Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:23]=1)[CH2:17][N:18]=[N+]=[N-])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CO.[H][H]>CCOCC>[CH2:25]([O:24][C:22]1[CH:21]=[C:16]([CH:15]=[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:23]=1)[CH2:17][NH2:18])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCOc1cc(CN=[N+]=[N-])cc(OCCCCCCCCCCCC)c1
Reactant: [H][H]
Solvent: CCOCC
Solvent: CO
Product: CCCCCCCCCCCCOc1cc(CN)cc(OCCCCCCCCCCCC)c1
Yield: 88 %

Procedure:
A thick walled bottle containing a stir bar was flushed out with nitrogen gas, and 5% Palladium on activated carbon (0.53 g, 10% by mass) was added along with a solution of 50% methanol and ether (approximately 10 mL). 3,5-didodecoxybenzyl azide (5.3 g, 12.6 mmol) was added using 50% methanol and ether (approximately 40 mL). The mixture was hydrogenated with hydrogen gas at 40 psi for approximately 1½ hour. The mixture was then filtered through celite with a controlled vacuum using 50% methanol and ether. The solvent was removed from the filtrate under reduced pressure and the trace solvent was removed with the high vacuum. This produced a 5.7 g yield or a 88% yield. The NMR characterization data for the derivative is as follows. 1NMR (300 MHz, CDCl3): 0.87 (t, J=6.6, 8H, CH2CH3), 1.15-1.6 (m, 36H, CH2(CH2)9), 1.76 (p, J=8.0, 4H, OCH2CH2), 3.79 (s, 2H, ArCH2), 3.92 (t, J=6.6, 4H, OCH2CH2), 6.33 (t, J=2.2, 1H, ArH), 6.40 (d, J=2.2, 2H, ArH).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[C:13]([NH2:15])[CH:14]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[NH2:16][C:11]1[CH:12]=[C:13]([NH:15][C:5](=[O:7])[CH3:6])[CH:14]=[C:9]([Cl:8])[CH:10]=1
Reactant: Nc1cc(N)cc(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(N)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DMAP (50 mg) and acetic anhydride (3.9 g, 37.9 mmol) were added sequentially and dropwise to a cold solution of 5-chloro-benzene-1,3-diamine (4.5 g, 31.6 mmol) in pyridine (22 mL) keeping the internal temperature below 0° C. The reaction mixture was allowed to warm to rt, stirred for 2 h, cooled to 0° C., quenched by addition of ice cooled water, and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH, 99:1) to afford the title compound. tR: 0.18 min (LC-MS 2); ESI-MS: 184.9 [M+H]+ (LC-MS 2); Rf=0.32 (hexane/EtOAc, 1:4).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C(O)=O.[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22][SH:23])=[CH:19][CH:18]=1)[CH3:15].S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH:32][CH2:33][CH2:34][NH:35][C:36](=[CH:40][N+:41]([O-:43])=[O:42])[N:37]1[CH2:39][CH2:38]1>O.CO.C(OCC)C>[CH3:15][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22][S:23][CH2:39][CH2:38][NH:37][C:36]([NH:35][CH2:34][CH2:33][OH:32])=[CH:40][N+:41]([O-:43])=[O:42])=[CH:19][CH:18]=1)[CH3:13]
Reactant: O=[N+]([O-])C=C(NCCO)N1CC1
Reactant: CN(C)Cc1ccc(CS)o1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NCCO)o1
Yield: 69.7 %

Procedure:
Ethyl ether (15 ml) and an excess of anhydrous sodium carbonate were added to a mixture in water of 0.13 g (0.5 mmole) of 5-[(dimethylamino)methyl]-2-furanmethanethiol oxalate (1:1), sodium dithionite (0.05 g) and anhydrous sodium carbonate (0.15 g). The mixture was filtered and the filtrate was evaporated under vacuum. 0.087 g (0.5 mmole) of N-(2-hydroxyethyl)-alpha-(nitromethylene)-1-aziridinemethaneamine and 4 ml of methanol were added to the residue. The mixture was evaporated to dryness and the residue was heated to 95°-100° C. for 1 hour and chromatographed over silica (methanol-0.88 NH3 ; 79:1). The appropriate eluate was evaporated under vacuum to give 0.12 g of N-[2-[[(5-[(dimethylamino)methyl]-2-furanyl)methyl]thio]ethyl]-N'-(2-hydroxyethyl)-2-nitro-1,1-ethenediamine having the same properties as the product prepared according to Example 1, paragraph (a).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.CC(C)([O-])C.[K+].[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:28]([N:41]=2)=[N:29][C:30]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH2:34])=[CH:31][CH:32]=3)=[C:21]([F:42])[CH:20]=1>CS(C)=O.C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:28]([N:41]=2)=[N:29][C:30]([C:33]2([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:2][CH2:34]2)=[CH:31][CH:32]=3)=[C:21]([F:42])[CH:20]=1
Reactant: C[S+](C)(C)=O
Reactant: C=C(c1ccccc1)c1ccc2sc(-c3ccc(C4OCCCO4)cc3F)nc2n1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2nc(C3(c4ccccc4)CC3)ccc2s1
Reaction time: 8 h

Procedure:
