (4.3, 171 mg, 0.45 mmol) was dissolved in isopropylamine (10 mL), and the resulting solution was stirred at room temperature for 16 h. The solvent was then evaporated and the residue dissolved in EtOAc (50 mL). The suspension was washed with H2O (20 mL) and brine (50 mL), then dried over MgSO4, filtered and evaporated to yield a yellow syrup. The residue was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 20% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a clear viscous residue which was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield a white solid which was recrystallized from MeOH/H2O to yield 76 mg (42%) of 4.19 as a white microcrystalline solid: mp 143-145 C; Rf 0.6 (20% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 9.90 (s, 1H), 8.19 (s, 1H), 7.73 (s, 1H), 7.26 (d, 1H, D2O exch.), 5.87 (d, 1H, D2O exch.), 5.68 (s, 1H, D2O exch.), 5.37 (d, 1H, D2O exch.), 5.29 (d, 1H), 4.35 (q, 1H), 4.10 (s, 1H), 4.07 (m, 1H), 4.00 (s, 1H), 3.70 (m, 2H), 1.28 (s, 6H). 13C-NMR (125 MHz, DMSO-d6): δ 181.55, 153.38, 133.43, 127.15, 123.96, 122.70, 119.37, 111.47, 99.04, 88.51, 85.88, 70.76, 69.80, 60.69, 48.99, 22.77, 22.55. HRMS (ES) m/z calcd. for C17H20Cl2N2O5.Na.CH3OH 457.0909, found 457.0912. Anal calcd for C17H20Cl2N2O5.¼ H2O: C, 49.53; H, 5.13; N, 6.80. Found: C, 49.83; H, 5.04; N, 6.51.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C.O>C1COCC1>[N+:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:11])=[O:10]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CN2CCCC2)c1
Temperature: 25 °C
Yield: 94 %

Procedure:
A solution of 1-bromomethyl-3-nitrobenzene (the compound of formula (R), 5 mmol, 1.08 g), pyrrolidine (11 mmol, 0.79 g), and 1.0 mL triethylamine (the compound of formula NRR′R″ wherein R═R′═R″=ethyl) in THF (35 mL) was heated at 60° C. for 1 hour. The reaction mixture was allowed to cool to ambient temperature overnight with stirring. Water was then added to the reaction mixture and the product was extracted into diethyl ether. The ether layer was dried over sodium sulfate, filtered, and evaporated to yield 1.03 g (94%) of 1-(3-nitro-benzyl)-pyrrolidine (the compound of formula (S)) which was used in the following reaction without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([CH3:26])[C@@H:13]([CH3:25])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[CH:7][C:6]=1[O:27][CH3:28].C[O-].[Na+].[N+:32]([C:35]1[NH:36][CH:37]=[CH:38][N:39]=1)([O-:34])=[O:33]>>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH2:14][C@H:13]([CH3:25])[C@H:12]([CH3:26])[CH2:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:36]3[CH:37]=[CH:38][N:39]=[C:35]3[N+:32]([O-:34])=[O:33])=[C:6]([O:27][CH3:28])[CH:7]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OCCBr)c(OC)c2)cc1OC
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OCCn3ccnc3[N+](=O)[O-])c(OC)c2)cc1OC
Yield: 52.7 %

