Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:8][CH2:9][C:10]([CH3:13])([NH2:12])[CH3:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14](ON1C(=O)CCC1=O)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C(Cl)Cl>[N:1]1([CH2:8][CH2:9][C:10]([NH:12][C:14](=[O:15])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:13])[CH3:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(N)CCN1CCCCCC1
Solvent: ClCCl
Product: CC(C)(CCN1CCCCCC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.1 %

Procedure:
Crude 4-(Azepan-1-yl)-2-methylbutan-2-amine (4.54 g, 24.6 mmol) was dissolved into DCM (120 mL). To this solution was added CbzOSu (6.13 g, 1 equiv, 24.6 mmol) in one portion. The reaction was left to stir at room temperature for 2 d. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (150 mL) and water (100 mL). The layers were separated and the organic layer washed with saturated sodium bicarbonate (2×100 mL), water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil (8.33 g). The crude oil was purified on an ISCO purification system with gradient elution from 1-5% methanol in DCM. The desired fraction was collected and concentrated to give a colorless oil (3.69 g, yield: 47.1%). LRMS (ESI+) for C19H30N2O2 (318.2); Found: 319 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH2:11])[CH2:8][N:7]1[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:5])[CH3:2].[OH:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](O)=[O:30]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]=2[OH:18])=[O:30])[CH2:8][N:7]1[CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:5])[CH3:2]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: CCOC(=O)[C@@H]1C[C@H](N)CN1CC1CCCC1
Product: CCOC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCC1

Procedure:
(2S,4S)-1-Cyclopentylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid ethyl ester was prepared from (2S,4S)-4-amino-1-cyclopentylmethyl-pyrrolidine-2-carboxylic acid ethyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C24H31N2O4 [(M+H)+] 411.0, obsd. 411.2.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:24])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:25](OC)=[O:26])[CH:7]=[CH:8][CH:9]=1.Cl.[OH-].[NH4+:33]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:24])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:25](=[O:26])[NH2:33])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Yield: 60 %

Procedure:
A solution of the 9-[(3-trifluoromethoxyphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (260 mg, 0.62 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was stirred vigorously for 132 hours. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 150 mg (60%) of the 9-[(3-trifluoromethoxyphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as an off-white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.85 (dd, 1H, J=1 and 8 Hz), 7.5-7.15 (m, 5H), 7.1 (d, 1H, J=8 Hz), 7.0 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.95 (d, 1H, J=8 Hz), and 5.65 (s, 2H). IR (KBr, cm−1) 3431, 3203, 1629, 1601, 1580, 1548, 1446, 1330, 1261, 1215, and 777. MS (ES) m/e 399, 401.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[C:6]([C:8]([O:13][CH3:14])([CH:10]([OH:12])[CH3:11])[CH3:9])[CH:7]=1.Br[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([O:15][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH:5]=[C:6]([C:8]([O:13][CH3:14])([CH:10]([OH:12])[CH3:11])[CH3:9])[CH:7]=1
Reactant: COC(C)(c1cc(O)cc(F)c1)C(C)O
Reactant: BrCc1ccc2ccccc2c1
Product: COC(C)(c1cc(F)cc(OCc2ccc3ccccc3c2)c1)C(C)O
Yield: 94 %

Procedure:
Using the procedure described in Example 12, (2RS,3SR)-2-(5-fluoro-3-hydroxyphenyl)-2-methoxybutan-3-ol was reacted with 2-bromomethylnaphthalene to give (2RS,3SR)-2-[5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-2-methoxybutan-3-ol in 94% yield, m.p. 62°-63° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)(=[O:3])[CH3:2].[S:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:29]2[CH:30]=[CH:31][S:27][CH:28]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccsc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(Br)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(-c2ccsc2)c1
Yield: 26 %

