Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[O:17][C:18]([C:22]([O:24]CC)=O)=[C:19]([CH3:21])[N:20]=2)[CH:12]([CH2:27][O:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1.CO.O>[CH2:35]([NH:42][C:22]([C:18]1[O:17][C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:5])([CH3:4])[CH3:6])=[O:9])[CH2:11][CH:12]2[CH2:27][O:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[N:20][C:19]=1[CH3:21])=[O:24])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1oc(N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)nc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)oc1C(=O)NCc1ccccc1
Reaction time: 3 h

Procedure:
Lithium hydroxide (56 mg, 1.3 mmol) was added to a solution of ethyl 2-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazin-1-yl)-4-methyloxazole-5-carboxylate (200 mg, 0.448 mmol) in THF (2 mL), MeOH (2 mL), and water (1 mL). After 3 h, 2.5 mL of the reaction mixture was removed and acidified to pH ˜3 with 1 N aqueous HCl. This was diluted with water (15 mL) and extracted with EtOAc (3×30 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting yellow oil was dissolved in DMF (3 mL) and benzylamine (0.027 mL, 0.246 mmol), triethylamine (0.094 mL, 0.672 mmol) and TBTU (108 mg, 0.336 mmol) were added. After 14 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 95% MeCN/0.1% TFA in H2O/0.1% TFA gradient). This gave the title compound as a brown solid. LC-MS: RT=7.79 min, [M+H]+=508.9.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:15][Sn:16](C)([CH3:18])[CH3:17]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([N:11]([CH3:12])[S:8]([C:5]1[CH:6]=[N:7][C:2]([Sn:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:14]
Reactant: CCN(C)S(=O)(=O)c1ccc(Cl)nc1
Reactant: C[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCN(C)S(=O)(=O)c1ccc([Sn](C)(C)C)nc1
Temperature: 90 °C
Yield: 40.2 %

Procedure:
6-chloro-N-ethyl-N-methylpyridine-3-sulfonamide (2.34 g, 10.0 mmol), tetramethyl tin (1.08 g, 10.00 mmol) and Pd(PPh3)4 (572 mg, 0.50 mmol) were mixed in dioxane (5 mL). After degassing, the mixture was heated to 90° C. At completion, the reaction was cooled to room temperature and concentrated. The residue was then flashed over alumina (20-100% chloroform/hexane eluent) to afford N-ethyl-N-methyl-6-(trimethylstannyl)pyridine-3-sulfonamide (1.46 g, 40% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[C:12]([CH3:19])[C:11]=1[O:20][CH3:21])[CH2:4][CH3:5])[CH3:2].[H][H]>[Pt]=O.CO>[CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[C:12]([CH3:19])[C:11]=1[O:20][CH3:21])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CCNC(=O)c1cc([N+](=O)[O-])cc(C)c1OC
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: CCN(CC)CCNC(=O)c1cc(N)cc(C)c1OC
Yield: 62 %

Procedure:
A mixture of N-(diethylaminoethyl)-2-methoxy-3-methyl-5-nitrobenzamide (4.25 g), platinum oxide (425 mg) and methanol (85 ml) is shaken in a hydrogen stream. After absorption of hydrogen stops, the reaction mixture is filtered to remove the catalyst. The filtrate is concentrated under vacuum and the residue is chromatographed on a column of alumina, which is eluated with methylene chloride to methylene chloride-2% methanol. The eluate is concentrated under vacuum and the residue is washed with isopropyl ether to give N-(diethylaminoethyl)-5-amino-2-methoxy-3-methylbenzamide (2.38 g) as crystals melting at 56° to 57° C.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:4]#[N:5].[O:21]([CH2:28][CH2:29][NH2:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[O:21]([CH2:28][CH2:29][NH:30][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]([F:20])([F:19])[F:18])[C:3]=1[C:4]#[N:5])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCOc1ccccc1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)c(C#N)c(Cl)n2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(C(F)(F)F)c(C#N)c(NCCOc3ccccc3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h

Procedure:
Compound F (300 mg, 1.00 mmol), 2-phenoxyethylamine (261 μl) and sodium hydrogencarbonate (837 mg) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction system was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-phenoxyethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-trifluoromethylnicotinonitrile (80 mg).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Cl-].[Ca+2].Cl>C1COCC1>[CH2:19]([N:18]([CH3:17])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CNCc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)c1ncccc1[N+](=O)[O-]