Procedure:
The Standard Procedure 2 was followed by use of 9a (38.2 mg, 0.0849 mmol, 1.0 equiv), sodium methoxide (10.1 mg, 0.187 mmol, 2.2 equiv), and 2-nitroimidazole (6b, 19.2 mg, 0.170 mmol, 2.0 equiv). After workup and purification with column chromatography (80% EtOAc in hexanes as eluant), 10b (21.6 mg, 0.0447 mmol) was obtained in 53% yield as a yellow gummy oil: 1H NMR (CDCl3, 400 MHz) δ 0.79 (d, J=6.8 Hz, 3H, CH3), 0.81 (d, J=6.8 Hz, 3H, CH3), 1.72-1.73 (m, 2H, 2×CH), 2.23-2.32 (m, 2H, 2×ArCH), 2.68-2.74 (m, 2H, 2×ArCH), 3.73 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.30 (t, J=4.6 Hz, 2H, CH2N), 4.80 (t, J=4.8 Hz, 2H, CH2O), 6.59-6.70 (m, 5H, 5×ArH), 6.75-6.77 (m, 1H, ArH), 7.13 (s, 1H, nitroimidazole C5-H), 7.34 (s, 1H, nitroimidazole C4-H); 13C NMR (CDCl3, 100 MHz) δ 16.04, 16.16, 38.69, 38.88, 39.05, 39.21, 49.64, 55.59, 55.72, 55.81, 68.30, 110.92, 112.16, 112.87, 115.24, 120.84, 121.02, 127.51, 128.03, 134.26, 136.84, 144.64, 145.10, 146.97, 148.60, 149.68; IR (neat) 2924 (s), 2853 (s), 1590 (w), 1539 (m), 1516 (s), 1456 (w), 1361 (s), 1261 (s), 1235 (s), 1030 (s) cm−1; HRMS (FAB) m/z calcd for C26H34N3O6 (M+H)+: 484.2448. found: 484.2457.
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.FC(F)(F)C(O)=O.[NH:30]1[CH2:33][CH:32]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:31]1>>[N:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][CH:32]1[CH2:33][N:30]([C:13]2[N:14]3[C:18]([N:19]=[C:11]4[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]=24)=[CH:17][CH:16]=[N:15]3)[CH2:31]1
Reactant: c1ccc(CC2CNC2)nc1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CC2CN(c3c4c(nc5ccnn35)CCNCC4)C2)nc1

Procedure:
The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 2-azetidin-3-ylmethyl-pyridine trifluoroacetate was used as the amine.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([O:17][C@H:18]3[CH2:22][N:21](C(OC(C)(C)C)=O)[C@H:20]([C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])[CH2:19]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:39]=[CH2:40])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1.[CH2:48]([O:51][C:52]([NH:54][C@H:55]([C:60](O)=[O:61])[CH2:56][CH2:57][CH2:58][CH3:59])=[O:53])[CH:49]=[CH2:50].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:48]([O:51][C:52]([NH:54][C@H:55]([C:60]([N:21]1[CH2:22][C@H:18]([O:17][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:39]=[CH2:40])[CH:13]=3)[N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:16]=2)[CH2:19][C@H:20]1[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])=[O:61])[CH2:56][CH2:57][CH2:58][CH3:59])=[O:53])[CH:49]=[CH2:50]
Reactant: C=Cc1ccc2nc(-c3ccccc3)cc(O[C@@H]3C[C@@H](C(=O)OCC[Si](C)(C)C)N(C(=O)OC(C)(C)C)C3)c2c1
Reactant: C=CCOC(=O)N[C@@H](CCCC)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C=CCOC(=O)N[C@@H](CCCC)C(=O)N1C[C@H](Oc2cc(-c3ccccc3)nc3ccc(C=C)cc23)C[C@H]1C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a flask containing 1-tert-butyl 2-[2-(trimethylsilyl)ethyl] (2S,4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate 5 (45 mg, 0.08 mmol) was added a 4 M solution of HCl in dioxane (1.4 mL, 5.6 mmol). After 1 h, LC-MS analysis indicated complete consumption of the starting material (5) and formation of the desired -Boc product. The volatile components were then removed in vacuo, and the crude material was taken up in DMF (1 mL). To this mixture was added alloc-Nle-OH (4) (26 mg, 0.12 mmol), DIPEA (0.144 mL, 0.8 mmol), and TBTU (39 mg, 0.12 mmol). After stirring at RT for 30 min, complete consumption of the amine was evidenced via LC-MS. The reaction mixture was then worked-up with 1N HCl and EtOAc. The organic layer was washed with brine and dried over MgSO4. The solvent was then removed in vacuo and the crude product was purified on silica (10-50% EtOAc/hexanes) to yield 50 mg (95% yield) of 2-(trimethylsilyl)ethyl N-[(allyloxy)carbonyl]-L-norleucyl-(4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]-L-prolinate 6. 1H NMR (500 MHz, CDCl3) ppm: mixture of amide rotamers: 8.07 (m, 3H), 7.97 (br s, 1H), 7.88 (m, 1H), 7.54-7.47 (m, 3H), 7.07 (s, 1H), 6.92 (dd, J=17.5 Hz, 10.5 Hz, 1H), 5.90 (d, J=17.5 Hz, 1H), 5.83 (m, 1H), 5.43-5.63 (m, 3H), 5.25-5.13 (m, 2H), 4.79 (app t, J=8 Hz, 1H), 4.65-4.37 (m, 4H), 4.26 (m, 2H), 4.10 and 4.08 (2 d, J=4.0 Hz and 4.5 Hz, 1H), 2.78 (m, 1H), 2.42 (m, 1H), 1.83 (m, 1H), 1.63 (m, 1H), 1.44-1.33 (m, 4H), 1.05-0.98 (m, 2H), 0.92 (m, 3H), 0.05 (s, 9H). LRMS (CI, [M+H]) Calc'd=658.4. Found=658.4. HRMS (APCI, [M+H]+) Calc'd for C37H48N3O6Si: 658.3307. found: 658.3348.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@:24]([CH3:30])([C:26](OC)=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH3:44]>>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@:24]([CH3:30])([C:26]([NH2:44])=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:43])([F:1])[F:42])[CH:8]=1
Reactant: COC(=O)[C@]1(C)CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Reactant: N
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@@](C)(C(N)=O)N2
Yield: 371.9 %

