Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH2:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19](C)[N:18]=[C:17](C)[CH:16]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(C1C=C(C)N=C(C)C=1)(=O)C>>[OH:1][C:2]([CH2:13][C:14](=[O:23])[C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(O)(CC(=O)c1cc(C)nc(C)c1)C(=O)OCC
Agent: CC(=O)c1cc(C)nc(C)c1
Product: CCOC(=O)C(O)(CC(=O)c1ccncc1)C(=O)OCC

Procedure:
A-6. Diethyl hydroxy[2-oxo-2-(2,6-dimethyl-4-pyridinyl)ethyl]propanedioate using 4-acetyl-2,6-dimethylpyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)([OH:12])=[O:11].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:22][S:19]([C:16]2[CH:17]=[CH:18][C:13]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(S(=O)(=O)N=Cc2ccc(Cl)cc2)cc1

Procedure:
In a similar manner to Example 2, 4.00 g (29 mmol) of 4-chlorobenzaldehyde, 5.72 g (29 mmol) of 4-carboxybenzenesulfonamide and 20 mg of TsOH in 150 mL of toluene were heated for 24 hours to provide 6.60 g (71%) of SULF-3 as a light tan powder: IR (Nujol) 3400-2500 (br), 1685, 1595, 1285, 1215, 1005 cm-1 ; 1H NMR (DMSO-d6, TMS ext std) δ 9.15 (s, 1), 8.2-7.3 (m, 8).
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[N+:29]([C:32]1[CH:37]=[CH:36][C:35]([N:38]2[C:42]([C:43]([F:46])([F:45])[F:44])=[C:41]([C:47](Cl)=[O:48])[CH:40]=[N:39]2)=[CH:34][CH:33]=1)([O-:31])=[O:30]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:47]([C:41]3[CH:40]=[N:39][N:38]([C:35]4[CH:36]=[CH:37][C:32]([N+:29]([O-:31])=[O:30])=[CH:33][CH:34]=4)[C:42]=3[C:43]([F:44])([F:45])[F:46])=[O:48])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1cnn(-c2ccc([N+](=O)[O-])cc2)c1C(F)(F)F
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3cnn(-c4ccc([N+](=O)[O-])cc4)c3C(F)(F)F)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(4-nitrophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride: ESMS m/e: 663.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([CH3:16])[CH:11]=[CH:12][C:13]([OH:15])=O.C(Cl)(=O)C(Cl)=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][CH2:32][NH2:33])=[CH:26][CH:25]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C.C1COCC1.CCOC(C)=O>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]=[CH:31][CH2:32][NH:33][C:13](=[O:15])[CH:12]=[CH:11][C:10]([CH3:16])=[CH:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:28][CH:29]=1
Reactant: CC(C=CC(=O)O)=Cc1ccc(Cl)cc1Cl
Reactant: NCC=Cc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C=CC(=O)NCC=Cc1ccc(Cl)cc1)=Cc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
5-(2,4-Dichlorophenyl)-4-methylpenta-2,4-dienoic acid (1 g, 0.0039 mol) was suspended in CH2Cl2 (10 mL). Oxalyl chloride (0.5 mL, 1.5 eq) was added, followed by 1 drop of DMF. After 2 hours the volatiles were removed, the residue taken up in THF (10 mL), and the mixture cooled to 0° C. A mixture of 3-(4-chlorophenyl)allylamine (0.7 g, 1.1 eq, 0.0042 mol, prepared as shown in Scheme 4) and Et3N (0.82 mL, 0.0042 mol, 1.5 eq) in THF (5 mL) was added dropwise. After 1 hour, TLC analysis showed complete conversion of the starting materials and the mixture was then diluted with EtOAc. The organic layer washed with NH4Cl(sat), dried (MgSO4), and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-10-20-30-40% EtOAc in hexanes) to give 1.25 g of 5-(2,4-dichlorophenyl)-4-methylpenta-2,4-dienoic acid [3-(4-chlorophenyl)allyl]amide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].[CH2:11]1[O:13][CH2:12]1.C1OC1C>[Cl-].C[N+](C)(C)C>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH:12]([OH:13])[CH3:11]
Reactant: Oc1c(Br)cc(Br)cc1Br
Reactant: C1CO1
Agent: CC1CO1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Product: CC(O)Oc1c(Br)cc(Br)cc1Br