Trimethylsulfoxonium iodide (0.16 g, 0.72 mmol) and potassium tert-butoxide (0.080 g, 0.72 mmol) were combined in 1.5 mL DMSO to give a clear solution. A slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylvinyl)thiazolo[4,5-b]pyridine (0.200 g, 0.48 mmol) in 4 mL THF was added dropwise, rinsing with 1 mL THF. The reaction mixture was stirred overnight, and was then quenched with sat'd aq. NH4Cl and EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The material was treated with DCM and passed through a Redi-Sep® pre-packed silica gel column (12 g) using 0-70% EtOAc/hexane. The product-containing fractions were concentrated to afford 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[4,5-b]pyridine as a pale yellow solid. MS (ESI) m/z: calculated: 432.1; Observed: 433.1 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:26])=[C:11]([F:25])[CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:33](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:33][N:17]1[C:18]2[C:13](=[CH:12][C:11]([F:25])=[C:10]([F:26])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14](=[O:24])[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16]1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCOC(=O)c1cnc2c(OCc3ccccc3)c(F)c(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c2c(OCc3ccccc3)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
After a mixture of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate (410 mg) and anhydrous potassium carbonate (315 mg) in dry dimethylformamide (10 ml) was stirred at room temperature for 3 hours, O-(2,4-dinitrophenyl)hydroxylamine (260 mg) was added. The mixture was stirred at room temperature for further 6.5 hours. After removal of the solvent under reduced pressure, water (12 ml) was added to the residue, and the mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration and washed with cold water and then with ether to give 405 mg of ethyl 1-amino-8-benzyloxy-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate. An analytical sample, mp 143°-144° C.; MS m/z 374 (M+), was prepared by recrystallization from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].Br[CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34]>O1CCCC1>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34])[C:18]3=[O:26])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N1CCC(N2CCC(n3c(=O)n(CCOC(C)=O)c4ccccc43)CC2)CC1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Three-hundred (300) mg of 1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one was dissolved in 15 ml of tetrahydrofuran, and to which 33 mg of 60% sodium hydride was added. After evolution of a gas ceased, 93 μl of (2-bromoethyl)acetate was added, heated to 40° C. and stirred for 2 hours. The reaction liquid was concentrated and the remaining matter was distributed between water and chloroform. The chloroform layer was separated, dried over anhydrous sodium sulfate, concentrated and the residue was purified by silica gel column chromatography (chloroform/methanol=19/1). Thus 354 mg of 1-[1-(1-methoxycarbonylpiperidin-4-yl)-piperidin-4-yl]-3-(2-acetoxy-ethyl)-1,3-dihydro-2H-benzimidazol-2-one was obtained. The product was dissolved in 10 ml of methanol, to which 35 mg of sodium borohydride was added and stirred for 7 hours at room temperature. The reaction liquid was concentrated, to which water was added and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=19/1), to provide 246 mg of the title compound as a colorless, amorphous substance.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:11]1[N:15]=[C:14]([NH:16][P:17]([O:21][CH3:22])([O:19][CH3:20])=[O:18])[S:13][N:12]=1)[C:7]([O:9]C)=[O:8])[CH:2]=[CH2:3].[OH-].[Na+:24].Cl>O1CCCC1>[CH2:1]([O:4][N:5]=[C:6]([C:11]1[N:15]=[C:14]([NH:16][P:17]([O:19][CH3:20])([O:21][CH3:22])=[O:18])[S:13][N:12]=1)[C:7]([O-:9])=[O:8])[CH:2]=[CH2:3].[Na+:24]
Reactant: C=CCON=C(C(=O)OC)c1nsc(NP(=O)(OC)OC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCON=C(C(=O)[O-])c1nsc(NP(=O)(OC)OC)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-allyloxyimino-2-(5-dimethoxyphosphorylamino-1,2,4-thiadiazol-3-yl)acetate (syn isomer) (37.3 g) in tetrahydrofuran (106 ml) was added 1N-aqueous sodium hydroxide (234 ml) and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was adjusted to pH 5 with 6N hydrochloric acid and washed with ethyl acetate. The aqueous layer was separated out, adjusted to pH 1.0 with 6N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue dissolved in methanol (50 ml) was added dropwise to a solution of sodium acetate (8.7 g) in methanol (90 ml) at ambient temperature under stirring, which was continued for one hour at the same temperature. To the mixture was added ethyl acetate (200 ml) and the resulting precipitate was collected by filtration, washed with ethyl acetate and dried to give sodium 2-allyloxyimino-2-(5-dimethoxyphosphorylamino-1,2,4-thiadiazol-3-yl)acetate (syn isomer) (32.6 g), mp. 168° to 173° C. (dec).