Procedure:
In a sealed tube a solution of methyl (2S,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-methyl-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 45, 75 mg, 0.121 mmol) in 7 N methanolic ammonia (5 ml, 35.0 mmol) was shaken at 40° C. for 5 days by PLS. Volatiles were removed in vacuo and the residue was purified by flash chromatography on silica gel using a SNAP 10 g as column and Dichloromethane/Methanol 98:2 as eluent affording the title compound (27 mg, 0.45 mmol, y=37.2%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12](Cl)=[O:13])([CH3:3])[CH3:2].[N+:15](=[CH2:17])=[N-:16]>C(Cl)Cl.CCOCC>[N+:15](=[CH:17][C:12](=[O:13])[CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])=[N-:16]
Reactant: C=[N+]=[N-]
Reactant: CC(C)c1ccccc1CCC(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)c1ccccc1CCC(=O)C=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
A solution of 3-(2-isopropylphenyl)propanoyl chloride (crude, 10.5 mmole) in methylene chloride was slowly added to a solution of diazomethane (generated from 6.95 g of 1-methyl-3-nitro-1-nitrosoguanidine) in ether (50 ml) cooled in an ice bath. The mixture was then warmed up to room temperature and stirred overnight. The mixture was concentrated in vacuo and purified by column chromatography (20% ethyl acetate/hexanes) to give 1-diazo-4-(2-isopropylphenyl)butan-2-one (1.87 g, 82% over 2 steps) as a bright yellow oil. 1H NMR (CDCl3) δ 7.10-7.30 (4H, m, phenyl), 5.21 (1H, broad s, diazo), 3.15 (1H, m, CH of iPr), 3.00 (2H, t, benzylic), 2.57 (2H, m), 1.24 (6H, d, 2 CH3 of iPr). Step 3:
Reaction SMILES: [NH2-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH:5]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][CH2:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)[CH2:4]1.[CH2:25](Br)[CH3:26].O>C1C=CC=CC=1>[CH2:25]([N:3]1[CH2:8][CH2:7][O:6][CH:5]([CH2:9][N:10]2[C:11]3[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=3[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=3)[CH2:4]1)[CH3:26]
Reactant: c1ccc2c(c1)CCc1ccccc1N2CC1CNCCO1
Reactant: CCBr
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCN1CCOC(CN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium amide (0.08 g) in benzene was added a solution of 5-(2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine (0.5 g) in benzene under ice cooling, and the resulting mixture was stirred at room temperature for 30 minutes. to the reaction mixture was added a solution of ethyl bromide (0.22 g) in benzene under ice cooling, and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was cooled, admixed with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-ethyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(N(CC)CC)C.C([O:40][C:41](=O)[C:42]([F:45])([F:44])[F:43])C.O>CO>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:41](=[O:40])[C:42]([F:45])([F:44])[F:43])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(NC(COCC1CCN(C(=O)C(F)(F)F)CC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Yield: 42.1 %

