Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:60])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:57][CH3:58])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([O:51][Si](C)(C)C)[CH2:50][CH2:49][CH2:48][CH2:47]4)=[C:40]([CH3:56])[CH:39]=3)[CH2:36][CH3:37])=[CH:31][C:30]=2[CH3:59])=[CH:25][CH:24]=1.O>O1CCCC1>[CH3:19][O:20][C:21](=[O:60])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:36][CH3:37])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([OH:51])[CH2:50][CH2:49][CH2:48][CH2:47]4)=[C:40]([CH3:56])[CH:39]=3)[CH2:57][CH3:58])=[CH:31][C:30]=2[CH3:59])=[CH:27][CH:28]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 0.094 mL, 0.094 mmol) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 52-(1); 36.5 mg, 0.063 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for two hours. The reaction mixture was then poured into water, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (25 mg, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:11])=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: O=C(O)Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(Cc1ccc(F)cc1)N1CCCCC1
Temperature: 105 °C

Procedure:
4-Fluorophenylacetic acid (280 g, 1.82 mol) was suspended in 1.9 L toluene followed by the careful addition of 185 mL thionyl chloride (303 g, 2.545 mol). The reaction was heated to 105° C. for 16 hr (overnight). The reaction was allowed to cool to room temperature and the volatiles were removed in vacuo. The crude acid chloride was dissolved in 1.9 L THF, cooled to 0° C., and 0.72 L piperidine (618 g, 7.27 mol) was added. The reaction vessel was allowed to warm to ambient temperature for 18 hr. The mixture was quenched with a saturated solution of aq. NaHCO3 and extracted several times with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and filtered on a fritted funnel. The volatiles were removed in vacuo and the crude residue was purified on silica gel and eluted with a mixture of EtOAc/heptanes (0-75% gradient elution). This furnished the title compound. 1H-NMR (CDCl3): δ 1.32-1.42 (m, 2H), 1.48-1.64 (m, 4H), 3.34-3.42 (m, 2H), 3.54-3.60 (m, 2H), 3.69 (s, 2H), 6.90-7.05 (m, 2H), 7.18-7.24 (m, 2H) ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:21]3[CH:22]=[CH:23][S:19][CH:20]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: OB(O)c1ccsc1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccsc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and thiophene-3-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-thiophen-3-yl-isoquinolin-3-yl)-amine. LC-MS m/e 307(MH+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:2]1.N1C2C(=CC=CN=2)C=[CH:17]1.[Al+3].[Cl-].[Cl-].[Cl-].BrC(C)C(Br)=O.NC(N)=S>>[CH3:17][C:14]1[S:13][C:12]([NH2:15])=[N:11][C:10]=1[C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1
Reactant: Nc1nc(-c2c[nH]c3ncccc23)cs1
Reactant: c1cnc2[nH]ccc2c1
Agent: CC(Br)C(=O)Br
Agent: NC(N)=S
Agent: [Al+3]
Product: Cc1sc(N)nc1-c1c[nH]c2ncccc12

Procedure:
The title compound was synthesized in 2 steps in a manner similar to that described for 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-ylamine, using 7-azaindole (1.0 g, 8.47 mmol), AlCl3 (3.4 g, 25.41 mmol, 3 eq),2-bromopropionylbromide (1.1 mL, 10.58 mmol) and thiourea (0.57 g, 7.5 mmol) (0.93 g, 41%, 2 steps) as a brown solid. Mass Spec.; MS 231 (M+1); 1H NMR(DMSO-d6, 500 MHz) δ 11.71 (s,1H), 8.36(dd, 1H), 8.21(dd,1H), 7.53(d,1H), 7.06(dd,1H), 6.67(brs,2H),2.31(s,3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].[CH3:28][O:29][CH2:30][CH2:31][NH2:32].COCCNS(C1C=CC=CC=1C1NC(=O)C2=C(C)N=C(CCC)N2N=1)(=O)=O>ClCCl.CO>[CH3:28][O:29][CH2:30][CH2:31][NH:32][S:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:14]2[NH:19][C:18](=[O:20])[C:17]3=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]3[N:15]=2)[CH:6]=1)(=[O:12])=[O:11]
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Reactant: COCCN
Agent: CCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3S(=O)(=O)NCCOC)nn12
Solvent: ClCCl
Solvent: CO
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)NCCOC)ccc3OCC)nn12

