Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C#CC1C=C2C(=CC=1)OC(C)(C)CC2(C)C)(C)C.C[Si]([C:25]#[C:26][C:27]1[CH:28]=[C:29]2[C:34](=[C:35]([CH:37]=[O:38])[CH:36]=1)[O:33][C:32]([CH3:40])([CH3:39])[CH2:31][C:30]2([CH3:42])[CH3:41])(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:26]([C:27]1[CH:28]=[C:29]2[C:34](=[C:35]([CH:37]=[O:38])[CH:36]=1)[O:33][C:32]([CH3:40])([CH3:39])[CH2:31][C:30]2([CH3:42])[CH3:41])#[CH:25]
Reactant: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)cc(C=O)c2O1
Agent: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(C=O)c2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A solution of 6-trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman (Compound 43, 1.78 g, 5.4 mmol) in methanol (20 mL) was treated with potassium carbonate (0.745 g, 5.4 mmol) and the resulting reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was filtered, the filtrate was evaporated in vacuo and the residue was subjected to flash column chromatography over silica gel (230-400 mesh) using 2-5% ethyl acetate in hexane as the eluent to afford the title compound (1.1 g, 85%).
Reaction SMILES: C([C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8]([CH2:16][O:17][CH3:18])[C:7]=2[CH:19]=1)=C.C[N+]1([O-])CC[O:24]CC1.C([O:31][CH2:32][CH3:33])(=O)C>CC(C)=O.C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[CH3:18][O:17][CH2:16][N:8]1[C:7]2[CH:19]=[C:3]([CH:32]([OH:31])[CH2:33][OH:24])[CH:4]=[CH:5][C:6]=2[S:11][C:10]2[N:12]=[CH:13][CH:14]=[N:15][C:9]1=2
Reactant: C[N+]1([O-])CCOCC1
Reactant: CCOC(C)=O
Reactant: C=Cc1ccc2c(c1)N(COC)c1nccnc1S2
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: COCN1c2cc(C(O)CO)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 30 ml of a solution of 2.6 g of 8-vinyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and 1.06 g of N-methylmorpholine oxide in acetone was added 4.2 ml of a 1% solution of osmium tetraoxide in tert-butanol and the resulting mixture was stirred at room temperature for 12 hours. Then it was distributed into an aqueous solution of sodium hydrogenthiosulfate and ethyl acetate. After filtering off the inorganic matters through celite, the organic layer was extracted, washed with water and dried over anhydrous sodium sulfate and the extract was filtered. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.35 g of the title compound as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:19]1[CH2:21][C@H:20]1[CH2:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2>>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:21][C@H:20]([OH:19])[CH2:22][O:23][C:24]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:25]=4[CH:26]=[CH:27][NH:28]5)[CH2:15][CH2:14]3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: O=[N+]([O-])c1ccc2c(C3CCNCC3)c[nH]c2c1
Product: O=[N+]([O-])c1ccc2c(C3CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-nitro-3-(piperidin-4-yl)-1H-indole (0.49 g, 2.0 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.40 g, 2.1 mmol). The product was isolated as a yellow crystalline solid. Yield 0.34 g (37%). mp 212°-214° C. FDMS m/e=434 (M+ of free base).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])C.[Na+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.BrC1CC1>CCO>[CH:5]1([S:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)[CH2:2][CH2:1]1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(S)cc1
Agent: BrC1CC1
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of sodium t-butoxide (317 mg, 3.3 mmol) in 15 mL EtOH at 0° C. was slowly added 4-methoxybenzenethiol (420 mg, 3 mmol). After completion of addition, the reaction was stirred at RT for 1 hour before cooling down to 0° C. Bromocyclopropane (417 mg, 3.45 mmol) was added slowly, and the mixture was brought to reflux for one hour, cooled and concentrated. Water (1 mL) was added and the mixture was extract with ethyl acetate. The organic phases were dried and purified by column chromatography eluting with 20% ethyl acetate/hexanes to give the desired product.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH2:29]([O:36][C:37]([NH:39][CH:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:2][O:3][CH:4]=[C:43]1[CH2:44][CH2:45][CH:40]([NH:39][C:37]([O:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[CH2:41][CH2:42]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC=C1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
Tetrahydrofuran (280 ml) was added to (methoxymethyl)triphenylphosphonium chloride (27.8 g, 81.1 mmol) and a solution (50.0 ml, 80.0 mmol) of 1.6M n-butyllithium in n-hexane was dropwise added at -40° C. over 30 minutes, which was followed by stirring for one hour. Then, a solution of 4-(benzyloxycarbonylamino)cyclohexanone (20.0 g, 81.0 mmol) dissolved in tetrahydrofuran (200 ml) was dropwise added over 30 minutes. The mixture was warmed to room temperature and stirred for 3.5 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the extract and the organic layer were combined. The mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give 7.02 g of 4-(benzyloxycarbonylamino)cyclohexylidenemethyl methyl ether as a colorless solid (32%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-])=O)[C:10]=1[OH:19])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([NH:5][S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([NH2:16])[C:10]=1[OH:19])(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: [Pd]
Product: CC(C)(C)NS(=O)(=O)c1c(Cl)ccc(N)c1O