Procedure:
To a solution of 3-chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (600 mg, 1.3 mmol) in 5 mL of methanol was added triethylamine (0.37 mL, 2.7 mmol) and trifluoroacetic acid ethyl ester (0.20 mL, 2.7 mmol). The reaction was allowed to stir at room temperature overnight after which time water was added and the resulting precipitate was isolated by filtration. Purification of the filtrate (SiO2: 10:2:0.5 DCM:hexane:isopropylamine) provided 297 mg (41%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][C@@H:35]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]4)=[O:33])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: Cc1c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c2) and commercially available tert-butyl(R)-3-amino-pyrrolidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][CH:10]=[CH:11][CH:12]=[CH:13][CH3:14])[CH2:3][C:4]([O:6]C)=O.[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([NH:19][C:4](=[O:6])[CH2:3][CH:2]([OH:1])[CH2:8][CH2:9][CH:10]=[CH:11][CH:12]=[CH:13][CH3:14])[CH:16]([CH3:18])[CH3:17]
Reactant: CC=CC=CCCC(O)CC(=O)OC
Reactant: CC(C)CN
Product: CC=CC=CCCC(O)CC(=O)NCC(C)C
Temperature: 90 °C
Reaction time: 24 h
Yield: 81.4 %

Procedure:
Methyl 3-hydroxy-6,8-decadienoate (9) (86.1 g, 0.43 mol) and isobutylamine (95.3 g, 1.3 mol) were put into a 500 ml capacity flask equipped with a stirrer, a thermometer and a reflux condenser, followed by heating to 90° C. and stirring for 24 hours. After recovering isobutylamine under a reduced pressure, and when heptane (700 ml) was added, followed by cooling to 0° C., a white solid was precipitated. This solid was filtered and dried under a reduced pressure to obtain N-isobutyl-3-hydroxy-6,8-decadienamide (10) (85.2 g, 0.35 mol, yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:12]3[C:16]([C:17](=[N:18][O:19][CH2:20][C:21]([O:23]CC)=[O:22])[C:7]4[C:8]=2[C:3]=1[CH:4]=[CH:5][N:6]=4)=[CH:15][CH:14]=[CH:13]3.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:12]3[C:16]([C:17](=[N:18][O:19][CH2:20][C:21]([OH:23])=[O:22])[C:7]4[C:8]=2[C:3]=1[CH:4]=[CH:5][N:6]=4)=[CH:15][CH:14]=[CH:13]3
Reactant: CCOC(=O)CON=c1c2nccc3c(Cl)ccc(c32)n2cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CON=c1c2nccc3c(Cl)ccc(c32)n2cccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a stirred suspension of 3-chloro-7-ethoxycarbonylmethoxyimino-7H-indolizino[5,6,7-ij]isoquinoline (0.356 g.) in ethanol (15 cc.) there is added N sodium hydroxide solution (1 cc.) followed by distilled water (35 cc.). After stirring for 1 hour at a temperature of about 20° C., a dark green solution is obtained which is neutralised by adding N hydrochloric acid (1 cc.). The resulting precipitate is filtered off, washed copiously with water and dried under reduced pressure. 3-Chloro-7-carboxymethoxyimino-7H-indolizino[5,6,7-ij]isoquinoline (0.28 g.), melting at 202° C. with decomposition, is thus obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[K].[K].C(C1C=CC(S(NC(=O)C(C2C=CC3OCOC=3C=2)OC2C=CC(C(O)=O)=CC=2CCC)(=O)=O)=CC=1)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[S:91]([NH2:95])([NH2:94])(=[O:93])=[O:92].C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:24])[NH:94][S:91](=[O:93])(=[O:92])[NH2:95])=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCCc1cc(C(=O)O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Reactant: NS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1cc(C(=O)NS(N)(=O)=O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
A solution of 158 mg (0.293 mmol) of N-(4-iso-propylbenzenesulfonyl)-α-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyphenylacetamide (free acid form of the product of Example 58) and 71 mg (0.440 mmol) of 1,1'-carbonyldiimidazole in 1 mL of dry tetrahydrofuran was refluxed for 3.5 hours. The reaction mixture was cooled to room temperature and 141 mg (1.47 mmol) of sulfamide and 110 μL (0.733 mmol) of DBU were added and the mixture was refluxed again. The reaction progress was monitored by analytical HPLC analysis using a Waters 600E HPLC system with a 4.6×250 mm 5 μM Zorbax-RX C8 at 40° C. and eluting isocratically 1.5 mL/min using 60% A (95-5 acetonitrile-water) 40% B (95-5 water-acetonitrile) each with 0.1% TFA where the column effluent was monitored at 254 nM with a Waters model 490 UV-visible detector. After 2.0 hour of additional refluxing, analytical HPLC analysis indicated that the coupling was complete. The reaction mixture was diluted with 2.5 mL of methanol and 2 mL of water, filtered and the filtrate partially purified was purified using a Varian 5500 HPLC by applying the compound in a 4.5 mL total volume (2.5 mL methanol and 2 mL water) onto two in series 21.2×250 mm Zorbax ODS C18 columns and eluting at 15 mL/min with 60% acetonitrile and 40% water both with 0.1% TFA. The column effluent was monitored 254 nM with a Kratos Spectroflow 783 UV detector. Combination and evaporation of the purified fractions afforded 50 mg (28%) of the title compound. The mixed fractions were combined and subjected to a second preparative HPLC chromatography using a linear gradient over 35 minutes from 65% water and 35% acetonitrile both with 0.1% TFA to 65% acetonitrile and 35% water both with 0.1% TFA, holding all other conditions from the previous chromatography. The purified fractions were combined and concentrated to afford 57 mg (31%) of the title compound, which was combined with the previously purified material to provide a total of 107 mg (59%) of the title compound as an amorphous solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/B(O)O)=[CH:5][CH:4]=1.Br[C:17]1[C:18]([NH:26][C:27](=[O:35])[CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:19][N:20]2[CH:25]=[CH:24][CH:23]=[N:22][C:21]=12>>[CH:30]1([CH2:29][CH2:28][C:27]([NH:26][C:18]2[C:17](/[CH:10]=[CH:9]/[C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=3)=[C:21]3[N:22]=[CH:23][CH:24]=[CH:25][N:20]3[N:19]=2)=[O:35])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: OB(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: O=C(CCC1CCCC1)Nc1nn2cccnc2c1Br
Product: O=C(CCC1CCCC1)Nc1nn2cccnc2c1/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
Trans-2-[4-(trifluoromethyl)phenyl]vinylboronic acid and the product from Example 153A were processed using the method analogous to that described in Example 110C to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.32-10.34 (bs, 1H), 9.10 (dd, J=6.9, 1.7 Hz, 1H), 8.69 (dd, J=4.1, 1.7 Hz, 1H), 7.70 (s, 4H), 7.64 (d, J=16.3 Hz, 1H), 7.34 (d, J=16.2 Hz, 1H), 7.14 (dd, J=6.9, 4.1 Hz, 1H), 2.49 (t, J=7.9 Hz, 2H), 1.76-1.86 (m, 3H), 1.45-1.70 (m, 6H), 1.07-1.18 (m, 2H); MS (ESI) m/z 429 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH:14]([CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]([C:22]([O:24]CC4C=CC=CC=4)=[O:23])=[CH:20][CH:19]=3)[O:13][C:12]2=[O:34])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N1CC(COC2C=CC(C(OCC3C=CC=CC=3)=O)=CC=2)OC1=O)(=O)C1C=CC=CC=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH:14]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:32][CH:33]=3)[O:13][C:12]2=[O:34])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC(COc3ccc(C(=O)OCc4ccccc4)cc3)OC2=O)cc1
Agent: O=C(OCc1ccccc1)c1ccc(OCC2CN(C(=O)c3ccccc3)C(=O)O2)cc1
Product: Cc1ccc(S(=O)(=O)N2CC(COc3ccc(C(=O)O)cc3)OC2=O)cc1
Yield: 62 %