Procedure:
By carrying out the operation analogously to example 13, starting from 3-bromophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VII, and 3-thiopheneboronic acid, the expected product is obtained in the form of white crystals with a yield of 26%.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CCCCCCCCC(=O)c1cc(C)ccc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCCCCCCCC(=O)c1cc(C)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
Methyl 10-(2-methoxy-5-methyl-phenyl)-10-oxo-decanoate (1.6 g) was dissolved in methylene chloride (30 ml), 1 M boron tribromide (7.5 ml) was added to the solution at −78° C., and the mixture was stirred at room temperature for 30 min. Water was added to the reaction solution, and the mixture was extracted with chloroform, and the chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give methyl 10-(2-hydroxy-5-methyl-phenyl)-10-oxo-decanoate (546 mg, yield 34%).
Reaction SMILES: Cl.[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]([CH3:40])[CH:17]([C:22]2[CH:39]=[CH:38][C:25]([O:26][CH2:27][CH2:28][CH2:29][NH:30]C(=O)OC(C)(C)C)=[CH:24][CH:23]=2)[C:18]([NH:20][OH:21])=[O:19])(=[O:15])=[O:14])=[CH:9][CH:8]=1)[C:3]#[C:4][CH3:5]>ClCCl>[NH2:30][CH2:29][CH2:28][CH2:27][O:26][C:25]1[CH:38]=[CH:39][C:22]([CH:17]([N:16]([S:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:2][C:3]#[C:4][CH3:5])=[CH:12][CH:11]=2)(=[O:15])=[O:14])[CH3:40])[C:18]([NH:20][OH:21])=[O:19])=[CH:23][CH:24]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)NO)c2ccc(OCCCNC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)NO)c2ccc(OCCCN)cc2)cc1
Reaction time: 1 h
Yield: 102.9 %

Procedure:
Hydrogen chloride gas was bubbled through a solution of 0.371 g (0.661 mmol) of tert-butyl 3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxyamino)-2-oxoethyl]phenoxy}propylcarbamate (from Example 187) dissolved in 5 mL of dichloromethane for 5 minutes. The reaction was stoppered at let sit at room temperature for 1 h and then the solvent was evaporated. The residue was triturated with ether, filtered and dried in vacuo to give 0.314 g of 2-[4-(3-aminopropoxy)phenyl]-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxyacetamide as a white solid. Electrospray Mass Spec 462.2 (M+H)+
Reaction SMILES: [N+:1](C1C=CC2C(C(O)=O)=CSC=2C=1)([O-])=O.[N+:16]([C:19]1[CH:30]=[CH:29][C:22]2[S:23][CH:24]=[C:25]([C:26](O)=[O:27])[C:21]=2[CH:20]=1)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:30]=[CH:29][C:22]2[S:23][CH:24]=[C:25]([C:26]([NH2:1])=[O:27])[C:21]=2[CH:20]=1)([O-:18])=[O:17]
Reactant: O=C(O)c1csc2cc([N+](=O)[O-])ccc12
Reactant: O=C(O)c1csc2ccc([N+](=O)[O-])cc12
Product: NC(=O)c1csc2ccc([N+](=O)[O-])cc12

Procedure:
are obtained as a mixture during the reaction of a mixture of 6-nitro-benzo[b]-thiophene-3-carboxylic acid and 5-nitro-benzo[b]thiophene-3-carboxylic acid (Example XLV). The crude product is chromatographed on silica gel, while the two products are obtained as a mixture and further reacted directly in Example XII (30).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[C:20]3[C:15](=[C:16]([C:21]([NH2:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:25]1[O:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:29]=1>>[CH2:33]([O:32][C:30]([C:27]1[O:26][C:25]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([NH:10][C:11]3[C:20]4[C:15](=[C:16]([C:21](=[O:22])[NH2:23])[CH:17]=[CH:18][CH:19]=4)[N:14]=[CH:13][N:12]=3)[CH3:9])[CH:3]=2)=[N:29][CH:28]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)c1cnc(Cl)o1
Reactant: CC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Product: CCOC(=O)c1cnc(Nc2cccc(C(C)Nc3ncnc4c(C(N)=O)cccc34)c2)o1