Procedure:
Following the general hydrogenation procedure outlined in example 15, crude N-(tert-butyl)6chloro-2-hydroxy-3-nitrobenzenesulfonamide (1 .54 g) was reduced with hydrogen and 10% Pd/C (670 mg). The crude product (1.23 g) was carried on to the next step without purification. 1H NMR (MeOD-d4): 8 6.82 (m, 2H), 1.22 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH2:12].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Product: CCOC(=O)CNc1ccc(C(F)(F)F)cc1Br

Procedure:
Prepared analogously to Example 166a starting from 2-bromo-4-trifluoromethyl-phenylamine and ethyl bromoacetate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](=O)(O)[O-].[Na+].CI.O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:15])[C:10]([O:12][CH3:18])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: C=CC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 27 h
Yield: 87.3 %

Procedure:
To a stirred mixture of 2(R/S)-(tert-butoxycarbonyl)amino-3,3-dimethyl-4-pentenoic acid (3.6 g, 15 mmol) and anhydrous sodium bicarbonate (3.78 g, 45 mmol) in 25 mL of DMF was added methyl iodide (1.03 mL, 17 mmol) dropwise. The mixture was stirred for 27 hours at room temperature, and then poured into water (100 mL). The mixture was extracted with 2:1 ethyl acetate:hexane (3×50 mL), and the combined organic layers were washed with 5% aq. sodium thiosulfate solution, water, sat. aq. sodium bicarbonate, and finally with brine. The organic layer was dried over magnesium sulfate, and concentrated to provide methyl 2(R/S)-(tert-butoxycarbonyl)amino-3,3-dimethyl-4-pentenoate (3.37 g, 87%) as a syrup which was used without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C@H:25]1[N:33]([C:34](=[O:53])[C@@H:35]([NH:39][C:40](=[O:52])[C@@H:41]([N:43](C)[C:44](=O)OC(C)(C)C)[CH3:42])[CH:36]([CH3:38])[CH3:37])[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH2:26]1)=[O:24])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C@H:25]1[N:33]([C:34](=[O:53])[C@@H:35]([NH:39][C:40](=[O:52])[C@@H:41]([NH:43][CH3:44])[CH3:42])[CH:36]([CH3:38])[CH3:37])[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH2:26]1)=[O:24])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1C(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1C(=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
TFA (0.5 mL, 6.49 mmol, Eq: 145) was added to a solution of tert-butyl (S)-(2S)-1-((2S)-1-(2-(2-benzoylphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (28 mg, 44.6 μmol, Eq: 1.00) in DCM (0.5 mL) and the resulting solution was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue treated with saturated aqueous NaHCO3 (10 mL). The resulting mixture was extracted with EtOAc (1×10 mL) and the organic layer was concentrated in vacuo. The crude residue was treated with MeOH/DCM/ether to give (S)-1-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2-benzoyl-phenyl)-amide as an off-white solid (21 mg), m/z=528 (M+H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O.C(OCC)C>[C:1]([O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: C=C(C)C(=O)OC1CCCCO1