Reaction SMILES: Br[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:18])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[N:3]=1.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29](B1OC(C)(C)C(C)(C)O1)=[CH:28][CH:27]=2.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([C:2]1[C:11]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[CH3:18])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=3)[N:3]=1)=[CH:28][CH:27]=2
Reactant: COC(=O)c1ccc2nc(Br)c(N3CCCC[C@@H]3C)nc2c1
Reactant: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
To a solution of (S)-methyl 2-bromo-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate (200 mg, 0.55 mmol) in ethylene glycol dimethyl ether (7 ml) was added 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (141 mg, 0.55 mmol), sodium carbonate (116 mg, 1.09 mmol), water (2 mL), and Pd(PPh3)4 (32 mg, 0.03 mmol). The resulting solution was stirred for 3 h at 90° C. and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (2% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(2-methyl-1H-indol-5-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate as a light yellow solid (142.1 mg, 62%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:5][C@H:6]([C:25]([N:27]1[C@@H:31]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:30][O:29][C:28]1=[O:39])=[O:26])[C@@H:7]([CH:9]1[CH2:13][CH:12]([O:14][CH2:15][CH:16]=[CH2:17])[CH2:11][N:10]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[OH:8].C([C@H]1COC(=O)N1C(=O)CCC1C=C(F)C=C(F)C=1)C1C=CC=CC=1.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC.CCN(C(C)C)C(C)C.C(O[C@H]1CN(C(OC(C)(C)C)=O)[C@@H](C=O)C1)C=C>C(Cl)Cl>[F:43][C:41]1[CH:40]=[C:4]([CH:3]=[C:2]([F:1])[CH:42]=1)[CH2:5][C@H:6]([C:25]([N:27]1[C@@H:31]([CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:30][O:29][C:28]1=[O:39])=[O:26])[C@@H:7]([C@H:9]1[CH2:13][C@@H:12]([O:14][CH2:15][CH:16]=[CH2:17])[CH2:11][N:10]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[OH:8]
Reactant: C=CCOC1CC([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N(C(=O)OC(C)(C)C)C1
Agent: C=CCO[C@@H]1C[C@H](C=O)N(C(=O)OC(C)(C)C)C1
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Agent: O=C(CCc1cc(F)cc(F)c1)N1C(=O)OC[C@@H]1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
Step A (5): 2R,4R)-tert-butyl 2-((1S,2S)-2-(3,5-difluorobenzyl)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-3-oxopropyl)-4-(allyloxy)pyrrolidine-1-carboxylate. To a solution of (S)-4-benzyl-3-(3-(3,5-difluorophenyl)propanoyl)oxazolidin-2-one (Preparation B, 1.47 g, 4.27 mmol) in CH2Cl2 (15 ml) at −78° C. was added Bu2BOTf (5.12 ml, 5.12 mmol, 1M in CH2Cl2) and Hunig's base (1.12 ml, 6.41 mmol). The resulting mixture was brought to 0° C. and stirred for 30 min. The mixture was again cooled to −78° C. and a solution of (2R,4R)-tert-butyl 4-(allyloxy)-2-formylpyrrolidine-1-carboxylate (Step A (4), 1.09 g, 4.27 mmol) in CH2Cl2 (10 ml) was added dropwise. When the addition was complete, the mixture was stirred at −78° C. for 5 min., then was allowed to warm to rt. After stirring at rt for 4 h. the mixture was concentrated in vacuo. Flash chromatography (silica gel, 0-75% ethyl acetate/hexane) gave 1.22 g (48%) of (2R,4R)-tert-butyl 2-((1S,2S)-2-(3,5-difluorobenzyl)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-3-oxopropyl)-4-(allyloxy)pyrrolidine-1-carboxylate as a slightly yellow oil: 1H NMR (CDCl3, 300 MHz) δ 1.49 (9H, s), 2.03-2.22 (2H, m), 2.31 (1H, d, J=12 Hz), 2.98 (1H, dd, J=3, 15 Hz), 3.07 (1H, t, J=12 Hz), 3.42-3.57 (3H, m), 3.97-4.11 (8H, m), 4.57 (2H, brd s), 5.17-5.30 (2H, m), 5.81-5.94 (1H, m), 6.61 (1H, t, J=9 Hz), 6.90 (2H, brd s), 7.00 (2H, brd s), 7.26 (3H, m). HPLC retention time: 2.04 min (method A). MS (ESI) (M+H)+ 601.37.