Procedure:
The mixture of 2-chloro-3-nitropyridine (15 g), Na2CO3 (10.03 g) and N-methylbenzylamine (24.42 mL) in THF (150 mL) was stirred at 80° C. under a dry atmosphere (CaCl2 tube) overnight. The mixture was neutralized with 1N HCl at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give N-benzyl-N-methyl-3-nitropyridin-2-amine (19 g) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:15].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[CH:44]1[O:56][C@H:55]([CH3:57])[C@@H:50]([O:51][C:52](=[O:54])[CH3:53])[C@H:45]1[O:46][C:47](=[O:49])[CH3:48])(=O)C.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:13])[CH3:14])[N:7]([C@@H:44]3[O:56][C@H:55]([CH3:57])[C@@H:50]([O:51][C:52](=[O:54])[CH3:53])[C@H:45]3[O:46][C:47](=[O:49])[CH3:48])[C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:15]
Reactant: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)Nc1nc2c(Cl)c(Cl)ccc2[nH]1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(NC(C)C)nc2c(Cl)c(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
4,5-Dichloro-N-(1-methylethyl)-1H-benzimidazol-2-amine (0.50 g, 2.0 mmol), N,O-bis(trimethylsilyl) acetamide (Aldrich, 0.55 mL, 2.2 mmol), and acetonitrile (Aldrich Sure Seal, 70 mL) were combined and refluxed under nitrogen for 15 min. The solution was cooled to rt and trimethylsilyl trifluoromethanesulfonate (Aldrich, 0.24 mL, 1.2 mmol) was added. After 10 min, 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose (0.69 g, 2.6 mmol) dissolved in acetonitrile (Aldrich Sure Seal, 10 mL) was added. The solution was stirred under nitrogen at rt for 12 h and then heated in an 80° C. oil bath for 2.5 h. The solution was then poured into 5% aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were dried with magnesium sulfate, filtered, and evaporated. The crude residue was purified on a silica gel column (2.5×20 cm, 230-400 mesh) with 97:3 dichloromethane-methanol to give the title compound (0.82 g, 1.8 mmol, 90%); 1H NMR (DMSO-d6) δ: 7.29 (s, 1H, Ar—H, J=8.4 Hz), 7.10 (s, 1H, Ar—H, J=8.4 Hz), 6.98 (d, 1H, NH, J=7.5 Hz), 6.10 (d, 1H, H-1′, J=6.3 Hz), 5.50-5.55 (m, 1H, CH), 5.15 (t, 1H, CH, J=6.0 Hz), 4.04-4.17 (m, 2H, CH), 2.14 (s, 3H, OAc), 2.01 (s, 3H, OAc), 1.48 (d, 3H, 5′-CH3, J=6.3 Hz), 1.24 (t, 6H, CH3, J=6.2 Hz).
Reaction SMILES: [NH2:1][C:2]([C:18]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]2[C:19]=1[CH:20]=[CH:21][N:22]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=2[N:8]=1)[C:3]([F:6])([F:5])[F:4].[C:37](OCC)(=O)[CH:38]=[O:39].CO.[BH4-].[Na+]>ClCCCl>[C:16]([C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C:2]([C:18]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([NH:1][CH2:37][CH2:38][OH:39])[C:3]([F:6])([F:5])[F:4])=[N:8][C:9]=2[CH:15]=1)#[N:17]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(N)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Reactant: CCOC(=O)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(NCCO)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F

Procedure:
A solution of (±)-tert-butyl 4-(1-amino-1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (50 mg, 0.100 mmol) and ethyl glyoxylate (50% in toluene) (39.7 μL, 0.200 mmol) in DCE (1.00 mL) was stirred at room temperature. After 50 minutes MeOH (1 mL) was added followed by NaBH4 (11.36 mg, 0.300 mmol). After 30 minutes additional NaBH4 (4 mg, 0.106 mmol) was added. After 25 more minutes additional NaBH4 (40 mg, 1.06 mmol) was added. After 15 more minutes the reaction was quenched with water, extracted twice with EtOAc, dried with MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-80% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 544.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(C1(C2C=CC=CC=2SC2C=CC(F)=CC=2)CCNCC1)#N.[C:46](OC(=O)C)(=[O:48])[CH3:47]>N1C=CC=CC=1>[C:46]([N:18]1[CH2:17][CH2:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([C:21]([OH:23])=[O:22])[CH2:20][CH2:19]1)(=[O:48])[CH3:47]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C1(c2ccccc2Sc2ccc(F)cc2)CCNCC1
Agent: N#CC1(c2ccccc2Sc2ccc(F)cc2)CCNCC1
Solvent: c1ccncc1
Product: CC(=O)N1CCC(C(=O)O)(c2ccccc2Sc2ccc(F)cc2)CC1

Procedure:
A mixture of 0.7 g of 4-[2-(4-fluorophenylthio)phenyl]-piperidine-4-carboxylic acid, free amino acid of Example 30, and 0.83 ml of acetic anhydride in 4.2 ml of pyridine is stirred at reflux for 4 hours. Thereafter, the excess pyridine is removed by rotary evaporation and the residue is taken up in 10 ml of water and treated with 10 ml of 1 N hydrochloric acid. The acidic mixture is extracted thrice with 20 ml portions of an ether-benzene (1:1) mixture and the combined extracts are successively washed twice with 40 ml portions of water, once with 15 ml of saturated sodium chloride solution and dried. The resulting product is recrystallized from acetone-ether to provide 1-acetyl-4-[2-(4-fluorophenylthio)phenyl]piperidine-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]([OH:13])([CH2:12][O:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1OCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 150 °C
Reaction time: 5 h
Yield: 86.3 %