Procedure:
By the same method, starting with 1.23 g (3 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 680 mg (9 mmol) of 2-methoxyethylamine, 900 mg (67%) of N-(2-methoxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-benzenesulphonamide are obtained. Rf=0.25 (dichloromethane/methanol=95:5)
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[S:11][CH:12]=2)=[CH:6][CH:5]=[N:4]1)[CH3:2].C1C(=O)N([Br:24])C(=O)C1>C1COCC1>[Br:24][C:6]1[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[C:8]1[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[S:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1nccc1-c1csc(C(=O)OC)c1
Solvent: C1CCOC1
Product: CCn1ncc(Br)c1-c1csc(C(=O)OC)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a solution of methyl 4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.45 g, 1.9 mmol) [see example 92(a)] in THF (5 mL) was added NBS (0.33 g, 2.5 mmol). The reaction mixture was heated to 70° C. under nitrogen. After 2 h, the reaction mixture was concentrated under vacuum and purified on silica (EtOAc/hexanes, 10-30%) to afford the title compound (0.47 g, 78%). LC-MS (ES) m/z=316 (M+H)+.
Reaction SMILES: C1(CC([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>ClCCl>[NH2:10][CH:11]1[C:31](=[O:32])[N:13]2[C:14]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)=[O:19])=[CH:15][CH2:16][S:17][C@H:12]12
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Temperature: 10 °C
Reaction time: 0.75 h
Yield: 101.7 %

Procedure:
To a suspension of p-nitrobenzyl 7-phenylacetamido-3-cephem-4-carboxylate (10.50 g.) in dry dichloromethane (100 ml.) was added dry pyridine (2.14 g.). Phosphorus pentachloride (5.50 g.) was added to the solution at -10° C., and the mixture was stirred at -5° C. for 45 minutes and further at 10° C. for an hour. After adding methanol (520 g.) to the resultant mixture, the mixture was stirred at -20° C. for 1.5 hours. The precipitates were collected by filtration, washed with dichloromethane (120 ml.) and diethyl ether (130 ml.) in turn, and then dried to give p-nitrobenzyl 7-amino-3-cephem-4-carboxylate (7.90 g.), m.p. 182° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][C@@H:13]3[C@H:9]2[CH2:10][N:11](C(OCC2C=CC=CC=2)=O)[CH2:12]3)=[CH:4][C:3]=1[CH3:25]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][C@@H:13]3[C@H:9]2[CH2:10][NH:11][CH2:12]3)=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(N2C[C@H]3CN(C(=O)OCc4ccccc4)C[C@H]32)cnc1Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N2C[C@H]3CNC[C@H]32)cnc1Cl
Temperature: 25 °C
Yield: 73.3 %

Procedure:
The product from Example 87A (220 mg, 0.61 mmol) in trifluoroacetic acid (6 mL) was heated at 60° C. for 2 hours, cooled to room temperature, concentrated, and purified by chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 90:10:1) to afford the title compound as an oil (100 mg, 80% yield). MS (DCI/NH3) m/z 224, 226 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:15]([CH3:16])[CH:14]=[N:13][CH:12]=3)[S:10][C:3]=12.[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[OH:27].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[O:27][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:15]([CH3:16])[CH:14]=[N:13][CH:12]=3)[S:10][C:3]=12
Reactant: Cn1cncc1-c1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1cncc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 190 °C
Yield: 42.6 %

