Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:19]([O:21]CC)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[NH3:29]>C(O)(C)C>[C:1]([NH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:19]([NH2:29])=[O:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CCOC(=O)c1[nH]c2ccccc2c1NC(=O)c1ccccc1
Solvent: CC(C)O
Solvent: O=P(Cl)(Cl)Cl
Product: NC(=O)c1[nH]c2ccccc2c1NC(=O)c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 3-Benzamido-2-carboethoxyindole (3.0 g) and phosphorous oxychloride (20 mL) was refluxed for 30 min. The reaction mixture was concentrated in vacuo and the residue was triturated with ether to afford a white solid. This solid was treated with 40 mL of isopropanol which had been previously saturated with ammonia and heated in a sealed tube at 120° C. for 40 min. The reaction mixture was again concentrated in vacuo and the residue was triturated with ether to afford 3-Benzamido-indole-2-carboxamide as a white solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:6]1[CH2:10][N:9]([C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH3:12])[C:8](=[O:21])[CH2:7]1)[CH2:3][CH:4]=[CH2:5].[H-].[Na+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>CN(C=O)C>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][O:1][C@@H:2]([C@H:6]2[CH2:10][N:9]([C@@H:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[CH3:12])[C:8](=[O:21])[CH2:7]2)[CH2:3][CH:4]=[CH2:5])=[CH:28][CH:27]=1
Reactant: C=CC[C@@H](O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@H](OCc1ccc(OC)cc1)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the alcohol 1.08 (480 mg 1.7 mmol) in 8 mL of DMF at 0° C. was added NaH (166 mg, 60% dispersion in oil, 4.2 mmol) and their reaction was stirred for 30 minutes at 0° C. p-Methoxybenzyl chloride (0.36 mL, 2.7 mmol) was added and the resulting mixture stirred at room temperature for 3 hr. The reaction was quenched with water, and the mixture was extracted with EtOAc. The combined organics were dried (MgSO4), filtered, and concentrated. The crude product was purified by flash chromatography (30-70% EtOAc in hexanes) to afford (R)-4-((R)-1-(4-methoxybenzyloxy)but-3-enyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.25.
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]5[O:28][CH2:29][O:30][C:23]=45)=[N:16][CH:17]=[N:18]3)=[CH:13][C:12]=2[O:31][CH3:32])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:33]=O.[OH-].[Na+]>C(O)=O>[OH:1][C:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]5[O:28][CH2:29][O:30][C:23]=45)=[N:16][CH:17]=[N:18]3)=[CH:13][C:12]=2[O:31][CH3:32])[CH2:7][CH2:6][N:5]([CH3:33])[CH2:4][CH2:3]1
Reactant: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCC1(O)CCNCC1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCC1(O)CCN(C)CC1
Temperature: 100 °C

Procedure:
A mixture of 7-[2-(4-hydroxypiperidin-4-yl)ethoxy]-6-methoxy-4-(2,3-methylenedioxyanilino)quinazoline (0.065 g), formaldehyde (40% aqueous solution; 0.2 ml) and formic acid (2 ml) was stirred and heated to 100° C. for 1.5 hours. The mixture was basified to pH9.5 by the addition of 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using an 80:17:3 mixture of methylene chloride, methanol and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound as a solid (0.021 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.8 (m, 4H), 2.05 (m, 2H), 2.8 (s, 3H), 3.15 (m, 2H), 3.3 (m, 2H), 4 (s, 3H), 4.35 (m, 2H), 6.05 (s, 2H), 6.95 (m, 3H), 7.4 (s, 1H), 8.1 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 453.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[O-:19][CH2:20][CH3:21].[Na+]>C(O)C>[CH2:20]([O:19][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[NH:5][C:6](=[O:8])[CH:7]=1)[CH3:21]
Reactant: CCCOc1ccccc1-c1nc(O)cc(Cl)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccccc1-c1nc(OCC)cc(=O)[nH]1