Procedure:
2-{3-[1-(8-Carbamoyl-quinazolin-4-ylamino)-ethyl]-phenylamino}-oxazole-5-carboxylic acid ethyl ester was prepared according to Example 549 starting 4-{[1-(3-aminophenyl)ethyl]amino}quinazoline-8-carboxamide and ethyl 2-chloro-1,3-oxazole-5-carboxylate. LCMS (M+1) 447.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[NH:17][CH:16]=[N:15][C:14]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][C:22]=1[CH3:33])=[O:19])=[O:12].[C:34]1([N:40]=[C:41]=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[NH:17][CH:16]=[N:15][C:14]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:28][CH2:29][N:30]([C:41]([NH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:42])[CH2:31][CH2:32]2)=[CH:23][C:22]=1[CH3:33])=[O:19])=[O:12]
Reactant: Cc1cc(N2CCNCC2)ccc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccccc2[nH]1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: Cc1cc(N2CCN(C(=O)Nc3ccccc3)CC2)ccc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N5-(1H-Benzo[d]imidazol-2-yl)-N4-(2-methyl-4-(piperazin-1-yl)phenyl)-1H-imidazole-4,5-dicarboxamide (1 equivalent) and dichloromethane were stirred for 5 minutes. Phenyl isocyanate (1.5 equiv) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure. The resulting crude product was purified by reverse phase HPLC (aqueous ammonium acetate/acetonitrile to give N5-1H-benzimidazol-2-yl-N4-(2-methyl-4-{4-[(phenylamino)carbonyl]piperazin-1-yl}phenyl)-1H-imidazole-4,5-dicarboxamide. 1H-NMR (400 MHz, DMSO-d6): δ 8.86 (s, br, 1H), 8.38 (s, br, 1H), 7.67 (m, 2H), 7.52 (m, 3H), 7.43 (m, 3H), 7.26 (m, 2H), 6.97 (m, 1H), 3.84 (s, br, 4H), 3.41 (s, br, 4H), 2.33 (s, 3H). MS (EI): 564 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16]3)[C:6]=2[N:21]=1.[H-].[Na+].[CH3:24]I.Cl>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:24])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16]3)[C:6]=2[N:21]=1
Reactant: CI
Reactant: C[C@@H]1CCC(N2CC(F)(F)C(=O)Nc3cnc(Cl)nc32)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CCC(N2CC(F)(F)C(=O)N(C)c3cnc(Cl)nc32)C1
Reaction time: 0.5 h

Procedure:
2-Chloro-7,7-difluoro-9-((3R)-3-methylcyclopentyl)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one was methylated on 5-position using sodium hydride and methyl iodide. After 30 minutes the reaction was deemed complete by LCMS, poured into ice, the solution acidified with 1N HCl, the product filtered off as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91-2.22 (m, 10 H) 3.34 (s, 3 H) 4.04-4.35 (m, 2 H) 4.72-5.04 (m, 1 H) 8.35 (s, 1 H). m/z 331.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:5][S:18]([C:15]1[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=1)(=[O:20])=[O:19]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(OC)cc1)C(C)C
Yield: 90 %