Procedure:
Monomers of type (e) are prepared by the reaction of 2,4,6--tribromophenol with an alphaolefin oxide such as ethylene oxide and propylene oxide, in the presence of 1 to 3 percent tetramethylammonium chloride at 80° to 100°C. for 3 to 6 hours to form 2,4,6-tribromophenoxyethanol. The reaction mixture is washed thoroughly with water after dissolving in solvent, dried with a drying agent, and stripped of solvent under reduced pressure at 40° to 60°C. The product is then analyzed for hydroxyl number. The yield of this intermediate is generally 40 to 60%. The intermediate is then reacted with maleic anhydride at 80° to 100°C. for 3 to 5 hours to form mono-2,4,6-tribromophenoxyethyl maleate.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[N:19]=[CH:20][N:21](S(N(C)C)(=O)=O)[C:22]=4[CH3:23])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>C(O)C>[F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[N:19]=[CH:20][NH:21][C:22]=4[CH3:23])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(CN2CCc3c(c4cccc(F)c4n3C)C2=O)ncn1S(=O)(=O)N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Reaction time: 6 h
Yield: 103.6 %

Procedure:
A stirred solution of 4-[(6-fluoro-2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido [4,3-b]indol-2-yl)methyl]-N,N,5-trimethyl-1H-imidazole-1-sulphonamide (92 mg) in absolute ethanol (5 ml) was treated with 2N hydrochloric acid (20 ml) and stirred under nitrogen at 100°-110° for 6 h, and then cooled. 2N Sodium hydroxide (60 ml) was added, and the mixture was extracted with ethyl acetate (2×75 ml). The combined, dried organic extracts were concentrated in vacuo to give a solid (71 mg) which was purified by FCC eluting with System A (100:8:1) to give the title compound (57 mg), m.p. 233°-234°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])CC2)[S:9][CH:10]=1)=[O:5])[CH3:2].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.C(O)C>CN(C)C=O>[Si:18]([O:17][CH:14]1[N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:16][CH2:15]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1csc(N2CCC(O)CC2)n1
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(N2CCC2O[Si](C)(C)C(C)(C)C)n1
Reaction time: 0.17 h
Yield: 103.3 %

Procedure:
To a solution of 1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-4-hydroxypiperidine (1.00 g, 3.90 mmol) (obtained as described in Reference Example 13(2)) in dimethylformamide (50 ml) were added t-butyldimethylsilyl chloride (1.2 g, 7.96 mmol) and imidazole (0.6 g, 8.8 mmol) in an ice bath. The reaction mixture was brought to room temperature in 10 minutes and then stirred for 18 hours. After checking the completion of the reaction, ethanol was added thereto in an ice bath, and the reaction mixture was then stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1) as the eluant to afford 4-t-butyidimethylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (1.38 g, yield 95%) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]([C:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=1)([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27]Cl)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(C)CC(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27][N:14]2[CH2:15][CH2:16][C:11]([C:2]([OH:1])([CH3:10])[C:3]3[CH:4]=[CH:5][C:6]([F:9])=[CH:7][CH:8]=3)=[CH:12][CH2:13]2)=[CH:22][CH:23]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: CC(O)(C1=CCNCC1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC(O)(C1=CCN(CCCC(=O)c2ccc(F)cc2)CC1)c1ccc(F)cc1