Procedure:
A stirred solution of 4-chloro-6-hydroxy-2-(2-propoxyphenyl)pyrimidine (0.5 g) and sodium ethoxide (from 0.18 g sodium) in ethanol (25 ml) was heated in a pressure vessel at 125° C. for 24 hours. The residue left after evaporation was dissolved in water (20 ml), acetic acid was added to precipitate a gum, and the mixture was extracted with chloroform. Evaporation of the extract gave a solid which was recrystallized from ether to yield the title compound, 0.07 g, m.p. 95.5-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([CH2:18][NH:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:20]([NH:19][CH2:18][C:7]2[C:6](=[O:29])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:8]=2)=[O:21])[CH2:24][CH2:25]1)(=[O:32])[CH3:31]
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCNCC1
Reactant: CC(=O)Cl
Product: CC(=O)N1CCC(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)CC1

Procedure:
1-(1-Acetyl-piperidin-4-yl)-3-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-yl-methyl)-urea was prepared starting from intermediate N and acetyl chloride. MS calcd. for C24H26ClN4O3 [(M+H)+] 453.2, obsd. 453.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: Ic1ccccn1
Product: COC(=O)CCc1ccc(C#Cc2ccccn2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (99 mg, 0.52 mmol) and 2-iodopyridine (0.07 mL, 0.66 mmol) according to the general procedure IC to give 69 mg (50%) of a pale yellow solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:3). Rf: 0.09 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 8.62-8.60 (m, 1H), 7.70-7.64 (m, 1H), 7.54-7.49 (m, 3H), 7.25-7.18 (m, 3H), 3.67 (s, 3H), 2.99-2.94 (t, 2H, J=7.8 Hz), 2.67-2.61 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 173.0, 150.0, 143.5, 141.6, 136.1, 132.2, 128.4, 127.1, 122.6, 120.2, 89.2, 88.4, 51.6, 35.2, 30.8; EI-MS calcd for C17H15NO2 (M+): 265. found: 265.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][N+:3]=1[O-:12].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:16][CH:13]2[CH2:15][CH2:14]2)=[CH:4][N+:3]=1[O-:12]
Reactant: O=[N+]([O-])c1cc(Br)[n+]([O-])cc1F
Reactant: NC1CC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)[n+]([O-])cc1NC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-5-fluoro-4-nitropyridine 1-oxide (3000 mg, 12.66 mmol) in THF (10 mL) was added cyclopropylamine (868 mg, 15.1 mmol). Solution was stirred at room temperature for 1 h. Mixture was partitioned between EtOAc and saturated aqueous NaHCO3. Organic layer was washed with brine and dried over MgSO4 to provide 2-bromo-5-(cyclopropylamino)-4-nitropyridine 1-oxide 2.67. Residue was used for next step without further purification. LC/MS found for C8H8BrN3O3 as (M+H)+ 275.9.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7](S(C)(=O)=O)[N:6]=[C:5]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15](S(C3C=CC=CC=3)(=O)=O)[CH:14]=2)[CH:4]=1.[C:31]1([Mg]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)C.[OH-].[Na+].Cl>COCCOC>[C:31]1([C:7]2[NH:8][C:3](=[O:2])[CH:4]=[C:5]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[N:6]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(S(C)(=O)=O)n1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: COCCOC
Product: O=c1cc(-c2c[nH]c3ncccc23)nc(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of EXAMPLE 1B (89 mg, 0.20 mmol) in 1,2-dimethoxyethane (2 mL) at 0° C. was added dropwise 3M phenylmagnesium bromide in diethyl ether (0.133 mL, 0.40 mmol)). The mixture was slowly warmed to room temperature and stirred for 15 minutes. To the solution was added dropwise 1M aqueous sodium hydroxide (2 mL, 2 mmol). The mixture was stirred at room temperature for 1 day and concentrated. The residue was dissolved in 12% aqueous HCl (0.62 mL, 2.25 mmol) and heated at 90° C. for 4 hours. The mixture was concentrated and purified by reverse phase HPLC to provide the title compound. MS (ESI) m/e 289 (M+H)+; 1H NMR (DMSO-d6) δ 6.78 (s, 1H), 7.25 (dd, J=7.93, 4.58 Hz, 1H), 7.54-7.65 (m, 3H), 8.24-8.34 (m, 3H), 8.44 (s, 1H), 8.69-8.75 (m, 1H), 12.32 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.C[Si]([N:56]=[C:57]=[O:58])(C)C>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:57]([NH2:56])=[O:58])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Reactant: C[Si](C)(C)N=C=O
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(N)=O)cc2)C1=O

