Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:19][CH:18]([O:20][C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH2:17]3)=[O:15])=[N:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:29]([C:31]1([CH2:37][OH:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:29]([C:31]1([CH2:37][OH:38])[CH2:36][CH2:35][N:34]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:18]3[CH2:19][N:16]([C:14]([C:12]4[O:13][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[N:10][N:11]=4)=[O:15])[CH2:17]3)=[CH:28][CH:27]=2)[CH2:33][CH2:32]1)[CH3:30]
Reactant: CCC1(CO)CCNCC1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCC1(CO)CCN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccc(OC)cc5)o4)C3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-(5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.55 g, 1.45 mmol in DCM (30 mL) were added (4-ethylpiperidin-4-yl)methanol (0.27 g, 1.88 mmol, 1.3 equiv) and sodium triacetoxyborohydride (0.615 g, 2.90 mmol, 2 equiv). The reaction mixture was stirred at room temperature overnight and thereafter transferred to a reparatory funnel, washed with a saturated solution of Na2CO3, dried (phase separator) and concentrated under reduced pressure. The crude product was purified by automatic flash column chromatography using Biotage (eluting with EtOAc (10 CV), then EtOAc/MeOH (containing 2 M NH3) 20:1) on a 50 g snap column, collecting at UV 291 nm). The pure product fractions were combined and evaporated to afford the product as a white solid. Recrystallisation from DCM/Et2O afforded 280 mg, 38% of the product as a white solid (purity >99%). 1H NMR (400 MHz, CDCl3): δ 0.82 (t, 3H), 1.37-1.56 (m, 6H), 2.30-2.46 (m, 4H), 3.45 (2×s, 4H), 3.89 (s, 3H), 4.33 (dd, 1H), 4.64 (dd, 1H), 4.74 (dd, 1H), 5.03-5.15 (m, 2H), 6.72 (d, 2H), 7.02 (d, 2H), 7.25 (d, 2H), 8.1 (d, 2H), MS (APCI+) m/z 507 [M+H]+.
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:63][O:64][C:65](=[O:77])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[CH2:16][S:17][CH2:18][C@H:19]([NH2:62])[C:20](=[O:61])[NH:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:60])[CH:37]([NH2:59])[CH2:38][S:39]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([SiH](C(C)C)C(C)C)(C)C>C(O)(C(F)(F)F)=O>[C:1]([O:14][C@H:15]([CH2:63][O:64][C:65](=[O:77])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[CH2:16][S:17][CH2:18][C@H:19]([NH2:62])[C:20](=[O:61])[NH:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:60])[CH:37]([NH2:59])[CH2:38][SH:39])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCCOCCOCCOCCCNC(=O)C(N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)CCCCCCCCCCC
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCCOCCOCCOCCCNC(=O)C(N)CS)OC(=O)CCCCCCCCCCC

Procedure:
(22R,26R)-4,22-diamino-5,21-dioxo-1,1,1-triphenyl-10,13,16-trioxa-2,24-dithia-6,20-diazaheptacosane-26,27-diyl didodecanoate was stirred in TFA (0.1 M) containing 5% triisopropylsilane at room temperature for 4 hours. The reaction was concentrated and purified by flash chromatography on an ISCO COMBIFLASH® system using a 0-20% MeOH/DCM gradient (20R,24R)-2,20-diamino-1-mercapto-3,19-dioxo-8,11,14-trioxa-22-thia-4,18-diazapentacosane-24,25-diyl didodecanoate. 1H NMR (DMSO d-6): δ 8.51 (t, 1H), 8.49 (t, 1H), 5.12 (m, 1H), 4.26-4.32 (dd, 1H), 4.08-4.12 (m, 1H), 3.86 (q, 2H), 3.46-3.52 (m, 8H), 3.40 (t, 4H), 3.35 (br s, 4H), 3.12-3.25 (m, 4H), 2.82-2.94 (m, 6H), 2.72-2.79 (dd, 1H), 2.29-2.34 (q, 4H), 1.68-1.72 (q, 4H), 1.49-1.52 (m, 4H), 1.21-1.34 (m, 32H), 0.86 (t, 6H). LRMS [M+H]=866.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:40]1[CH:45]=[CH:44][CH2:43][CH2:42][CH2:41]1.CO>O1CCOCC1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:27][CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45][O:40]4)[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 84 %

Procedure:
36.1 g (0.093 mole) of 3β-hydroxy-5-cholenic acid methyl ester was dissolved in 722 ml of dioxane at room temperature, and 1.81 g (0.05 mole of p-toluenesulfonic acid was added. Then, 26.83 ml (0.294 mole) of dihydropyrane was added dropwise over a period of 10 minutes. The temperature rose to 23°-27° C. The solution was stirred for two more hours at room temperature and then adjusted to pH 8 with 3.4 ml of a mixture of 1:1 methanol 29% ammonium hydroxide. An oily precipitate began forming. A semi-solid residue was obtained after the solvent was evaporated. The residue was dissolved in 1.1 liters of chloroform, washed with a 15% sodium bicarbonate solution, then with water. The chloroform solution was dried, decolorized with charcoal and evaporated. The solid residue was dissolved in 1.5 liters of boiling methanol, allowed to cool to room temperature and then filtered. The dried product weighed 34.5 g, mp 114°-115° C. (989-161-A). From the filtrate an additional amount of 8.0 g was isolated, which was recrystallized again from methanol and then from n-heptane. The second crop was 4.1 g, making a total of 38.6 g of 3β-(2-tetrahydropyranyloxy)-5-cholenic acid methyl ester, yield 84%. Anal. Calcd for C30H48O4, M. W. 472.715: C, 76.22; H, 10.24; O, 13.54. Found: C, 76.37; H, 10.21; O, 13.28 (989-161-A). NMR (989-157-A) (CDCl3): δ5.22-5.43 (m,1H, vinyl), ##STR17## 3.20-4.10 (br m, 3H, adjacent to oxygen), 3.63 (s, 3H, --OCH3), 1.00 (s, 3H, C-19 --CH3), 0.66 (s, 3H, C-18 --CH3). IR (989-157-A) (CHCl3) 2940, 2860, 1730, 1440, 1170, 1135, 1110, 1075, 1030, 1020 cm-1.
Reaction SMILES: [B-](F)(F)(F)F.[N+:6](=[O:8])=[O:7].N1C(C)=CC(C)=CC=1C.[CH3:18][C@H:19]([NH:22][C:23](=[S:41])[C@H:24]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][OH:21]>C(#N)C>[CH3:18][C@H:19]([NH:22][C:23](=[S:41])[C@H:24]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][O:21][N+:6]([O-:8])=[O:7]
Reactant: C[C@@H](CO)NC(=S)[C@@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC#N
Product: C[C@@H](CO[N+](=O)[O-])NC(=S)[C@@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Yield: 49.5 %

Procedure:
In 25 ml of dry acetonitrile were dissolved 1.24 g of nitronium tetrafluoroboron (85% content), 1.12 g of 2,4,6-collidine was added thereto with stirring under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. Then, a solution obtained by dissolving 2.5 g of N-[(1S)-1-methyl-2-hydroxyethyl]-(2R)-2-t-butoxycarbonylamino-3-t-butoxycarbonylthiopropanamide in 25 ml of dry acetonitrile was added to the mixture and the resulting mixture was stirred at room temperature for 3 hours. Then, the solvent was distilled off under reduced pressure and the thus obtained residue was purified by silica gel column chromatography employing cyclohexane-ethyl acetate (4:1) as an eluent to obtain 1.39 g of the desired compound as pale yellow crystals.
Reaction SMILES: N#N.N[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[F:14])[C:7]([O:9][CH3:10])=[O:8].C=O.[BH3-][C:18]#[N:19].[Na+].[C:21]([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[CH3:21][N:19]([CH3:18])[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[F:14])[C:7]([O:9][CH3:10])=[O:8]
Reactant: [BH3-]C#N
Reactant: COC(=O)c1ccc(F)c(N)c1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: N#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(F)c(N(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of methyl 3-amino-4-fluorobenzoate (1.55 g, 9.16 mmol), paraformaldehyde (8.25 g, 91.63 mmol) and NaBH3CN (1.73 g, 27.49 mmol) was treated with acetic acid (90 mL) and the resulting mixture was stirred at rt for 4 h. Sat. aq. Na2CO3 was added to the reaction mixture and the pH was adjusted to 7-8. The mixture was extracted with CH2Cl2 (3×55 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 05c with a Waters Atlantis T3, 5 μm, 4.6×30 mm column: tR=0.76 min; [M+H]+=198.38.