Procedure:
In this embodiment, 0.1 mol of methacrylic acid and 8.6 grams (0.11 mol) of 3,4-dihydro-2H-pyran was dissolved in 150 ml of CH2Cl2. Small amounts of p-toluene sulfonic acid were then added to the resultant solution. The resultant solution was allowed to react at room temperature for four hours to form a reaction product. Then, the reaction product was dissolved in an excess amount of water to which diethyl ether was added to extract the reaction product. After drying the reaction product with a magnesiumsulfate solution, tetrahydropyranyl methacrylate was obtained through vacuum distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH2:32]([NH:36][C:37](=[O:69])[CH2:38][C@H:39]([O:61][Si](C(C)(C)C)(C)C)[C@@H:40]([NH:48][C:49](=O)[O:50]C1C=CC([N+]([O-])=O)=CC=1)[CH2:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:33][CH2:34][CH3:35]>C(Cl)Cl.CCOCC>[CH2:32]([NH:36][C:37](=[O:69])[CH2:38][C@H:39]([OH:61])[C@@H:40]([NH:48][C:49]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH2:18]1)=[O:50])[CH2:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:33][CH2:34][CH3:35]
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Reactant: CCCCNC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CC1CCCCC1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNC(=O)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A solution of methyl 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate (40 mg, 0.12 mmol) and DIEA (0.10 mL, 0.55 mmol) in CH2Cl2 (1 mL) was added to 4-nitrophenyl (2S,3S)-5-(butylamino)-3-(tert-butyldimethylsilyloxy)-1-cyclohexyl-5-oxopentan-2-ylcarbamate (39 mg, 0.07 mmol). The mixture was stirred at rt for 3 h, diluted with ether (100 mL), washed with 5% aq HCl (20 mL) and 1 M aq NaOH (20 mL) and dried over MgSO4. Removal of the solvent left an oil (43 mg) which was dissolved in MeCN (2 mL) and treated with Et4N+F− (25 mg, 0.18 mmol). The solution was stirred at rt for 3 h and submitted directly to preparative HPLC to afford Methyl 2-((R)-((R)-1-((2S,3S)-5-(butylamino)-1-cyclohexyl-3-hydroxy-5-oxopentan-2-ylcarbamoyl)piperidin-3-yl)(3-chlorophenyl)methoxy)ethylcarbamate (30 mg, 38%) as an oil. 1H NMR (CD3OD) 0.92 (t, 3H), 1.0-1.9 (22H), 2.26 (m, 1H), 2.35 (m, 1H), 2.92 (m, 2H), 3.17 (m, 2H), 3.23 (m, 2H), 3.30 (2H), 3.61 (s, 3H), 3.80 (br d, 1H), 3.88 (br d, 1H), 3.94 (m, 1H), 4.03 (d, 1H), 4.15 (br d, 1H), 7.21 (d, 1H), 7.34 (3H); LC-MS (16 min) tR=9.89 min, m/z=623. It is noted that although the compound described in this example was the only compound prepared, the other compounds of the invention described herein could be prepared in accordance with the methods taught herein.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[OH:23]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[OH:23])=[O:6]
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Cl)c([N+](=O)[O-])cc1O)c1ccc(Cl)c(Cl)c1
Yield: 76.8 %

Procedure:
3,4-dichlorobenzoyl chloride (2) (38.0 g, 0.18 mol) was added to a stirred slurry of 2-amino-4-chloro-5-nitrophenol (1) (34.0 g, 0.18 mol) in ethyl acetate (250 ml) and the mixture refluxed for 2 h. After cooling the precipitate was filtered and then slurried in hot ethyl acetate (200 ml) and filtered again to give 50 g (77%) 2-(3,4-dichlorobenzamido)-4-chloro-5-nitrophenol (3).
Reaction SMILES: [O:1]=[C:2]1[NH:9][CH:8]=[C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[C:3]1[C:4]#N.S(=O)(=O)(O)O.[OH-:21].[Na+].[OH2:23]>>[O:1]=[C:2]1[NH:9][CH:8]=[C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[C:3]1[C:4]([OH:23])=[O:21]
Reactant: N#Cc1cc(-c2cccnc2)c[nH]c1=O
Reactant: [OH-]
Reactant: O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cc(-c2cccnc2)c[nH]c1=O

Procedure:
A mixture containing 41 g. of 1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinonitrile and 410 ml. of 50% aqueous sulfuric acid was refluxed for two hours and then poured into 1.5 kg. of a mixture of ice and water. The acidic mixture was neutralized with 35% aqueous sodium hydroxide solution and the mixture cooled. The separated solid was collected, washed with water and dried in vacuo at 80° C. to yield 47 g. of 1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinic acid which was used directly without further purification in the next step described below as Example C-2.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9](=[O:18])[NH:10][CH2:11][CH2:12][CH2:13][C:14](NO)=O)=[CH:5][CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:40][C:41](=[O:49])[CH2:42][CH2:43]CCCCN)C1C=CC=CC=1>>[CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9](=[O:18])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:43][CH2:42][C:41]([OH:49])=[O:40])=[CH:5][CH:4]=1
Reactant: NCCCCCCC(=O)OCc1ccccc1
Reactant: CN(C)c1ccc(CNC(=O)NCCCC(=O)NO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CN(C)c1ccc(CNC(=O)NCCCCCCC(=O)O)cc1