Procedure:
After dissolving 120 mg of 6-(tert-butoxycarbonyl)-1-oxa-6-azaspiro[2.5]octane in 10 ml of N,N-dimethylformamide, 67 mg of 2-methylphenol and 86 mg of potassium carbonate were added and the mixture was stirred at 150° C. for 5 hours. After cooling it to room temperature, water was added and extraction was performed with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (156 mg, 86% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([N+:12]([O-])=O)[C:5]=1[NH2:15].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([NH2:12])[C:5]=1[NH2:15]
Reactant: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(OC)cc(N)c1N

Procedure:
A slurry of 2-amino-5-methoxy-3-nitro-benzoic acid methyl ester (1 g, 4.4 mmol) and 10% Pd/C (0.2 g, 20%) in methanol was hydrogenated with a hydrogen balloon for 6 h. After the reaction was completed, the mixture was filtered through a celite bed and the filtrates were evaporated to dryness. The obtained residue was purified over silica gel column using (30% ethyl acetate/hexane) as eluent to obtain the title compound as off white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][C:14]([CH:16]1[CH2:20][CH2:19][N:18]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:17]1)=[O:15])[CH3:12].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O1CCCC1>[CH2:11]([O:13][C:14]([C:16]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:20][CH2:19][N:18]([C:21](=[O:30])[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1CCN(C(=O)c2ccc(OC)cc2)C1
Reactant: CCOC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)CCN(C(=O)c2ccc(OC)cc2)C1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
Lithium bis(trimethylsilyl)amide (1000 mL of a 1.0M solution in tetrahydrofuran, 1.0 mol) was added to a stirred solution of 1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (±) (268 g, 0.97 mol) (see Preparation 2) in THF (1600 mL) at −70° C. The mixture was stirred for 20 mins at −70° C. then ethyl chloroformate (104 mL, 1.09 mol) was added over 15 minutes. The resulting mixture was stirred at −60° C. for 1 hour. The reaction mixture was quenched with 10% citric acid aqueous solution (1200 mL) at −50° C. then warmed to room temperature. The organic layer was separated, washed with saturated aqueous NaHCO3 (1200 mL) and water (1200 mL) then concentrated under reduced pressure to afford the title compound as an orange oil (316.0 g, 94%).
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[Cl:20])[N:16]=[C:15]([CH3:21])[CH:14]=[CH:13]2)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO.O>[C:30]([O:29][C@@H:9]([C:10]1[C:11]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[Cl:20])[N:16]=[C:15]([CH3:21])[CH:14]=[CH:13]2)[CH2:8][OH:7])([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(Cl)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(Cl)cc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
To a stirred solution of (S)-2-tert-butoxy-2-(7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-yl)ethyl pivalate (1J) (22 mg, 0.045 mmol) in THF and methanol (3 mL/1 mL) was added 1 M NaOH solution (1 mL, excess) at 0° C. The mixture was stirred at room temperature for 16 hours and diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 1K (11 mg, 61%). LCMS-ESI+ (m/z): 404.2, 406.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[CH2:12][N:13]3[C:17]([C@@H:19]([NH:24][C:25]([C:27]2[NH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:9])=[N:6][CH:7]=1.[CH3:36][N:37]([CH3:47])[C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:36][N:37]([CH3:47])[C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][C@@H:14]4[CH2:16][C@H:11]3[CH2:12][N:13]4[C:17]([C@@H:19]([NH:24][C:25]([C:27]3[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[O:9])=[N:6][CH:7]=2)=[CH:40][CH:39]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(-c2ccc(C(=O)N3C[C@@H]4C[C@H]3CN4C(=O)[C@@H](NC(=O)c3cc4ccccc4[nH]3)C(C)(C)C)nc2)cc1
Temperature: 80 °C
Yield: 41.8 %