Procedure:
In a similar manner to that in Example 1(2)-b, a reaction was carried out using (±)-valine methyl ester and 4-methoxybenzenesulfonyl chloride to afford the desired compound (yield 90%) as a white powder.
Reaction SMILES: [CH3:1][C:2](=[CH2:17])[CH2:3][N:4]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:5]1[C:6]([O:8]C(C)(C)C)=[O:7]>ClCCl.FC(F)(F)C(O)=O>[CH3:17][C:2](=[CH2:1])[CH2:3][N:4]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:5]1[C:6]([OH:8])=[O:7]
Reactant: C=C(C)CN1C(=O)CC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)CN1C(=O)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-dimethylethyl 1-(2-methyl-2-propen-1-yl)-5-oxoprolinate (0.099 g, 0.41 mmol) was dissolved in a mixture of dichloromethane (2 ml) and trifluoroacetic acid (2 ml) and stirred overnight at room temperature. The solvent was evaporated (azeotroping with toluene to remove traces of trifluoroacetic acid) to give crude 1-(2-methyl-2-propen-1-yl)-5-oxoproline as a brown oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl[CH2:24][CH2:25][N:26]([CH2:34][CH2:35]Cl)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:24][CH2:25][N:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH2:35]1)=[O:22])[CH3:2]
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OCC(CC)CC)cc1
Product: CCOC(=O)C1(S(=O)(=O)c2ccc(OCC(CC)CC)cc2)CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(2-ethyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester (6.4 g, 20 mmol) and bis-(2-chloro-ethyl)-benzyl amine (6.44 g, 24 mmol). Yield 8 g (82%); yellow oil; MS: 488 (M+H)+
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([CH3:4])=[CH2:3].[F:7][C:8]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]([CH3:23])[CH3:22])=[C:12]([F:24])[C:11]([F:25])=[C:10]([F:26])[C:9]=1[F:27].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH:21]([C:16]1[CH:17]=[C:18]2[C:19]([CH2:3][CH:2]([CH3:4])[C:1]2=[O:5])=[CH:20][C:15]=1[O:14][C:13]1[C:8]([F:7])=[C:9]([F:27])[C:10]([F:26])=[C:11]([F:25])[C:12]=1[F:24])([CH3:23])[CH3:22]
Reactant: C=C(C)C(=O)O
Reactant: CC(C)c1ccccc1Oc1c(F)c(F)c(F)c(F)c1F
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1Cc2cc(Oc3c(F)c(F)c(F)c(F)c3F)c(C(C)C)cc2C1=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
A mixture of 39.3 g (0.46 mol) of methacrylic acid and 115 g (0.38 mol) of 1-(pentafluorophenoxy)-2-isopropylbenzene was added dropwise to Eaton's reagent (prepared from 99 g of P4O10 and 500 ml of MeSO3H) for 1 h at 70° C. The resulting mixture was stirred at 70° C. for 1 h, then cooled to room temperature, and poured on 1000 cm3 of ice. The crude product was extracted with 3×200 ml of dichloromethane. The organic extract was washed with aqueous K2CO3, dried over Na2SO4, and then evaporated to dryness. The product was purified by flash chromatography on silica gel 60 (40-63 um; eluent: n-hexane-dichloromethane=5:1, vol., then n-hexane-dichloromethane-ether=50:25:1, vol.) to give 30.1 g (20%) of the title indanone. Additionally, 39.4 g of the starting 1-(pentafluorophenoxy)-2-isopropylbenzene was isolated also.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25](O)=[O:26])=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(Cl)CCl.[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:36][NH2:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:36][NH:37][C:25]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:11]=1[CH:22]([CH3:23])[CH3:24])=[O:26]
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccn3)c2c1
Reactant: NCc1cc(F)cc(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1ccc2c(C(=O)NCc3cc(F)cc(F)c3)c(C(C)C)n(Cc3ccccn3)c2c1

Procedure:
Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 40, 80 mg, 0.22 mmol) in CH2Cl2 (5 ml) was added EDC (84 mg, 0.42 mmol) and DMAP (40 mg, 0.32 mmol), followed by 3,5-difluorobenzyl amine (47 mg, 0.32mmol). The crude material was purified by chromatography on silica gel (0→40% EtOAc-hexanes) to yield the title compound as an off white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[NH:10][C:9]2=[O:17])[N:3]=1.[CH3:18][C:19]([CH3:21])=O.[OH-].[K+].C(Br)C=C>O>[CH2:21]([N:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:8]([C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=2)[C:9]1=[O:17])[CH:19]=[CH2:18]
Reactant: Cc1cccc(-n2c(=O)[nH]c3cccnc32)n1
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: C=CCBr
Solvent: O
Product: C=CCn1c(=O)n(-c2cccc(C)n2)c2ncccc21
Reaction time: 8 h