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:27]([C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)(=[O:29])[CH3:28]>ClCCl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([S:36]([C:32]5[CH:31]=[C:30]([C:27](=[O:29])[CH3:28])[CH:35]=[CH:34][CH:33]=5)(=[O:38])=[O:37])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Reactant: CC(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(S(=O)(=O)N2CCN3C[C@H](Oc4cnc(C5CC5)cn4)C[C@H]3C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
To (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine (1 mmol, Example 27B) and triethylamine (1.5 mmol) in dichloromethane (6 mL) was added 3-acetylbenzene-1-sulfonyl chloride (1.1 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature for 18 hours. The mixture was concentrated, and the residue was purified by chromatography on silica gel (ethyl acetate) to give the title compound (370 mg) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.81 (m, 2H), 0.91 (m, 2H), 1.75 (m, 1H), 1.89 (m, 1H), 2.06 (m, 2H), 2.19 (m, 2H), 2.30 (m, 3H), 3.67 (s, 2H), 2.97 (m, 1H), 3.54 (m, 1H), 3.65 (m, 1H), 3.80 (m, 1H), 5.19 (m, 1H), 7.83 (m, 1H), 8.00 (m, 1H), 8.15 (m, 3H), 8.30 (m, 1H); MS (ESI) m/z 444 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.C(O)C.[OH-].[Pd+2].[OH-]>[N:15]1([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH:19]=[CH:18][N:17]=[N:16]1
Reactant: c1ccc(COc2ccc(-n3ccnn3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1ccc(-n2ccnn2)cc1

Procedure:
1-[4-(benzyloxy)phenyl]-1H-1,2,3-triazole (200 mg, 0.8 mmol) was dissolved in 1.6 mL of a mixture of ethyl acetate and ethanol (1:1). The solution was degassed and purged with nitrogen. Palladium hydroxide (20% w/w on carbon, 55.9 mg, 0.08 mmol) was added and the reaction was degassed and purged with hydrogen three times. The hydrogenation was continued at room temperature under a hydrogen balloon overnight. The catalyst was removed by filtration through a plug of silica gel, which was washed thoroughly with acetone. Concentration afforded the product as white solid. LRMS calc: 161.1; obs: 162.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])([F:6])[F:5].C(N(CC)CC)C.[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[S:22]([O:1][CH2:2][CH2:3][C:4]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])([F:6])[F:5])([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOP(=O)(OCC)C(F)(F)CCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C(F)(F)CCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 2 h

Procedure:
Diethyl 3-hydroxy-1,1-difluoro-propylphosphonate [1225194-19-3] (4.4 g, 0.019 mol) was dissolved in CH2Cl2 (20 mL) and triethylamine (7.7 g) and treated with TsCl (5.4 g, 0.029 mol) followed by DMAP (0.23 g, 0.0019 mol) at rt for 2 h. After 2 h, an additional portion of TsCl (0.6 g) was added. After 30 m, the reaction mixture was partitioned between water and CH2Cl2. The organic layer was filtered and concentrated in vacuo. The residue was dissolved in 1:1 hexanes:CH2Cl2 (100 mL) and applied to 85 g flash silica gel (topped with Na2SO4 and equilibrated with hexanes). The column was eluted with hexanes-ethyl acetate. Intermediate 23 weighed 6.3 g (94%). 1H NMR (CDCl3) 7.2-7.8 (AB, 4H); 3.9-4.4 (m, 6H); 2.0-3.0 (m, 5H), 1.4 (t, 6H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C([O-])([O-])=[O:33].[Na+].[Na+].O>OS(O)(=O)=O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([CH:23]5[CH2:24][N:25]([C:27]([CH3:31])([CH3:30])[C:28]([NH2:29])=[O:33])[CH2:26]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(C(C)(C)C#N)C3)cc1OCC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(C(C)(C)C(N)=O)C3)cc1OCC2