Procedure:
A mixture of N-[(1S)-1-({(1S,4S)-5-[(5-bromo-2-pyridinyl)carbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1H-indole-2-carboxamide (100 mg, 0.186 mmol), [4-(dimethylamino)phenyl]boronic acid (31 mg, 0.186 mmol), Pd(Ph3P)4 (10 mg, 0.009 mmol), potassium carbonate (26 mg, 0.186 mmol) in toluene (6 mL), ethanol (2 mL), and water (0.5 mL) was heated to 80° C. for 10 h under a nitrogen atmosphere. The solution was concentrated and the resulting residue was purified by reverse phase HPLC. Concentration of the desired fractions containing product afforded the title compound (45 mg) as a pale brown solid. LCMS (m/z): 579.3 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm: 0.90-1.20 (m, 9H), 1.80-2.20 (m, 2H), 2.90-3.15 (m, 6H), 3.50-4.20 (m, 4H), 4.60-5.60 (m, 4H), 6.90-7.70 (m, 9H), 7.80-8.10 (m, 2H), 8.60-8.85 (m, 1H), 9.15-9.45 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=O)[NH:12][C:13]2[CH:18]=[C:17]([F:19])[C:16]([Cl:20])=[CH:15][C:14]=2[NH2:21])=[CH:6][CH:5]=1>CC(O)=O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]3[CH:18]=[C:17]([F:19])[C:16]([Cl:20])=[CH:15][C:14]=3[N:21]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC(=O)Nc2cc(F)c(Cl)cc2N)cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Cc2nc3cc(Cl)c(F)cc3[nH]2)cc1
Yield: 94.1 %

Procedure:
Compound 72 (333 mg, 0.99 mmol) was dissolved in AcOH (10 ml) and the solution was refluxed, for 24 h. AcOH was evaporated and the residue was dissolved in AcOEt, washed with aqueous NH4Cl, NaHCO3 and brine, and dried over MgSO4 Evaporation of EtOAc provided the title compound 73 as a brownish powder (297 mg, 95%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=[O:14])[O:11][C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C1(C)C(C)=CC=CC=1.CS(O)(=O)=O>O>[C:1]1([CH:7]2[CH2:8][C:9](=[O:11])[N:15]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:12](=[O:14])[CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(c2ccccc2)CC(=O)O1
Reactant: Nc1ccncc1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1CC(c2ccccc2)CC(=O)N1c1ccncc1
Reaction time: 48 h

Procedure:
The starting material is prepared as follows: The mixture of 19 g of 3-phenylglutaric anhydride, 10.3 g of 4-aminopyridine, 350 ml of xylene and 2.5 g of methane sulfonic acid is refluxed on a water separator while stirring for 2 days. The hot solution is decanted from some insolubles, cooled, filtered an the residue triturated with hot isopropanol, to yield the 4-phenyl-1-(4-pyridyl)-piperidin-2,6-dione meling at 229°-230°; the analogously prepared 4-(p-methoxyphenyl)-1-(4-pyridyl)-piperidine-2,6-dione melts at 168°-169°.
Reaction SMILES: [Cl:1][Si](C)(C)C.[CH3:6][N:7]([CH3:36])[C:8]1([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([NH:17][CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:16])[CH2:10][CH2:9]1>CC(CC)=O>[ClH:1].[CH3:36][N:7]([CH3:6])[C:8]1([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([NH:17][CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2cccc(F)c2)CCC(CC(=O)NCCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Chlorotrimethylsilane (0.164 ml, 1.3 mmol) was added to a solution of the more polar diastereoisomer of 2-[4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]-N-[2-(1H-indol-3-yl)ethyl]acetamide (372 mg, 0.776 mmol) in ethyl methyl ketone (30 ml) and the mixture was stirred at RT for 1.5 h. The reaction mixture was concentrated to 10 ml, ether (60 ml) was added and the mixture was stirred at RT for 20 min. The hydrochloride was obtained as a colourless solid in a yield of 87% (348 mg) (Example 51).
Reaction SMILES: [CH3:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[OH:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1>O1CCCC1>[CH3:1][C:2]1[C:10]([O:11][CH:17]2[CH2:18][CH2:13][CH2:14][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[OH:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1
Reactant: Cc1c(O)ccc2[nH]ncc12
Agent: CC(C)(C)OC(=O)N1CCCC(O)C1
Solvent: C1CCOC1
Product: Cc1c(OC2CCCN(C(=O)OC(C)(C)C)C2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of dibenzyl dicarboxylate (10.1 g, 33.9 mmol) in tetrahydrofuran (50 ml) was added dropwise to a mixture of the 5-hydroxy-4-methyl-1H-indazole (4.17 g, 28.1 mmol) obtained in Example 402, t-butyl 3-hydroxypiperidine-1-carboxylate (5.62 g, 27.9 mmol) and tetrahydrofuran (100 ml) under ice-cooling. After 30 minutes, the mixture thus obtained was warmed up to room temperature and stirred for 16 hours. The reaction mixture was concentrated and then a 1N-aqueous sodium hydroxide solution (250 ml) was added thereto, followed by extraction with chloroform (150 ml) (three times). The organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=3/1 to 2/1) to obtain a crude product t-butyl 3-[(4-methyl-1H-indazol-5-yl)oxy]piperidine-1-carboxylate (a mixture with t-butyl 3-hydroxypiperidine-1-carboxylate, 3.46 g).