Procedure:
A mixture of 2.0 g of 4-(α-hydroxy-α-methyl-4-fluorobenzyl)-1,2,5,6-tetrahydropyridine, 2.5 g of 4'-fluoro-4-chlorobutyrophenone, 3.0 g of sodium carbonate, a crystal of sodium iodide, in 100 ml of 4-methyl-2-pentanone is stirred and refluxed for 72 hours. It is cooled, filtered, and the filtrate evaporated under reduced pressure. Diethyl ether is added to the residue and the resulting solution extracted with 5% aqueous hydrochloric acid. The aqueous solution is made basic with ammonium hydroxide and extracted with diethyl ether. The extract is dried, evaporated and the residue recrystallized from isopropanol, to give the 4'-fluoro-4-[4-(α-hydroxy-α-methyl-4-fluorobenzyl)-1,2,5,6-tetrahydropyridyl]-butyrophenone melting at 95°.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:14][CH:15]=1>C(#N)C.CCOC(C)=O.O>[NH2:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:14][C:15]=1[Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cnc(N)cn1
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(N)c(Br)n1
Temperature: 20 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
Add 1.79 g (10.05 mmol) of N-bromosuccinimide to a solution of 1.4 g (9.14 mmol) of methyl 5-aminopyrazine-2-carboxylate in 10 mL of acetonitrile. Stir the reaction mixture for 2 h at 20° C. then distribute in 100 mL of EtOAc/water 1:1 mixture. Wash the organic phase with 2×50 mL of water, dry over Na2SO4 and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 50% of EtOAc. After concentration under reduced pressure, we obtain 1.66 g of methyl 5-amino-6-bromopyrazine-2-carboxylate in the form of yellow wax.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:10])[O:7][C:6]=1[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:4].[Li+].[OH-].C1COCC1>O>[Br:10][C:8]1[O:7][C:6]([CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=1
Reactant: COC(=O)c1cc(Br)oc1CNCc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNCc2oc(Br)cc2C(=O)O)cc1
Yield: 100.1 %

Procedure:
A solution of 5-bromo-2-[(4-methoxy-benzylamino)-methyl]-furan-3-carboxylic acid methyl ester (643.8 mg, 1.82 mmol) and LiOH (115 mg, 2.74 mmol) in 1:1 THF:H2O (30 mL) is refluxed for 3 hours. The solvent is evaporated in vacuo to afford the title compound (620 mg, 99%) which is used in the next step without further purification.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:5]([CH:9]=O)=[CH:6][S:7][CH:8]=1.[N:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:12]=[N-:13]>C(O)C.CCOCC.O>[CH2:18]([O:17][C:15](=[O:16])[C:14]([N:11]=[N+:12]=[N-:13])=[CH:9][C:5]1[C:4]([O:3][CH3:2])=[CH:8][S:7][CH:6]=1)[CH3:19]
Reactant: COc1cscc1C=O
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Na]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=Cc1cscc1OC)N=[N+]=[N-]
Temperature: -15 °C
Yield: 55.1 %

Procedure:
Sodium (20.0 g, 0.870 mol) was dissolved in absolute ethanol (550 mL) and the resulting solution cooled to −15° C. A mixture of 4-methoxy-3-thiophenaldehyde (32.4 g, 0.228 mol) and ethyl azidoacetate (118 g, 0.914 mol) in absolute ethanol (30 mL) and ether (30 mL) was added slowly such that the temperature of the reaction mixture did not rise above −10° C. The mixture warmed to −40° C. over 40 min accompanied by vigorous gas evolution. After 3 h the mixture was diluted with water (1 L) and the resulting precipitate was collected via vacuum filtration to provide 31.8 g (55%) of the title compound. Recrystallization (hexanes) of an analytical sample provided yellow crystals: mp 88-90° C. 1H NMR (CDCl3) 88.14 (d, J=3.3 Hz, 1H), 6.94 (s, 1H), 6.19 (d, J=3.3 Hz, 1H), 4.35 (q, J=7.0 Hz, 2H), 3.86 (s, 3H), 1.41 (t, J=7.0 Hz, 3H); MS ES+m/e 254 (p+1); IR (KBr, cm−1) 2114, 1700, 1256. Anal. Calcd for C10H11N3O3S: C, 47.42; H, 4.38; N, 16.59. Found: C, 47.09; H, 4.46; N, 15.87.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])[C:2]([NH2:4])=[NH:3].[CH2:10]([CH:18]1[CH2:20][CH:19]1[C:21](Cl)=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1>[CH2:10]([CH:18]1[CH2:20][CH:19]1[C:21]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][NH:1][C:2]([NH2:4])=[NH:3])=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCC1CC1C(=O)Cl
Reactant: N=C(N)NCCCCN
Solvent: c1ccncc1
Product: CCCCCCCCC1CC1C(=O)NCCCCNC(=N)N
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To 457.2 mg. of 1-amino-4-guanidinobutane (IV) suspended in 60 ml. of dry pyridine was added 2-(n-octyl)cyclopropanecarbonyl chloride. This suspension was stirred at room temperature for 40 hours. At the end of 40 hours the solid material was filtered and the filtrate concentrated to a viscous oil, which was chromatographed on silica gel using 30% methanol in CHCl3, resulting in 497.7 mg. of desired material, characterised by EIMS with M+ at m/e 310 for C17H34 -N4O.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])=[CH:5][CH:4]=1.[BH4-].[Na+].[OH-].[Na+].O>CO.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH2:11][OH:12])[CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1ccc(Oc2cccc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-methoxyphenoxy)benzaldehyde (5.0 g, 21.9 mmol) in methanol (35 mL) was added a solution of sodium borohydride (0.86 g, 22.8 mmol) in an aqueous solution of 2N sodium hydroxide (2.5 mL), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, which was neutralized with acetic acid, then, extracted with ethyl acetate, washed with brine, then, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain (3-(4-methoxy-phenoxy)-phenyl)-metanol (5.3 g, quantitatively) as a colorless oil.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11]
Reactant: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Yield: 95 %