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Example 36, Step A) and trimethylsilyl isocyanate according to the procedure described in Example 37, Step A. 1H NMR (200 MHz, CD3OD): δ 1.40 (s, 6H), 1.82 (m, 1H), 2.15-2.60 (m, 3H), 4.12 (s, 2H), 4.32 (m, 1H), 4.85 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.32 (d, 15 Hz, 1H), 7.05-7.43 (m, 17H). FAB-MS: calculated for C37H39N5O5 633; found 644 (M+H, 100%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24].C(OC(C)C)(C)C>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)cn1
Reactant: CC(C)C(=O)Cl
Solvent: CC(C)OC(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)C(C)C)cn1
Yield: 91 %

Procedure:
As described for example 179b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-ylamine (150 mg, 0.53 mmol) was converted, using isobutyrylchloride instead of acetyl chloride, to the title compound (170 mg, 91%) which was obtained as a white solid after trituration with diisopropylether. MS: m/e=352.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[C:29]([O:32][CH2:33][CH2:34]O)(=[O:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:29]([O:32][CH2:33][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: COc1ccc(-c2[nH]c(-c3ccc(O)cc3)nc2C(=O)Nc2nccs2)cc1
Reactant: CC(=O)OCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2[nH]c(-c3ccc(OCCOC(C)=O)cc3)nc2C(=O)Nc2nccs2)cc1

Procedure:
2-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 2-hydroxyethyl acetate, triphenylphosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 2-(4-(2-acetoxyethyloxy)phenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[S:11][CH2:12][CH2:13][CH2:14][Cl:15].O.O.[Sn](Cl)Cl.[OH-].[NH4+:22]>C(O)C.Cl>[Br:1][C:2]1([NH2:22])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]1[S:11][CH2:12][CH2:13][CH2:14][Cl:15]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cccc(Br)c1SCCCCl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC1(Br)C=CC=CC1SCCCCl
Temperature: 0 °C
Yield: 93.2 %