Reaction SMILES: [CH2:1]([O:3][PH:4](=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:15]1[CH2:19]O[CH2:17][CH2:16]1>>[C:1]1([O:3][PH:4](=[O:8])[O:5][C:6]2[CH:17]=[CH:16][CH:15]=[CH:19][CH:7]=2)[CH:19]=[CH:15][CH:16]=[CH:17][CH:2]=1
Reactant: CCO[PH](=O)OCC
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=[PH](Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
and triflate 13 isomer B (115 mg, 0.274 mmol) in THF (2 mL) was added Cs2CO3 (119 mg, 0.366 mmol). After the reaction mixture was stirred for 30 min at room temperature, the mixture was partitioned between EtOAc and water. The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was chromatographed on silica gel (eluting 60-80% EtOAc/hexane) to give a mixture. The mixture was further purified by HPLC on C18 reverse phase chromatography (eluting 55% CH3CN/water) to give phosphonate 14 isomer B (28 mg, 18%) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ 7.71 (d, 2H), 7.26 (m, 6H), 6.94 (m, 5H), 5.66 (d, 1H), 5.17 (m, 1H), 4.99 (m, 2H), 4.55 (m, 1H), 4.42 (m, 1H), 4.16 (m, 2H), 3.97 (m, 1H), 3.85 (m, 5H), 3.72 (m, 3H), 3.13 (m, 1H), 2.97 (m, 4H), 2.80 (m, 2H), 1.83 (m, 1H), 1.60 (m, 6H), 1.22 (m, 3H), 0.93 (d, 3H), 0.88 (d, 3H). 31P NMR (300 MHz, CDCl3) δ 15.3. Resolution of Compound 14 Diastereomers
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][C:12]3=[O:25])[CH:9]=2)[C:4]2[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C:3]1=2.[ClH:37]>CO.CCOCC>[ClH:37].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][C:12]3=[O:25])[CH:9]=2)[C:4]2[CH2:26][CH2:27][NH:28][CH2:29][C:3]1=2
Reactant: Cn1c2c(c3ccc(N4CCN(CCc5ccccc5)CC4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccccc5)CC4=O)cc31)CCNC2
Reaction time: 18 h
Yield: 33 %

Procedure:
tert-Butyl 9-methyl-7-(2-oxo-4-phenethylpiperazin-1-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (35 mg, 0.071 mmol) was dissolved in MeOH (2 mL), and 2 N HCl in Et2O (10 mL) was added. The reaction was allowed to proceed for 18 h. The mixture was concentrated, and the residue was partitioned between CH2Cl2 and sat. Na2CO3 solution. The organic phase was removed, and the aqueous phase was back extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. The residue was dissolved in MeOH (1 mL), treated with 2 N HCl in Et2O (12 μL, 0.024 mmol), and concentrated to provide the title compound (10 mg, 33%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.60 (d, J=8.3 Hz, 1H), 7.45 (s, 1H), 7.41-7.34 (m, 4H), 7.33-7.27 (m, 1H), 7.67 (d, J=8.2 Hz, 1H), 4.54 (s, 2H), 4.24-4.15 (m, 2H), 4.15-4.03 (m, 2H), 3.91-3.76 (m, 2H), 3.72 (s, 3H), 3.61-3.54 (m, 4H), 3.22-3.16 (m, 2H), 3.14-3.08 (m, 2H); ESI MS m/z 389 [M+H]+; HPLC (Method B) 94.4% (AUC), tR=10.2 min.