Procedure:
A mixture of the compound 16 (1.52 g, 6.09 mmol), 2-fluoro-4-nitrophenol (3.87 g, 24.6 mmol) and K2CO3 (4.31 g, 31.2 mmol) in Ph2O (20 mL) was heated at 190° C. overnight. DCM (250 mL) was added to the resultant dark-brown mixture, which was then extracted with aqueous 1M HCl. The aqueous layer was collected, washed with DCM and basified with NH4OH. The resultant cloudy mixture was extracted with DCM. The organic phase was combined, filtered; the filtrate was washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resultant yellow solid was purified by flash chromatography, eluent EtOAc/MeOH (80:20) to afford title-compound 17 as a yellow solid (0.96 g, 43% yield). MS (m/z): 371.0 (M+H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][OH:13]>>[Br:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][O:13][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: CC(CO)(CCCBr)c1ccccc1
Product: CC(CCCBr)(COC1CCCCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.8 %

Procedure:
Under N2 atmosphere, 3,4-dihydro-2H-pyran (8.19 g, 98 mmol) was added drop-wise to a stirred solution of 5-bromo-2-methyl-2-phenyl-pentan-1-ol (20 g, 78 mmol) at −5° C. The reaction mixture was allowed to warm to rt and stirred for 5 h. The solution was filtered through aluminum oxide (100 g), which was washed with CH2Cl2 (500 mL). The filtrate was concentrated in vacuo to furnish 2-(5-bromo-2-methyl-2-phenyl-pentyloxy)-tetrahydropyran (25.23 g, 96.2%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 7.26-7.08 (m, 5H), 4.45 (m, 1H), 3.72 (m, 1H), 3.58 (m, 1H), 3.35-3.05 (m, 2H), 3.28 (t, J=6.6, 2H), 1.95-1.39 (m, 10H), 1.25 (s, 3H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 145.37, 128.14, 126.51, 126.03, 99.06, 98.92, 61.91, 61.80, 41.82, 41.74, 37.58, 37.43, 34.65, 30.61, 27.88, 25.58, 23.03, 22.89, 19.39, 19.32. HRMS (HR, LSIMS, nba): Calcd. for C17H26O2Br (MH+): 341.1116, found: 341.1127.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[N:3]=[C:2]1[NH2:13].C(=O)([O-])[O-].[K+].[K+].[CH3:20][N:21]1[C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=[N:22]1>O1CCCC1>[S:1]1[C:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[N:3]=[C:2]1[NH:13][C:26]([C:25]1[N:21]([CH3:20])[N:22]=[CH:23][CH:24]=1)=[O:27]
Reactant: Nc1nc2c(s1)Cc1ccccc1-2
Reactant: Cn1nccc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nccc1C(=O)Nc1nc2c(s1)Cc1ccccc1-2
Yield: 30.8 %

Procedure:
To a mixture 8H-Indeno[1,2-d]thiazol-2-ylamine 1b (Prepared in Example 1, Step 2, 320 mg; 1.70 mmol) and potassium carbonate (3.10 g; 22.4 mmol) in dry tetrahydrofuran (10 mL) under nitrogen was added 2-methyl-2H-pyrazole-3-carbonyl chloride (516 mg; 3.57 mmol). The slurry was then heated to reflux for 3 hr. The solvent was removed in vacuo, and the residue diluted with water and extracted with ethyl acetate. The organic layer was washed with 50 mL of 1N hydrochloric acid solution followed by brine solution and dried (sodium sulfate) filtered and concentrated in vacuo. The crude product was purified by trituration with diethyl ether to provide 155 mg of 2-Methyl-2H-pyrazole-3-carboxylic acid (8H-indeno[1,2-d]thiazol-2-yl)-amide 9. EI-HRMS m/e calcd for C15H12N4OS (M+) 296.0732, found 296.0731.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:21](=[O:22])[CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:24])([F:12])[F:25])=[CH:19][CH:18]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1[nH]ccc1C
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2ccc(C(F)(F)F)cc2)c1C