Procedure:
A mixture of 1 g. of 1,3-dihydro-3-(2-methylpyridin-6-yl)imidazo[4,5-b]pyridin-2-one in 100 ml. of acetone and 450 mg. of powdered potassium hydroxide was stirred 10 minutes and 1.1 g. of allyl bromide was added. After refluxing for 1.5 hours, the mixture was allowed to stand overnight at room temperature. The mixture was diluted with water and the acetone was evaporated causing crystallization of 325 mg. of 1-allyl-1,3-dihydro-3-(2-methylpyridin-6yl)imidazo[4,5-b]pyridin-2-one, m.p. 111°-112° C.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9]([O:13][C:14]([NH:16][C:17]([CH3:22])([C:19](O)=[O:20])[CH3:18])=[O:15])([CH3:12])([CH3:11])[CH3:10].CN(C)CCCN=C=NCC>ClCCl>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:19](=[O:20])[C:17]([NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])([CH3:22])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)ON1C(=O)CCC1=O

Procedure:
A stirred solution of N-hydroxysuccinimide (112 g, 0.973 mol), N-t-butoxycarbonyl-α-methylalanine (197 g, 0.969 mol), and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (186 g, 0.970 mol) in anhydrous dichloromethane (1.4 L) was stirred at room temperature for about 18 hours under nitrogen atmosphere. The reaction mixture was washed three times each with saturated sodium bicarbonate solution and then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound of part 1-D as a white solid (256 g, 88%): PBMS (M+18)+ 318; 1H NMR=250 MHz (CDCl3) δ: 4.91 (NH, br, s, 1H), 2,84 (—CO(CH2)2CO—, s, 4H), 1.67 (Me, s, 6H), 1.48 (BOC, s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([OH:23])=O)=[CH:6][N:5]2[C:24]=1[CH3:25].[B-](F)(F)(F)F.[CH3:31][N:32](C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.CN>C(Cl)Cl>[CH2:19]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=1[CH2:11][NH:10][C:9]1[C:4]2[N:5]([C:24]([CH3:25])=[C:2]([CH3:1])[N:3]=2)[CH:6]=[C:7]([C:21]([NH:32][CH3:31])=[O:23])[CH:8]=1)[CH3:20]
Reactant: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCc1cccc(C)c1CNc1cc(C(=O)NC)cn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.9 %

Procedure:
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g, 0.44 mmol) and o-Benzotriazol-1-yl-N,N,N′,N′-Tetramethyluronium tetrafluoroborate (TBTU) (0.14 g, 0.44 mmol) were added to methylene chloride (10 ml) and the reaction mixture was stirred at room temperature for 15 min. Methylamine (0.1 g, 3.2 mmol) was added and the reaction mixture was stirred at ambient temperature for 1.5 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using ethylacetate:methylene chloride (1:1) as eluent. The yield was treated with diethyl ether to give 40 mg (26%) of the desired product.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][C:13]=1[CH:14]=O.[C:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1)(=[O:29])[CH3:28]>>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][C:13]=1/[CH:14]=[CH:28]/[C:27]([C:30]1[CH:31]=[CH:32][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:34][CH:35]=1)=[O:29]
Reactant: COc1cc(OCc2nc3ccccc3[nH]2)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Product: COc1cc(OCc2nc3ccccc3[nH]2)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1-c1cccs1
Yield: 56 %

Procedure:
The title compound was prepared by condensing 2-(1H-benzoimidazol-2-ylmethoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-113A) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Light orange solid, 56% yield, mp 235–237° C. (dec). 1H-NMR (300 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.19 (d, 2H, J=8.4 Hz), 8.11 (d, 1H, J=15.4 Hz), 7.98 (d, 1H, J=15.4 Hz), 7.89 (d, 2H, J=8.4 Hz), 7.66–7.70 (m, 3H), 7.53–7.55 (m, 3H), 7.22–7.27 (m, 2H), 7.12–7.15 (m, 2H), 5.59 (s, 2H), 4.01 (s, 3H). MS (ESI) m/z=546 ([M+H]+, 100%). Anal. Calcd. for C28H23N3O5S2: C, 61.64; H, 4.25; N, 7.70; S, 11.75. Found: C, 61.49; H, 4.47; N, 7.74; S, 11.58.