Procedure:
1-Bromo-2-[(3-chloropropyl)thio]-3-nitrobenzene (6.78 g, 21.9 mmol) was dissolved in ethyl alcohol (125 mL) and cooled in an ice bath to 0° C. Tin (II) chloride dihydrate (7.4 g, 32.8 mmol) was dissolved in concentrated hydrochloric acid (25 mL) and then added to the first solution over 20 minutes. The reaction was then allowed to warm to room temperature and stirred over night. Reaction mixture was cooled to 0° C. in an ice bath and another (1.5 eq, 7.4 g) of tin (II) chloride dihydrate in concentrated hydrochloric acid (25 mL) was added. This was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature and stirred until loss of starting material. Reaction was then basified to pH 12 with ammonium hydroxide and then filtered. The filtrate was then concentrated to a aqueous slurry, the slurry was then diluted with water (100 mL) and extracted with ethyl acetate (3×300 mL). Organic extracts were dried over magnesium sulfate and filtered. The filtrate was concentrated to give 1-bromo-2-[(3-chloropropyl)thio]-benzenamine (5.7 g, 93.2%). 1H NMR (CDCl3, 300 MHz): δ7.02-60.87 (m, 2H), 6.65 (dd, 1H, J=7.7, 1.9 Hz), 4.63 (s-broad, 2H), 3.68 (t, 2H, J=6.4 Hz), 2.92 (t, 2H, J=6.95 Hz), 2.04-1.95 (m, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][CH:5]=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:11]([C:3]1[C:2]([N:1]=[CH:15][N:16]([CH3:18])[CH3:17])=[N:7][C:6]([CH2:8][CH2:9][CH3:10])=[CH:5][N:4]=1)#[N:12]
Reactant: CCCc1cnc(C#N)c(N)n1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CCCc1cnc(C#N)c(N=CN(C)C)n1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A mixture of 3-amino-5-propylpyrazine-2-carbonitrile (0.140 g, 0.863 mmol) (prepared according to the method of Taylor and LaMattina, JOC 1977, 47, 1523) and dimethylformamide dimethylacetal (0.123 g, 1.04 mmol, 1.2 eq) in toluene (10 mL) was heated under reflux for 2 h. The mixture was cooled to room temperature and the solvent evaporated under reduced pressure to provide the title compound (0.188 mg, 100%) as a thick oil.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:10]2[CH:9]=[C:8]([O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]3[N:28]=[CH:29][N:30]([CH3:32])[CH:31]=3)(=[O:26])=[O:25])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[O:35]=[C:33]1[N:1]([C@H:2]2[C@@H:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:10]3[CH:9]=[C:8]([O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]4[N:28]=[CH:29][N:30]([CH3:32])[CH:31]=4)(=[O:26])=[O:25])[CH:7]=[CH:6][C:5]=3[CH2:4][CH2:3]2)[C:8](=[O:20])[CH:7]2[CH:34]1[CH2:6]2
Reactant: CC(=O)Cl
Reactant: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)[C@H](Cc2ccccc2F)[C@H](N)CC3)c1
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)[C@H](Cc2ccccc2F)[C@H](N2C(=O)C4CC4C2=O)CC3)c1

Procedure:
cis-N-(2-{[7-Amino-8-(2-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide (60 mg, 0.105 mmol) in acetyl chloride (2 mL, 28.1 mmol) was heated under reflux for 30 min. The acetyl chloride was evaporated in vacuo. The crude product dissolved in dichloromethane and washed successively with saturated sodium bicarbonate and saturated sodium chloride and dried (magnesium sulfate). The crude product was used for next step without further purification. Yield: 38 mg (colorless foam).
Reaction SMILES: [CH:1]1([C@H:4]([OH:30])[CH2:5][O:6][C:7]2[C:25]([F:26])=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][C:8]=2[CH2:9][N:10]([CH3:21])[C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].N1C=CN=C1>CN(C=O)C>[Si:31]([O:30][C@@H:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5][O:6][C:7]1[C:25]([F:26])=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][C:8]=1[CH2:9][N:10]([CH3:21])[C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1OC[C@@H](O)C1CC1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1OC[C@@H](O[Si](C)(C)C(C)(C)C)C1CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 73 %