Procedure:
Compound 5 was prepared using the methodology described for the preparation of compound 2, by substituting 4-amino-butyric acid benzyl ester toluene-4-sulfonic acid with 7-amino-heptanoic acid benzyl ester toluene-4-sulfonic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm) 10.33 (br, s, 1H), 8.66 (br s, 1H), 7.05 (d, J=8.7 Hz, 2H), 6.67 (d, J=8.7 Hz, 2H), 6.04 (t, J=5.7 Hz, 1H), 5.79 (t, J=5.7 Hz, 1H), 4.05 (d, J=6.0 Hz, 2H), 2.97 (dt, J=6.6, 6.6 Hz, 2H), 2.84 (s, 6H), 1.93 (t, J=7.5 Hz, 2H), 1.47 (m, 2H), 1.34 (m, 2H), 1.22 (m, 4H)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:17])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.[CH3:18]O>[OH-].[Pd+2].[OH-]>[OH:17][C:11]1([C:14]([O:16][CH3:18])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CO
Reactant: O=C(O)C1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Product: COC(=O)C1(O)CCNCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 1-benzyl-4-hydroxypiperidine-4-carboxylic acid (1.2 g, 5.10 mmol) in MeOH (15 mL) was added palladium hydroxide and the resulting mixture was stirred at rt for 6 h under H2 atmosphere. After completion of reaction (by TLC), the reaction was passed through celite and the filtrate evaporated under reduced pressure to give the desired product (1 g). MS: 160.18 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH:24]=2)[CH:16]=1)([O-:22])=[O:21]
Reactant: CC1(C)C=C(c2cc([N+](=O)[O-])ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C=C(c2cc([N+](=O)[O-])ccc2N2CCNCC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
A solution of 4-[4-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (300 mg, 0.676 mmol) produced in Example (88b) in dichloromethane (3 mL) was stirred at an external temperature of 0° C. Trifluoroacetic acid (1 mL) was gradually added dropwise thereto over a period of 15 minutes. The reaction mixture was allowed to warm to room temperature while stirring for 90 minutes. While cooled in an ice bath, saturated aqueous solution of sodium hydrogencarbonate to the mixture to make the mixture basic. Extraction was performed with ethyl acetate, and the separated organic layer was washed with water and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 180 mg of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2].[CH2:20]=O.C[NH:23][CH3:24].[C-]#N.[K+]>CCO>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH2:20][C:24]#[N:23])=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: C=O
Reactant: CCc1cccc(CC)c1-c1cc2cc[nH]c2cn1
Reactant: CNC
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Product: CCc1cccc(CC)c1-c1cc2c(CC#N)c[nH]c2cn1

Procedure:
A mixture of 5-(2,6-Diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (1 g, 4.5 mmol), formaldehyde (37% solution in water, 1.4 mL, 18 mmol), dimethylamine (2 M solution in MeOH, 18 mL, 18 mmol) and EtOH (50 mL) is heated to reflux for 2.5 h. All volatiles are removed under reduced pressure. The residue is mixed with toluene, which is subsequently removed under reduced pressure. The residue is dissolved in DMF (15 mL), KCN (2.6 g, 40 mmol) is added and the mixture was refluxed for 2 h. DMF is removed under reduced pressure, and the residue is purified by chromatography on silica gel (EtOAc) to afford [5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-acetonitrile as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][N:10]1[CH3:18].[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]3[N:29]([CH:31]=[C:32]([NH:34][C:35]([CH:37]4[CH2:39][CH2:38]4)=[O:36])[N:33]=3)[CH:30]=2)=[C:22]([F:42])[CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:40]=[CH:41][C:20]([NH:19][C:15]([C:12]5[C:13](=[O:14])[N:9]([C:3]6[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=6[F:1])[N:10]([CH3:18])[CH:11]=5)=[O:17])=[CH:21][C:22]=4[F:42])=[CH:30][N:29]3[CH:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cn1cc(C(=O)O)c(=O)n1-c1ccc(F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1F
Yield: 76.2 %

Procedure:
In the same manner as in Example 46 and using 2-(2,4-difluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (330 mg, 1.3 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (250 mg, 0.77 mmol), HATU (490 mg, 1.3 mmol), N,N-diisopropylethylamine (340 mg, 2.6 mmol) and N,N-dimethylformamide (15 mL) as starting materials, the title compound (330 mg, 76%) was obtained as a white solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1>C(Cl)Cl.[Al]>[Br:1][CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1
Reactant: N#Cc1ccc(COCCO)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(COCCBr)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.6 %

Procedure:
A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) was added to resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) in DCM (2.5 mL), and the reaction was stirred at rt for 10 min. A solution of 4-{[(2-hydroxyethyl)oxy]methyl}benzonitrile (95 mg, 0.536 mmol) in DCM (1.5 mL) was added to the reaction, and the residual alcohol was transferred with additional DCM (1.5 mL). The reaction vial was capped, wrapped in aluminum foil, and stirred at rt for 20 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (60 mg, 47%). The product was characterized by 1H NMR (400 MHz) in CDCl3.