Reaction SMILES: [CH2:1]([C:5]([O:10][C:11]1[CH:33]=[CH:32][C:14]2[C:15]3[N:19]([CH2:20][CH2:21][O:22][C:13]=2[CH:12]=1)[CH:18]=[C:17]([C:23]1[N:24]([CH:29]([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[N:27]=1)[N:16]=3)([CH2:8][OH:9])[CH2:6][OH:7])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[CH:29]([N:24]1[C:23]([C:17]2[N:16]=[C:15]3[N:19]([CH2:20][CH2:21][O:22][C:13]4[CH:12]=[C:11]([O:10][C:5]([CH2:8][O:9][S:42]([CH3:41])(=[O:44])=[O:43])([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][O:7][S:42]([CH3:41])(=[O:44])=[O:43])[CH:33]=[CH:32][C:14]=43)[CH:18]=2)=[N:27][C:26]([CH3:28])=[N:25]1)([CH3:31])[CH3:30]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(CO)(CO)CC(C)C)cc2OCC3)n(C(C)C)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(COS(C)(=O)=O)(COS(C)(=O)=O)CC(C)C)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-isobutyl-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-propane-1,3-diol (88.6 mg, 0.194 mmol) and Et3N (81.1 μL, 0.582 mmol) in DCM (10 mL) cooled at 0° C. was added methanesulfonyl chloride (37.9 μL, 0.485 mmol) and stirring at RT was continued for 1.5 h. The mixture was diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo affording the title compound as a colourless gum (quantitative). LCMS (Method B): RT 3.46 min [M+H]+ 612.
Reaction SMILES: C1(C[C@H]2[C@H](C[C@H](C=O)C(C)C)OC(C)(C)N2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])CCCCC1.[I-].N1C=CC=CC=1C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[NH2:57][C@H:58]([C@@H:66]([OH:80])[CH2:67][C@@H:68]([CH:77]([CH3:79])[CH3:78])[CH:69]=[CH:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][N:72]=1)[CH2:59][CH:60]1[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1.C(OC([N:88]1[CH:115]=[N:114][C:90]([CH2:91][C@@H:92]([C:111]([OH:113])=O)[NH:93][C:94](=[O:110])[C@@H:95]([CH2:103][C:104](=[O:109])[C:105]([CH3:108])([CH3:107])[CH3:106])[CH2:96][C:97]2[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=2)=[CH:89]1)=O)(C)(C)C>CO>[CH:60]1([CH2:59][C@H:58]([NH:57][C:111](=[O:113])[C@@H:92]([NH:93][C:94](=[O:110])[C@@H:95]([CH2:103][C:104](=[O:109])[C:105]([CH3:107])([CH3:106])[CH3:108])[CH2:96][C:97]2[CH:98]=[CH:99][CH:100]=[CH:101][CH:102]=2)[CH2:91][C:90]2[N:114]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:115]=[N:88][CH:89]=2)[C@@H:66]([OH:80])[CH2:67][C@@H:68]([CH:77]([CH3:78])[CH3:79])/[CH:69]=[CH:70]/[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][N:72]=2)[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1
Reactant: CC(C)[C@@H](C=Cc1ccccn1)C[C@H](O)[C@@H](N)CC1CCCCC1
Reactant: CC(C)[C@@H](C=O)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Reactant: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc2ccccc2)C(=O)O)c1
Agent: Cl
Agent: [I-]
Agent: c1ccc([P+](Cc2ccccn2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CC(C)[C@@H](/C=C/c1ccccn1)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cncn1C(=O)OC(C)(C)C)NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1

Procedure:
This compound was prepared in an analogous manner to that described above by reacting t-butyl (4S,5S)-4-(cyclohexylmethyl)-5-[(S)-2-formyl-3-methylbutyl]-2,2-dimethyl-3-oxazolidinecarboxylate with 2-pyridylmethyl-triphenylphosphonium iodide, cleaving off the Boc protecting group with simultaneous opening of the oxazolidine ring with hydrochloric acid in methanol and reacting the resulting (2S,3S,5S)-2-amino-1-cyclohexyl-5-isopropyl-7-(2-pyridyl)-6-hepten-3-ol with 1-(t-butoxycarbonyl)-N-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamoyl]-L-histidine.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6][C:5]=1[N+:19]([O-:21])=[O:20].[OH-].[Li+].CCOCC>CO.O>[C:15]([O:14][C:12]([NH:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]([N+:19]([O-:21])=[O:20])=[C:4]([CH:9]=1)[C:3]([OH:22])=[O:2])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