Procedure:
3-Methyl-4-[2-(4-trifluoromethylphenyl)-acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (100) was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (4-trifluoromethylphenyl)-acetyl chloride following the procedure described in Example 32. Crude yield: 96%. 1H-NMR (400 MHz, CDCl3): δ 1.38 (t, 3H), 2.61 (s, 3H), 4.11 (s, 2H), 4.35 (q, 2H), 7.37 (m, 2H), 7.51 (d, 1H), 7.58 (m, 2H), 9.29 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ 11.71, 14.41, 46.90, 60.78, 123.70, 124.70, 125.49, 126.75, 129.41, 129.85, 130.00, 161.98, 193.49 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.71, 14.41; CH2 carbons: 46.90, 60.78; CH carbons: 123.70, 124.70, 125.49, 126.75, 129.41, 129.85, 130.00 ppm. LC/MS: 73.23%, n/z=339.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([S:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH2:20]>C(O)(C(F)(F)F)=O.Cl>[F:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2](=[O:20])[CH:11]=2)=[CH:14][CH:15]=1
Reactant: O
Reactant: Fc1ccc(Sc2cc(Cl)nc3ccccc23)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(Sc2ccc(F)cc2)c2ccccc2[nH]1

Procedure:
A solution of 2-chloro-4-(4-fluoro-phenylsulfanyl)-quinoline (145 mg, 0.50 mmol) in TFA (2 mL) and HCl (6 N, 2 mL) was heated under microwave radiation at 120° C. for 20 min. After cooling down, 20 mL of water was added. The precipitate was collected by filtration and washed with water for several times. The product was air dried (115 mg, 85%) and was pure enough without further purification. Note: the solubility of the product in organic solvent is very poor. 1H NMR (500 MHz, DMSO-d6) δ 11.6 (bs, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.71 (m, 2H), 7.56 (t, J=8.0 Hz, 1H), 7.43 (m, 3H), 7.33 (d, J=8.0 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 5.56 (s, 1H); LCMS (EI) m/z 272.0 (M+), 273.0.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:8])[CH3:7].CN([CH:21]=[O:22])C>CCOC(C)=O>[CH:6]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:21]=[O:22])=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CC(C)c1cc2ccccc2[nH]1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1[nH]c2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
POCl3 (0.86 ml, 9.4 mmol) was added dropwise to anhydrous DMF (4 ml) at 0° C. with stirring. After 30 min, this solution was added dropwise to a solution of 2-isopropyl-1H-indole (Compound 38, 1.24 g, 7.8 mmol) in DMF (16 ml) at 0° C. under argon. The reaction was stirred for 1 h while it warmed up to room temperature. The reaction was diluted with EtOAc, washed with aq. NaHCO3, brine, dried over Na2SO4, and concentrated in vacuo. The residual solid was washed with Et2O to yield 2-isopropyl-1H-indole-3-carbaldehyde (Compound 39) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:22])=[O:21])=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:23])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:22])(=[O:32])=[O:21])=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:23])=[CH:4][CH:3]=1
Reactant: CS(=O)c1ccc(C2CCCC(=O)N2c2ccc(Cl)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C2CCCC(=O)N2c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a solution of 1.70 g of 1-(4-chlorophenyl)-6-(4-methylsulfinylphenyl)-2-piperidone in 50 ml of methylene chloride was added 1.02 g of m-chloroperbenzoic acid with stirring at 5° to 10° C. over 30 minutes. After stirring at 5° to 10° C. for 1 hour and at room temperature for 1 hour, the mixture was made alkaline with a saturated aqueous sodium hydrogen carbonate solution. The methylene chloride layer was washed with water, dried, and concentrated. The residue was recrystallized from nitroethane to give 1.54 g of 1-(4-chlorophenyl)-6-(4-methylsulfonylphenyl)-2-piperidone as colorless prisms.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:21]([CH:18]([N:13]1[C:12]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH2:19][CH3:20])[CH3:22]
Reactant: CCC(CC)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1ccccc1
Product: CCC(CC)n1nc2c(c1-c1ccccc1)CCNCC2
Yield: 42.9 %