Procedure:
0.26 g (0.5 mmol) of ethyl 1-[(R)-2-tert-butoxycarbonylamino-3-(4-chlorophenyl)-propionyl]-4-cyclohexylpiperidine-4-carboxylate is diluted in 4 mL of DCM and 1 mL of trifluoroacetic acid, and the solution is stirred for 2 hours at room temperature and then quenched by adding aqueous 1N NaOH solution and extracted with dichloromethane. The organic phase is dried and then evaporated. 200 mg of ethyl 1-[(R)-2-amino-3-(4-chlorophenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate in the form of a colourless oil are obtained in a yield of 95%.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH:8]([C:11]1[CH:15]=[C:14]([C:16]2[CH:32]=[CH:31][C:19]([O:20][CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)[N:13]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[N:12]=1)([CH3:10])[CH3:9]>ClCCl>[ClH:1].[CH:8]([C:11]1[CH:15]=[C:14]([C:16]2[CH:32]=[CH:31][C:19]([O:20][CH2:21][CH2:22][NH2:23])=[CH:18][CH:17]=2)[N:13]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[N:12]=1)([CH3:10])[CH3:9]
Reactant: COc1ccc(-n2nc(C(C)C)cc2-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(C)C)cc2-c2ccc(OCCN)cc2)cc1

Procedure:
4M Hydrochloric acid/dioxane (2 ml) was added to a solution of tert-butyl 2-{4-[3-isopropyl-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]-phenoxy}ethylcarbamate obtained by Example 2 (382 mg) in dichloromethane (3 ml) at 0° C.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:25])[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:23]=2[N:22]([CH:24]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]3=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>O1CCCC1>[OH:8][CH:1]([C:9]1[C:10](=[O:25])[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:23]=2[N:22]([CH:24]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]3=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cn2c3ccccc3c3cccc(c1=O)c32
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=c1c(C(O)c2ccccc2)cn2c3ccccc3c3cccc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
5-benzoyl-4H-pyrido[3,2,1-jk]carbazole-4-one (80 mg) produced in Example 145 was dissolved in anhydrous tetrahydrofuran (80 ml), and lithium aluminium tri-t-butoxyhydride (76 mg) was added to the solution in an ice bath, and the mixture was stirred for 30 minutes. Saturated aqueous solution of ammonium chloride of an adequate amount was added to the reaction mixture, and the mixture was heated to room temperature, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residual crude crystals were re-precipitated from hexane and ethyl acetate to obtain the title compound (35 mg, 44%).
Reaction SMILES: CN[C:3]([C:5]1[CH:25]=[CH:24][C:8]2[O:9][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[C:6]=1[CH3:26])=[O:4].[OH-:27].[Na+]>C(O)CO>[CH3:26][C:6]1[C:7]2[O:11][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9][C:8]=2[CH:24]=[CH:25][C:5]=1[C:3]([OH:27])=[O:4]
Reactant: [OH-]
Reactant: CNC(=O)c1ccc2c(c1C)OC(c1ccccc1)(c1ccccc1)O2
Agent: [Na+]
Solvent: OCCO
Product: Cc1c(C(=O)O)ccc2c1OC(c1ccccc1)(c1ccccc1)O2
Yield: 34.4 %