Procedure:
The same procedure of Example 13 was repeated except that benzyl 4-[3-(4-methylbenzenesulfonyl)-2-oxooxazolidin-5-yl]methoxybenzoate (compound 123) obtained in Example 5 was used in lieu of benzyl 4-(3-benzoyl-2-oxooxazolidin-5-yl)methoxybenzoate to give the title compound (compound 135) in a yield of 62%.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.C1CCCCC1>[Pd].CO>[CH3:17][S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCCCC1
Product: CS(=O)(=O)N1CCNCC1

Procedure:
A mixture of N-benzyl-N'-methanesulphonylpiperazine (12.4 g), cyclohexane (5.1 ml), 10% Pd/C (2 g) and methanol (120 ml) was heated under reflux for 7 hours to give 1-methanesulphonylpiperazine (m.p. 90°-91° C.).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[N:17]1([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:23]
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCCCC2=O)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C1CCCCN1C1CCNCC1

Procedure:
2-Oxo-[1,4′]bipiperidinyl-1′-carboxylic acid benzyl ester (2.5 g) and Pearlman's catalyst (0.50 g) was stirred in ethanol (30 mL) under hydrogen (1 atm). After 20 hours the reaction as filtered through celite and concentrated. The title compound was obtained as a white solid (1.45 g). MS: m/z=183 (M+H).