A mixture of 5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester (52.5 g, 169.3 mmol), lithium hydroxide (4.86 g, 203.1 mmol) in methanol (546 mL) and water (273 mL) was stirred with a mechanical stirrer at room temp overnight. The methanol was evaporated, and to the aqueous solution, was added 1 N HCl (270 mL) to form the precipitate. Ether (350 mL) was added, and the mixture was stirred at 0° C. for 2 hours. The mixture was evaporated. To the residue, was added water (500 mL). The aqueous layer was extracted with methylene chloride (3×100 mL). The combined organic layers were separated, dried over magnesium sulfate, and concentrated to give 5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid as a brown oil (21.0 g, 41% yield). The product was used in the next step without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[CH:32][C:31]([S:34]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]([CH3:45])[CH3:44])[CH2:39][CH2:38]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[CH:29]=[CH:30][C:31]([S:34]([N:37]5[CH2:42][CH2:41][CH:40]([N:43]([CH3:45])[CH3:44])[CH2:39][CH2:38]5)(=[O:35])=[O:36])=[CH:32][N:33]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Reactant: CN(C)C1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCN(S(=O)(=O)c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1

Procedure:
Compound 362 was prepared as an off-white solid (TFA salt) from compound 4 and compound 363 using chemistry similar to that described in example 200. 1H NMR (400 MHz, CD3OD) δ ppm 9.56 (1 H, s), 9.25 (1 H, s), 8.66-8.75 (2 H, m), 8.58 (2 H, s), 8.18 (1 H, dd, J=8.8, 2.5 Hz), 5.50 (1 H, quin, J=8.8 Hz), 4.01 (2 H, d, J=12.5 Hz), 3.22 (1 H, tt, J=12.1, 3.8 Hz), 2.86 (6 H, s), 2.44-2.60 (4 H, m), 2.12-2.35 (6 H, m), 1.74-2.01 (4 H, m). LCMS-ESI (POS), M/Z, M+1: Found 521.2.
Reaction SMILES: Cl.[C:2]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([C:18]2[S:19][CH:20]=[C:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:22]=2)[CH:8]=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[OH:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32](O)=[O:33]>>[C:2]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([C:18]2[S:19][CH:20]=[C:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:32](=[O:33])[CH2:31][C:30]([CH3:36])([OH:29])[CH3:35])[CH2:27][CH2:28]3)[N:22]=2)[CH:8]=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(C3CCNCC3)cs2)c1-c1ccc(F)cc1
Reactant: CC(C)(O)CC(=O)O
Agent: Cl
Product: CC(C)(O)CC(=O)N1CCC(c2csc(-c3cnn(C(C)(C)C)c3-c3ccc(F)cc3)n2)CC1

Procedure:
Using 4-{2-[1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}piperidine monohydrochloride and 3-hydroxy-3-methylbutyric acid and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][C:10]([O:12]CC)=[O:11])=[CH:7][N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:18][CH:17]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:20][CH:21]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
After a mixture of ethyl 3-ethoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-ylacetate (618 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-ethoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-ylacetic acid (502 mg, yield: 86%). This was, recrystallized from ethanol-hexane. Melting point: 125–126° C.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].[CH2:25](Cl)[CH:26]1[O:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH2:25][CH:26]3[CH2:27][CH2:28][CH2:29][O:30]3)[CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24]
Reactant: CCOC(=O)c1cn(CC2CCNC2)c2ccc(I)cc2c1=O
Reactant: ClCC1CCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CC2CCN(CC3CCCO3)C2)c2ccc(I)cc2c1=O
Temperature: 70 °C
Reaction time: 36 h
Yield: 32 %

Procedure:
Ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 126, 500 mg, 1.08 mmol) was suspended in dimethyl formamide (3 mL) then tetrahydrofurfuryl chloride (1 mL) and potassium carbonate powder (400 mg, 22.2 mmol) were added. The reaction was stirred at 70° C. for 36 h. Water (15 mL) was added and the suspension was extracted with ethyl acetate (3×10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was chromatographed on a 4 g Analogix column using 0-10% methanol in dichloromethane. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 181 mg (32% yield) of ethyl 6-iodo-4-oxo-1-((1-((tetrahydrofuran-2-yl)methyl)pyrrolidin-3-yl)methyl)-1,4-dihydroquinoline-3-carboxylate as an off white solid.