Procedure:
A solution of 1.60 g of N,4-dimethyl-2,2-diphenyl-1,3-benzodioxole-5-carboxamide and 1.00 g of sodium hydroxide in 10 ml of ethylene glycol was heated to 190° C. for 2.5 hours. After cooling, the mixture was partitioned between water and ethyl acetate. The aqueous phase was washed with ethyl acetate, adjusted to pH 2 by the addition of 3N hydrochloric acid, and then the product was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the solid residue was crystallized from ethanol to give 0.53 g of 4-methyl-2,2-diphenyl-1,3-benzodioxole-5-carboxylic acid, m.p. 263°-265° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[NH2:39][C:40]1[O:44][C:43]([C:45]2[CH:46]=[C:47]([OH:60])[CH:48]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:50]=2)=[N:42][N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[NH2:39][C:40]1[O:44][C:43]([C:45]2[CH:50]=[C:49]([C:2]3[C:10]4[C:9]([NH:11][C@H:12]([C:14]5[N:19]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)[C:18](=[O:26])[C:17]6=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]6[N:15]=5)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=3)[CH:48]=[C:47]([OH:60])[CH:46]=2)=[N:42][N:41]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(O)cc(-c3nnc(N)o3)c2)OC1(C)C
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: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(-c5nnc(N)o5)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 13.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (250 mg, 0.42 mmol) was treated with 3-(5-amino-1,3,4-oxadiazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (200 mg, 0.66 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.03 mmol), aqueous solution 2M of sodium carbonate (300 μl, 2.83 mmol) and 5 ml N,N-dimethylformide as a solvent according to the method described in Preparation 186 heating at 100° C. for 48 h. The crude was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 40 mg (13% yield) of the title compound. Purity 95%.
Reaction SMILES: C([N:8]1[CH2:15][CH:14]([CH3:16])[CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)C1C=CC=CC=1>CO.[Pd]>[CH3:16][CH:14]1[CH:13]2[CH:9]([CH2:10][NH:11][CH2:12]2)[NH:8][CH2:15]1
Reactant: CC1CN(Cc2ccccc2)C2CNCC12
Agent: [Pd]
Solvent: CO
Product: CC1CNC2CNCC12

Procedure:
4.1 g (19 mmol) of 2-benzyl-4-methyl-2,7-diazabicyclo[3.3.0]octane in 80 ml of methanol are hydrogenated on 1 g of palladium/active carbon (10% Pd) at 100° C. and 100 bar. The catalyst is filtered off, the filtrate is concentrated, and the residue is distilled.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([C:12]2([C:16](=[O:18])[CH3:17])[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[C:1]1([C@H:7]([NH:9][C:10]([C:12]2([C:16]3([O:21][CH2:20][CH2:19][O:18]3)[CH3:17])[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCO
Reactant: CC(=O)C1(C(=O)N[C@H](C)c2ccccc2)CCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C[C@@H](NC(=O)C1(C2(C)OCCO2)CCC1)c1ccccc1

Procedure:
A mixture, of 13.9 g of N-[1-(R)-phenylethyl]-1-acetyl-1-cyclobutanecarboxamide, 15 ml of ethylene glycol, a catalytic amount of p-toluenesulfonic acid and 100 ml of benzene was heated under reflux for 3 hrs. The water formed in the reaction was removed using a Dean-Stark apparatus. After cooling, the mixture was washed with a saturated sodium bicarbonate aqueous solution, then washed with water and then dried. The solvent was removed under reduced pressure to yield 16.5 g of the titled compound as a colorless oil.