Procedure:
The title compound (40 mg) was prepared as in Example 177, Steps C and D, using 150 mg of 2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 120 mg of phenylboronic acid. MS (ESI): exact mass calculated for C18H25N3, 283.20. found, m/z 284.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.48-7.38 (m, 3H), 7.24-7.19 (m, 2H), 3.77-3.70 (m, 1H), 3.36-3.31 (m, 2H), 3.24-3.19 (m, 2H), 3.14-3.09 (m, 2H), 2.71-2.65 (m, 2H), 1.85-1.75 (m, 2H), 1.68-1.58 (m, 2H), 0.61 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH2:1]([O:4][NH:5][C@H:6]1[CH2:11][NH:10][C@H:9]([C:12]([NH2:14])=[O:13])[CH:8]=[C:7]1[CH3:15])[CH:2]=[CH2:3].[CH2:16]([O:19]N[C@H]1CN[C@@H](C(N)=O)C=C1C)C=C.C(N(CC)C(C)C)(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]1[C:16](=[O:19])[N:10]2[CH2:11][C@H:6]1[C:7]([CH3:15])=[CH:8][C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCON[C@H]1CN[C@@H](C(N)=O)C=C1C
Reactant: C=CCON[C@H]1CN[C@H](C(N)=O)C=C1C
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O
Temperature: 25 °C
Yield: 64.8 %

Procedure:
To a solution of (2S,5R)-5-(allyloxyamino)-4-methyl-1,2,5,6-tetrahydropyridine-2-carboxamide and (2R,5R)-5-(allyloxyamino)-4-methyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 22, 0.429 g, 2.03 mmol) and N,N-diisopropylethylamine (1.415 mL, 8.12 mmol) in acetonitrile (170 mL) at 0° C. was added triphosgene (0.241 g, 0.81 mmol) as a solution in acetonitrile (1.5 mL). The triphosgene solution was added at a rate of 0.1 mL/min. Once addition was complete the reaction was warmed to room temperature and stirred over weekend. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded (2S,5R)-6-(allyloxy)-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (0.312 g, 64.8%) as a light yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([C@H:21]3[CH2:25][O:24]C(C)(C)[O:22]3)=[CH:16][N:15]=2)[CH2:10][C@@H:9]1[CH3:28])=O)(C)(C)C.Cl.C(OCC)C>C(Cl)Cl.CO.O1CCOCC1>[F:20][C:19]1[CH:18]=[C:17]([C@H:21]([OH:22])[CH2:25][OH:24])[CH:16]=[N:15][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][C@@H:9]([CH3:28])[CH2:10]1
Reactant: C[C@H]1CN(c2ncc([C@H]3COC(C)(C)O3)cc2F)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H]1CN(c2ncc([C@H](O)CO)cc2F)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 113.1 %

Procedure:
To a solution of 116 (1.71 g, 4.33 mmol) in DCM (9.60 mL) and MeOH (1.50 mL) was added 4N HCl in dioxane (6.49 mL) to form a reaction mixture. The reaction mixture was stirred at a temperature of about 25° C. in a closed vessel for 16 h. Thereafter, the resulting suspension was stirred with diethyl ether. The solid precipitate was collected on filter paper and washed several times with diethyl ether to provide 1.25 g of 117 as a tan solid (88% yield) which, being >99% pure as analyzed by LC/MS, was used directly in the next step.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33](O)=[O:34])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:36][CH:37]4[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]4)=[O:34])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:16]=23)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Product: COc1cc(-c2ccnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c7) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.