Procedure:
To a solution of 21E (99 mg, 0.237 mmol) in DMF (3 mL), was added tert-butyldimethylsilyl chloride (178 mg, 1.183 mmol) and imidazole (81 mg, 1.183 mmol). The reaction mixture was stirred at rt for 60 h., then was quenched with water, extracted with EtOAc (2×). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography to give 21F (92 mg, 0.173 mmol, 73.0% yield). MS (ESI) m/z: 533.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 3-oxopiperazine-1-carboxylic acid benzyl ester (4.68 g, 20 mmol) in 20 mL of DMF at) 0° C. is added sodium hydride (60%, 880 mg, 22 mmol). The suspension is stirred at ambient temperature for one t-butyl bromoacetate (4.68 g, 24 mmol) is added. The resulting mixture is stirred at ambient temperature overnight. After dilution with ethyl acetate (200 mL), the mixture is washed with brine (3×50 mL). The crude residue obtained from concentration of the organic phase is chromatographied on silica gel (30% ethyl acetate/Hexane) to give 5.57 g (80%) of 4-tert-butoxycarbonylmethyl-3-oxopiperazine-1-carboxylic acid benzyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[F:24][C:25]([F:41])([F:40])[CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:36][CH2:35][CH:34]2[C:37]([O-])=[O:38])[CH2:29][CH2:28]1.[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:37]([CH:34]2[CH2:35][CH2:36][N:33]2[CH:30]2[CH2:29][CH2:28][N:27]([CH2:26][C:25]([F:40])([F:24])[F:41])[CH2:32][CH2:31]2)=[O:38])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=C([O-])C1CCN1C1CCN(CC(F)(F)F)CC1
Agent: [Li+]
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2CCN2C2CCN(CC(F)(F)F)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)azetidine-2-carboxylate 20G carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)azetidine-2-carbonyl)pyrrolidine-2-carboxamide 1:1 epimers as an off-white solid (65%). MS ISP (m/e): 602.3 (100) [(M+H)]]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=[O:12])=[CH:5][NH:6]2.[H-].[Na+].[CH2:15](I)[CH3:16]>CN(C=O)C.ClCCl>[CH2:15]([N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[C:4]([CH:11]=[O:12])=[CH:5]1)[CH3:16]
Reactant: Cc1cccc2[nH]cc(C=O)c12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1cc(C=O)c2c(C)cccc21
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a solution of 4-methyl-1H-indole-3-carbaldehyde (150 mg. 0.942 mmol) in dry DMF (1 mL) was added NaH (26 mg, 1.08 mmol) in 3 portions. When the evolution of gas was complete, the reaction vial was sealed and agitated for 5 m, after which time ethyl iodide (0.086 mL, 1.1 mmol) was added and agitation was continued overnight. The mixture was diluted with dichloromethane (10 mL), washed with water (2×5 mL), and brine (5 mL), dried and concentrated. This mixture was purified by flash chromatography using a gradient of ethyl acetate/hexane to provide 1-ethyl-4-methyl-1H-indole-3-carbaldehyde (111 mg, 63%). This intermediate (371 mg, 2 mmol) was dissolved in THF (3 mL) and NaBH4 (38 mg, 5 mmol) was added followed by 3 drops of water. The reaction mixture was agitated for 4 h then added to a saturated solution of NaHCO3 (10 mL). This mixture was stirred for 1 h and the intermediate, (1-ethyl-4-methyl-1H-indol-3-yl)-methanol was isolated by filtration and dried (330 mg, 88% yield). This intermediate was then convened to the title compound using methods similar to those described in Example 31. LCMS (ESMS): m/z 420 (M+H+).
Reaction SMILES: [Br-:1].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:22]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][C:35]3[C:42]([C:43]([F:46])([F:45])[F:44])=[CH:41][C:38]([CH2:39]O)=[CH:37][C:36]=3[C:47]([F:50])([F:49])[F:48])[CH:32]=2)[NH:27][CH:26]=1)([CH3:24])[CH3:23].N1C=CC=CC=1>C(#N)C>[CH:22]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][C:35]3[C:42]([C:43]([F:46])([F:45])[F:44])=[CH:41][C:38]([CH2:39][Br:1])=[CH:37][C:36]=3[C:47]([F:50])([F:49])[F:48])[CH:32]=2)[NH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CO)cc3C(F)(F)F)cc12
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CBr)cc3C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.273 g (3.02 mmol) of triphenylphosphine dibromide are added under argon in portions at 0° C. to a solution of 0.97 g (2.32 mmol) of benzyl alcohol derivative from Example VI in 15 ml of acetonitrile and 0.3 ml (3.72 mmol) of pyridine. After 15 minutes the cooling bath is removed and the mixture is stirred for 2 hours at room temperature. The reaction solution is concentrated in vacuo, and the residue is dissolved in a little toluene and purified by chromatography on silica gel 60 by means of toluene.