Reaction time: 3.25 h
Yield: 54 %

Procedure:
2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile (0.17 g, 0.41 mmol) was dissolved in conc. H2SO4, (2 mL) and the mixture allowed to stand at room temperature for 3.25 hr before adding to ice. The resultant solution was basified with Na2CO3, further water added, and the mixture extracted with 10% MeOH in DCM. The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 205 as a white solid (97 mg, 54%). 1H NMR δ (ppm) (CDCl3): 8.46 (1H, d, J=8.29 Hz), 7.84 (1H, s), 7.61 (1H, s), 7.13 (1H, s), 7.08 (1H, d, J=8.39 Hz), 6.95 (1H, s), 6.01-5.91 (1H, m), 5.27 (1H, s), 4.50-4.40 (4H, m), 3.62 (3H, s), 3.33 (2H, s), 1.56 (6H, d, J=6.63 Hz), 1.23 (6H, s). LCMS: RT=2.53 min, M+H+=436
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][N:27]2[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.C1C=C(Cl)C=C(C(OO)=[O:42])C=1>CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][N+:27]2([O-:42])[CH2:28][CH:29]([C:31]([OH:33])=[O:32])[CH2:30]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C1C[N+]([O-])(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Reaction time: 0.17 h

Procedure:
A slurry of 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-phenyl)methyl)azetidine-3-carboxylic acid (0.084 g, 0.18 mmol) and mCPBA (0.063 g, 0.37 mmol) in 5 mL 10% MeOH/DCM was stirred rapidly at ambient temperature. After about 10 min, the reaction mixture became clear. After 10 additional minutes precipitates formed. After 10 additional minutes, the reaction mixture was filtered, rinsing with DCM. The solid was collected and dried in vacuo to give 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylic acid N-oxide as a mixture of isomers. The isomers were separated by RPHPLC (A=0.2% formic acid in water; B=0.04% formic acid in acetonitirle; 30×100, Gemini Axia, Sum) to give (1r,3s)-3-carboxy-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidine 1-oxide and (1s,3r)-3-carboxy-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidine 1-oxide. MS (ESI) m/z: Calculated: 475.1; Observed: 476.1 (M++1).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][S:26]([CH3:28])=[O:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:29])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.FC(F)(F)C([NH2:35])=O>>[O:30]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][S:26]([CH3:28])(=[NH:35])=[O:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:29])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCS(C)=O)c2c1
Reactant: NC(=O)C(F)(F)F
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCS(C)(=N)=O)c2c1

Procedure:
The title compound was prepared in analogy to Example 76 in Scheme 33 by using 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(methylsulfinyl)ethyl]quinolin-4-amine (prepared in analogy to Example 74) and trifluoroacetamide. MS obsd. (ESI+) [(M+H)+] 459, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J=7.33 Hz, 1 H), 7.96 (d, J=7.33 Hz, 1 H), 7.73-7.66 (m, 2 H), 7.60-7.55 (m, 1 H), 7.52 (s, 1 H), 7.46-7.40 (m, 1 H), 6.17 (s, 1 H), 5.26 (brs, 2 H), 4.50 (brs, 2 H), 3.98 (t, J=6.69 Hz, 2 H), 3.68 (brs, 2 H), 3.59 (t, J=6.82 Hz, 2 H), 3.14 (s, 3 H), 2.45 (s, 3 H).